CN104093415B - 抗乙酰透明质酸剂疗法的同伴诊断剂及其使用方法 - Google Patents

抗乙酰透明质酸剂疗法的同伴诊断剂及其使用方法 Download PDF

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CN104093415B
CN104093415B CN201280064239.4A CN201280064239A CN104093415B CN 104093415 B CN104093415 B CN 104093415B CN 201280064239 A CN201280064239 A CN 201280064239A CN 104093415 B CN104093415 B CN 104093415B
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P·江
H·M·谢泼德
L·黄
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Abstract

本发明提供鉴定对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶进行癌症治疗的方法和诊断剂。本发明提供用于检测和定量生物学样品中的乙酰透明质酸以及监测用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗癌症的诊断剂。本发明还提供用于实施所述方法的组合和试剂盒。

Description

抗乙酰透明质酸剂疗法的同伴诊断剂及其使用方法
相关申请
本申请要求以下文件的优先权：2011年10月24日提交的题为“乙酰透明质酸降解酶疗法的同伴诊断剂及其使用方法”的美国临时申请系列号61/628,187，2011年11月11日提交的题为“乙酰透明质酸降解酶疗法的同伴诊断剂及其使用方法”的美国临时申请第61/559,011号，2011年12月16日提交的题为“乙酰透明质酸降解酶疗法的同伴诊断剂及其使用方法”的美国临时申请第61/630,765号以及2012年10月16日提交的题为“抗乙酰透明质酸剂疗法的同伴诊断剂及其使用方法”的美国临时申请第61/714,700号。上述每个申请的主题整体援引加入本文。
本申请涉及同一天提交的题为“抗乙酰透明质酸剂疗法的同伴诊断剂及其使用方法”的美国专利申请第13/694,071号，其要求美国临时申请系列号61/628,187；61/559,011；61/630,765和61/714,700的优先权。
上述相关申请的主题整体援引加入本文。
电子提供的序列表的援引加入
与本申请一起提交序列表的电子版，其内容整体援引加入本文。电子文件创建于2012年10月24日，大小为1827千字节，并且题为3096seqPC1.txt。
技术领域
本发明提供鉴定用乙酰透明质酸降解酶治疗癌症的对象的方法和诊断剂。本发明提供用于检测和定量生物学样品中的乙酰透明质酸以及监测用乙酰透明质酸降解酶治疗癌症的诊断剂。本发明还提供用于实施所述方法的组合和试剂盒。
背景技术
乙酰透明质酸降解酶已在治疗上使用，通常作为分散剂和铺展剂与其他治疗剂组合使用。乙酰透明质酸降解酶还可以用于治疗乙酰透明质酸相关疾病和病症的单一药剂疗法。例如，肿瘤和癌症与乙酰透明质酸的积累有关，并且用乙酰透明质酸降解酶治疗抑制肿瘤的生长，增加血管灌注并提高化疗剂递送至肿瘤。需要改善用乙酰透明质酸降解酶治疗的患者的治疗的方法和试剂。
发明内容
本文提供一种选择对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗肿瘤的方法。在提供的方法中，使来自患有肿瘤或癌症的对象的组织或体液样品与不是制备自或分离自动物软骨的乙酰透明质酸结合蛋白(HABP)接触。检测乙酰透明质酸结合蛋白对所述样品的结合，从而确定所述样品中乙酰透明质酸的量，其中如果所述样品中乙酰透明质酸的量为或高于预定的阈值水平，则选择所述对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶进行治疗。
本文提供一种选择对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗肿瘤的方法，其中使来自患有肿瘤或癌症的对象的体液与不是制备自或分离自动物软骨的乙酰透明质酸结合蛋白(HABP)接触，并且通过具有比色或荧光信号的固相结合测定实现所述HABP对所述样品的结合，从而确定所述样品中乙酰透明质酸的量，其中当预定的阈值水平为高HA时，选择对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶进行治疗。在所述方法的一些实例中，预定的阈值水平为至少或高于0.025μg HA/ml样品、0.030μg/ml、0.035μg/ml、0.040μg/ml、0.045μg/ml、0.050μg/ml、0.055μg/ml、0.060μg/ml、0.065μg/ml、0.070μg/ml、0.08μg/ml、0.09μg/ml、0.1μg/ml、0.2μg/ml、0.3μg/ml或更高。
本文提供一种选择对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗肿瘤的方法，其中使来自患有肿瘤或癌症的对象的肿瘤组织样品与不是制备自或分离自动物软骨的乙酰透明质酸结合蛋白(HABP)接触，并且通过组织化学实现所述HABP对所述样品的结合，从而确定所述样品中乙酰透 明质酸的量，其中当预定的阈值水平为至少+2(HA+2)或至少+3(HA+3)的HA评分时，选择对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶进行治疗。在一些实例中，预定的阈值水平为至少+3(HA+3)的HA评分(高水平)。在其他实例中，预定的阈值水平为至少肿瘤(细胞和基质)中HA阳性像素比肿瘤组织中总染色的百分比为至少10％、10％-25％或大于25％。例如，预定的阈值水平为至少肿瘤(细胞和基质)中HA阳性像素比肿瘤组织中总染色的百分比为至少11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％或40％。
本文还提供一种选择对象用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗肿瘤的方法，其中然后用所述抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗所述对象。在一些实例中，所述抗乙酰透明质酸剂为乙酰透明质酸降解酶，其以以下剂量范围量或大约以下剂量范围量给药：0.01μg/kg(所述对象)-50μg/kg、0.01μg/kg-20μg/kg、0.01μg/kg-15μg/kg、0.05μg/kg-10μg/kg、0.75μg/kg-7.5μg/kg或1.0μg/kg-3.0μg/kg，以及以每周2次、每周1次、每14天1次、每21天1次或每月1次的给药频率给药。在所述方法的具体实例中，在给药乙酰透明质酸降解酶之前或给药所述乙酰透明质酸降解酶之后给药皮质类固醇，通常以足以改善对象中来自给药的乙酰透明质酸降解酶的副作用的量给药。例如，给药的皮质类固醇的量为或大约为0.1-20mg、0.1-15mg、0.1-10mg、0.1-5mg、0.2-20mg、0.2-15mg、0.2-10mg、0.2-5mg、0.4-20mg、0.4-15mg、0.4-10mg、0.4-5mg、0.4-4mg、1-20mg、1-15mg或1-10mg。
本文还提供一种预测用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗对象的效力的方法。在提供的方法中，使来自用或已用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗的对象的组织或体液与不是制备自或分离自动物软骨的乙酰透明质酸结合蛋白(HABP)接触，并且检测所述乙酰透明质酸结合蛋白对所述样品的结合，从而确定所述样品中乙酰透明质酸的量，其中检测到与用所述抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗或抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的最后剂量之前相比乙酰透明质酸减少，则表明治疗是有效的。
本文还提供一种监测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗对象的方法。在提供的方法中，使来自患有肿瘤或癌症的对象的组织或体液样品与不是制备自或分离自动物软骨的乙酰透明质酸结合蛋白(HABP)接触，并且检测结合所述样品的乙酰透明质酸结合蛋白的量，从而确定所述样品中乙酰透明质酸的量，并且将乙酰透明质酸的水平与对照或参考样品比较，从而确定相对于所述对照或参考样品，所述样品中乙酰透明质酸的量，其中乙酰透明质酸的量是治疗进展的指示物。
本文还提供预测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗对象的效力和监测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗对象的方法，其中基于相对于所述对照或参考样品，所述样品中乙酰透明质酸的确定量来改变治疗，从而如果所述样品中乙酰透明质酸的量为所述对照或参考样品中的量或在其之上，则继续治疗或逐步增加剂量和/或剂量方案；或者如果所述样品中乙酰透明质酸的量低于所述对照或参考样品中的量，则继续治疗，减少剂量和/或剂量方案，或者终止。在一些实例中，所述对照或参考样品是来自健康对象的样品，是来自用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗之前的对象的基线样品，或者是来自抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的最后剂量之前的对象的样品。在一些实例中，所述对象患有肿瘤或癌症，所述样品为肿瘤组织样品，并且通过组织化学进行检测。在其他实例中，所述对象患有肿瘤或癌症，所述样品为体液，并且通过固相结合测定进行检测。在一些实例中，所述固相结合测定为微量滴定板测定，并且比色或通过荧光检测结合。
在本文提供的任何方法中，使所述样品与HABP接触的步骤可以在pH5.6-6.4或大约在pH5.6-6.4下进行例如，使所述样品与HABP接触的步骤可以在约5.8、5.9、6.0、6.1或6.2的pH下进行。在一些实例中，所述HABP特异性结合HA，具有通过解离常数(Kd)表示的至少低于或低于或1x10-7M、9x10-8M、8x10-8M、7x10-8M、6x10-8M、5x10-8M、4x10-8M、3x10-8M、2x10-8M、1x10-8M、9x10-9M、8x10-9M、7x10-9M、6x10-9M、5x10-9M、4x10-9M、3x10-9M、2x10-9M、1x10-9M或更低Kd的结合亲和力。
在上文提供的任何方法中，所述HABP可以重组或合成产生。在一些 实例中，所述HABP包含连接模块。在其他实例中，所述HABP包含两个或更多个连接模块。在其他实例中，所述连接模块或多个模块是所述分子的唯一的HABP部分。因此，本文提供这样的方法，其中所述HABP包含选自以下的连接模块：CD44、LYVE-1、HAPLN1/连接蛋白、HAPLN2、HAPLN3、HAPLN4、聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖、磷酸蛋白聚糖(phosphacan)、TSG-6、稳定素(Stabilin)-1、稳定素-2、CAB61358和KIAA0527。在所述方法的一些实例中，所述HABP包含一部分的CD44、LYVE-1、HAPLN1/连接蛋白、HAPLN2、HAPLN3、HAPLN4、聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖、磷酸蛋白聚糖、TSG-6、稳定素-1、稳定素-2、CAB61358或KIAA0527，包括连接模块或连接模块之足以结合HA的部分。在具体实例中，所述HABP为肿瘤坏死因子刺激的基因(TSG-6)蛋白或TSG-6的连接模块或TSG-6的连接模块的足以结合HA的部分。在本文的方法的其他实例中，所述HABP包含C型乙酰透明质酸结合蛋白的G1结构域，例如选自以下的G1结构域：聚集蛋白聚糖G1、多能聚糖G1、神经聚糖G1和短小蛋白聚糖G1。在具体实例中，所述G1结构域是所述分子的唯一的HABP部分。
在本文提供的方法的一些实例中，所述HABP包含SEQ ID NO:207、222、360、361、371-394、416-418和423-426中任一个所示的氨基酸序列，或者具有表现出与SEQ ID NO:207、360、361、371-394、416-418和423-426中任一个所示的氨基酸序列的至少65％、70％、75％、80％、85％、90％、91％、92％、93％、95％、95％、96％、97％、98％、99％或更多序列相同性且特异性结合HA的氨基酸序列，或者为其HA结合结构域或其足以特异性结合HA的部分。在示例性实例中，所述HABP包含TSG-6连接模块(LM)或其足以特异性结合HA的部分。例如，所述TSG-6-LM包含SEQ ID NO:207、360、417或418所示的氨基酸序列，或者包含与SEQID NO:207、360、417或418所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。在所述方法的具体实例中，所述HABP包含SEQ ID NO:207所示的连接模块，或者包含与SEQ ID NO:207所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。在其他实例中，所述HABP包含表现出与SEQ ID NO:207、360、417或418所 示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的连接模块，其中所述HABP特异性结合HA。
在本文提供的方法的一些实例中，修饰所述TSG-6连接模块以减少或消除对肝素的结合。例如，对肝素的结合减少至少1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。在本文提供的方法的一些实例中，TSG-6连接模块在对应于SEQ ID NO:360所示的氨基酸残基20、34、41、54、56、72或84的氨基酸位置处包含氨基酸置换，其中通过与SEQ ID NO:360所示的TSG-6-LM比对来鉴定相应的氨基酸残基。例如，所述氨基酸置换在SEQ ID NO:207所示的TSG-6-LM中，并且所述氨基酸置换或多个置换在氨基酸残基21、35、42、55、57、73或85处。所述氨基酸置换可以置换为选自以下的非碱性氨基酸残基：Asp(D)、Glu(E)、Ser(S)、Thr(T)、Asn(N)、Gln(Q)、Ala(A)、Val(V)、Ile(I)、Leu(L)、Met(M)、Phe(F)、Tyr(Y)和Trp(W)。在另一实例中，所述TSG-6连接模块包含对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A或K41A的氨基酸置换，或者在另一TSG-6-LM中相应残基处的置换。在另一实例中，所述TSG-6连接模块包含对应于SEQ IDNO:360所示的TSG-6-LM中氨基酸置换K20A、K34A和K41A的氨基酸置换，或者在另一TSG-6-LM中相应残基处的置换。例如，所述HABP包含SEQ ID NO:361或416所示的连接模块，或者包含与SEQ ID NO:361或416所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。
在本文提供的方法的一些实例中，所述HABP包含表现出与SEQ ID NO:361或416所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的连接模块，其中所述HABP特异性结合HA。在具体实例中，所述HABP包含SEQ ID NO:361或SEQ ID NO:416所示的连接模块。在其他实例中，所述连接模块是所述HABP的唯一的TSG-6部分。在本文提供的方法的一些实例中，所述HABP为多聚体，所述多聚体包含直接或通过接头间接连接至多聚化结构域的第一HA结合结构域，以及直接或通过接头间接连接至多 聚化结构域的第二HA结合结构域。例如，所述HA结合结构域为连接模块或G1结构域。所述第一和第二HA结合结构域可以相同或不同。在一具体实例中，所述第一和第二HA结合结构域为TSG-6连接模块，其特异性结合HA的变体或其足以特异性结合HA的部分。例如，所述TSG-6-LM包含SEQ ID NO:207、360、361、416、417或418所示的氨基酸序列，或者包含与SEQ ID NO:207、360、361、416、417或418所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。例如，所述连接模块表现出与SEQ IDNO:207、360、361、416、417或418所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性，其中所述HABP特异性结合HA。在本文提供的一些方法中，所述连接模块包含SEQ ID NO:207、360、361、416、417或418所示的氨基酸序列。
在提供的方法中，所述HABP、HA结合结构域、连接模块或其部分可以连接至选自以下的多聚化结构域：免疫球蛋白恒定区(Fc)、亮氨酸拉链、互补疏水区、互补亲水区、相容的蛋白-蛋白相互作用结构域、在两个分子之间形成分子间二硫键的游离硫醇以及形成稳定多聚体的相同或相似大小的突起成腔(protuberance-into-cavity)和补偿腔(compensatory cavity)。在一具体实例中，所述多聚化结构域为Fc结构域或其实现多聚化的变体。例如，所述Fc结构域来自IgG、IgM或IgE，或者所述Fc结构域具有SEQ ID NO:359所示的氨基酸序列。在本发明提供的方法的某些情况下，所述HABP为包含TSG-6连接模块和免疫球蛋白Fc结构域的融合蛋白。例如，所述HABP为TSG-6-LM-Fc，其具有SEQ ID NO:212所示的氨基酸序列或者表现出与SEQ ID NO:212的至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列，例如表现出与SEQ ID NO:212所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列，其中所述HABP特异性结合HA。在具体实例中，所述HABP具有SEQ ID NO:212或215所示的氨基酸序列。在本文提供的任何方法中，所述HABP可以为TSG-6-LM-Fc/ΔHep，其具有SEQID NO:215所示的氨基酸序列或者表现出与SEQ ID NO:215的至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列，例如表现出与SEQ ID NO:215所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列，其中所述HABP特异性结合HA。
在本文提供的具体方法中，所述HABP为TSG-6或其乙酰透明质酸结合结构域。在本文提供的方法的一些实例中，所述HABP或TSG-6具有至少1x108M-1、2x108M-1、3x108M-1、4x108M-1、5x108M-1、6x108M-1、7x108M-1、8x108M-1、9x108M-1、1x109M-1或更高的对HA的结合亲和力。在其他实例中，所述HABP或TSG-6缀合至可检测地标记或可以被检测的可检测部分。例如，所述HABP或TSG-6是生物素化的。
在本文提供的方法的一些实例中，所述样品为间质组织样品，例如来自肿瘤的间质组织样品。本文的方法中采样的组织可以是固定的、石蜡包埋的、新鲜的或冷冻的。在一些实例中，所述样品采自来自实体瘤的活组织检查，例如，通过细针活组织检查、CT指导的细针活组织检查、穿刺活组织检查、内窥镜活组织检查、支气管镜活组织检查、支气管灌洗、切取活组织检查、切除活组织检查、钻取活组织检查、刮削活组织检查、皮肤活组织检查、骨髓活组织检查以及电圈切除术(LEEP)获得。在其他实例中，所述样品为液体样品，其为血液、血清、尿、汗液、精液、唾液、脑脊液或淋巴样品。在本文提供的任何方法中，所述样品可以获得自哺乳动物。在一示例性实例中，所述哺乳动物为人。
在本文提供的任何方法中，所述肿瘤可以为癌症，所述癌症选自乳腺癌、胰腺癌、卵巢癌、结肠癌、肺癌、非小细胞肺癌、原位癌(ISC)、鳞状细胞癌(SCC)、甲状腺癌、子宫颈癌、子宫癌、前列腺癌、睾丸癌、脑癌、膀胱癌、胃癌、肝癌、黑素瘤、神经胶质瘤、视网膜母细胞瘤、间皮瘤、骨髓瘤、淋巴瘤和白血病。在一些实例中，所述肿瘤为癌症，所述癌症为晚期癌症、转移癌症和未分化的癌症。
在本文提供的任何方法中，所述抗乙酰透明质酸剂可以为降解乙酰透明质酸的物质或者可以为抑制乙酰透明质酸合成的物质。例如，所述抗乙酰透明质酸剂可以为乙酰透明质酸降解酶。在另一实例中，所述抗乙酰透明质酸剂或者是抑制乙酰透明质酸合成的物质。例如，所述抗乙酰透明质酸剂为抑制乙酰透明质酸合成的物质如针对HA合成酶的正义或反义核酸 分子或者是小分子药物。例如，抗乙酰透明质酸剂为4-甲基伞形酮(MU)或其衍生物，或者来氟米特或其衍生物。这类衍生物包括例如4-甲基伞形酮(MU)的衍生物，为6,7-二羟基-4-甲基香豆素或5,7-二羟基-4-甲基香豆素。
在本文提供的方法的其他实例中，所述乙酰透明质酸降解酶为透明质酸酶。在一些实例中，所述乙酰透明质酸降解酶为PH20透明质酸酶或者其缺少C-末端糖基磷脂酰肌醇(GPI)粘附位点或一部分GPI粘附位点的截短形式。在具体实例中，所述透明质酸酶为选自以下的PH20：人、猴、牛、绵羊、大鼠、小鼠或豚鼠PH20。例如，所述乙酰透明质酸降解酶为人PH20透明质酸酶，其在中性条件下有活性且是N-糖基化的，并且选自(a)透明质酸酶多肽，其为全长PH20或PH20的C-末端截短形式，其中所述截短形式包括至少SEQ ID NO:1的氨基酸残基36-464，例如36-481、36-482、36-483，其中所述全长PH20具有SEQ ID NO:2所示的氨基酸序列；或者(b)透明质酸酶多肽，其包含与所述多肽或SEQ ID NO:2所示的氨基酸序列的截短形式具有至少85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性的氨基酸序列；或者(c)(a)或(b)的透明质酸酶多肽，其包含氨基酸取代，其中所述透明质酸酶多肽具有的氨基酸序列与SEQ ID NO:2所示的多肽或与其相应的截短形式具有至少85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性。在示例性实例中，所述乙酰透明质酸降解酶是包含命名为rHuPH20的组合物的PH20。
在其他实例中，所述抗乙酰透明质酸剂是通过缀合至聚合物而进行修饰的乙酰透明质酸降解酶。所述聚合物可以为PEG，并且所述抗乙酰透明质酸剂为聚乙二醇化的乙酰透明质酸降解酶。因此，在本文提供的方法的一些实例中，所述乙酰透明质酸降解酶通过缀合至聚合物来进行修饰。例如，所述乙酰透明质酸降解酶缀合至PEG，因此所述乙酰透明质酸降解酶是聚乙二醇化的。在示例性实例中，所述乙酰透明质酸降解酶为聚乙二醇化的PH20酶(PEGPH20)。在本文提供的方法中，皮质类固醇可以是选自以下的糖皮质激素：可的松、地塞米松、氢化可的松、甲泼尼龙、泼尼松龙和泼尼松。
本文还提供一种试剂盒，其包含用于检测样品中乙酰透明质酸的量的乙酰透明质酸结合剂(HABP)以及乙酰透明质酸降解酶，其中所述HABP不是制备自动物软骨。所述HABP可以重组或合成产生。在一些实例中，所述HABP包含一个连接模块。在其他实例中，所述HABP包含两个或更多个连接模块。在一些实例中，所述连接模块或多个模块是所述分子的唯一的HABP部分。例如，所述HABP包含选自以下的连接模块：CD44、LYVE-1、HAPLN1/连接蛋白、HAPLN2、HAPLN3、HAPLN4、聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖、磷酸蛋白聚糖、TSG-6、稳定素-1、稳定素-2、CAB61358和KIA0527，或者其包含连接模块的部分或连接模块之足以结合HA的部分。在其他实例中，所述HABP包含C型乙酰透明质酸结合蛋白的G1结构域，例如选自以下的G1结构域：聚集蛋白聚糖G1、多能聚糖G1、神经聚糖G1和短小蛋白聚糖G1。在具体实例中，所述G1结构域是所述分子的唯一的HABP部分。
在一些实例中，所述试剂盒包含HABP，所述HABP包含SEQ ID NO:207、222、360、361、371-394和416-418和423-426中任一个所示的氨基酸序列，或者表现出与SEQ ID NO:207、360、361、371-394、416-418和423-426中任一个所示的氨基酸序列的至少65％、70％、75％、80％、85％、90％、91％、92％、93％、95％、95％、96％、97％、98％、99％或更多序列相同性且特异性结合HA的氨基酸序列，或者其HA结合结构域或其足以特异性结合HA的部分。在示例性实例中，所述HABP包含TSG-6连接模块(LM)或其足以特异性结合HA的部分。例如，所述TSG-6-LM包含SEQ ID NO:207、360、417或418所示的氨基酸序列，或者包含与SEQ IDNO:207、360、417或418所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。在一些实例中，所述HABP包含表现出与SEQ ID NO:360所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的连接模块，其中所述HABP结合HA。在具体实例中，所述HABP包含SEQ ID NO:207、360、417或418所示的连接模块。
在本文提供的试剂盒的一些实例中，修饰所述TSG-6连接模块以减少或消除对肝素的结合。例如，对肝素的结合减少至少1.2倍、1.5倍、2倍、 3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。在一些实例中，TSG-6连接模块在对应于SEQ ID NO:360所示的氨基酸残基20、34、41、54、56、72或84的氨基酸位置处包含氨基酸置换，其中通过与SEQ ID NO:360所示的TSG-6-LM比对来鉴定相应的氨基酸残基。例如，所述氨基酸置换可以置换为选自以下的非碱性氨基酸残基：Asp(D)、Glu(E)、Ser(S)、Thr(T)、Asn(N)、Gln(Q)、Ala(A)、Val(V)、Ile(I)、Leu(L)、Met(M)、Phe(F)、Tyr(Y)和Trp(W)。因此，本文提供试剂盒，其中所述TSG-6连接模块包含对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A或K41A的氨基酸置换，或者在另一TSG-6-LM中相应残基处的置换。例如，所述TSG-6连接模块包含对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A和K41A的氨基酸置换，或者在另一TSG-6-LM中相应残基处的置换。本文还提供试剂盒，其中所述HABP包含SEQ ID NO:361或416所示的连接模块，或者包含与SEQ ID NO:361或416所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。例如，所述HABP包含表现出与SEQ ID NO:361或416所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的连接模块，其中所述HABP特异性结合HA。在具体实例中，所述HABP包含SEQ ID NO:361或416所示的连接模块。在其他实例中，所述连接模块是所述HABP的唯一的TSG-6部分。
在本文提供的试剂盒的一些实例中，所述HABP为多聚体，所述多聚体包含直接或通过接头间接连接至多聚化结构域的第一HA结合结构域，以及直接或通过接头间接连接至多聚化结构域的第二HA结合结构域。例如，所述HA结合结构域为连接模块或G1结构域。所述第一和第二HA结合结构域可以相同或不同。在一具体实例中，所述第一和第二HA结合结构域为TSG-6连接模块，其特异性结合HA的变体或其足以特异性结合HA的部分。例如，所述TSG-6-LM包含SEQ ID NO:207、360、361、416、417或418所示的氨基酸序列，或者包含与SEQID NO:207、360、361、416、417或418所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。例如，所述连接模块表现出与SEQ ID NO:207、360、 361、416、417或418所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性，其中所述HABP特异性结合HA。在本文提供的一些方法中，所述连接模块包含SEQ ID NO:207、360、361、416、417或418所示的氨基酸序列。
在提供的试剂盒中，所述HABP可以通过选自以下的多聚化结构域连接：免疫球蛋白恒定区(Fc)、亮氨酸拉链、互补疏水区、互补亲水区、相容的蛋白-蛋白相互作用结构域、在两个分子之间形成分子间二硫键的游离硫醇以及形成稳定多聚体的相同或相似大小的突起成腔和补偿腔。在一具体实例中，所述多聚化结构域为Fc结构域或其实现多聚化的变体。例如，所述Fc结构域来自IgG、IgM或IgE，或者所述Fc结构域具有SEQ ID NO:359所示的氨基酸序列。在本发明提供的方法的某些情况下，所述HABP为包含TSG-6连接模块和免疫球蛋白Fc结构域的融合蛋白。例如，所述HABP为TSG-6-LM-Fc，其具有SEQ ID NO:212或215所示的氨基酸序列或者表现出与SEQ ID NO:212或215的至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列，例如表现出与SEQ ID NO:212或215所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列，其中所述HABP特异性结合HA。在具体实例中，所述HABP具有SEQ ID NO:212或215所示的氨基酸序列。在本文提供的任何方法中，所述HABP可以为TSG-6-LM-Fc/ΔHep，其具有SEQ ID NO:215所示的氨基酸序列或者表现出与SEQ ID NO:215的至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列，例如表现出与SEQ ID NO:215所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列，其中所述HABP特异性结合HA。
在本文提供的试剂盒的具体实例中，所述HABP为TSG-6或其乙酰透明质酸结合结构域。在本文提供的方法的一些实例中，所述HABP具有至少107M-1的对HA的结合亲和力(通过结合常数(Ka)表示)，例如，至少1x108M-1、2x108M-1、3x108M-1、4x108M-1、5x108M-1、6x108M-1、7x108M-1、8x108M-1、9x108M-1、1x109M-1或更高。例如，所述HABP具有至少低于或低于1x10-7M、9x10-8M、8x10-8M、7x10-8M、6x10-8M、 5x10-8M、4x10-8M、3x10-8M、2x10-8M、1x10-8M、9x10-9M、8x10-9M、7x10-9M、6x10-9M、5x10-9M、4x10-9M、3x10-9M、2x10-9M、1x10-9M或更低Kd的结合亲和力(通过解离常数(Kd)表示)。在其他实例中，所述HABP缀合至可检测地标记或可以被检测的可检测部分。例如，所述HABP是生物素化的。
本文还提供试剂盒，其包含用于检测样品中乙酰透明质酸的量的乙酰透明质酸结合剂(HABP)以及抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)，其中所述HABP不是制备自动物软骨。本文提供的任何试剂盒还可以包含用于检测所述HABP的试剂。在本文提供的试剂盒的任何实例中，所述抗乙酰透明质酸剂可以是上文或本文其他地方所述的任何抗乙酰透明质酸剂。例如，所述抗乙酰透明质酸剂可以为乙酰透明质酸降解酶如透明质酸酶。例如，所述乙酰透明质酸降解酶为PH20透明质酸酶或者其缺少C-末端糖基磷脂酰肌醇(GPI)粘附位点或一部分GPI粘附位点的截短形式。在一些实例中，所述PH20选自人、猴、牛、绵羊、大鼠、小鼠或豚鼠PH20。例如，所述乙酰透明质酸降解酶为人PH20透明质酸酶，其中性条件下有活性且是N-糖基化的，并且选自(a)透明质酸酶多肽，其为全长PH20或PH20的C-末端截短形式，其中所述截短形式包括至少SEQ ID NO:1的氨基酸残基36-464，其中所述全长PH20包含SEQ ID NO:2所示的氨基酸序列；或者(b)透明质酸酶多肽，其包含与所述多肽或SEQID NO:2所示的氨基酸序列的截短形式具有至少85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性的氨基酸序列；或者(c)(a)或(b)的透明质酸酶多肽，其包含氨基酸取代，其中所述透明质酸酶多肽具有的氨基酸序列与SEQ ID NO:2所示的多肽或与其相应的截短形式具有至少85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性。在具体实例中，所述乙酰透明质酸降解酶是包含命名为rHuPH20的组合物的PH20。在一些实例中，所述乙酰透明质酸降解酶通过缀合至聚合物如PEG来进行修饰，并且所述乙酰透明质酸降解酶是聚乙二醇化的。因此本文提供一种试剂盒，其中所述乙酰透明质酸降解酶为聚乙二醇化的PH20酶(PEGPH20)。本文还提供试剂盒，其还包含皮质类固醇。本文提供的任 何试剂盒还可以包含关于其组分使用的标签或包装插页。
本文提供使用乙酰透明质酸结合蛋白(HABP)选择对象用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗肿瘤的方法，其中所述HABP不是制备或分离自动物软骨。本文还提供包含乙酰透明质酸结合蛋白(HABP)的药物组合物，其用于选择对象用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗肿瘤，其中所述HABP不是制备或分离自动物软骨。
本文提供使用乙酰透明质酸结合蛋白(HABP)预测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗对象的效力的方法，其中所述HABP不是制备或分离自动物软骨。本文还提供包含乙酰透明质酸结合蛋白(HABP)的药物组合物，其用于预测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗对象的效力，其中所述HABP不是制备或分离自动物软骨。
在本文提供的任何用途或药物组合物中，所述HABP可以包含连接模块或多个模块或者G1结构域。在一些实例中，所述HABP包含TSG-6连接模块(LM)、其结合HA的变体或其足以结合HA的部分。在一具体实例中，修饰所述TSG-6连接模块以减少或消除对肝素的结合。在一些实例中，所述HABP包含SEQ ID NO:207、212、215、222、360、361、371-394和416-418和423-426中任一个所示的氨基酸序列，或者表现出与SEQ ID NO:207、212、215、222、360、361、371-394和416-418和423-426中任一个所示的氨基酸序列的至少65％、70％、75％、80％、85％、90％、91％、92％、93％、95％、95％、96％、97％、98％、99％或更多序列相同性且特异性结合HA的氨基酸序列，或者其HA结合结构域或其足以特异性结合HA的部分。
本文还提供TSG-6-LM多聚体，所述多聚体包含直接或通过接头间接连接至多聚化结构域的第一连接模块，以及直接或通过接头间接连接至多聚化结构域的第二连接模块，其中所述第一和第二多肽不包含TSG-6的全长序列。在一些实例中，所述连接模块是所述第一多肽和所述第二多肽的唯一的TSG-6部分。所述第一和第二连接模块可以相同或不同。在一些实例中，所述连接模块包含SEQ ID NO:207、360、417或418所示的氨基酸序列，或者包含与SEQ ID NO:207、360、417或418所示的氨基酸序列具有至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。例如，所 述连接模块表现出与SEQ ID NO:207、360、417或418所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性，并且特异性结合HA。在一些实例中，所述连接模块包含SEQID NO:207、360、417或418所示的氨基酸序列。
在一些实例中，修饰所述TSG-6连接模块以减少或消除对肝素的结合。对肝素的结合可以减少至少1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。在一些实例中，所述TSG-6连接模块在对应于SEQ ID NO:360所示的氨基酸残基20、34、41、54、56、72或84的氨基酸位置处包含氨基酸置换，其中通过与SEQID NO:360所示的TSG-6-LM比对来鉴定相应的氨基酸残基。例如，所述氨基酸置换在SEQ IDNO:207所示的TSG-6-LM中，并且所述氨基酸置换或多个置换在氨基酸残基21、35、42、55、57、73或85处。在一些实例中，所述氨基酸置换可以置换为选自以下的非碱性氨基酸残基：Asp(D)、Glu(E)、Ser(S)、Thr(T)、Asn(N)、Gln(Q)、Ala(A)、Val(V)、Ile(I)、Leu(L)、Met(M)、Phe(F)、Tyr(Y)和Trp(W)。例如，所述TSG-6连接模块包含对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A或K41A的氨基酸置换，或者在另一TSG-6-LM中相应残基处的置换。在一具体实例中，所述TSG-6连接模块包含对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A和K41A的氨基酸置换，或者在另一TSG-6-LM中相应残基处的置换。在一些实例中，所述连接模块包含SEQ ID NO:361或416所示的氨基酸序列，或者包含与SEQID NO:361或416所示的氨基酸序列至少65％氨基酸序列相同性且特异性结合HA的氨基酸序列。例如，所述连接模块表现出与SEQ ID NO:361或416所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性，并且特异性结合HA。在具体实例中，所述连接模块包含SEQ ID NO:361或416所示的氨基酸序列。
本文还提供TSG-6-LM多聚体，其中所述多聚化结构域选自免疫球蛋白恒定区(Fc)、亮氨酸拉链、互补疏水区、互补亲水区、相容的蛋白-蛋白相互作用结构域、在两个分子之间形成分子间二硫键的游离硫醇以及形成 稳定多聚体的相同或相似大小的突起成腔和补偿腔。在一些实例中，所述多聚化结构域为Fc结构域或其实现多聚化的变体。例如，所述Fc结构域来自IgG、IgM或IgE。在一具体实例中，所述Fc结构域具有SEQ ID NO:359所示的氨基酸序列。
本文还提供TSG-6-LM多聚体，其包含TSG-6连接模块和免疫球蛋白Fc结构域。在一些实例中，所述TSG-6-LM多聚体包含SEQ ID NO:212或215所示的氨基酸序列，或者表现出与SEQ ID NO:212或215的至少65％氨基酸序列相同性的氨基酸序列。例如，所述TSG-6多聚体包含表现出与SEQ ID NO:212或215所示的氨基酸序列的至少70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性且特异性结合HA的氨基酸序列。在具体的实例中，所述TSG-6-LM多聚体包含SEQ ID NO:212或215所示的氨基酸序列。在一些实例中，所述TSG-6-LM多聚体对HA的结合亲和力为至少107M-1，例如至少1x108M-1、2x108M-1、3x108M-1、4x108M-1、5x108M-1、6x108M-1、7x108M-1、8x108M-1、9x108M-1、1x109M-1或更低。
本文还提供通过体内成像方法，利用任何上文提供的HABP检测HA来选择对象、预测效力和/或监测治疗的方法。体内成像方法可以为磁共振成像(MRI)、单光子发射计算机断层扫描(SPECT)、计算机断层扫描(CT)、计算机轴向断层扫描(CAT)、电子束计算机断层扫描(EBCT)、高解析度计算机断层扫描(HRCT)、内摆线体层摄影、正电子发射断层扫描(PET)、闪烁扫描法、γ照相机、β+检测仪、γ检测仪、荧光成像、低亮度成像、X-射线和/或生物发光成像。在这类方法中，所述HABP直接或间接缀合至提供信号或诱导信号的部分，所述信号在体内是可检测的。
具体实施方式
提纲
A.定义
B.乙酰透明质酸结合蛋白和同伴诊断剂
1.疾病中的乙酰透明质酸积累以及与预后的关系
2.用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗肿瘤以及对治 疗的反应性
3.乙酰透明质酸结合蛋白(HABP)试剂和诊断
4.同伴诊断和预后方法
C.用作同伴诊断剂的乙酰透明质酸结合蛋白(HABP)
1.具有连接模块或G1结构域的HA结合蛋白
a.A型：TSG-6亚组
i.TSG-6
ii.稳定素-1和稳定素-2
b.B型：CD44亚组
i.CD44
ii.LYVE-1
c.C型：连接蛋白亚组
i.HAPLN/连接蛋白家族
(1)HAPLN1
(2)HAPLN2
(3)HAPLN3
(4)HAPLN4
(5)聚集蛋白聚糖
(6)短小蛋白聚糖
(7)多能聚糖
(8)神经聚糖
(9)磷酸蛋白聚糖
2.没有连接模块的HA结合蛋白
a.HABP1/C1QBP
b.排卵蛋白(Layilin)
c.RHAMM
d.其他
3.HA结合蛋白的修饰
a.HABP的多聚体
i.肽接头
ii.异双功能连接剂
iii.多肽多聚化结构域
(1)免疫球蛋白结构域
(a)Fc结构域
(2)亮氨酸拉链
(3)亚基之间的蛋白-蛋白相互作用
iv.其他多聚化结构域
b.提高HA结合的突变
c.修饰HA结合蛋白用于检测
i.缀合至可检测的蛋白或部分
4.选择HA结合蛋白用于诊断用途
D.测定和分类
1.测量乙酰透明质酸的测定
a.组织化学和免疫组织化学方法
b.固相结合测定
c.体内成像测定
2.对象的分类
E.用抗乙酰透明质酸剂治疗所选的对象
1.抗乙酰透明质酸剂
a.抑制乙酰透明质酸合成的物质
b.乙酰透明质酸降解酶
i.透明质酸酶
(1)哺乳动物型透明质酸酶
(a)PH20
(2)其他透明质酸酶
(3)其他乙酰透明质酸降解酶
ii.可溶性乙酰透明质酸降解酶
(1)可溶性人PH20
(2)rHuPH20
iii.乙酰透明质酸降解酶的糖基化
iv.修饰的(聚合物缀合的)乙酰透明质酸降解酶
2.药物组合物和制剂
3.剂量和给药
a.聚乙二醇化的乙酰透明质酸降解酶的给药
4.组合治疗
F.制备乙酰透明质酸降解酶和乙酰透明质酸结合蛋白的核酸和所编码的多肽的方法
1.载体和细胞
2.表达
a.原核细胞
b.酵母细胞
c.昆虫细胞
d.哺乳动物细胞
e.植物
3.纯化技术
4.乙酰透明质酸降解酶多肽的聚乙二醇化
G.抗乙酰透明质酸剂的评价活性和监测效果的方法
1.评价副作用的方法
2.评价与抗乙酰透明质酸剂的活性(例如乙酰透明质酸降解酶活性)相关的生物标记
a.评价乙酰透明质酸降解酶活性的测定
b.测量HA分解代谢物
c.肿瘤代谢活性
d.增加的表观扩散和增强的肿瘤灌注
3.肿瘤大小和体积
4.药物动力学和药效学测定
H.试剂盒和制成品
I.实施例
A.定义
除非另有定义，本文使用的所有技术和科学术语具有与本发明所属领域技术人员通常理解的相同意义。整个公开中提到的所有专利、专利申请、公开的申请和出版物、GENBANK序列、网站和其他公开的材料，除非另有说明，整体援引加入本文。如果本文的术语有多种定义，则以本节中的为准。当提及URL或者其他这样的标识符或地址时，应当理解这些标识符可以改变，并且在网络上特定的信息可以交流，但是等同的信息是已知的，并且可以例如通过搜索网络和/或适当的数据库容易地找到。对其引用证明了这些信息的可得性和公开传播。
如本文所用，同伴诊断指诊断方法和或试剂，其用来鉴定对用特定疗法敏感的对象或者监测治疗和/或鉴定对象或亚组或其他组的对象的有效剂量。为了本文的目的，同伴诊断剂指试剂，例如修饰的TSG-6蛋白，其用来检测样品中的乙酰透明质酸。同伴诊断剂指所述试剂，并且还指用所述试剂进行的测试。
如本文所用，乙酰透明质酸(HA；也称作透明质酸或透明质酸盐)指天然存在的N-乙酰葡糖胺和D-葡糖醛酸的重复二糖单元的聚合物。某些肿瘤产生乙酰透明质酸。
如本文所用，关于组织或体液样品中HA的量或水平，“高HA”指与正常或健康组织或体液样品相比，所述组织或体液样品中HA的程度或范围。如果量为相应的正常或健康组织中HA的量或水平的至少或至少约2.5倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、60倍、70倍或更高，则HA的量高。应当理解HA的量可以利用诸如固相结合测定或组织化学的方法来确定并定量或半定量。例如，所述量可以基于血浆水平的比较或者通过组织化学确定的染色强度(例如阳性像素百分比)的比较。例如，如果通过组织化学或其他方法的HA评分为HA+3和/或如果有超过25％肿瘤切片的HA染色，则存在高HA。例如，如果强阳性染色(例如褐色染色)比总染色区域总和的比例超过25％强阳性染色比总染色的肿瘤组织，则存在高HA。
如本文所用，HA评分指细胞成员和肿瘤基质上HA阳性水平的半定量评分。评分可以这样确定，通过使用HABP的HA的组织化学方法如免疫组织化学或假免疫组织化学方法检测肿瘤组织如福尔马林固定且石蜡包埋 的组织中的HA。细胞和基质上染色的程度可以在显微镜下视觉确定或者通过可用的计算机算法程序和软件确定。例如，可以利用HA染色的像素计数算法(例如Aperio谱软件以及测量或定量或半定量染色程度的其他标准方法)定量分析图像。将肿瘤分级或评分，在超过25％肿瘤切片的强HA染色下为HA高(HA+3)；在10-25％肿瘤切片的强HA染色下为HA中等(HA+2)；而在低于10％肿瘤切片的强HA染色下为HA低(HA+1)。例如，可以计算并评分强阳性染色(例如褐色染色)比总染色区域总和的比例，其中如果所述比例超过25％强阳性染色比总染色，则将肿瘤组织评分为HA+3，如果所述比例为10-25％的强阳性染色比总染色，则将肿瘤组织评分为HA+2，如果所述比例低于10％的强阳性染色比总染色，则将肿瘤组织评分为HA+1，并且如果强阳性染色比总染色的比例为0，则将肿瘤组织评分为0。Aperio方法及其软件是本领域技术人员已知的(参见例如美国专利第8,023,714号；美国专利第7,257,268号)。
如本文所用，乙酰透明质酸结合蛋白(HA结合蛋白；HABP)或透明质酸粘素(hyaladherin)指特异性结合HA以允许检测所述HA的任何蛋白。结合亲和力是具有至少约或至少107M-1的结合常数Ka的结合亲和力。对于本文提供的方法和同伴诊断产物，HA结合蛋白是重组产生或合成的蛋白，不是来源于生物来源或生理来源如软骨的蛋白。HA结合蛋白包括HA结合结构域，包括结合HA的连接模块及其足以特异性结合HA的部分以允许其检测。因此，HABP包括包含乙酰透明质酸结合区或结构域或其足以特异性结合HA的部分的任何蛋白。示例性乙酰透明质酸结合区为连接模块(连接结构域)或G1结构域。足够部分包括结合结构域或连接模块的至少10、20、30、40、50、60、70、80、90、95个或更多个连续氨基酸。HA结合蛋白还包括融合蛋白，所述融合蛋白包含HA结合蛋白以及一种或多种额外的多肽，包括多聚化结构域。示例性HA结合蛋白包括但不限于聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖、磷酸蛋白聚糖、TSG-6、TSG-6突变体，例如本文提供的那些，包括包含HA结合结构域及其足以结合HA的连接模块的多肽。
如本文所用，乙酰透明质酸结合结构域或HA结合结构域指以具有至少约或至少106M-1或107M-1或更大的结合常数Ka或者少于10-6M或10-7 M或更少的解离常数Kd的结合亲和力特异性结合乙酰透明质酸的HABP多肽的区域或结构域。示例性乙酰透明质酸结合结构域包括例如连接模块(本文也称为连接结构域)或G1结构域，或者连接模块或G1结构域之足以特异性结合HA的部分。
如本文所用，关于“HABP的唯一部分”为连接模块或G1结构域或者其语法变体表示HABP分子(例如TSG-6连接模块)由连接模块或G1结构域组成或者基本上由连接模块或G1结构域组成，但是不包括完整的参考HABP的氨基酸全长序列。因此，HABP仅包含乙酰透明质酸结合区或其足以特异性结合HA的部分。应当理解HABP可以包含额外的非HABP氨基酸序列，包括但不限于对应于可检测部分或能够被检测的部分或多聚化结构域的序列。
如本文所用，关于修饰的HA结合蛋白，修饰指改变，通常改善用于本文提供的诊断方法中的检测的HA结合蛋白的一种或多种特性的修饰。修饰包括增加所述蛋白对HA的亲和力和/或特异性的突变。
如本文所用，结构域指结构上和/或功能上可区别或可定义的多肽的部分(3个或更多个，一般5个或7个或更多个氨基酸的序列)。例如，结构域包括那些可以形成由一个或多个结构基序(例如通过环区连接的α螺旋和/或β链的组合)组成的蛋白内的独立折叠结构的结构域，和/或通过功能活性如激酶活性识别的结构域。蛋白可以具有一个或一个以上不同结构域。例如，可以通过其中序列与相关家族成员的同源性，例如定义胞外域的同源性和基序来鉴定、定义或区分结构域。在另一实例中，可以通过其功能，例如通过酶促活性如激酶活性，或者与生物分子相互作用的能力如DNA结合、配体结合和多聚化来区分结构域。独立的结构域可以表现出功能或活性，从而独立的或融合至另一分子的结构域可以发挥活性，例如蛋白水解活性或配体结合。结构域可以是来自多肽的氨基酸的线性序列或氨基酸的非线性序列。许多多肽包含多个结构域。
如本文所用，融合蛋白指包含通过肽键直接或间接连接的来自两种或更多种蛋白或肽的两个或更多个部分的嵌合蛋白。
如本文所用，多聚化结构域指促进多肽分子与另一多肽分子的稳定相互作用的氨基酸序列，所述另一多肽分子包含互补多聚化结构域以与第一 个结构域形成稳定的多聚体，所述互补多聚化结构域可以是相同或不同的多聚化结构域。一般来说，多肽直接或间接连接至多聚化结构域。示例性多聚化结构域包括免疫球蛋白序列或其部分，亮氨酸拉链，疏水区，亲水区，相容的蛋白-蛋白相互作用结构域，例如但不限于PKA的R亚基和锚定结构域(AD)，形成两个分子之间的分子间二硫键的游离硫醇以及形成稳定多聚体的相同或相似大小的突起成腔(即洞中的旋钮(knob into hole))和补偿腔。例如，多聚化结构域可以为免疫球蛋白恒定区。免疫球蛋白序列可以为免疫球蛋白恒定结构域，例如来自IgG1、IgG2、IgG3或IgG4亚型，IgA，IgE，IgD以及IgM的Fc结构域或其部分。
如本文所用，“洞中的旋钮”(在本文中也称作突起成腔)指工程化的特定多聚化结构域，从而这类结构域之间和/或之中的空间相互作用不仅促进稳定的相互作用，而且还促进从单体的混合物形成异源二聚体(或多聚体)多于同源二聚体(或同源多聚体)。这可以例如通过构建突起和腔来实现。突起可以通过用较大的侧链(例如酪氨酸或色氨酸)从第一多肽的界面代替小氨基酸侧链来构建。任选地通过用较小的氨基酸侧链(例如，丙氨酸或苏氨酸)代替大氨基酸侧链在第二多肽的界面上产生与突起相同或相似大小的补偿“腔”。
如本文所用，互补多聚化结构域指相互作用以形成多肽的稳定多聚体的两个或更多个多聚化结构域，所述多肽连接至每个这样的结构域。互补多聚化结构域可以是相同的结构域或者结构域家族的成员，例如Fc区、亮氨酸拉链以及旋钮和孔。
如本文所用，“Fc”或“Fc区”或“Fc结构域”指包含抗体重链的恒定区但不包括第一恒定区免疫球蛋白结构域的多肽。因此，Fc指IgA、IgD和IgE的最后两个恒定区免疫球蛋白结构域，或者IgE和IgM的最后三个恒定区免疫球蛋白结构域。任选地，Fc结构域可以包括全部或部分的柔性铰链N-末端至这些结构域。对于IgA和IgM，Fc可以包括J链。对于IgG的示例性Fc结构域，包含免疫球蛋白结构域Cγ2和Cγ3，以及任选存在的Cγ1与Cγ2之间的铰链的全部或部分。Fc区的边界可以变化，但是通常包括至少部分铰链区。此外，Fc还包括任何等位或物种变体或者任何变异或修饰形式，例如改变结合FcR或改变Fc介导的效应子功能的任何变异或修饰形式。 包括修饰的Fc结构域在内的其他Fc结构域的示例性序列是已知的。
如本文所用，“Fc嵌合体”指嵌合多肽，其中一个或多个多肽直接或间接连接至Fc区或其衍生物。通常，Fc嵌合体组合免疫球蛋白的Fc区与另一多肽，例如ECD多肽。修饰的Fc多肽的衍生物是本领域技术人员已知的。
如本文所用，关于乙酰透明质酸结合蛋白，“多聚体”指包含多个HA结合位点，例如至少2、3或4个HA结合位点的HABP。例如，HABP多聚体指包含至少2个连接模块的HABP，所述连接模块每个均能够结合HA。例如，可以通过直接或间接连接两个或更多个连接模块(例如TSG-6连接模块)来产生多聚体。可以利用多聚化结构域如Fc蛋白促进连接。
如本文所用，等位变体或等位变异指不同于基因的参考形式的基因编码的多肽(即由等位基因编码)。通常基因的参考形式编码来自物种的群体或单个参照成员的多肽的野生型形式和/或优势形式。通常，包括物种之间和之中的变体的等位基因变体与来自相同物种的野生型和/或优势形式具有至少80％、90％或者更大的氨基酸相同性；相同性程度取决于基因以及比较是种间或种内比较。一般来说，种内等位基因变体与野生型和/或优势形式具有至少约80％、85％、90％或95％或更大的相同性，这包括与多肽的野生型和/或优势形式的96％、97％、98％、99％或更大的相同性。
如本文所用，物种变体指物种之间和之中相同多肽的变体。一般来说，种间变体与来自另一物种野生型和/或优势形式具有至少约60％、70％、80％、85％、90％或95％或更大的相同性，这包括与多肽的野生型和/或优势形式的96％、97％、98％、99％或更大的相同性。
如本文所用，修饰指多肽的氨基酸序列或核酸分子的核苷酸序列的修饰，并且分别包括氨基酸和核苷酸的缺失、插入和置换。
如本文所用，组合物指任何混合物。其可以是溶液、悬浮液、液体、粉末、糊剂、水性、非水性或者它们的任何组合。
如本文所用，组合指两个或更多个项目之间或之中的任何关联。组合可以是两个或更多个不同项目，例如两个组合物或两个收集品，可以是它们的混合物，例如两个或更多个项目的单一混合物，或者它们的任何变异。组合的元件一般是功能上关联或相关的。试剂盒是包装的组合，任选地包 括其组合或元件的使用说明。
如本文所用，正常水平或值可以以本领域技术人员已知的各种方式定义。通常，正常水平指整个健康群体中HA的表达水平。正常水平(或参考水平)是基于健康对象的测量，例如来自指定来源(即血液、血清、组织或其他来源)。通常，正常水平会指定为“正常范围”，其通常指中间95％的健康群体的值的范围。参考值与正常水平在本文中可交换使用，但是可以不同于正常水平，这取决于对象或来源。参考水平通常取决于特定部分群体的正常水平。因此，为了本文的目的，正常或参考水平是受试患者可以比较的预定标准或对照。
如本文所用，升高的水平指列举的或正常的阈值之上的任何水平的HA的量或表达。
如本文所用，生物学样品指获得自大分子和生物分子的活的或病毒来源的任何样品，并且包括可以获得核酸或蛋白或其他大分子的对象的任何细胞类型或组织。生物学样品可以是直接获得自生物来源的样品，或者是加工的样品。例如，扩增的分离的核酸构成生物学样品。生物学样品包括但不限于体液如血液、血浆、血清、脑脊液、滑液、尿和汗，来自动物的组织和器官样品，包括活组织检查肿瘤样品。
如本文所用，检测包括允许蛋白可视(通过眼睛或设备)的方法。可以利用蛋白特异性的抗体使蛋白可视。蛋白的检测还可以通过将蛋白与包括表位标签或标记在内的标签融合来促进。
如本文所用，标记指可检测的化合物或组合物，其直接或间接缀合至多肽以产生标记的多肽。标记可以通过其本身检测(例如，放射性同位素标记或荧光标记)，或者在酶促标记的情况下，可以催化可检测的底物化合物组合物的化学改变。标记的非限制性实例包括荧光部分、绿色荧光蛋白或萤光素酶。
如本文所用，亲和力指两个分子之间如乙酰透明质酸结合蛋白与乙酰透明质酸之间相互作用的强度。通常通过平衡结合常数(Ka)或平衡解离常数(Kd)测量亲和力。本文所述的分子之间的结合亲和力通常具有至少约106l/mol、107l/mol、108l/mol、109l/mol或更大(一般107-108l/mol或更大)的结合常数(Ka)的结合亲和力。本文的分子的结合亲和力还可以基于至少低 于或低于或10-7M、10-8M、10-9M、10-10M、10-11M、10-12M或更低的解离常数(Kd)来描述。
如本文所用，关于其足以结合HA的部分表示结合分子表现出对HA的至少或至少约107-108M-1的Ka或者1x10-7M或1x10-8M或更少的解离常数(Kd)。
如本文所用，关于两个分子，例如关于乙酰透明质酸结合蛋白和HA，特异性(在本文中也称作选择性地)指与对其他分子的亲和力相比，这两个分子互相表现出更大的亲和力。因此，对HA具有更大特异性的乙酰透明质酸结合蛋白(HABP)表示其以比结合HA更低的亲和力结合其他分子，例如肝素。特异性结合通常导致选择性结合。
如本文所用，“G1结构域”指C型HA结合蛋白的HA结合结构域。G1结构域包含Ig模块和两个连接模块。包含G1结构域的示例性蛋白包括HAPLN1/连接蛋白、HAPLN1、HAPLN2、HAPLN3、HAPLN4、聚集蛋白聚糖、多能聚糖、短小蛋白聚糖、神经聚糖和磷酸蛋白聚糖。
如本文所用，在本文中可交换使用的连接模块或连接结构域是蛋白中存在并促进结合HA的乙酰透明质酸结合结构域，并且其参与胞外基质的组装、细胞粘附和迁移。例如，来自人TSG-6的连接模块包含排列在疏水核心周围的两个α螺旋和两个反向平行的β折叠。这定义了连接模块超家族的共有折叠，所述连接模块超家族包括CD44、TSG-6、软骨连接蛋白、聚集蛋白聚糖以及如本文所述的其他蛋白。
如本文所用，“Ig模块”指参与C型HABP之间结合的C型HABP的G1结构域部分。C型乙酰透明质酸的Ig模块互相相互作用以与乙酰透明质酸形成稳定的三级结构。
如本文所用，“固相结合测定”指其中使抗原与配体接触的体外测定，其中所述抗原或配体之一结合固体支持物。所述固相可以是其中组分物理地固定至固体支持物的固相。例如，固体支持物包括但不限于微量滴定板、膜(例如，硝化纤维素)、珠、试纸(dipstick)、薄层色谱板或其他固体介质。当抗原-配体相互作用时，可以去除(例如通过洗涤)不需要的或非特异性的组分并检测抗原-配体复合物。
如本文所用，预测用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗的 效力表示同伴诊断剂可以是用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗的预后指标。例如，基于用同伴诊断剂检测乙酰透明质酸或其他标记的结构，可以确定抗乙酰透明质酸剂如乙酰透明质酸降解酶可能会在治疗对象中具有一些效果。
如本文所用，预后指标指指示特定结果的概率的参数，例如治疗会对特定疾病或对象有效的概率。
如本文所用，样品中升高的HA指与来自健康样品的相应样品中存在的水平相比或者与预定的标准相比样品中HA的量增加。
如本文所用，升高的乙酰透明质酸水平指作为疾病的结果或者除此以外在疾病中观察到的特定组织、体液或细胞中乙酰透明质酸的量，这取决于疾病或疾病状况。例如，作为存在富含乙酰透明质酸的肿瘤的结果，透明质酸(HA)水平可以在体液如血液、尿、唾液和血清中和/或在肿瘤组织或细胞中升高。所述水平可以与标准品或其他合适的对照比较，例如来自没有HA相关疾病的对象如没有肿瘤的对象的可比样品。
如本文所用，对应的残基指在对齐的位点出现的残基。通过本领域技术人员已知的任何方法比对相关或变异的多肽。这类方法通常最大化匹配，并且包括诸如利用手动比对和通过利用许多可用的比对程序(例如，BLASTP)的方法以及本领域技术人员已知的其他方法。通过比对多肽序列，本领域技术人员可以利用保守或相同的氨基酸残基作为指导鉴定对应的残基。对应位置还可以基于结构比对，例如通过利用计算机模拟的蛋白结构比对。在其他情况下，可以鉴定对应区域。
如本文所用，抗乙酰透明质酸剂指调节乙酰透明质酸(HA)合成或降解，从而改变组织或细胞中乙酰透明质酸水平的任何物质。为了本文的目的，与不存在所述物质相比，抗乙酰透明质酸剂降低组织或细胞中的乙酰透明质酸水平。这类物质包括调节编码HA合成酶(HAS)以及参与乙酰透明质酸代谢的其他酶或受体的遗传物质的表达的化合物，或者调节合成或降解包括HAS功能或活性的乙酰透明质酸的蛋白的化合物。所述物质包括小分子、核酸、肽、蛋白或其他化合物。例如，抗乙酰透明质酸剂包括但不限于反义或正义分子、抗体、酶、小分子抑制剂以及HAS底物类似物。
如本文所用，乙酰透明质酸降解酶指催化将乙酰透明质酸聚合物(也称 作透明质酸或HA)切割为较小分子量的片段的酶。乙酰透明质酸降解酶的实例为透明质酸酶，以及具有解聚乙酰透明质酸的能力的特定软骨素酶和裂解酶。是乙酰透明质酸降解酶的示例性软骨素酶包括但不限于软骨素ABC裂解酶(也称作软骨素酶ABC)、软骨素AC裂解酶(也称作硫酸软骨素裂解酶或硫酸软骨素消除酶)和软骨素C裂解酶。软骨素ABC裂解酶包含两种酶，硫酸软骨素-ABC endolyase(EC4.2.2.20)和硫酸软骨素-ABC exolyase(EC4.2.2.21)。示例性硫酸软骨素-ABC endolyase和硫酸软骨素-ABC exolyase包括但不限于来自普通变形杆菌(Proteus vulgaris)和Pedobacter heparinus的那些(普通变形杆菌硫酸软骨素-ABCendolyase在SEQ ID NO:98中示出；Sato et al.(1994)Appl.Microbiol.Biotechnol.41(1):39-46)。来自细菌的示例性软骨素酶AC包括但不限于来自Pedobacter heparinus(在SEQ ID NO:99中示出)、Victivallis vadensis(在SEQ ID NO:100中示出)和金黄节杆菌(Arthrobacter aurescens)的那些(Tkalec et al.(2000)Applied and EnvironmentalMicrobiology66(1):29-35；Ernst et al.(1995)Critical Reviews in Biochemistryand Molecular Biology30(5):387-444)。来自细菌的示例性软骨素酶C酶包括但不限于来自链球菌(Streptococcus)和黄杆菌(Flavobacterium)的那些(Hibi et al.(1989)FEMS-Microbiol-Lett.48(2):121-4；Michelacci et al.(1976)J.Biol.Chem.251:1154-8；Tsuda et al.(1999)Eur.J.Biochem.262:127-133)。
如本文所用，透明质酸酶指一类乙酰透明质酸降解酶。透明质酸酶包括细菌透明质酸酶(EC4.2.2.1或EC4.2.99.1)，来自水蛭、其他寄生虫和甲壳动物(EC3.2.1.36)的透明质酸酶以及哺乳动物型透明质酸酶(EC3.2.1.35)。透明质酸酶包括任何非人来源，包括但不限于小鼠、犬、猫、野兔、鸟、牛、绵羊、猪、马、鱼、蛙科动物、细菌以及来自水蛭、其他寄生虫和甲壳动物的任何透明质酸酶。示例性非人透明质酸酶包括来自牛(SEQ ID NO:10、11、64和BH55(美国专利第5,747,027号和第5,827,721号)、黄蜂(SEQ ID NO:12和13)、蜜蜂(SEQ ID NO:14)、白脸大黄蜂(SEQ ID NO:15)、胡蜂(SEQ ID NO:16)、小鼠(SEQ ID NO:17-19、32)、猪(SEQ ID NO:20-21)、大鼠(SEQ ID NO:22-24、31)、兔(SEQ ID NO:25)、羊(SEQID NOS:26、27、63和65)、黑猩猩(SEQ ID NO:101)、猕猴(SEQ ID NO:102)、 猩猩(SEQ IDNO:28)、食蟹猴(SEQ ID NO:29)、豚鼠(SEQ ID NO:30)、节杆菌(Arthrobacter sp.)(菌株FB24(SEQ ID NO:67))、噬菌蛭弧菌(Bdellovibrio bacteriovorus)(SEQ ID NO:68)、痤疮丙酸杆菌(Propionibacterium acnes)(SEQ ID NO:69)、无乳链球菌(Streptococcusagalactiae)((SEQ ID NO:70)；18RS21(SEQ ID NO:71)；血清型Ia(SEQ ID NO:72)；血清型III(SEQ ID NO:73))、金黄色葡萄球菌(Staphylococcus aureus)(菌株COL(SEQ ID NO:74)；菌株MRSA252(SEQ ID NOS:75和76)；菌株MSSA476(SEQ ID NO:77)；菌株NCTC8325(SEQID NO:78)；菌株牛RF122(SEQ ID NO:79和80)；菌株USA300(SEQ ID NO:81))、肺炎链球菌(Streptococcus pneumoniae)((SEQ ID NO:82)；菌株ATCC BAA-255/R6(SEQ ID NO:83)；血清型2，菌株D39/NCTC7466(SEQ ID NO:84))、化脓性链球菌(Streptococcus pyogenes)(血清型M1(SEQ ID NO:85)；血清型M2，菌株MGAS10270(SEQ ID NO:86)；血清型M4，菌株MGAS10750(SEQ ID NO:87)；血清型M6(SEQ ID NO:88)；血清型M12，菌株MGAS2096(SEQ IDNOS:89和90)；血清型M12，菌株MGAS9429(SEQ ID NO:91)；血清型M28(SEQ ID NO:92))、猪链球菌(Streptococcus suis)(SEQ ID NO:93-95)；费氏弧菌(Vibrio fischeri)(菌株ATCC700601/ES114(SEQ ID NO:96))的透明质酸酶，以及Streptomyces hyaluronolyticus透明质酸酶，其为透明质酸特异性的，并且不切割软骨素或硫酸软骨素(Ohya,T.andKaneko,Y.(1970)Biochim.Biophys.Acta198:607)。透明质酸酶还包括人来源的那些透明质酸酶。示例性人透明质酸酶包括HYAL1(SEQ ID NO:36)、HYAL2(SEQ ID NO:37)、HYAL3(SEQ ID NO:38)、HYAL4(SEQ ID NO:39)和PH20(SEQ ID NO:1)。透明质酸酶中还包括可溶性透明质酸酶，包括绵羊和牛PH20、可溶性人PH20和可溶性rHuPH20。可商购的牛或绵羊可溶性透明质酸酶的实例包括(绵羊透明质酸酶)、(牛透明质酸酶)和HydaseTM(牛透明质酸酶)。
如本文所用，“纯化的牛睾丸透明质酸酶”指纯化自牛睾丸提取物的牛透明质酸酶(参见美国专利号2,488,564、2,488,565、2,806,815、2,808,362、2,676,139、2,795,529、5,747,027和5,827,721)。可商购的纯化的牛睾丸透明质酸酶的实例包括和HydaseTM，以及牛透明质酸酶，包括 但不限于可获得自Sigma Aldrich、Abnova、EMDChemicals、GenWay Biotech,Inc.、Raybiotech,Inc.和Calzyme的那些牛透明质酸酶。还包括重组产生的牛透明质酸酶，例如但不限于通过表达SEQ ID NO:190-192中任一个所示的核酸分子产生的那些牛透明质酸酶。
如本文所用，“纯化的绵羊睾丸透明质酸酶”指纯化自绵羊睾丸提取物的绵羊透明质酸酶(参见美国专利号2,488,564、2,488,565和2,806,815以及国际PCT申请号WO2005/118799)。可商购的纯化的绵羊睾丸提取物的实例包括以及绵羊透明质酸酶，包括但不限于可获得自Sigma Aldrich、Cell Sciences、EMD Chemicals、GenWay Biotech,Inc.、Mybiosource.com和Raybiotech,Inc.的那些绵羊透明质酸酶。还包括重组产生的绵羊透明质酸酶，例如但不限于通过表达SEQ ID NO:66和193-194中任一个所示的核酸分子产生的那些绵羊透明质酸酶。
如本文所用，“PH20”指存在于精子中并且在中性条件下是有活性的一类透明质酸酶。PH-20存在于精子表面和溶酶体衍生的顶体，其中PH-20结合顶体内膜。PH20包括任何来源的PH20，包括但不限于人、黑猩猩、食蟹猴、猕猴、小鼠、牛、绵羊、豚鼠、兔和大鼠来源。示例性PH20多肽包括来自人(SEQ ID NO:1)、黑猩猩(SEQ ID NO:101)、猕猴(SEQ ID NO:102)、食蟹猴(SEQ ID NO:29)、奶牛(SEQ ID NOS:11和64)、小鼠(SEQ ID NO:32)、大鼠(SEQID NO:31)、兔(SEQ ID NO:25)、绵羊(SEQ ID NOS:27、63和65)和豚鼠(SEQ ID NO:30)的PH20多肽。
所指的乙酰透明质酸降解酶包括前体乙酰透明质酸降解酶多肽和成熟乙酰透明质酸降解酶多肽(如其中信号序列已被去除的乙酰透明质酸降解酶多肽)，其具有活性的截短形式；并且包括等位基因变体和物种变体，剪接变体编码的变体，以及其他变体，包括与SEQ ID NO:1和10-48、63-65、67-102所示的前体多肽或其成熟形式具有至少40％、45％、50％、55％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％或更多序列相同性的多肽。例如，所指的乙酰透明质酸降解酶还包括SEQ ID NO:50-51所示的人PH20前体多肽变体。乙酰透明质酸降解酶还包括含有化学或翻译后修饰的乙酰透明质酸降解酶以及不含化学或翻译后修饰的乙酰透明质酸降解酶。这类修饰包括但不限于聚乙二醇化、白蛋白化、糖基化、法尼 基化(farnysylation)、羧基化、羟基化、磷酸化和其他本领域已知的多肽修饰。截短的PH20透明质酸酶是其任何C-末端缩短的形式，特别是当N-糖基化时截短且在中性条件下有活性的形式。
如本文所用，“可溶性PH20”指在生理条件下可溶的任何形式的PH20。例如，可溶性PH20可以通过在37℃下其分配入X-114溶液的水相来鉴定(Bordier et al.,(1981)J.Biol.Chem.,256:1604-7)。膜锚定PH20，如包括GPI-锚定的PH20在内的脂质锚定PH20，会分配入去污剂丰富相，但是用磷脂酶-C处理后会分配入去污剂贫乏相或水相。可溶性PH20包括膜锚定PH20，其中与PH20锚定至膜相关的一个或多个区域已被去除或修饰，其中可溶性形式保留透明质酸酶活性。可溶性PH20还包括重组可溶性PH20，以及包含在天然来源中或纯化自天然来源的可溶性PH20，例如来自绵羊或奶牛的睾丸提取物。这类可溶性PH20的实例为可溶性人PH20。
如本文所用，可溶性人PH20或sHuPH20包括在C-末端缺少全部或部分糖基磷脂酰肌醇(GPI)锚序列的PH20多肽，从而在表达时，多肽在生理条件下是可溶的。溶解性可以通过任何在生理条件下证明溶解性的合适方法来评价。这类方法的实例为X-114测定，其评价分配入水相并且如上文和实施例中所述。此外，如果在CHO细胞如CHO-S细胞中产生，则可溶性人PH20多肽是表达并分泌入细胞培养基中的多肽。然而，可溶性人PH20多肽不限于在CHO细胞中产生的可溶性人PH20多肽，其可以在任何细胞中或通过任何方法产生，包括重组表达和多肽合成。所指的在CHO细胞中的分泌是定义性的。因此，如果多肽可以在CHO细胞中表达和分泌并且是可溶的，即当用X-114提取时分配入水相，则无论是否是这样产生的，其均为可溶性PH20多肽。sHuPH20多肽的前体多肽可以包括信号序列，如异源或非异源(即天然)信号序列。前体的实例为包括信号序列的前体，如在氨基酸位置1-35处的天然35氨基酸信号序列(参见，例如SEQ ID NO:1的氨基酸1-35)。
如本文所用，“延长的可溶性PH20”或“esPH20”包括可溶性PH20多肽，其包含直至GPI锚附着信号序列的残基以及来自GPI-锚附着信号序列的一个或多个连续残基，从而esPH20在生理条件下是可溶的。生理条件下的溶解性可以通过本领域技术人员已知的任何方法来测定。例如，其可以通过 如上文和实施例中所述的X-114测定来评价。此外，如上文所述，如果在CHO细胞如CHO-S细胞中产生，则可溶性PH20是表达并分泌入细胞培养基中的多肽。然而，可溶性人PH20多肽不限于在CHO细胞中产生的可溶性人PH20多肽，其可以在任何细胞中或通过任何方法产生，包括重组表达和多肽合成。所指的在CHO细胞中的分泌是定义性的。因此，如果多肽可以在CHO细胞中表达和分泌并且是可溶的，即当用X-114提取时分配入水相，则无论是否是这样产生的，其均为可溶性PH20多肽。除残基36-490之外，人可溶性esPH20多肽还包括从SEQ ID NO:1的氨基酸残基位置491开始的一个或多个连续氨基酸，从而所得的多肽是可溶的。示例性人esPH20可溶性多肽为具有对应于SEQ ID NO:1的氨基酸36-491、36-492、36-493、36-494、36-495、36-496和36-497的氨基酸残基的多肽。其实例为具有SEQ ID NO:151-154和185-187中任一个所示的氨基酸序列的人esPH20可溶性多肽。还包括等位基因变体和其他变体，如任何与SEQ ID NO:151-154和185-187的相应多肽具有40％、45％、50％、55％、65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更大序列相同性的变体，其保持在中性条件下是有活性的并且是可溶的。所指的序列相同性指具有氨基酸取代的变体。
如本文所用，所指的“esPH20”包括前体esPH20多肽和成熟esPH20多肽(例如其中信号序列已被去除的esPH20多肽)；其具有酶促活性(保留全长形式的至少1％、10％、20％、30％、40％、50％或更多)并且可溶的截短形式；并且包括等位基因变体和物种变体；剪接变体编码的变体；以及其他变体，包括与SEQ ID NO:1和3所示的前体多肽或其成熟形式具有至少40％、45％、50％、55％、65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性的多肽。
如本文所用，所指的“esPH20”还包括含有化学或翻译后修饰的esPH20以及不含有化学或翻译后修饰的esPH20。这类修饰包括但不限于聚乙二醇化、白蛋白化、糖基化、法尼基化(farnysylation)、羧基化、羟基化、磷酸化和其他本领域已知的多肽修饰。
如本文所用，“可溶性重组人PH20 (rHuPH20)”指包含在中国仓鼠卵巢(CHO)细胞中重组表达和分泌的人PH20的可溶形式的组合物。可溶性 rHuPH20由包括信号序列的核酸分子编码，并且如SEQ ID NO:49所示。将编码可溶性rHuPH20的核酸在分泌成熟多肽的CHO细胞中表达。当在培养基中产生时，在C-末端具有异质性，从而产物包括多种物质(species)的混合物，其可以包括各种丰度的PH20(例如，SEQ ID NO:4-SEQ ID NO:9)的任一个或多个氨基酸36-481和36-482。
相似地，对于其他形式的PH20如esPH20，重组表达的多肽及其组合物可以包括在C-末端表现出异质性的多种物质。例如，通过表达SEQ ID NO:151的多肽而产生的重组表达的esPH20的组合物可以包括具有较少氨基酸的形式，如36-496、36-495，SEQ ID NO:151编码具有氨基酸36-497的esPH20。
如本文所用，“N-联部分”指多肽的天冬酰胺(N)氨基酸残基，其能够被多肽的翻译后修饰糖基化。人PH20的示例性N-联部分包括SEQ ID NO:1所示的人PH20的氨基酸N82、N166、N235、N254、N368和N393。
如本文所用，“N-糖基化的多肽”指包含至少3个N-联氨基酸残基的寡糖键的PH20多肽或其截短形式，例如与SEQ ID NO:1的氨基酸残基N235、N368和N393对应的N-联部分。N-糖基化的多肽可以包括3、4、5个和多达所有N-联部分连接至寡糖的多肽。N-联寡糖可以包括甘露低聚糖，复杂、杂合或硫酸化的寡糖，或者其他寡糖和单糖。
如本文所用，“N-部分糖基化的多肽”指最少包含一个N-乙酰葡糖胺聚糖的多肽，所述N-乙酰葡糖胺聚糖连接至至少3个N-联部分。部分糖基化的多肽可以包括各种聚糖形式，包括单糖、寡糖和支化的糖形式，包括那些通过用EndoH、EndoF1、EndoF2和/或EndoF3处理多肽形成的形式。
如本文所用，“去糖基化的PH20多肽”指PH20多肽，其中少于所有可能的糖基化位点是糖基化的。可以影响去糖基化，例如通过去除糖基化、通过阻止糖基化或者通过修饰多肽以消除糖基化位点。特定的N-糖基化位点不是活性所需要的，而其余的是。
如本文所用，“聚乙二醇化”指聚合物分子如聚乙二醇(聚乙二醇化部分PEG)共价或其他稳定连接至乙酰透明质酸降解酶如透明质酸酶，通常以便增加乙酰透明质酸降解酶的半衰期。
如本文所用，“缀合物”指直接或间接连接至一个或多个其他多肽或化 学部分的多肽。这样的缀合物包括融合蛋白、通过化学缀合产生的缀合物和通过任何其他方法产生的缀合物。例如，缀合物指直接或间接连接至一个或多个其他多肽或化学部分的可溶性PH20多肽，其中至少一个可溶性PH20多肽直接或间接连接至其他多肽或化学部分，只要所述缀合物保留透明质酸酶活性。
如本文所用，“融合”蛋白指核酸序列编码的多肽，所述核酸序列含有来自一个核酸分子的编码序列和来自另一个核酸分子的编码序列，其中所述编码序列在相同的阅读框中，从而当融合构建体在宿主细胞中转录和翻译时，产生含有两个蛋白的蛋白。两个分子可以在构建体中相邻或被接头(linker)多肽分开，所述接头多肽包含1、2、3个或更多个，但通常少于10、9、8、7或6个氨基酸。融合构建体编码的蛋白产物称作融合多肽。
如本文所用，“聚合物”指缀合至多肽，即直接或通过接头间接稳定连接至多肽的任何高分子量的天然或合成部分。这类聚合物通常增加血清半衰期，并且包括但不限于唾液酸部分、聚乙二醇化部分、葡聚糖和糖以及其他部分，如糖基化部分。例如，透明质酸酶如可溶性PH20或rHuPH20可以缀合至聚合物。
如本文所用，透明质酸酶底物指被透明质酸酶切割和/或解聚的底物(例如蛋白或多糖)。一般来说，透明质酸酶底物为糖胺聚糖。示例性透明质酸酶底物为乙酰透明质酸(HA)。
如本文所用，乙酰透明质酸相关疾病、病症或疾病状况指任何疾病或疾病状况，其中乙酰透明质酸水平作为起因、结果或者在疾病或疾病状况中观察到的其他方式而升高。乙酰透明质酸相关疾病和疾病状况与组织或细胞中升高的乙酰透明质酸表达、增加的组织液压力、减少的血管容积和/或组织中增加的水含量相关。乙酰透明质酸相关疾病、病症或疾病状况可以通过给药包含抗乙酰透明质酸剂，如乙酰透明质酸降解酶，如透明质酸酶，如可溶性透明质酸酶的组合物来治疗，单独或者与另一疗法和/或物质组合或者除另一疗法和/或物质之外给药。示例性疾病和疾病状况包括但不限于炎性疾病和乙酰透明质酸丰富的癌症。乙酰透明质酸丰富的癌症包括例如肿瘤，包括实体瘤如晚期癌症、转移癌、未分化癌、卵巢癌、原位癌(ISC)、鳞状细胞癌(SCC)、前列腺癌、胰腺癌、非小细胞肺癌、乳腺癌、 结肠癌和其他癌症。乙酰透明质酸相关疾病和疾病状况的实例还有与升高的组织液压力相关的疾病，如与椎间盘压力(disc pressure)相关的疾病和水肿，例如器官移植、中风、脑外伤或其他损伤引起的水肿。示例性乙酰透明质酸相关疾病和疾病状况包括与升高的组织液压力、减少的血管容积和/或组织中增加的水含量相关的疾病和疾病状况，包括癌症、椎间盘压力和水肿。在一实例中，乙酰透明质酸相关疾病状况、疾病或病症的治疗包括对于增加的组织液压力(IFP)、减少的血管容积和组织中增加的水含量中的一个或多个的改善、减轻或其他有益效果。
如本文所用，“活性”指多肽或其部分与全长(完整)蛋白相关的功能活性或多种活性。例如，多肽的活性片段可以表现出全长蛋白的活性。功能活性包括但不限于生物学活性、催化或酶促活性、抗原性(结合或与多肽竞争结合抗多肽抗体的能力)、免疫原性、形成多聚体的能力以及特异性结合多肽的受体或配体的能力。
如本文所用，“透明质酸酶活性”指酶促催化切割透明质酸的能力。用于透明质酸酶的美国药典(USP)XXII测定通过测量较高分子量的透明质酸或乙酰透明质酸的量来间接测定透明质酸酶活性，将酶切(enzyme)后剩余的(HA)底物与HA在37℃下反应30min(USPXXII-NF XVII(1990)644-645United States Pharmacopeia Convention,Inc,Rockville,MD)。在测定中可以使用参考标准溶液以确定任何透明质酸酶的相对活性，以单位计。确定透明质酸酶的透明质酸酶活性的体外测定为本领域已知并且在本文中描述，所述透明质酸酶例如PH20，包括可溶性PH20和esPH20。示例性测定包括微浊度测定，其通过检测在未切割的透明质酸与血清白蛋白结合时形成的不溶性沉淀物来间接测量透明质酸酶对透明质酸的切割；以及生物素化的透明质酸测定，其通过用链霉抗生物素蛋白-辣根过氧化物酶缀合物和生色底物检测剩余的非共价结合微量滴定板的生物素化的透明质酸来间接测量透明质酸的切割。例如，参考标准可以用来产生标准曲线来确定测试的透明质酸酶的活性，以单位计。
如本文所用，特异性活性指活性单位/mg蛋白。通过在280nm处溶液的吸收定义透明质酸酶的毫克，假设约1.7的摩尔消光系数，以M-1cm-1的单位计。
如本文所用，“在中性条件下有活性”指PH20多肽在中性pH(例如在pH7.0或约pH7.0)下酶促催化透明质酸的切割的能力。一般来说，与非C-末端截短或N-部分糖基化的相应在中性条件下是有活性的PH20的透明质酸酶活性相比，在中性条件下是有活性的和可溶性PH20，例如C-末端截短或N-部分糖基化的PH20具有或具有约30％、40％、50％、60％、70％、80％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％、100％、110％、120％、130％、140％、150％、200％、300％、400％、500％、1000％或更多的活性。
如本文所用，“GPI-锚附着信号序列”是在ER腔内指导预形成的GPI-锚添加到多肽的C-末端氨基酸序列。GPI-锚附着信号序列存在于GPI-锚定的多肽的前体多肽中，如GPI-锚定的PH20多肽。C-末端GPI-锚附着信号序列通常包含8-20个氨基酸的主要疏水区，其前面为紧接ω-位点或GPI-锚附着位点下游的8-12个氨基酸的亲水间隔区。GPI-锚附着信号序列可以利用本领域公知的方法来鉴定。这些方法包括但不限于计算机方法和算法(参见，例如Udenfriend et al.(1995)Methods Enzymol.250:571-582,Eisenhaber et al.,(1999)J.Biol.Chem.292:741-758,Fankhauser et al.,(2005)Bioinformatics21:1846-1852,Omaetxebarria et al.,(2007)Proteomics7:1951-1960,Pierleoni et al.,(2008)BMC Bioinformatics9:392)，包括在诸如ExPASy蛋白质组学工具站点(例如万维网站点expasy.ch/tools/)的生物信息网站上容易获得的方法和算法。
如本文所用，“核酸”包括DNA、RNA及其类似物，包括肽核酸(PNA)及其混合物。核酸可以为单链或双链。当提到探针或引物时，单链分子是预期的，所述探针或引物任选地被标记，例如用诸如荧光或放射性标记的可检测标记来标记。这类分子通常具有使其靶标在统计学上独特的长度或者具有用于检测或吸出文库的低拷贝数(通常少于5，一般少于3)。一般来说，探针或引物包含至少14、16或30个连续的核苷酸，其序列与所关注的基因互补或相同。探针和引物的长度可以为10、20、30、50、100或更多个核酸。
如本文所用，肽指长度大于或等于2个氨基酸，并且长度少于或等于40个氨基酸的多肽。
如本文所用，存在于本文提供的各种氨基酸序列中的氨基酸根据它们已知的3-字母或1-字母缩写来识别(表1)。存在于各种核酸片段中的核苷酸用本领域常规使用的标准单字母命名来命名。
如本文所用，“氨基酸”是包含氨基和羧酸基团的有机化合物。多肽包含两个或更多个氨基酸。为了本文的目的，氨基酸包括20种天然存在的氨基酸、非天然氨基酸和氨基酸类似物(即其中α-碳具有侧链的氨基酸)。
如本文所用，“氨基酸残基”指多肽在其肽键处化学消化(水解)而形成的氨基酸。本文所述的氨基酸残基推定为“L”异构形式。命名为“D”异构形式的残基可以取代任何L-氨基酸残基，只要多肽保留期望的功能特性。NH2指多肽的氨基端存在的游离氨基。COOH指多肽的羧基端存在的游离羧基。与J.Biol.Chem.,243:3557-3559(1968)中所述的标准多肽命名一致，并且采用37C.F.R.§§1.821-1.822，氨基酸残基的缩写如表1所示：
本文中通过式来表示的所有氨基酸残基序列均具有氨基端至羧基端的常规方向从左至右的的方向。此外，短语“氨基酸残基”定义为包括对应表(表 1)中列出的氨基酸以及修饰和稀有的氨基酸，如在援引加入本文的37C.F.R.§§1.821-1.822中提到的氨基酸。此外，应当注意，氨基酸残基序列的开始或末尾的破折号表示肽键，其连接至一个或多个氨基酸残基的另一序列，连接至氨基端基团如NH2，或者连接至羧基端基团如COOH。
如本文所用，“天然存在的α-氨基酸”是在自然界中发现的20种α-氨基酸的残基，其通过装载的tRNA分子与其在人中的同源mRNA密码子的特异性识别来掺入蛋白。因此，非天然存在的氨基酸包括，例如除20种天然存在的氨基酸以外的氨基酸或氨基酸类似物，并且包括但不限于氨基酸的D-立体异构体。示例性非天然氨基酸如本文所述并且为本领域技术人员已知。
如本文所用，DNA构建体是单链或双链、线性或环状DNA分子，其包含以自然中不存在的方式结合和并列的DNA片段。DNA构建体作为人为操纵的结果存在，并且包括所操纵的分子的克隆和其他拷贝。
如本文所用，“DNA片段”是具有特定属性的较大的DNA分子的部分。例如，编码特定多肽的DNA片段是诸如质粒或质粒片段的较长DNA分子的部分，当从5’至3’方向阅读时，其编码所述特定多肽的氨基酸序列。
如本文所用，术语多核苷酸表示从5’至3’端阅读的脱氧核糖核苷酸或核糖核苷酸碱基的单链或双链聚合物。多核苷酸包括RNA和DNA，并且可以从天然来源分离，体外合成或者制备自天然和合成分子的组合。多核苷酸分子的长度在本文中用核苷酸(缩写为“nt”)或碱基对(缩写为“bp”)来表示。当上下文允许时，术语核苷酸用于单链和双链分子。当术语用于双链分子时，其用于表示全长并且会理解为等同于术语碱基对。本领域技术人员会认识到双链多核苷酸的两条链的长度可以略有不同，并且其末端可以错开；因此在双链多核苷酸分子内不是所有的核苷酸是配对的。一般这样不配对的末端长度不会超过20个核苷酸。
如本文所用，两个蛋白或核酸之间的“相似性”指所述蛋白的氨基酸序列或所述核酸的核苷酸序列之间的相关性。相似性可以基于残基序列的相同性和/或同源性程度以及其中所含的残基。用于评价蛋白或核酸之间的相似性程度的方法是本领域技术人员已知的。例如，在评价序列相似性的一种方法中，以获得序列之间最大水平相同性的方式比对两个氨基酸或核苷 酸序列。“相同性”指氨基酸或核苷酸序列不变的程度。氨基酸序列以及某种程度上核苷酸序列的比对还可以考虑氨基酸(或核苷酸)中的保守性差异和/或常见取代。保守性差异是保留所涉及的残基的物理化学特性的差异。比对可以是整体的(在序列的整个长度比较序列并且包括所有残基的比对)或局部的(仅包括最相似区域或多个区域的部分序列的比对)。
“相同性”本身具有本领域公认的含义并且可以利用公开的技术进行计算。(参见，例如Computational Molecular Biology,Lesk,A.M.,ed.,Oxford University Press,NewYork,1988；Biocomputing:Informatics and Genome Projects,Smith,D.W.,ed.,Academic Press,New York,1993；Computer Analysis of Sequence Data,Part I,Griffin,A.M.,and Griffin,H.G.,eds.,Humana Press,New Jersey,1994；SequenceAnalysis in Molecular Biology,von Heinje,G.,Academic Press,1987；and SequenceAnalysis Primer,Gribskov,M.and Devereux,J.,eds.,M Stockton Press,New York,1991)。虽然存在许多测量两种多核苷酸或多肽之间的相同性的方法，但是术语“相同性”是技术人员公知的(Carrillo,H.and Lipton,D.,(1988)SIAM J Applied Math48:1073)。
如本文所用，同源(关于核酸和/或氨基酸序列)表示约大于或等于25％的序列同源性，通常大于或等于25％、40％、50％、60％、70％、80％、85％、90％或95％的序列同源性；如有必要，可以具体说明精确的百分比。为了本文的目的，除非另有说明，术语“同源性”和“相同性”经常可互换使用。一般来说，为了确定同源性或相同性百分比，将序列比对以获得最高等级的匹配(参见，例如：Computational Molecular Biology,Lesk,A.M.,ed.,OxfordUniversity Press,New York,1988；Biocomputing:Informatics and Genome Projects,Smith,D.W.,ed.,Academic Press,New York,1993；Computer Analysis of SequenceData,Part I,Griffin,A.M.,and Griffin,H.G.,eds.,Humana Press,New Jersey,1994；Sequence Analysis in Molecular Biology,von Heinje,G.,Academic Press,1987；和Sequence Analysis Primer,Gribskov,M.and Devereux,J.,eds.,M Stockton Press,NewYork,1991；Carrillo,H.and Lipton,D.,(1988)SIAM J Applied Math48:1073)。通过序列同源性，保守氨基酸的数目通过标准比对算法程序来确定，并且可以与各个供应者(supplier)建立的默认空位罚分一起使用。基本上同源的核酸分子通常在中等严格性 或高度严格性下与所关注的核酸在整个长度上杂交。还考虑包含代替杂交核酸分子中的密码子的简并密码子的核酸分子。
任何两个分子是否具有至少60％、70％、80％、85％、90％、95％、96％、97％、98％或99％“相同”或“同源”核苷酸序列或氨基酸序列可以利用已知的计算机算法如“FASTA”程序来确定，例如在Pearson et al.(1988)Proc.Natl.Acad.Sci.USA85:2444中利用默认参数(其他程序包括GCG程序包(Devereux,J.,et al.,Nucleic Acids Research12(I):387(1984))、BLASTP、BLASTN、FASTA(Altschul,S.F.,et al.,J Mol Biol215:403(1990))；Guide to Huge Computers,Martin J.Bishop,ed.,Academic Press,San Diego,1994,andCarrillo,H.and Lipton,D.,(1988)SIAM J Applied Math48:1073)。例如，国家生物技术信息中心数据库的BLAST功能可以用来确定相同性。其他可商购或公开的程序包括DNAStar“MegAlign”程序(Madison,WI)和威斯康辛大学遗传学计算机集团(UWG)“Gap”程序(Madison WI)。例如，蛋白和/或核酸分子的同源性或相同性百分比可以通过利用GAP计算机程序比较序列信息来确定(例如Needleman et al.(1970)J.Mol.Biol.48:443，由Smithand Waterman((1981)Adv.Appl.Math.2:482修订)。简单地说，GAP程序将相似性定义为用比对的相似的符号(即核苷酸或氨基酸)的数目除以两个序列中较短序列的总符号数目。GAP程序的默认参数可以包括：(1)一元比较矩阵(1表示相同，0表示不同)和Gribskov etal.(1986)Nucl.Acids Res.14:6745的加权比较矩阵，如Schwartz and Dayhoff,eds.,ATLAS OF PROTEIN SEQUENCE AND STRUCTURE,National Biomedical ResearchFoundation,pp.353-358(1979)所述；(2)每个空位罚分3.0并且每个空位中的每个符号另外罚分0.1；以及(3)末端空位不罚分。
因此，如本文所用，术语“相同性”或“同源性”表示测试和参考多肽或多核苷酸之间的比较。如本文所用，术语至少“90％相同”指相对于多肽的参考核酸或氨基酸序列同源性百分数为90至99.99。90％或更高水平的相同性表明，假设为了例证目的，比较了长度为100个氨基酸的测试和参考多肽。在测试多肽中不超过10％(即100中的10)的氨基酸与参考多肽的氨基酸不同。相似的比较可以在测试和参考多核苷酸之间进行。这类差异可以表示为随机分布在多肽的整个长度的点突变，或者它们可以集中在一个或 多个位置，具有不同长度至高达最大允许例如10/100氨基酸差异(约90％相同性)。差异定义为核酸或氨基酸取代、插入或缺失。在约85-90％以上的同源性或相同性水平，结果应当独立于程序和空位参数设置；这样高水平的相同性通常可以容易地通过手动比对而不依赖于软件来评价。
如本文所用，比对的序列指使用同源性(相似性和/或相同性)比对核苷酸或氨基酸序列中的相应位置。通常，比对50％或更多相同性相关的2个或更多个序列。一组比对的序列指在相应位置比对的2个或更多个序列，并且可以包括比对与基因组DNA序列比对的来自诸如EST和其他cDNA的RNA的序列。
如本文所用，“引物”指在适当的条件下(例如在4种不同核苷三磷酸以及诸如DNA聚合酶、RNA聚合酶或逆转录酶的聚合试剂的存在下)，在适当的缓冲液中及合适的温度下可以作为模板指导的DNA合成的起始点的核酸分子。应当理解某些核酸分子可以用作“探针”和“引物”。然而，引物具有用于延伸的3’羟基。引物可以用于各种方法，包括例如聚合酶链式反应(PCR)、逆转录酶(RT)-PCR、RNA PCR、LCR、多重PCR、锅柄PCR、捕获PCR、表达PCR、3'和5'RACE、原位PCR、连接介导的PCR和其他扩增方案。
如本文所用，“引物对”指一组引物，其包括与待扩增(例如通过PCR)序列5'端的互补物(complement)杂交的5'(上游)引物以及与待扩增序列的3'端杂交的3'(下游)引物。
如本文所用，“特异性杂交”指通过互补碱基配对，核酸分子(例如寡核苷酸)退火至靶核酸分子。本领域技术人员熟悉影响特异性杂交的体外和体内参数，例如特定分子的长度和组成。与体外杂交特别有关的参数还包括退火和洗涤温度、缓冲液组成以及盐浓度。用于去除非特异性结合的核酸分子的示例性洗涤条件在高严格性下为0.1x SSPE、0.1％SDS、65℃，而在中等严格性下为0.2x SSPE、0.1％SDS、50℃。等同的严格性条件是本领域已知的。技术人员可以很容易调整这些参数以实现适合特定应用的核酸分子与靶核酸分子的特异性杂交。当提到两个核苷酸序列时，互补表示这两个核苷酸的序列能够杂交，通常在相反的核苷酸之间具有少于25％、15％或5％的错配。如果需要，会具体说明互补性的百分比。通常选择两个 分子，从而它们在高严格性条件下会杂交。
如本文所用，与产物基本上相同表示足够相似从而所关注的特性充分不变，因而基本上相同的产物可以用于代替所述产物。
如本文所用，还应当理解，如相关领域技术人员所理解的，术语“基本上相同”或“相似”随上下文变化。
如本文所用，等位基因变体或等位基因变异指占据相同染色体位点的基因的任何两种或更多种可选形式。等位基因变异通过突变自然发生，并且可以导致群体内的表型多态性。基因突变可以是沉默的(在编码的多肽中没有变化)，或者可以编码具有改变的氨基酸序列的多肽。术语“等位基因变体”在本文中还用于表示基因的等位基因变体编码的蛋白。通常基因的参考形式编码来自物种的群体或单个参照成员的多肽的野生型形式和/或优势形式。通常，包括物种之间和之中的变体的等位基因变体与来自相同物种的野生型和/或优势形式具有至少80％、90％或者更大的氨基酸相同性；相同性程度取决于基因以及比较是种间或种内比较。一般来说，种内等位基因变体与野生型和/或优势形式具有至少约80％、85％、90％、95％或更大的相同性，这包括与多肽的野生型和/或优势形式的96％、97％、98％、99％或更大的相同性。本文所指的等位基因变体一般指相同物种的成员之间的蛋白变异。
如本文所用，在本文中与“等位基因变体”可交换使用的“等位基因”指基因或其部分的可选形式。等位基因占据同源染色体上的相同基因座或位置。当对象具有基因的两个相同等位基因时，则认为该对象对于该基因或等位基因是纯合的。当对象具有基因的两个不同等位基因时，则认为该对象对于该基因是杂合的。特定基因的等位基因可以单个核苷酸或几个核苷酸互不相同，并且可以包括诸如核苷酸取代、缺失和插入的修饰。基因的等位基因还可以是包含突变的基因形式。
如本文所用，物种变体指不同物种之间多肽的变体，包括不同哺乳动物物种，如小鼠和人。例如对于PH20，本文提供的物种变体的实例为灵长类PH20，例如但不限于人、黑猩猩、猕猴和食蟹猴。一般来说，物种变体具有70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或更大的序列相同性。例如，物种变体之间和之中的相应残基可 以通过比较和比对序列以最大化匹配的核苷酸或残基数目来确定，从而序列之间的相同性等于或大于95％、等于或大于96％、等于或大于97％、等于或大于98％或者等于或大于99％。然后给出所关注的位置在参考核酸分子中的指定编号。比对可以手动或通过目视来完成，特别是当序列相同性大于80％时。
如本文所用，人蛋白是由人基因组中存在的核酸分子如DNA编码的蛋白，包括其所有等位基因变体和保守变异。如果修饰是基于人蛋白的野生型或优势序列，则蛋白的变体或修饰为人蛋白。
如本文所用，剪接变体指通过基因组DNA的初级转录物的差别加工产生的变体，所述差别加工导致了多于一类mRNA。
如本文所用，修饰指多肽的氨基酸序列或核酸分子的核苷酸序列的修饰，并且分别包括氨基酸和核苷酸的缺失、插入和置换(例如取代)。修饰的实例为氨基酸取代。氨基酸取代的多肽可以表现出与不含氨基酸取代的氨基酸的65％、70％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或更多的序列相同性。氨基酸取代可以是保守的或非保守的。一般来说，多肽的任何修饰保留所述多肽的活性。修饰多肽的方法对于本领域技术人员是常规的，例如通过利用重组DNA方法。
如本文所用，合适的保守氨基酸取代是本领域技术人员已知的，并且一般可以进行而不改变所得分子的生物活性。一般来说，本领域技术人员认识到多肽的非必需区中的单个氨基酸取代基本上不改变生物活性(参见，例如，Watson et al.Molecular Biologyof the Gene,4th Edition,1987,The Benjamin/Cummings Pub.co.,p.224)。这类取代可以按照以下表2所示的那些取代进行：
其他取代也是允许的，并且可以凭经验或根据已知的保守取代来确定。
如本文所用，术语启动子表示包含提供RNA聚合酶结合和转录起始的DNA序列的基因部分。启动子序列通常但不总是在基因的5’非编码区中发现。
如本文所用，分离或纯化的多肽或蛋白或其生物学活性部分基本上不含细胞物质或来自蛋白所源自的细胞或组织的其他污染蛋白，或者当化学合成时基本上不含化学前体或其他化学成分。如果通过标准分析方法测定制品看起来不含容易检出的杂质，则可以确定其基本上不含杂质，所述分 析方法例如薄层色谱(TLC)、凝胶电泳和高效液相色谱(HPLC)，本领域技术人员将这些方法用于评价这样的纯度或者足够纯从而进一步纯化不会可检测地改变物质的物理和化学特性，如酶促和生物学活性。纯化化合物以制备基本上化学纯的化合物的方法是本领域技术人员已知的。然而，基本上化学纯的化合物可以是立体异构体的混合物。在这种情况下，进一步纯化可以增加化合物的特定活性。
因此，关于基本上纯化的多肽如基本上纯化的可溶性PH20指基本上不含细胞物质的蛋白制品，包括其中所述蛋白分离自其分离或重组产生的细胞的细胞组分的蛋白制品。在一实施方案中，术语基本上不含细胞物质包括酶蛋白制品，其具有少于约30％(按干重)的非酶蛋白(在本文中也称作污染蛋白)，通常少于约20％非酶蛋白或10％非酶蛋白或者少于约5％非酶蛋白。当酶蛋白为重组产生时，其还基本上不含培养基，即培养基少于酶蛋白制品体积的约20％、10％或5％或者20％、10％或5％。
如本文所用，术语基本上不含化学前体或其他化学成分包括酶蛋白制品，其中所述蛋白分离自蛋白合成中涉及的化学前体或其他化学成分。该术语包括酶蛋白的制品，其具有少于约30％(按干重)、20％、10％、5％或更少的化学前体或非酶化学成分或组分。
如本文所用，对于合成，例如合成核酸分子或合成基因或合成肽，指通过重组方法和/或通过化学合成方法产生的核酸分子或多肽分子。
如本文所用，通过重组方法或利用重组DNA方法产生表示使用分子生物学公知的方法表达克隆的DNA编码的蛋白。
如本文所用，载体(或质粒)指用于将异源核酸引入细胞以表达或复制的离散单元。载体通常保持游离，但是可以设计为使基因或其部分整合入基因组的染色体。还考虑人工染色体的载体，例如酵母人工载体和哺乳动物人工染色体。这类媒介物的选择和使用是本领域技术人员公知的。
如本文所用，表达载体包括能够表达DNA的载体，所述DNA可操作地连接至调节序列如启动区，所述调节序列能够影响此类DNA片段的表达。这类额外的片段可以包括启动子和终止子序列，并且任选地可以包括一个或多个复制起点、一个或多个选择标记、增强子、加A信号。表达载体一般源自质粒或病毒DNA，或者可以包含这两者的元件。因此，表达载 体指重组DNA或RNA构建体，例如质粒、噬菌体、重组病毒或其他载体，当引入适当的宿主细胞时，导致克隆DNA的表达。适当的表达载体是本领域技术人员公知的，并且包括在真核细胞和/或原核细胞中可复制的表达载体以及保持游离的表达载体或者整合入宿主细胞基因组的表达载体。
如本文所用，载体还包括“病毒载体”或“病毒的载体”。病毒的载体是工程化的病毒，其可操作地连接至外源基因以将外源基因转移(作为媒介物或穿梭(shuttle))入细胞。
如本文所用，当涉及DNA片段时，“可操作地”或“可操作地连接”表示片段被排列从而它们发挥与其预期目的一致的功能，例如转录从启动子的下游和任何转录序列的上游起始。启动子通常是转录体系结合以起始转录并通过编码片段至终止子的结构域。
如本文所用，术语“评价”旨在包括在某种意义上获得样品中存在的蛋白如酶或其结构域的活性的绝对值的定量和定性测定，并且还获得指示活性水平的指数、比值、百分比、视觉或其他值。评价可以是直接或间接的。例如，实际检测的化合物种类当然不需要是酶促切割产物本身，但是例如可以是其衍生物或某些其他物质。例如，切割产物的检测可以是可检测的部分如荧光部分。
如本文所用，生物学活性指化合物的体内活性或者体内给予化合物、组合物或其他混合物所导致的生理反应。因此，生物学活性涵盖这类化合物、组合物和混合物的疗效和药物活性。生物学活性可以在设计为测试或使用此类活性的体外系统中观察。因此，为了本文的目的，透明质酸酶的生物学活性是其降解透明质酸。
如本文所用，当涉及两个核酸序列时，等同表示所关注的两个序列编码相同的氨基酸序列或等同的蛋白。当等同用于指两个蛋白或肽时，其表示这两个蛋白或肽具有基本上相同的氨基酸序列，仅有基本上不改变所述蛋白或肽的活性或功能的氨基酸取代。当等同指特性时，该特性不需要表现为相同的程度(例如，两个肽可以表现出相同类型酶促活性的不同速率)，但是活性通常基本上相同。
如本文所用，“调节(modulate)”和“调节(modulation)”或“改变”指分子如蛋白的活性的改变。示例性活性包括但不限于生物学活性，如信号转导。 调节可以包括活性的增加(即上调或激动活性)、活性的减少(即下调或抑制)或活性的任何其他改变(例如周期性、频率、持续时间、动力学或其他参数的变化)。调节可以取决于上下文，并且通常调节是与指定状态比较，例如野生型蛋白、组成型状态的蛋白或者在指定细胞类型或条件下表达的蛋白。
如本文所用，组合物指任何混合物。其可以是溶液、悬浮液、液体、粉末、糊剂、水性、非水性或者它们的任何组合。
如本文所用，组合指两个或更多个项目之间或之中的任何关联。组合可以是两个或更多个不同项目，例如两个组合物或两个收集品，可以是它们的混合物，例如两个或更多个项目的单一混合物，或者它们的任何变异。组合的元件一般是功能上关联或相关的。例如，组合可以是本文提供的组合物的组合。
如本文所用，试剂盒指组分的组合，例如本文的组合物与为了以下目的的另一项目的组合，所述目的包括但不限于重建、激活以及用于递送、给药、诊断和评价生物学活性或特性的仪器/装置。试剂盒任选地包括使用说明。
如本文所用，“疾病或病症”指有机体中由原因或条件导致的病理状况，并且通过可识别的症状来表征，所述原因或条件包括但不限于感染、后天条件、遗传条件。本文所关注的疾病和病症为乙酰透明质酸相关疾病和病症。
如本文所用，“治疗”患有疾病或疾病状况的对象表示所述对象的症状部分或全部缓解，或者在治疗后保持不变。因此，治疗包括预防、治疗和/或治愈。预防指防止潜在疾病和/或防止症状恶化或疾病发展。
如本文所用，药学有效物质包括任何治疗剂或生物活性剂，包括但不限于例如化疗剂、麻醉剂、血管收缩剂、分散剂、常规治疗药物，包括小分子药物和治疗性蛋白。
如本文所用，治疗表示任何方式，其中疾病状况、病症或疾病或者其他指征被改善或以其他方式有益改变。
如本文所用，疗效表示由对象的治疗导致的效果，其改变、通常改良或改善疾病或疾病状况的症状，或者治愈疾病或疾病状况。治疗有效量指向对象给药之后引起疗效的组合物、分子或化合物的量。
如本文所用，术语“对象”指动物，包括哺乳动物，如人。
如本文所用，“患者”指表现出疾病或病症的症状的人对象。
如本文所用，“个体”可以为对象。
如本文所用，大约相同表示在本领域技术人员会认为相同的量内或者在误差可接受的范围内。例如，通常，对于药物组合物，认为在至少1％、2％、3％、4％、5％或10％以内的量大约相同。这样的量可以根据对象对特定组合物中的变异的耐受性而变化。
如本文所用，剂量给药方案指给药的物质的量和给药频率，所述物质例如包含乙酰透明质酸降解酶如可溶性透明质酸酶或其他物质的组合物。剂量给药方法是待治疗的疾病或疾病状况的函数，因此可以变化。
如本文所用，给药频率指治疗的连续给药之间的时间。例如，频率可以为天、周或月。例如，频率可以为每周一次以上，例如每周2次、每周3次、每周4次、每周5次、每周6次或每天。频率还可以为1周、2周、3周或4周。特定频率是治疗的特定疾病或疾病状况的函数。一般来说，频率为每周一次以上，并且一般为每周2次。
如本文所用，“给药周期”指在连续给药中重复的酶和/或第二物质的给药剂量方案的重复计划。例如，示例性给药周期为28天周期，每周2次给药3周，然后一周停止剂量给药。
如本文所用，当基于mg/kg对象提到剂量时，认为平均人对象具有约70kg-75kg的质量，例如70kg。
如本文所用，通过治疗改善特定疾病或病症的症状，如通过给药药物组合物或其他治疗，指疾病状况的症状或副作用的任何减轻，无论永久或暂时的，持续或短暂的，例如与给药乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶相关或者在给药乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶时出现的副作用的减少。
如本文所用，防止或预防指发展疾病或疾病状况的风险降低。
如本文所用，“治疗有效量”或“治疗有效剂量”指至少足以产生疗效的物质、化合物、材料或包含化合物的组合物的量。因此，其为防止、治愈、改善、阻滞或部分阻滞疾病或病症的症状所必需的量。
如本文所用，单位剂型指适合人和动物对象并且如本领域已知的独立 包装的物理上分离的单位。
如本文所用，单剂量制剂指作为单剂量的制剂。
如本文所用，用于直接给药的制剂表示组合物不需要进一步稀释用于给药。
如本文所用，“制成品(article of manufacture)”指制造和销售的产品。如整个本申请所用，该术语旨在涵盖抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如透明质酸酶，以及包装物品中所含的第二物质组合物。
如本文所用，流体指可以流动的任何组合物。因此流体包括半固体形式的组合物、糊剂、溶液、水性混合物、凝胶、洗剂、乳膏剂以及其他这样的组合物。
如本文所用，细胞提取物或裂解物指由裂解或破裂的细胞制成的制品或级分。
如本文所用，动物包括任何动物，例如但不限于灵长类，包括人、大猩猩和猴；啮齿类，如小鼠和大鼠；禽类，如鸡；反刍动物，如山羊、奶牛、鹿、绵羊；猪和其他动物。非人动物排除人作为预期动物。本文提供的透明质酸酶来自任何来源，动物、植物、原核生物和真菌。大多数透明质酸酶为动物来源，包括哺乳动物来源。一般透明质酸酶为人来源。
如本文所用，抗癌治疗包括给药药物和其他物质用于治疗癌症，并且还包括治疗方案如手术和辐射。抗癌治疗包括抗癌剂的给药。
如本文所用，抗癌剂指抗癌治疗中使用的任何物质或化合物。这些包括任何物质，当单独使用或与其他化合物组合使用时，其可以减轻、减少、改善、防止、或者置于或维持与肿瘤和癌症相关的临床症状或诊断标记的缓解状态，并且可以与本文提供的组合物组合使用。示例性抗癌剂包括但不限于乙酰透明质酸降解酶如本文提供的聚乙二醇化的乙酰透明质酸降解酶，其单独使用或与其他抗癌剂组合使用，例如化疗剂、多肽、抗体、肽、小分子或基因治疗载体、病毒或DNA。
如本文所用，对照指与测试样品基本上相同的样品，除了其不用测试参数处理，或者如果其为血浆样品，则其可以来自不受所关注的疾病状况影响的正常志愿者。对照还可以是内参。
如本文所用，单数形式“一个(a)”、“一个(an)”和“这个(the)”包括复数指 代，除非上下文另有明确指定。因此，例如提到包含或含有“胞外域”的化合物包括具有一个或多个胞外域的化合物。
如本文所用，范围和量可以表达为“约”特定值或范围。约还包括确切的量。因此“约5个碱基”表示“约5个碱基”，并且还表示“5个碱基”。一般来说，“约”包括预期在实验误差内的量。
如本文所用，“任选”或“任选地”表示随后描述的事件或情况发生或不发生，并且该描述包括所述事件或条件发生的情况和不发生的情况。例如，任选取代的基团表示该基团未取代或被取代。
如本文所用，除非另有说明，任何保护基团、氨基酸和其他化合物的缩写与其常见用法、公认的缩写或IUPAC-IUB生物化学命名委员会(参见(1972)Biochem.11:1726)一致。
B.乙酰透明质酸结合蛋白和同伴诊断剂
本文提供灵敏和特异性的方法以检测和密切监测与疾病相关的乙酰透明质酸(HA)，特别是在肿瘤组织的胞外基质(ECM)中。本文提供的同伴诊断方法是基于这样的发现，HA积累特异性地与侵袭性疾病相关并预测侵袭性疾病，特别是关于癌症。此外，本文提供的同伴诊断方法还基于这样的发现，与乙酰透明质酸相关疾病和疾病状况相关的HA代谢途径中涉及的其他标记如透明质酸酶合成酶或透明质酸酶相比，HA特异性地提供优越的预后和治疗选择信息。因此，本文提供的方法利用表现出特异性、高亲和力和低可变性的改良的乙酰透明质酸结合蛋白(HABP)用于HA的特异性和灵敏的检测。本文还提供改良的HABP试剂。
在一实例中，本文提供的改良的HABP，例如C节中描述的任何改良的HABP可以为同伴诊断剂，用于选择患有HA相关疾病如HA相关肿瘤的患者，用抗乙酰透明质酸剂或乙酰透明质酸降解酶进行治疗，例如E节所示的任何抗乙酰透明质酸剂或乙酰透明质酸降解酶(例如透明质酸酶或修饰的透明质酸酶如聚乙二醇化的PH20，即PEGPH20)。在这样的实例中，所述方法可用于分类患者以选择疗法如癌症疗法，并且具体涉及测量HA水平，所述HA水平与对抗乙酰透明质酸剂疗法的反应性相关，例如乙酰透明质酸降解酶疗法，如通过PEGPH20治疗患有晚期肿瘤的患者的疗法。
在另一实例中，本文提供的改良的HABP，例如C节中描述的任何改良的HABP还可以用于监测用抗乙酰透明质酸剂或乙酰透明质酸降解酶如E节所示的任何抗乙酰透明质酸剂或乙酰透明质酸降解酶(例如透明质酸酶或修饰的透明质酸酶如聚乙二醇化的PH20，即PEGPH20)治疗的效力或反应性的方法，其通过在治疗期间检测HA水平来监测。因此，改良的HABP可以与抗乙酰透明质酸剂如乙酰透明质酸降解酶疗法联用，以便监测HA水平并以与临床反应相关的方式根据特定患者和疾病过程调整和/或改变疗法以个性化患者的个体治疗。
本文还提供包含抗乙酰透明质酸剂如乙酰透明质酸降解酶(例如下文E节提供的任何乙酰透明质酸降解酶)和改良的HABP(例如下文C节提供的任何改良的HABP)，以及任选存在的其他同伴试剂的组合和试剂盒，用于选择、监测和/或治疗HA相关疾病和疾病状况，特别是癌症。
1.疾病中的乙酰透明质酸积累以及与预后的关系
乙酰透明质酸(HA；也称为透明质酸或透明质酸盐)为线性糖胺聚糖(GAG)聚合物，其包含通过GlcUA-β1,3-GlcNAc-β1,4-键连接的重复N-乙酰葡糖胺和D-葡糖醛酸二糖亚基。乙酰透明质酸通过一类乙酰透明质酸合成酶HAS1、HAS2和HAS3合成。这些酶通过在新生多糖挤压通过细胞时将葡糖醛和N-乙酰葡糖胺添加至新生多糖来延长乙酰透明质酸而发挥作用。除了HA合成酶，HA水平通常通过其透明质酸酶分解代谢来维持，特别是转换酶透明质酸酶1(Hyal1)。通过生物合成和分解代谢平衡HA的动态转换以保持正常组织中的恒定浓度。
HA是胞外基质(ECM)的组分。其广泛分布于组织中，并且位于胞外、细胞周围基质以及细胞内。HA具有广泛的生物学功能如有助于组织稳态和生物力学、细胞增殖、免疫粘附和激活以及动态细胞过程期间的细胞迁移。这些过程由HA与已知为透明质酸粘素的HA结合蛋白的相互作用介导，例如TSG-6、多能聚糖、间-α-胰蛋白酶抑制物、CD44、淋巴管内皮细胞HA受体(LYVE-1-1)和RHAMM。
乙酰透明质酸积累与许多恶性和自身免疫性疾病状况有关(H,etal.(2009)Pharmacol Rev61:198-223；Whatcott CJ,et al.(2011)Cancer Discovery1:291-296)。例如，某些疾病与乙酰透明质酸的表达和/或产生相关，包括炎性疾病和癌症。HA与这类疾病的发展所涉及的各种生物学过程相联(参见例如Itano et al.(2008)SeminCancer Biol18(4):268-274；Tammi et al.(2008)Semin Cancer Biol18(4):288-295)。
具体地，HA为肿瘤基质的组分，并且存在于许多实体瘤中。肿瘤病灶内HA的积累防止细胞-细胞接触，促进上皮-间充质转换，通过其受体RHAMM和CD44参与p53肿瘤抑制途径并募集肿瘤相关的巨噬细胞(Itano et al.(2008)Cancer Sci99:1720-1725；Camenischet al.(2000)J Clin Invest106:349-360；Thompson et al.(2010)Mol.Cancer Ther.9:3052-64)。富含HA的细胞周围基质的组装是可以促进转移行为的间充质细胞增殖和迁移的前提。特征在于HA积累的肿瘤还表现出肿瘤水吸收，并且具有高组织间隙液压(IFP)，其可以抑制肿瘤对全身性施用的治疗剂如化疗剂的穿透和可接近性。此外，还已显示通过Hyal1降解产生的HA寡聚体导致血管发生或凋亡，这可以有助于肿瘤发病机理。
HA积累与HAS基因表达和/或HYAL基因表达相关(Kosaki et al.(1999)CancerRes.59:1141-1145；Liu et al.(2001)Cancer Res.61:5207-5214；Wang et al.(2008)PLoS3:3032；Nykopp et al.(2010)BMC Cancer10:512)。本领域的研究已各种各样地显示HA、HAS或Hyal1可以用作癌症的预后指示。而且，研究已表明通过反义方法选择性抑制Hyal1，或者通过使用4-甲基伞形酮选择性抑制通过HAS的乙酰透明质酸合成是治疗肿瘤的方法(Kakizaki et al.(2004)J.Biol.Chem.279:33281-33289)。此外，透明质酸酶如下文讨论的PH20也已用来治疗乙酰透明质酸相关疾病和疾病状况(参见例如Thompson et al.(2010)Mol.Cancer Ther9:3052-3064)。
如实施例所示，本文现在发现细胞的HA表型，特别是肿瘤细胞周围基质的信息与肿瘤侵袭性相关，并且HA水平的测定特异性地预测合成HA的肿瘤细胞形成细胞周围基质的能力。具体地，本文发现在HA积累的潜在标记中，包括HAS1,2,3；Hyal1或2；或者HA，仅HA测定与细胞周围基质形成相关，从而预测肿瘤细胞形成HA-聚集蛋白聚糖介导的细胞周围基质的能力，从而预测肿瘤侵袭性。因此，为了诊断以预测或预后肿瘤疗法的目的，考虑HA结合蛋白(HABP)。如本文所述，肿瘤HA产生可以利 用HABP作为探针来定量测量，并且乙酰透明质酸的HABP表现出与细胞周围基质形成的相关性，但是未发现细胞周围基质形成与HAS或HyalmRNA的相对水平之间的关系。这些发现表明直接测量肿瘤细胞相关HA而不是HA代谢途径涉及的其他标记提供细胞周围基质形成的可靠预测。
2.用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗肿瘤以及对治疗的反应性
本文还发现测量的HA积累的量或程度还与对抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如PH20治疗的反应性相关。抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如PH20表现出可用于疾病和疾病状况的单一物质或组合疗法的特性，所述疾病和疾病状况表现出乙酰透明质酸(透明质酸，HA)的积累。这类乙酰透明质酸相关疾病、疾病状况和/或病症包括癌症和炎性疾病。乙酰透明质酸丰富的癌症包括但不限于肿瘤，包括实体瘤如晚期癌症、转移癌、未分化癌、卵巢癌、原位癌(ISC)、鳞状细胞癌(SCC)、前列腺癌、胰腺癌、非小细胞肺癌、乳腺癌、结肠癌和其他癌症。
例如，已显示HA降解酶如透明质酸酶，例如PH20从肿瘤去除HA，导致肿瘤体积减小、IFP减少、肿瘤细胞增殖减缓并通过允许肿瘤渗透增加来增强共给药的化疗药物和生物剂的效力(参见例如美国公开申请第20100003238号和国际公开PCT申请第WO2009/128917号；Thompson et al.(2010)Mol.Cancer Ther9:3052-3064)。
通过修饰可以利用透明质酸酶如PH20降解HA以用作乙酰透明质酸相关疾病和病症的治疗剂的能力，以便增加全身半衰期。增加的半衰期不仅允许去除HA，而且由于其在血浆中持续存在及其降解HA的能力，还降低或减少疾病组织如肿瘤内HA的再生程度。因此，维持血浆酶水平可以去除HA如肿瘤HA，而且还抵消HA再合成。聚乙二醇化是建立的技术，其用来增加治疗性蛋白在体内的半衰期，因此使得它们能够用于全身性治疗方案。抗乙酰透明质酸剂，如乙酰透明质酸降解酶，如透明质酸酶的聚乙二醇化将其在体内的半衰期从少于一分钟延长至约48-72小时，并且允许富含HA的肿瘤的全身性治疗(参见例如美国公开申请第20100003238号和国际公开PCT申请第WO2009/128917号；Thompson et al.(2010)MolCancer Ther9:3052-3064)。
本文发现抗乙酰透明质酸剂，特别是乙酰透明质酸降解酶，例如透明质酸酶，如PH20或PEGPH20对肿瘤细胞的生长抑制活性与HA水平的程度相关。如实施例所示，可以基于肿瘤中HA表达量将肿瘤表征为表型组(例如HA+1、HA+2、HA+3)。高肿瘤相关的HA(评分为HA+3)导致动物模型中肿瘤生长加速，并且通过乙酰透明质酸降解酶(例如PEGPH20)导致更大的肿瘤抑制。例如，与HA+3表型相关的肿瘤生长抑制为97％，而对于HA+2或HA+1表型，其分别仅为44％和16％。数据表明一些肿瘤的持续生长依赖于肿瘤微环境中HA的密度和量，并且从HA丰富(例如HA+3)的肿瘤减少HA比从HA中等或贫乏的肿瘤(例如，HA+2、HA+1)或HA缺陷的肿瘤减少HA对肿瘤生长具有更显著的效果。因此，如本文所示，如利用HABP所测量的，肿瘤组织中HA积累的程度是抗乙酰透明质酸剂(例如，PEGPH20)介导的体内抑制肿瘤生长水平的预测。
3.乙酰透明质酸结合蛋白(HABP)试剂和诊断
基于上文和本文实施例中提供的结果，利用HABP检测的生物标记HA已特异性地与对抗乙酰透明质酸治疗如乙酰透明质酸降解酶治疗(例如PEGPH20)的反应相关。因此，本文提供一种利用HABP用于预后的方法，而且还用于预测对抗乙酰透明质酸剂如乙酰透明质酸降解酶(例如透明质酸酶或修饰的透明质酸酶如聚乙二醇化的PH20，即PEGPH20)的敏感性程度，并且因此预测反应性。
对于作为试剂的价值，期望HABP的灵敏性和特异性以及可重复性，这是由于可变性。例如，利用现有试剂，组织中HA的检测和测量受到限制。目前，用来通过免疫组织化学染色检测或测量组织中的HA的方法主要依赖于动物软骨组织来源的HA结合蛋白或结构域。这些包括通过用4M胍HCl提取然后通过利用HA偶联的树脂亲和色谱纯化自牛鼻软骨蛋白聚糖的HABP。所得的动物来源的HA包括两个主要组分：聚集蛋白聚糖G1结构域和连接模块。由于批与批的变化，以及制备HABP的方法中所用的不同修饰，关于HABP染色模式的差异，本领域中存在可变性，并且染色谱中的差异使得研究之间难以比较。因此，由于其作为组分的异质混合物 存在且其制备没有验证的过程，本文提供可选的HABP蛋白与抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)联合用于疾病预后以及预测治疗效力的同伴诊断。
因此，用于本文提供的方法的HABP试剂包括不是纯化自动物软骨的HABP的任何HABP，例如不是如本领域所用利用如E-Laurent et al.(1985)Ann.Rheum.Dis.44:83-88)所述的方法或其修改的方法纯化自骨鼻软骨的HABP。用于本文的方法的示例性HABP如C节所述。这类蛋白包括例如包含一个或多个HA结合结构域的HABP，包括结合HA的一个或多个连接模块。在一些实例中，所述HABP包含聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖、磷酸蛋白聚糖、HAPLN-1、HAPLN-2、HAPLN-3、HAPLN-4、稳定素-1、稳定素-2、CAB61358、KIAA0527或TSG-6蛋白的HA结合结构域(例如连接模块)。在一些实例中，所述HABP包含聚集蛋白聚糖G1结构域、多能聚糖G1结构域、神经聚糖G1结构域、短小蛋白聚糖G1结构域或磷酸蛋白聚糖G1结构域。在一些实例中，所述HABP包含聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖或磷酸蛋白聚糖的G1结构域以及选自HAPLN-1、HAPLN-2、HAPLN-3或HAPLN-4的连接蛋白。在一些实例中，所述HABP包含TSG-6、稳定素-1、稳定素-2、CAB61358或KIAA0527的连接模块。
在一些实例中，所述HABP为修饰的HABP，例如修饰的聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖、磷酸蛋白聚糖、HAPLN-1、HAPLN-2、HAPLN-3、HAPLN-4、稳定素-1、稳定素-2、CAB61358、KIAA0527或TSG-6蛋白，如TSG-6-LM-Fc。在一些实例中，所述HABP为修饰的HABP，修饰以提高其对HA的结合，例如TSG-6-LM-FcΔHep。
具体地，本文提供的HABP1)可以在表达系统如哺乳动物表达系统中重组产生；2)表现出改良的生物物理特性如稳定性和/或溶解性；3)可以通过简单的纯化方法如通过一步亲和纯化方法纯化；4)能够通过与结合测定相容的方法检测，特别是免疫组织化学或ELISA方法；5)可以以多聚体形式表达(例如通过二聚化)以表现出增加的或高的对HA的亲和力；和/或6)与其他GAG相比表现出对HA的特异性。
在一实例中，本文提供HABP用于本文的方法，其为单一模块HA蛋 白，可以在表达系统中重组产生。具体地，本文提供包含连接模块的HABP试剂。例如，本文提供的HABP为A型类别的HABP，其仅包含连接模块(LM)或其足以结合乙酰透明质酸的部分。这类HABP的实例为肿瘤坏死因子刺激的基因(TSG)-6-LM(SEQ ID NO:360所示的连接模块)、稳定素-1-LM或稳定素-2-LM(分别为SEQ ID NO:371或372所示的连接模块)、CAB61358-LM(SEQ ID NO:373所示的连接模块)或KIAA0527-LM(SEQ ID NO:374所示的连接模块)。
在另一实例中，本文提供HABP用于本文的方法，其直接或间接连接至多聚化结构域。HABP的HA结合结构域如连接模块可以直接或间接连接，例如共价连接、非共价连接或化学连接以形成两个或更多个HA结合结构域的多聚体。HA结合结构域可以相同或不同。具体地，HA结合结构域为连接结构域或模块。因此，可以通过两个或更多个连接结构域的二聚化形成多聚体。在一实例中，多聚体可以通过不同HA-连接结构域上的半胱氨酸残基之间的二硫键连接。例如，多聚化结构域可以包括一部分免疫球蛋白分子，例如一部分免疫球蛋白恒定区(Fc)。在另一实例中，多聚体可以包括通过共价或非共价相互作用连接至肽部分的HA结合结构域，所述肽部分融合至多肽。这类肽可以是肽接头(间隔物)，或者是具有促进多聚化的特性的肽。在另外的实例中，多聚体可以在两个多肽之间通过化学键形成，例如通过异双功能接头。下文提供多聚化结构域的描述。HABP多聚体的实例为融合至Fc的连接模块(LM)。例如，用于本文的方法的HABP试剂的实例为TSG-6-LM-Fc。
在另一实例中，本文提供例如通过氨基酸置换修饰的HABP用于本文的方法，以便表现出与其他GAG相比增加的对乙酰透明质酸的特异性。例如，本文提供突变的TSG-6-LM，其在氨基酸残基20、34、41、54、56、72和/或84处，特别是氨基酸残基20、34、41和/或54处(对应于SEQ ID NO:206所示的氨基酸残基)包含氨基酸置换。置换氨基酸可以是任何其他氨基酸残基，并且一般为非碱性氨基酸残基。例如，氨基酸置换可以置换为Asp(D)、Glu(E)、Ser(S)、Thr(T)、Asn(N)、Gln(Q)、Ala(A)、Val(V)、Ile(I)、Leu(L)、Met(M)、Phe(F)、Tyr(Y)或Trp(W)。氨基酸置换或多个置换赋予减少的对肝素的结合。与不含氨基酸置换的TSG-6-LM对肝素的 结合相比，结合可以减少至少1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。用作本文提供的方法中的试剂的TSG-6-LM突变体的实例为K20A/K34A/K41A。因此，例如，对肝素的结合减少，从而对乙酰透明质酸的特异性增加。突变的TSG-6-LM可以直接或间接缀合至多聚化结构域以产生多聚体。例如，用于本文的方法的试剂的实例为TSG-6-LM(K20A/K34A/K41A)-Fc。
任何试剂可以单独使用或在同伴诊断方法中组合使用。例如，在夹心ELISA或竞争ELISA中，可以使用两种或更多种上述试剂。如下文所述，本文提供的任何HABP可以直接或间接缀合至能够检测的部分。在一些实例中，可以利用第二试剂如结合HABP的抗体检测例如肿瘤样品中结合HA的HABP。在一些实例中，修饰HABP以允许检测HA结合。例如，可以将HABP缀合至可检测的分子，所述可检测的分子允许直接检测或者通过第二物质如结合修饰的HABP并偶联至可检测的蛋白的抗体进行检测，所述可检测的蛋白例如荧光探针或可检测的酶，如辣根过氧化物酶。
4.同伴诊断和预后方法
本文提供的HABP可以单独使用或者在诊断、预后或监测方法中组合使用，所述方法利用对患者的各种生物学样品进行的结合测定，所述患者患有乙酰透明质酸相关疾病或疾病状况，或者有风险或怀疑患有乙酰透明质酸相关疾病或疾病状况。例如，所述HABP可以用于对患者的测定，所述患者患有实体瘤或者有发展实体瘤或其他癌症的风险。在具体实例中，在本文的方法中使用TSG-6-LM、TSG-6-LM-Fc或者其变体或突变体，例如表现出对肝素的结合减少且对乙酰透明质酸的特异性增加的变体或突变体。诊断和预后方法可以与用乙酰透明质酸降解酶的疗法联用，以便分类和/或选择治疗的患者或者改变或修改治疗进程。
在本文提供的示例性方法中，诊断和预后方法是用抗乙酰透明质酸剂的疗法的同伴方法，所述抗乙酰透明质酸剂如乙酰透明质酸降解酶，例如透明质酸酶或修饰的透明质酸酶如PH20或PEGPH20。HA检测可以告知治疗选择、开始、剂量定制或终止，因此可以用来个性化用抗乙酰透明质 酸剂如乙酰透明质酸降解酶治疗。
例如，HABP同伴诊断方法可以用来确定易于患乙酰透明质酸相关疾病或疾病状况(例如癌症)或者患有乙酰透明质酸相关疾病或疾病状况(例如癌症)的对象是否会受益于接受用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗，或者预测其对接受用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗有反应。在所述方法中，可以确定来自易于患有或已知患有乙酰透明质酸相关疾病或疾病状况(例如癌症)的对象的样品的HA表达水平，并且将来自对象的样品中的HA表达水平与分类对抗乙酰透明质酸剂如乙酰透明质酸降解酶的反应性的预定HA水平进行比较。确定分类对用乙酰透明质酸降解酶治疗的反应性的HA的阈值水平在本领域技术人员的水平之内。例如，本文发现升高的HA积累与肿瘤生长抑制之间存在显著相关性，从而肿瘤生长抑制反应与通过肿瘤组织的免疫组织化学定量的HA+3表型相关。因此，在本文提供的同伴诊断方法中，利用本文提供的HABP试剂通过免疫组织化学方法或适合评分的其他方法评价肿瘤样品的HA水平。如果通过本领域技术人员已知和本文所述的方法确定的HA表型为HA+3，则选择对象作为用乙酰透明质酸降解酶如透明质酸酶或修饰的透明质酸酶(例如PH20或PEGPH20)治疗的候选。评价体液如血液或血浆中的HA可以利用相似的定量和分类方法。本文提供治疗的乙酰透明质酸降解酶如PH20或PEGPH20的剂量和方案。
利用本领域技术人员已知的任何结合测定，本文提供的HABP试剂可以检测HA，所述结合测定包括但不限于酶联免疫吸附测定(ELISA)或其他相似的免疫测定，包括夹心ELISA或竞争ELISA测定；免疫组织化学(IHC)；流式细胞术或蛋白印迹。所述结合测定可以对获得自患者体液的样品、任何类型的细胞或组织样品进行，包括来自血浆、尿、肿瘤或怀疑的肿瘤组织(包括新鲜、冷冻以及固定或石蜡包埋的组织)、淋巴结组织或骨髓。
一旦确定样品中HA的量，可以将该量与对照或阈值水平比较。例如，如果确定HA的量在样品中升高，则选择对象作为肿瘤疗法的候选。本文提供分层肿瘤样品或体液样品用于治疗的对象的诊断、预后或选择的示例性方法。
在一实例中，一种诊断方法利用肿瘤组织、肿瘤细胞或包含来自患者 的蛋白的体液的样品。在所述方法中，可以利用如本文所提供的HABP如TSG-6-LM、TSG-6-LM-Fc或者它们的变体或突变体确定HA的存在和表达水平。确定和/或评分HA的表达水平，并且将其与疾病相关的预定HA表型进行比较。如下文所述，可以通过相同的检测测定和使用相同的HABP试剂所确定的相应正常样品中HA水平的比较或知识来确定这些预定值。根据特定疾病、用于HA检测的测定和/或使用的HABP检测试剂确定疾病诊断的阈值水平在本领域技术人员的水平之内。例如，在体液如血浆中，大于0.015μg/mL，并且一般大于0.02μg/mL、0.03μg/mL、0.04μg/mL、0.05μg/mL、0.06μg/mL或更高的HA水平与肿瘤或癌症的存在相关。在另一实例中，在肿瘤组织的免疫组织化学方法中，具有HA+2或HA+3的评分可以确定为疾病。如果水平为疾病的指示，则诊断患者患有肿瘤。
在另一实例中，一种预后方法利用肿瘤组织、肿瘤细胞或包含来自患者的蛋白的体液的样品。在所述方法中，可以利用如本文所提供的HABP如TSG-6-LM、TSG-6-LM-Fc或者它们的变体或突变体确定HA的存在和表达水平。确定和/或评分HA的表达水平，并且将其与疾病相关的预定HA表型进行比较。如下文所述，可以通过相同的检测测定和使用相同的HABP试剂所确定的相应正常样品或疾病对象的样品中HA水平的比较或知识来确定这些预定值。根据特定疾病、用于HA检测的检测和/或使用的HABP检测试剂确定疾病预后的阈值水平在本领域技术人员的水平之内。HA的表达水平指示患者中疾病进展的预期进程。例如，如通过免疫组织化学方法利用定量评分方案评价的高水平的HA(例如HA+3)与跨越一定范围的癌症类型的恶性疾病的存在相关。在另一实例中，体液如血浆中大于0.06μg/mLHA的HA水平还与晚期疾病阶段有关。
在同伴诊断方法的另一实例中，可以监测来自以前用乙酰透明质酸降解酶治疗的对象的样品中HA表达的水平以确定给药所述物质的对象是否获得有效的药物血液水平，以便优化剂量给药或时间安排。
以下章节描述用于诊断和预后方法的进行HA检测方法的示例性HABP试剂和测定，特别是作为用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗的同伴。还描述抗乙酰透明质酸剂，包括乙酰透明质酸降解酶剂，用于治疗乙酰透明质酸相关疾病和病症以及具有这类物质(例如乙酰透明 质酸降解酶)的HABP试剂的试剂盒和组合。可以利用任何所述HABP试剂和测定检测方法单独或与用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的疗法联用来进行任何上述方法。
C.用作同伴诊断剂的乙酰透明质酸结合蛋白(HABP)
本文提供的方法涉及利用乙酰透明质酸结合蛋白(HABP)定量或半定量测量样品中的乙酰透明质酸，例如来自具有肿瘤或怀疑具有肿瘤的对象的肿瘤或流体样品。如本文所述，表达升高的或高水平乙酰透明质酸的肿瘤对用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗有反应，并且通过抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)抑制肿瘤的程度与乙酰透明质酸积累的程度或量相关，而与其他标记如内源乙酰透明质酸合成酶或透明质酸酶的表达无关。与D节所述的检测HABP的测定一致，提供用于本文的方法的HABP允许样品中HA的特异性和灵敏的检测。
本文提供的HABP同伴诊断剂可以与用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗剂的疗法或E节中描述的任何疗法联用，以便选择或鉴定预测对治疗反应的患者和/或监测治疗和治疗的效力，从而提供改良的乙酰透明质酸相关疾病或疾病状况的治疗方案。例如，本文提供的HABP同伴诊断剂可以用来选择和/或监测患有肿瘤或癌症的对象或患者。此外，HABP同伴诊断剂还可以用于乙酰透明质酸相关疾病或疾病状况如肿瘤或癌症的其他诊断和预后方法。
本文提供乙酰透明质酸结合蛋白用于本文提供的方法以检测和定量样品中的乙酰透明质酸。所述乙酰透明质酸结合蛋白可以包含全长HABP多肽，或者其包含HABP的HA结合结构域的部分，或者其足以结合HA的部分。通常，所述HABP或其包含HA结合结构域的部分或其足以结合HA的部分，或者它们的变体或多聚体表现出具有至少低于或低于或1x10-7M的解离常数(Kd)的结合亲和力，并且一般至少低于或低于或9x10-8M、8x10-8M、7x10-8M、6x10- 8M、5x10-8M、4x10-8M、3x10-8M、2x10-8M、1x10-8M、9x10-9M、8x10-9M、7x10-9M、6x10-9M、5x10-9M、4x10-9M、3x10-9M、2x10-9M、1x10-9M或更低的Kd。如本文所讨论的，表现的结合亲和力一般在实现最佳或接近最佳结合乙酰透明质酸的条件下表 现。在一实例中，pH条件可以影响结合。例如，作为本文的同伴诊断剂，利用TSG-6试剂，包括TSG-6-LM或其足以结合HA的部分、其变体及其多聚体的结合测定一般在pH5.8-6.4或约pH5.8-6.4的pH下进行，例如约或pH6.0。
乙酰透明质酸结合蛋白具有两种类型：具有包含一个或两个连接模块的HA结合结构域的乙酰透明质酸结合蛋白，以及具有不是连接模块的HA结合结构域的乙酰透明质酸结合蛋白。在具体实例中，本文提供的同伴诊断剂源自仅具有赋予HA结合的单一连接结构域的HABP结合分子，其可以简化表达、制备和纯化方法。
本文提供的HABP可以源自已知的HABP或者可以合成产生。在一些实例中，HABP可以基于已知HABP的HA结合结构域的保守残基合成产生。本文提供的HABP还可以源自产生自HA结合蛋白的筛选方法如噬菌体展示或基于亲和力的筛选方法的HABP。
可以修饰本文提供的HABP，包括HABP的HA结合结构域，或者其足以结合HA的部分，以便改善用于本文提供的方法的HABP的一个或多个特性。例如，可以修饰本文提供的HABP或其HA结合片段以增加哺乳动物表达系统中的蛋白表达，改善生物物理特性如稳定性和溶解性，改善蛋白纯化和检测，增加对HA的特异性和/或增加对HA的亲和力，只要它们保留结合HA的能力。例如，可以修饰本文提供的用于所述方法的HABP或其HA结合片段以与其他糖胺聚糖相比，增加其对乙酰透明质酸的特异性。在另一实例中，可以将本文提供的用于所述方法的HABP或其HA结合片段直接或间接连接至多聚化结构域以增加分子上HA结合位点的数目，因此增加结合HA的亲和力。
此外，为了用作本文的同伴诊断剂，可以修饰任何HABP或其部分(例如连接模块或其足以结合HA的部分)以促进检测。例如，通过直接或间接缀合至生物素、荧光部分、放射性标记或其他可检测的标记来修改同伴诊断剂。
下文提供用作本文的同伴诊断剂的示例性HABP及其修饰的描述。
1.具有连接模块或G1结构域的HA结合蛋白
本文提供HA结合蛋白(HABP)或其部分(包含至少一个连接模块或连接结构域，并且一般至少两个或更多个连接模块)作为同伴诊断试剂用于本文的方法。在一些实例中，所述HABP包含G1结构域，所述G1结构域包含两个连接模块。通过连接模块介导结合HA。也称为蛋白聚糖串联重复的连接模块长度为约100个氨基酸(aa)，具有以模式Cys1-Cys4和Cys2-Cys3二硫键连接的4个半胱氨酸。连接模块的三维结构由两个α-螺旋和两个三链反向平行β-折叠组成。
有三类包含连接模块的蛋白：包含单一连接模块的A结构域类型蛋白；包含通过N-和C-末端侧翼区延伸的单一连接模块的B结构域类型蛋白；以及具有称为G1结构域的延长结构的C结构域类型蛋白，所述G1结构域包含一个N-末端V-类型Ig样结构域，然后是一对连续的两个连接模块。建模和比较研究已证实与HA相互作用相关的包含连接模块的蛋白之间和之中某些氨基酸的高解析度和保守(Blundell et al.(2005)J.Biol.Chem.,280:18189-18201)。例如，对应于Tyr59和Tyr78(参考SEQ ID NO:360所示的TSG-6-LM编号)的中心HA结合氨基酸残基通过基于与TSG-6-LM(例如SEQ ID NO:360所示)比对在相应位置相同或保守的氨基酸(例如还可以对GlcNAc环堆叠的芳香或大或平面的疏水残基，例如Phe、His、Leu或Val)在包含连接模块的HABP之间保守。而且，如通过比对确定的，在其他连接模块中也发现在对应于SEQ ID NO:360所示的位置11和81的位置的碱性残基。
用于本文提供的方法的包含连接模块的HA结合蛋白包括但不限于TSG-6(例如SEQID NO:206所示的前体和SEQ ID NO:222所示的缺少信号序列的成熟蛋白；或者SEQ ID NO:207、360、417或418所示的LM，其代表如文献报道的各种长度的LM)、稳定素-1(例如SEQ IDNO:223所示或其成熟形式；或者SEQ ID NO:371所示的LM)、稳定素-2(例如SEQ ID NO:224所示或其成熟形式；或者SEQ ID NO:372所示的LM)、CD44(例如SEQ ID NO:227所示或其成熟形式；或者SEQ ID NO:375所示的LM)、LYVE-1(例如SEQ ID NO:228所示或其成熟形式；或者SEQ ID NO:376所示的连接模块)、HAPLN1(例如HAPLN1-1和HAPLN1-2；例如，SEQ ID NO:229所示或其成熟形式；或者SEQ ID NO:377或378所示的LM或多个 LM)、HAPLN2(例如HAPLN2-1和HAPLN2-2；例如SEQ ID NO:230所示或其成熟形式；或者SEQ ID NO:379或380所示的LM或多个LM)、HAPLN3(例如HAPLN3-1和HAPLN3-2；例如SEQ ID NO:231所示或其成熟形式；或者SEQ ID NO:381或382所示的LM或多个LM)、HAPLN4(例如HAPLN4-1和HAPLN4-2；例如SEQ ID NO:232所示或其成熟形式；或者SEQ ID NO:383或384所示的LM或多个LM)、聚集蛋白聚糖(例如聚集蛋白聚糖1、聚集蛋白聚糖2、聚集蛋白聚糖3和聚集蛋白聚糖4；例如SEQID NO:233所示或其成熟形式；或者SEQ ID NO:385、386、387或388所示的LM或多个LM)、多能聚糖(例如多能聚糖1和多能聚糖2；例如SEQ ID NO:235所示或其成熟形式；或者SEQ IDNO:391或392所示的LM或多个LM)、短小蛋白聚糖(例如短小蛋白聚糖1和短小蛋白聚糖2；例如SEQ ID NO:234所示或其成熟形式；或者SEQ ID NO:389或390所示的LM或多个LM)、神经聚糖(例如神经聚糖1和神经聚糖2；例如SEQ ID NO:236所示或其成熟形式；例如SEQ IDNO:393或394所示的LM或多个LM)以及磷酸蛋白聚糖(例如SEQ ID NO:340所示或其成熟形式)。提供用于本文的方法的HABP的实例为TSG-6。
在本文的具体实例中，用于本文的方法的HABP包含至少一个连接模块，并且在某些情况下包含至少两个或至少三个连接模块。所述HABP可以是包含连接模块的全长HABP。例如，用于本文的方法的同伴诊断试剂可以包含SEQ ID NO:206和223-236中任一个所示的氨基酸序列，其成熟形式，或者表现出与SEQ ID NO:206和223-236中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列。例如，用作本文的同伴诊断剂的HABP可以为全长TSG-6，其具有SEQ ID NO:222所示的氨基酸序列，或者表现出与SEQ ID NO:222所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列。
在其他实例中，用于本文的方法的同伴诊断试剂仅包含源自SEQ ID NO:206和223-236中任一个所示的全长HABP或其成熟形式(缺少信号序列)的连接模块或连接模块之足以结合HA的部分。在一些实例中，包含连 接模块或多个模块的HABP不是SEQ ID NO:206和223-236中任一个所示的HABP或其成熟形式(缺少信号序列)的完整序列。应当理解HABP或连接模块的部分一般为连续的氨基酸序列，其一般长度为至少50个氨基酸，60、70、80、90、100、200、300或更多个氨基酸。在一些实例中，所述连接模块或多个模块是同伴诊断结合分子的唯一的HABP部分。例如，用于本文的方法的同伴诊断试剂仅包含全长HABP的一部分，并且具有SEQ ID NO:207、360、361、371-394和416-418中任一个所示的氨基酸序列，或者表现出与SEQ ID NO:207、360、361、371-394和416-418中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列。
在本文的实例中，用于本文的方法的同伴诊断试剂包含G1结构域或其足以特异性结合HA的部分。包含G1结构域的HABP可以源自SEQ ID NO:233-236中任一个所示的HABP或其成熟形式。在一些实例中，包含G1结构域的HABP不是SEQ ID NO:233-236中任一个所示的HABP或其成熟形式的完整序列。应当理解包含G1结构域的HABP的部分一般为连续的氨基酸序列，其一般长度为至少100个氨基酸，例如150、200、250、300、400或更多个氨基酸。在一些实例中，所述G1结构域是同伴诊断结合分子的唯一的HABP部分。例如，用于本文的方法的同伴诊断试剂仅包含全长HABP的一部分，并且具有G1结构域，所述G1结构域具有SEQ ID NO:423-426中任一个所示的氨基酸序列，或者表现出与SEQ ID NO:423-426中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列。
在一些实例中，所述同伴诊断剂可以包含一个以上连接模块，例如2个或3个连接模块。所述连接模块可以来自相同或不同HABP。所述同伴诊断剂可以包含直接或间接连接的连接模块以形成单一多肽。在其他实例中，所述同伴诊断剂可以包含如通过二硫键化学连接的不同多肽所示的连接模块。提供用于本文的方法的HABP片段的实例为TSG-6的连接模块(TSG-6-LM)，或者其足以结合HA的部分。
在一些实例中，所述HABP为包含直接或通过多聚化结构域间接连接 的两个或更多个连接模块的多聚体，以便实现二聚体或三聚体分子的形成并产生多个HA结合位点。例如，用于本文的方法的同伴诊断剂是通过表达直接或间接连接至编码多聚化结构域如免疫球蛋白的Fc部分的核酸分子所产生的同伴诊断剂，所述核酸分子编码SEQ ID NO:207、360、361、371-394和416-418中任一个所示的连接模块，或者表现出与SEQ ID NO:207、360、361、371-394和416-418中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列。因此，所得的HABP多聚体或LM-多聚体包含直接或间接连接至多聚化结构域的SEQ ID NO:207、360、361、371-394和416-418中任一个所示的第一多肽，或者表现出与SEQ ID NO:207、360、361、371-394和416-418中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列；以及直接或间接连接至多聚化结构域的SEQ ID NO:207、360、361、371-394和416-418中任一个所示的第二多肽，或者表现出与SEQ ID NO:207、360、361、371-394和416-418中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列。第一和第二多肽中的连接模块的序列可以相同或不同。提供用于本文的方法的HABP多聚体的实例为包含两条多肽链的多聚体，其中每条链包含直接或间接连接至实现多聚化的多聚化结构域的TSG-6-LM、其结合HA的变体或其足以结合HA的部分。例如，本文提供用于所述方法的是TSG-6-LM:Fc分子(参见例如SEQ ID NO:212或215)。
下文提供包含连接结构域的示例性HABP的描述，包括结构和功能描述。任何所述HABP或其部分，例如仅包含连接结构域或其足以结合HA的部分的片段可以用作本文的方法中的同伴诊断试剂。应当理解提到氨基酸，包括用来描述连接结构域或其他结构域的结构域组织的如SEQ ID NO所示的具体序列，是为了说明的目的而不表示限制提供的实施方案的范围。应当理解多肽及其结构域的描述是介于同源性分析和与相似分子的比对在理论上衍生的。因此，确切的基因座可以变化，并且对于每个HABP不必相同。因此，具体结构域如具体连接结构域可以长或短几个氨基酸(1、2、 3或4个)。
a.A型：TSG-6亚组
本文提供HABP作为同伴诊断剂用于本文的方法，其为A型亚组的成员，包含结合乙酰透明质酸的单个连接模块。A型HABP结合具有6个糖的最小链长度的HA，己糖(HA6)或更大。可以在本文提供的方法中用作同伴诊断剂的A型亚组的成员包括但不限于TSG-6、稳定素-1、稳定素-2、CAB61358和KIAA0527，它们的连接模块或者足以结合HA的连接模块的部分。
i.TSG-6
在本文提供的方法中提供用作同伴诊断试剂的A型亚组HABP的实例为TSG-6，或其连接模块，连接模块之足以结合HA的部分，其变体或其多聚体。肿瘤坏死因子刺激的基因-6(TSG-6，肿瘤坏死因子α诱导的蛋白6，TNFAIP6；SEQ ID NO:206)是由单个N-末端连接模块和C-末端CUB结构域组成的～35kDa分泌糖蛋白。在许多细胞类型中通过包括细胞因子和生长因子在内的炎症因子诱导TSG-6的表达。通过其连接模块，TSG-6是多形核白细胞迁移的有效抑制物。TSG-6与丝氨酸蛋白酶抑制物间-α-抑制物(IαI)形成稳定的复合物，并且增强IαI的抗纤溶酶活性。TSG-6对于HA丰富的细胞周围包衣和胞外基质的形成和重塑也很重要。
通常翻译人TSG-6转录物(SEQ ID NO:205)以形成在N-末端包含17个氨基酸信号序列的277个氨基酸前体肽(SEQ ID NO:206)。因此，成熟的TSG-6(在SEQ ID NO:222中示出)是包含SEQ ID NO:206的氨基酸18-277的260个氨基酸蛋白(Lee et al.(1992)J CellBiol116:545-557)。TSG-6包括两个主要结构域，连接模块和CUB结构域。TSG-6的连接模块在文献中不同地报道为位于SEQ ID NO:206的氨基酸35-129、36-128、36-129或36-132(分别如SEQ ID NO:207、360、417或418所示)。应当理解由于比对的差异，关于结构域的基因座可以有几个氨基酸的不同。因此，为了本文的目的，TSG-6-LM是SEQ ID NO:207、360、417或418中任一个所示或者与这样的序列有1、2或3个氨基酸不同的连接模块。CUB结构域位于SEQ ID NO:206的氨基酸135-246。人TSG-6在SEQ ID NO:206的残基N118和N258处具有两个潜在的N-联聚糖。此外，SEQ ID NO:206的残基T259和T262是磷酸化的(Molina et al.(2007)Proc Natl Acad Sci USA104:2199-2204)。人TSG-6具有在前蛋白TSG-6(SEQ IDNO:206)的残基C58-C127、C82-C103、C135-C161和C188-C210处形成4个二硫键的8个天然半胱氨酸。
TSG-6连接模块(SEQ ID NO:360)具有相对小的大小和良好表征的结构。确定并发现TSG-6连接结构域的三维结构具有与其他已知的连接模块相同的折叠，包含排列在大疏水核心周围的两个α螺旋和两个反向平行的β折叠(Kohda et al.(1996)Cell86:767-775)。此外，已研究TSG-6的连接模块与HA的相互作用，发现TSG-6(SEQ ID NO:360)的连接结构域的Tyr12、Tyr59、Phe70、Tyr78、Trp88的芳香环和碱性残基Lys11、Lys72、Asp77、Arg81和Glu86对于结合HA很重要(参见，例如，Kahmann et al.(2000)Structure8:763-774；Mahoney et al.(2001)J Biol Chem276:22764-22771；Kohda et al.(1996)Cell,88:767-775；Blundell et al.(2003)J Biol Chem278:49261-49270；Lesley et al.(2004)J BiolChem279:25745-25754；Blundell et al.(2005)J Biol Chem280:18189-18201)。结构研究还显示连接模块中仅包含单个HA结合位点，基于HA结合中最直接牵涉的残基Lys11、Tyr12、Tyr59、Phe70和Tyr78的结构图，其位于分子的一个区域(参见例如Mahoney et al.(2001)JBiol Chem276:22764-22771)。
TSG-6的连接模块表现出对几种糖胺聚糖的结合活性。例如，研究已显示所述连接模块结合HA、硫酸软骨素-4(C4S)、蛋白聚糖聚集蛋白聚糖的G1-结构域、肝素和IαI的尿抑胰酶素链(参见例如，Milner et al.(2003)Journal of Cell Science,116:1863-1873；Mahoney et al.(2005)Journal of Biological Chemistry,280:27044-27055)。TSG-6结合肝素和HA由TSG-6的LM中的不同结合位点介导。TSG-6-LM结合乙酰透明质酸所涉及的残基为Lys11、Tyr12、Tyr59、Phe70和Tyr78，其中与野生型相比，突变体K11Q、Y12F、Y59F、F70V和Y78F具有低10-100倍的HA结合亲和力；TSG-6-LM中参与结合肝素的残基为Lys20、Lys34、Lys41、Lys54、Arg56和Arg84，其中突变体K20A、K34A、K41A和K54A表现出受损的肝素结合特性；而参与TSG-6-LM结合尿抑胰酶素的残基与HA结合位点重叠但不相同 (Mahoney et al.(2005)Journal of Biological Chemistry,280:27044-27055)。
TSG-6结合乙酰透明质酸是pH依赖性的，在pH5.6-6.4或约pH5.6-6.4，例如pH5.8-pH6.0或约pH5.8-pH6.0的酸性pH下表现出结合活性。
本文提供用作本文的方法中的同伴诊断剂的TSG-6多肽，其HA结合结构域，例如TSG-6连接模块，或者其足以结合HA的片段可以包括SEQ ID NO:206、207、222、360、417或418中的任一个，或者其变体，例如表现出与SEQ ID NO:206、207、222、360、417或418中任一个的至少65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性的变体。示例性变体包括例如物种变体、等位基因变体以及包含保守和非保守氨基酸突变的变体。天然的人TSG-6的等位基因变体包括例如包含氨基酸置换Q144R的TSG-6(SEQ ID NO:407,Nentwich et al.(2002)J Biol Chem277:15354-15362)。TSG-6在物种之间高度保守，小鼠和人蛋白>94％相同。用作本文提供的方法中的同伴诊断剂的TSG-6或其HA结合片段的物种变体还包括但不限于小鼠(SEQ ID NO:252)、兔(SEQ ID NO:253)、牛(SEQ ID NO:254)、马(SEQ ID NO:409)、黑猩猩(SEQ ID NO:408)、狗、(SEQ ID NO:410)、小鼠(SEQ ID NO:411)、鸡(SEQ ID NO:412)、蛙非洲爪蟾(Xenopuslaevis)(SEQ ID NO:413)、斑马鱼(SEQ ID NO:414)，它们的成熟形式或连接模块或其足以结合HA的部分。
用于所提供的方法的TSG-6或其HA结合片段的变体包括具有氨基酸修饰的变体，所述氨基酸修饰为氨基酸置换(取代)、缺失或插入。示例性修饰为氨基酸置换，例如在对应于SEQ ID NO:360、417或418所示的TSG-6中的残基的氨基酸残基4、6、8、13、20、29、34、41、45、54、67、72或96中任一处的氨基酸置换。置换氨基酸可以是任何其他氨基酸残基。本文提供的用作本文提供的方法中的同伴诊断试剂的TSG-6多肽或其HA结合片段的示例性氨基酸置换包括修饰的TSG-6多肽或其HA结合片段，其包含对应于H4K、H4S、E6A、E6K、R8A、K13A、K20A、H29K、K34A、K41A、H45S、K54A、N67L、N67S、K72A、H96K、K34A/K54A或K20A/K34A/K41A的至少一个氨基酸置换，对应于SEQ ID NO:360、417或418所示的TSG-6中的残基(参见，例如，Mahoney et al.(2005)J Biol Chem 280:27044-27055,Blundell et al.(2007)J BiolChem282:12976-12988,Lesley et al.(2004)J Biol Chem279:25745-25754,Kahmann etal.(2000)Structure15:763-774)。应当理解对于TSG-6结合HA重要或必需的残基，例如上文所述或本领域技术人员已知的任何残基，一般是不变的，并且不可以改变。因此，例如，TSG-6的连接模块中的SEQ ID NO:360的氨基酸残基11、12、59、70、78和81一般不变且不改变。此外，应当理解导致不适当的折叠或扰乱连接模块的折叠的氨基酸修饰一般不变。因此，例如，提供用于本文的方法的修饰的TSG-6不含SEQ ID NO:360的氨基酸修饰H4S、H29A、H45A、H45K、R56A、D77A、R84A和D89A中的任一个或多个(Mahoney et al.(2005)J BiolChem280:27044-27055,Blundell et al.(2007)J Biol Chem282:12976-12988,Lesley etal.(2004)J Biol Chem279:25745-25754)。
具体地，所述修饰，例如氨基酸置换或多个置换，是与不含所述修饰的TSG-6相比，赋予改变如改良的活性的修饰。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加TSG-6对HA的结合亲和力，增加TSG-6对HA的特异性，和/或增加TSG-6的溶解性。例如，本文提供TSG-6变体、HA结合结构域或其足以结合HA的部分用于本文的方法，其通过减少TSG-6结合包括肝素、硫酸软骨素-4、硫酸乙酰肝素和硫酸皮肤素在内的其他糖胺聚糖来增加TSG-6对HA的特异性。与不含所述修饰的TSG-6-LM的结合相比，对不是乙酰透明质酸的其他糖胺聚糖的结合可以减少至少1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。例如，本文提供突变的TSG-6-LM，其在氨基酸残基20、34、41、54、56、72和/或84处，特别是氨基酸残基20、34、41和/或54处(对应于SEQ IDNO:206所示的氨基酸残基)包含氨基酸置换。置换氨基酸可以是任何其他氨基酸残基，并且一般为非碱性氨基酸残基。例如，氨基酸置换可以置换为Asp(D)、Glu(E)、Ser(S)、Thr(T)、Asn(N)、Gln(Q)、Ala(A)、Val(V)、Ile(I)、Leu(L)、Met(M)、Phe(F)、Tyr(Y)或Trp(W)。氨基酸置换或多个置换赋予减少的对肝素的结合。例如，减少TSG-6结合肝素的能力的变体是本领域技术人员已知的。这类变体是包括对应于K20A、K34A、K41A和K54A的至少一个突变的变体，包括变体K34A/K54A或K20A/K34A/K41A(Mahoney et al. (2005)J Biol Chem280:27044-27055)。减少或降低结合肝素的示例性变体为SEQ ID NO:361或416所示的变体TSG-6-LM。
本文提供的用于本文提供的方法的TSG-6多肽的实例为包含至少一个HA结合结构域如TSG-6连接模块的TSG-6多肽。因此，本文提供TSG-6连接模块或其变体用于所提供的方法。这样的多肽试剂的实例是具有SEQ ID NO:207、360、361、416、417或418所示的氨基酸序列，或者具有表现出与SEQ ID NO:207、360、361、416、417或418中任一个的至少65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、95％、99％或更多序列相同性的氨基酸序列的多肽试剂。例如，可以修饰TSG-6连接模块以改变其特异性、亲和力或溶解性，只要其保留结合HA的能力。
在另一实例中，通过二聚化或多聚化，例如通过融合至多聚化结构域如Fc结构域来增加TSG-6连接模块的亲和力(参见下文C3节)。因此，可以修饰TSG-6连接模块以产生包含直接或通过多聚化结构域间接连接的两个或更多个连接模块的多聚体，以便实现二聚体或三聚体分子的形成并产生多个HA结合位点。例如，用于本文的方法的同伴诊断剂是通过表达直接或间接连接至编码多聚化结构域如免疫球蛋白的Fc部分的核酸分子所产生的同伴诊断剂，所述核酸分子编码SEQ ID NO:207、360、361、417或418中任一个所示的连接模块，或者编码具有表现出与SEQ ID NO:207、360、361、417或418中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列的连接模块。因此，所得的TSG-6-LM多聚体包含直接或间接连接至多聚化结构域的SEQ ID NO:207、360、361、417或418中任一个所示的第一多肽，或者表现出与SEQ ID NO:207、360、361、417或418中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列；以及直接或间接连接至多聚化结构域的SEQ ID NO:207、360、361、417或418中任一个所示的第二多肽，或者表现出与SEQ ID NO:207、360、361、417或418中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性 的氨基酸序列。一般来说，实现HA结合的LM或其足够部分是多聚体的唯一的TSG-6部分。例如，本文提供用于所述方法的是TSG-6-LM:Fc分子(参见例如SEQ ID NO:212或215)。
在另一实例中，将TSG-6连接模块连接至Fc结构域以增加其溶解性(参见下文C3节)。
ii.稳定素-1和稳定素-2
在本文提供的方法中提供用作同伴诊断试剂的A型亚组HABP的实例为稳定素-1或稳定素-2，或者它们的连接模块，连接模块之足以结合HA的部分，它们的变体或它们的多聚体。稳定素-1(也称为STAB1、CLEVER-1、KIAA0246、FEEL-1、FEX-1和FELE-1；SEQ ID NO:223)和稳定素-2(也称为STAB2、FEEL-2、CD-44样前体FELL2、DKFZp434E0321、FEX2和胞吞作用的乙酰透明质酸受体/HARE；SEQ ID NO:224)为成束蛋白样乙酰透明质酸(HA)受体同系物家族的I型跨膜成员。两者均包含7个成束蛋白样粘附结构域、多个EGF样重复以及乙酰透明质酸结合的连接模块。稳定素-1和稳定素-2均在血窦内皮和巨噬细胞上表达，虽然各自功能上不同。稳定素-1参与两个细胞内运输途径：受体介导的胞吞作用和再循环；以及内含体间隔与跨高尔基网络(TGN)之间的穿梭。稳定素-2作为HA和AGE修饰的蛋白的清除受体发挥作用。
稳定素-1的前体序列如SEQ ID NO:223所示。稳定素-1的连接模块位于SEQ IDNO:223的2208-2300，并且如SEQ ID NO:371所示。稳定素-2的前体序列如SEQ ID NO:224所示，并且稳定素-2的连接模块位于SEQ ID NO:224的氨基酸2198-2290且如SEQ ID NO:372所示。
本文提供的用作本文的方法中的同伴诊断剂的稳定素-1或稳定素-2多肽，其HA结合结构域，例如稳定素-LM模块或其足以结合HA的片段包括SEQ ID NO:371或372所示的连接模块，或者其表现出与SEQ ID NO:371或372中的任一个的至少65％、70％、75％、80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性的变体。所述变体包括表现出特异性结合HA的变体。变体包括等位基因变体、物种变体或包含氨基酸修饰(例如以增加对HA的亲和力或特异性)的其他变体。 提供用于本文的方法的稳定素-1的物种变体包括但不限于小鼠(SEQ ID NO:255)和牛(SEQ ID NO:256)，而提供用于本文的方法的稳定素-2的物种变体包括但不限于小鼠(SEQ ID NO:257)和大鼠(SEQ ID NO:258)。
本文还提供表现出增加的对HA的亲和力的稳定素-1-LM或稳定素-1-LM多聚体用作本文的方法中的同伴诊断剂。例如，用于本文的方法的同伴诊断剂是通过表达直接或间接连接至编码多聚化结构域如免疫球蛋白的Fc部分的核酸分子所产生的同伴诊断剂，所述核酸分子编码SEQ ID NO:371或372中任一个所示的连接模块，或者编码具有表现出与SEQID NO:371或372中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列的连接模块。因此，所得的LM多聚体包含直接或间接连接至多聚化结构域的SEQ ID NO:371或372中任一个所示的第一多肽，或者表现出与SEQ ID NO:371或372中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列；以及直接或间接连接至多聚化结构域的SEQ ID NO:371或372中任一个所示的第二多肽，或者表现出与SEQ ID NO:371或372中任一个所示的序列的至少65％、70％、75％、80％、84％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％序列相同性的氨基酸序列。
b.B型：CD44亚组
本文提供HABP作为同伴诊断试剂用于本文的方法，其为具有HA结合结构域的B型亚组的成员，所述HA结合结构域包含结合乙酰透明质酸的具有N-和C-末端延伸的单个连接模块。不像A型/TSG-6亚组的HA结合结构域，连接结构域的两侧序列对于B型结构域的结构完整性必不可少，并且是结合HA所需要的。用于本文提供的方法的HABP的B型亚组的成员包括但不限于CD44和LYVE-1，或者它们的HA结合片段。
i.CD44
提供用于本文的方法的B型亚组HABP为CD44、CD44的HA结合结 构域或其足以结合HA的部分。CD44为80-至250-kDa的I型跨膜糖蛋白，其结合乙酰透明质酸以及各种胞外和细胞表面配体。CD44具有各种功能，参与胞外基质的粘附、组织和转换并介导炎症期间淋巴细胞的迁移。CD44与HA相互作用的能力由许多因素调控，包括受体聚集以及胞外域的糖基化的改变。由于10个变异外显子的可变剪接，CD存在许多同种型，其全部包含乙酰透明质酸结合结构域，所述乙酰透明质酸结合结构域包含连接模块。示例性CD44全长序列如SEQ IDNO:227所示。CD44的乙酰透明质酸结合结构域长度为约160个氨基酸(SEQ ID NO:341)，并且包含两侧有通过二硫键连接的N-和C-末端延伸的连接模块(SEQ ID NO:341所示的CD44HA结合结构域的Cys9和Cys110)。Arg41和Arg78对于HA结合极为重要(对应于SEQ IDNO:341所示的CD44HA结合结构域的氨基酸Arg22和Arg59)，而Tyr42和Tyr79(对应于SEQ IDNO:341所示的CD44HA结合结构域的氨基酸Tyr23和Tyr60)对于CD44功能活性必不可少。CD44的连接模块如SEQ ID NO:375所示。因此本文提供保留结合HA的能力的CD44片段用于本文的方法，例如，包含连接结构域以及N-和C-末端两侧结构域的CD44片段或者其足以实现结合HA的部分。
本文还提供变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。用于本文提供的方法的CD44的物种变体包括但不限于小鼠(SEQ ID NO:259)、大鼠(SEQ ID NO:260)、牛(SEQ ID NO:261)、狗(SEQ ID NO:262)、马(SEQ ID NO:263)、仓鼠(SEQ ID NO:264)、狒狒(SEQ ID NO:265)和金地鼠(SEQ ID NO:266)。用于所提供的方法的CD44的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的CD44相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加CD44对HA的结合亲和力，增加CD44对HA的特异性，和/或增加CD44的溶解性。
ii.LYVE-1
本文提供B型亚组HABP用于本文提供的方法，其为LYVE-1、LYVE-1的HA结合结构域或其足以结合HA的部分。淋巴管内皮细胞乙酰透明质 酸(HA)受体-1(LYVE-1，也称为CRSBP-1、HAR和XLKD1；SEQ ID NO:228)为60-kDa的I型跨膜糖蛋白，其在淋巴管内皮的腔和远腔(ablumenal)表面上表达，并且还在肝血窦内皮细胞上表达。LYVE-1参与HA内化以降解以及将HA从组织转运入淋巴管的腔。LYVE-1指导的HA定位至淋巴管表面还影响免疫应答或肿瘤转移方面。LYVE-1的连接模块位于SEQ ID NO:228的氨基酸40-129，并且如SEQ ID NO:376所示。因此本文提供保留结合HA的能力的LYVE-1片段用于本文的方法，例如，包含连接结构域以及N-和C-末端两侧结构域的LYVE-1片段或者其足以实现结合HA的部分。
本文还提供变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。LYVE-1的物种变体包括但不限于小鼠(SEQ ID NO:267)和牛(SEQ ID NO:268)。用于所提供的方法的LYVE-1的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的LYVE-1相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加LYVE-1对HA的结合亲和力，增加LYVE-1对HA的特异性，和/或增加LYVE-1的溶解性。
c.C型：连接蛋白亚组
本文提供HABP用作本文的方法中的同伴诊断试剂，其为C型亚组的成员，具有包含免疫球蛋白(Ig)结构域(介导连接蛋白与其他C型HA结合蛋白之间的结合)和两个连接模块(两个均为结合HA所必需的)的HA结合结构域。所述Ig结构域和两个连接模块共同组成C型HABP的G1结构域。用于本文提供的方法的HABP的C型亚组的成员包括但不限于HAPLN1/连接蛋白、HAPLN2、HAPLN3、HAPLN4、聚集蛋白聚糖、多能聚糖、短小蛋白聚糖、神经聚糖和磷酸蛋白聚糖，或者它们的HA结合片段。
i.HAPLN/连接蛋白家族
乙酰透明质酸和蛋白聚糖连接蛋白(HAPLN)家族由4个分泌的蛋白聚糖构成，所述蛋白聚糖结合乙酰透明质酸并包含一个Ig-型C2-系列结构域和两个连接结构域。
(1)HAPLN1
本文提供用于所述方法的C型亚组HABP为HAPLN1、HAPLN1的HA结合结构域或其足以结合HA的部分。乙酰透明质酸和蛋白聚糖连接蛋白1(HAPLN1，也称作连接蛋白和CRTL1；SEQ ID NO:229)通过稳定HA与硫酸软骨素蛋白聚糖的相互作用而有助于胞外基质稳定性和柔性。HALPN1包含结合HA的两个连接模块(SEQ ID NO:229的氨基酸159-253和氨基酸260-350)以及结合聚集蛋白聚糖的G1结构域的Ig模块的Ig模块(SEQ ID NO:229的氨基酸53-160)。HAPLN1通过形成包含与聚集蛋白聚糖和HAPLN1垂直连接的HA线性骨架的三元复合物来稳定HA与聚集蛋白聚糖的关联。聚集蛋白聚糖和HAPLN1互相平行，而HA在两个HAPLN1连接模块和两个聚集蛋白聚糖连接模块之间运行。所述复合物产生抗变形的凝胶样物质。HAPLN1还稳定HA与其他硫酸软骨素蛋白聚糖如多能聚糖、神经聚糖和短小蛋白聚糖的相互作用，与聚集蛋白聚糖相似，所述硫酸软骨素蛋白聚糖也具有包含Ig模块的G1结构域和两个连接模块。
HAPLN1的G1结构域包含Ig结构域和2个连接模块。HAPLN1的G1结构域的Ig结构域位于SEQ ID NO:229的氨基酸53-160。HAPLN1的G1结构域的连接模块位于SEQ ID NO:229的氨基酸159-253和259-350，并且如SEQ ID NO:377和378所示。因此，本文提供保留结合HA的能力的HAPLN1片段用于本文的方法，例如，包含G1结构域的HAPLN1片段或者其足以实现结合HA的部分。例如，本文提供包含至少两个连接模块的HAPLN1的HA结合片段用于本文的方法。
通常，为了用作检测HA的诊断剂，将HAPLN1与另一HA结合蛋白组合提供，所述另一HA结合蛋白包含HA结合区，例如另一C型HABP如聚集蛋白聚糖、多能聚糖、短小蛋白聚糖、神经聚糖或磷酸蛋白聚糖的G1结构域。
本文还提供变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。HAPLN1的物种变体包括但不限于牛(SEQ ID NO:269and273)、小鼠(SEQ ID NO:270)、大鼠(SEQ ID NO:271)、鸡(SEQ ID NO:272)、马(SEQ ID NO:274)和猪(SEQ ID NO:275)。用于所提供的方法的HAPLN1的变体或其HA结合 片段包括具有氨基酸修饰并且与不含所述修饰的HAPLN1相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加HAPLN1对HA的结合亲和力，增加HAPLN1对HA的特异性，和/或增加HAPLN1的溶解性。
(2)HAPLN2
本文提供C型亚组HABP用于本文提供的方法，其为HAPLN2、HAPLN2的HA结合结构域或其足以结合HA的部分。乙酰透明质酸和蛋白聚糖连接蛋白2(HAPLN2；SEQ ID NO:230)，也称作脑连接蛋白1，主要在脑中表达。HAPLN2的G1结构域包含Ig结构域和2个连接模块。HAPLN2的G1结构域的Ig结构域位于SEQ ID NO:230的氨基酸49-149。HAPLN2的G1结构域的连接模块位于SEQ ID NO:230的氨基酸148-241和247-337，并且如SEQ ID NO:379和380所示。
因此，本文提供保留结合HA的能力的HAPLN2片段用于本文的方法，例如，包含G1结构域的HAPLN2片段或者其足以实现结合HA的部分。例如，本文提供包含至少两个连接模块的HAPLN2的HA结合片段用于本文的方法。通常，为了用作检测HA的诊断剂，将HAPLN2与另一HA结合蛋白组合提供，所述另一HA结合蛋白包含HA结合区，例如另一C型HABP如聚集蛋白聚糖、多能聚糖、短小蛋白聚糖、神经聚糖或磷酸蛋白聚糖的G1结构域。
本文还提供变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。HAPLN2的物种变体包括但不限于小鼠(SEQ ID NO:276)、大鼠(SEQ ID NO:277)和牛(SEQ ID NO:278)。用于所提供的方法的HAPLN2的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的HAPLN2相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加HAPLN2对HA的结合亲和力，增加HAPLN1对HA的特异性，和/或增加HAPLN2的溶解性。
(3)HAPLN3
本文提供用于本文的方法的C型亚组HABP为HAPLN3、HAPLN3的HA结合结构域或其足以结合HA的部分。乙酰透明质酸和蛋白聚糖连接蛋白3,(HAPLN3；SEQ ID NO:231)在透明质酸结合和细胞粘附中发挥功能。HAPLN3在乳腺癌中上调，因此可能与癌症发展和转移相关。HAPLN3的G1结构域包含Ig结构域和2个连接模块。HAPLN3的G1结构域的Ig结构域位于SEQ ID NO:231的氨基酸62-167。HAPLN3的G1结构域的连接模块位于SEQ ID NO:231的氨基酸166-260和266-357，并且如SEQ ID NO:381和382所示。
因此，本文提供保留结合HA的能力的HAPLN3片段用于本文的方法，例如，包含G1结构域的HAPLN3片段或者其足以实现结合HA的部分。例如，本文提供包含至少两个连接模块的HAPLN3的HA结合片段用于本文的方法。通常，为了用作检测HA的诊断剂，将HAPLN3与另一HA结合蛋白组合提供，所述另一HA结合蛋白包含HA结合区，例如另一C型HABP如聚集蛋白聚糖、多能聚糖、短小蛋白聚糖、神经聚糖或磷酸蛋白聚糖的G1结构域。
本文还提供变体用于本文的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。HAPLN3的物种变体包括但不限于小鼠(SEQ ID NO:279)、大鼠(SEQ ID NO:280)和牛(SEQ ID NO:281)。用于所提供的方法的HAPLN3的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的HAPLN3相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加HAPLN3对HA的结合亲和力，增加HAPLN3对HA的特异性，和/或增加HAPLN3的溶解性。
(4)HAPLN4
本文提供C型亚组HABP用于本文的方法，其为HAPLN4、HAPLN4的HA结合结构域或其足以结合HA的部分。乙酰透明质酸和蛋白聚糖连接蛋白4(HAPLN4；SEQ ID NO:232)，也称作脑连接蛋白2，主要在脑中表达。HAPLN4参与神经细胞周围基质的发育。人和小鼠HAPLN4享有91％氨基酸序列相同性。HAPLN4的G1结构域包含Ig结构域和2个连接模块。 HAPLN4的G1结构域的Ig结构域位于SEQ ID NO:232的氨基酸60-164。HAPLN4的G1结构域的连接模块位于SEQ ID NO:232的氨基酸163-267和273-364，并且如SEQ ID NO:383和384所示。
因此，本文提供保留结合HA的能力的HAPLN4片段用于本文的方法，例如，包含G1结构域的HAPLN4片段或者其足以实现结合HA的部分。例如，本文提供包含至少两个连接模块的HAPLN4的HA结合片段用于本文的方法。通常，为了用作检测HA的诊断剂，将HAPLN4与另一HA结合蛋白组合提供，所述另一HA结合蛋白包含HA结合区，例如另一C型HABP如聚集蛋白聚糖、多能聚糖、短小蛋白聚糖、神经聚糖或磷酸蛋白聚糖的G1结构域。
本文还提供HAPLN4的变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。HAPLN4的物种变体包括但不限于小鼠(SEQ ID NO:282)、牛(SEQ ID NO:283)和大鼠(SEQ ID NO:284)。用于所提供的方法的HAPLN4的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的HAPLN4相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加HAPLN4对HA的结合亲和力，增加HAPLN4对HA的特异性，和/或增加HAPLN4的溶解性。
(5)聚集蛋白聚糖
本文提供C型亚组HABP用于本文的方法，其为聚集蛋白聚糖、聚集蛋白聚糖的HA结合结构域或其足以结合HA的部分。聚集蛋白聚糖(SEQ ID NO:233)属于硫酸软骨素(CS)蛋白聚糖家族，该家族还包括多能聚糖、短小蛋白聚糖、神经聚糖和磷酸蛋白聚糖。每个聚集蛋白聚糖分子包含分别约100和30个硫酸角质素和糖胺聚糖(GAG)侧链。聚集蛋白聚糖通过其N-末端的连接模块和Ig结构域与乙酰透明质酸非共价地相关。它是软骨中最丰富的蛋白聚糖，并且有助于这种组织的承载能力。
聚集蛋白聚糖的G1结构域位于SEQ ID NO:233的氨基酸45-352。聚集蛋白聚糖的G1结构域的Ig结构域位于SEQ ID NO:233的氨基酸45-154，并且如SEQ ID NO:423所示。聚集蛋白聚糖的G1结构域的连接模块位于 SEQ ID NO:233的氨基酸153-247和254-349，并且如SEQ ID NO:385和386所示。连接模块3和4如SEQ ID NO:387和388所示。因此，本文提供保留结合HA的能力的聚集蛋白聚糖片段用于本文的方法，例如，包含G1结构域的聚集蛋白聚糖片段或者其足以实现结合HA的部分。
本文还提供聚集蛋白聚糖的变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。聚集蛋白聚糖的物种变体包括但不限于猪(SEQ ID NO:285)、鸡(SEQ ID NO:286)、小鼠(SEQ ID NO:287)、牛(SEQ ID NO:288)、狗(SEQ ID NO:289)、大鼠(SEQ ID NO:290)和兔(SEQ ID NO:291)。用于所提供的方法的聚集蛋白聚糖的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的聚集蛋白聚糖相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加聚集蛋白聚糖对HA的结合亲和力，增加聚集蛋白聚糖对HA的特异性，和/或增加聚集蛋白聚糖的溶解性。
(6)短小蛋白聚糖
本文提供C型亚组HABP用于本文的方法，其为短小蛋白聚糖、短小蛋白聚糖的HA结合结构域或其足以结合HA的部分。短小蛋白聚糖(SEQ ID NO:234)为基质蛋白的聚集蛋白聚糖/多能聚糖蛋白聚糖家族的160kDa成员。其来源于脑并用作乙酰透明质酸与其他基质分子如生腱蛋白和纤蛋白之间的接头。短小蛋白聚糖的G1结构域位于SEQ ID NO:234的氨基酸51-356，并且如SEQ ID NO:424所示。短小蛋白聚糖的G1结构域的Ig结构域位于SEQ IDNO:234的氨基酸51-158。短小蛋白聚糖的G1结构域的连接模块位于SEQ ID NO:234的氨基酸157-251和258-353，并且如SEQ ID NO:389和390所示。因此，本文提供保留结合HA的能力的短小蛋白聚糖片段用于本文的方法，例如，包含G1结构域的短小蛋白聚糖片段或者其足以实现结合HA的部分。例如，本文提供包含至少两个连接模块的短小蛋白聚糖的HA结合片段用于本文的方法。
本文还提供短小蛋白聚糖的变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合 HA的能力。短小蛋白聚糖的物种变体包括但不限于大鼠(SEQ ID NO:292)、小鼠(SEQ ID NO:293)、牛(SEQ ID NO:294)和猫(SEQ ID NO:295)。用于所提供的方法的短小蛋白聚糖的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的短小蛋白聚糖相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加短小蛋白聚糖对HA的结合亲和力，增加短小蛋白聚糖对HA的特异性，和/或增加短小蛋白聚糖的溶解性。
(7)多能聚糖
本文提供C型亚组HABP用于本文的方法，其为多能聚糖、多能聚糖的HA结合结构域或其足以结合HA的部分。多能聚糖(SEQ ID NO:235)是存在于各种组织中的大胞外基质蛋白聚糖。它起着重要的结构作用，在发育和疾病期间形成松散的水合基质。它还直接或间接与细胞相互作用以调节这类生理过程如细胞粘附、存活、增殖和运动性。多能聚糖的G1结构域位于SEQ ID NO:235的氨基酸38-349，并且如SEQ ID NO:425所示。多能聚糖的G1结构域的Ig结构域位于SEQ ID NO:235的氨基酸38-151。多能聚糖的G1结构域的连接模块位于SEQID NO:235的氨基酸150-244和251-346，并且如SEQ ID NO:391和392所示。因此，本文提供保留结合HA的能力的多能聚糖片段用于本文的方法，例如，包含G1结构域的多能聚糖片段或者其足以实现结合HA的部分。例如，本文提供包含至少两个连接模块的多能聚糖的HA结合片段用于本文的方法。
本文还提供多能聚糖的变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。多能聚糖的物种变体包括但不限于小鼠(SEQ ID NO:296)、大鼠(SEQ ID NO:297)、豚尾猴(SEQ ID NO:298)、牛(SEQ ID NO:299)和鸡(SEQ ID NO:300)。用于所提供的方法的多能聚糖的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的多能聚糖相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加多能聚糖对HA的结合亲和力，增加多能聚糖对HA的特异性，和/或增加多能聚糖的溶解性。
(8)神经聚糖
本文提供C型亚组HABP用于本文的方法，其为神经聚糖、神经聚糖的HA结合结构域或其足以结合HA的部分。也称作CSPG3和1D1的神经聚糖(SEQ ID NO:236)为分泌的硫酸软骨素蛋白聚糖，其主要在中枢神经系统中表达。预测人神经聚糖在Met635之后被切割，导致N-末端(神经聚糖-130)和C-末端(神经聚糖-C)片段。神经聚糖和神经聚糖-C由星形胶质细胞产生并在轴突束和神经元细胞体周围的基质中积累。据发现神经聚糖-130主要在神经胶质细胞的细胞质中。神经聚糖通过与各种基质和跨膜分子相互作用来抑制神经元粘附和神经突增生。神经聚糖的G1结构域位于SEQ ID NO:236的氨基酸53-359，并且如SEQ ID NO:426所示。神经聚糖的G1结构域的Ig结构域位于SEQ ID NO:236的氨基酸53-161。神经聚糖的G1结构域的连接模块位于SEQ ID NO:236的氨基酸160-254和261-356，并且如SEQ IDNO:393和394所示。因此，本文提供保留结合HA的能力的神经聚糖片段用于本文的方法，例如，包含G1结构域的神经聚糖片段或者其足以实现结合HA的部分。例如，本文提供包含至少两个连接模块的神经聚糖的HA结合片段用于本文的方法。
本文还提供变体用于所提供的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。神经聚糖的物种变体包括但不限于小鼠(SEQ ID NO:301)、大鼠(SEQ ID NO:302)和黑猩猩(SEQ ID NO:303)。用于所提供的方法的神经聚糖的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的神经聚糖相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加神经聚糖对HA的结合亲和力，增加神经聚糖对HA的特异性，和/或增加神经聚糖的溶解性。
(9)磷酸蛋白聚糖
本文提供C型亚组HABP用于本文提供的方法，其为磷酸蛋白聚糖、磷酸蛋白聚糖的HA结合结构域或其足以结合HA的部分。磷酸蛋白聚糖(SEQ ID NO:340)为分离自大鼠脑的硫酸软骨素蛋白聚糖，其结合神经元和神经细胞-粘附分子，并且通过异嗜性结合细胞表面和胞外基质分子以及通 过与跨膜磷酸酶的配体竞争来调节神经组织中的细胞相互作用和其他发育过程。磷酸蛋白聚糖与人受体类型蛋白酪氨酸磷酸酶(RPTPζ/β)的胞外部分具有76％相同性，并且代表较大跨膜蛋白的mRNA间接变体。
本文还提供变体用于本文的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。磷酸蛋白聚糖的物种变体包括但不限于大鼠磷酸蛋白聚糖(SEQ ID NO:237)。用于所提供的方法的磷酸蛋白聚糖的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的磷酸蛋白聚糖相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加磷酸蛋白聚糖对HA的结合亲和力，增加磷酸蛋白聚糖对HA的特异性，和/或增加磷酸蛋白聚糖的溶解性。
2.没有连接模块的HA结合蛋白
在一些实例中，本文提供不含连接模块的HA结合蛋白用于本文的方法。用于本文提供的方法的没有连接模块的HA结合蛋白包括但不限于HABP1/C1QBP、排卵蛋白、RHAMM、IαI、CDC37、PHBP、SPACR、SPACRCAN、CD38、IHABP4和PEP-1，或者它们的HA结合片段。
a.HABP1/C1QBP
本文提供乙酰透明质酸结合蛋白1、HABP1的HA结合结构域或其足以结合HA的部分用于本文的方法。乙酰透明质酸结合蛋白1(HABP1；SEQ ID NO:240)，也称作C1qBP/C1qR和p32，为普遍存在的酸性糖蛋白，其在精子发生中发挥功能并作为促炎分子的受体。HABP1结合胞外的乙酰透明质酸、玻连蛋白、补体组分C1q、HMW激肽原以及细菌和病毒蛋白。胞内的HABP1结合包含C1q球状结构域的分子、PKC的多种同种型、线粒体Hrk、肾上腺素能和GABA-A受体、mRNA剪接因子ASF/SF2以及CBF转录因子。
本文还提供变体用于本文的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。用于所提供的方法的HABP1的变体或其HA结合片段包括具有氨基酸修饰并且 与不含所述修饰的HABP1相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加HABP1对HA的结合亲和力，增加HABP1对HA的特异性，和/或增加HABP1的溶解性。
b.排卵蛋白
本文提供排卵蛋白、排卵蛋白的HA结合结构域或其足以结合HA的部分用于本文的方法。排卵蛋白(SEQ ID NOS:238和239)是与C-型凝集素有同源性的跨膜蛋白，并且按照其跨膜片段中的L-A-Y-I-L-I六个氨基酸基序来命名。排卵蛋白特异性地结合乙酰透明质酸，并且在大多数动物组织的胞外基质和体液中发现。因此其可以在组织重塑、发育、稳态和疾病期间调节细胞行为和功能。
本文还提供变体用于本文的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。排卵蛋白的物种变体包括但不限于小鼠(SEQ ID NO:304)、中国仓鼠(SEQ ID NO:305)和大鼠(SEQ ID NO:306)。用于所提供的方法的排卵蛋白的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的排卵蛋白相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加排卵蛋白对HA的结合亲和力，增加排卵蛋白对HA的特异性，和/或增加排卵蛋白的溶解性。
c.RHAMM
本文提供RHAMM、RHAMM的HA结合结构域或其足以结合HA的部分用于本文的方法。HA介导的运动性的受体(RHAMM；SEQ ID NO:242)是膜相关的蛋白，大小为～59-80kDa。RHAMM在大多数细胞类型上表达并发挥功能以对HA结合反应，介导粘附和细胞运动性。本文还提供变体用于本文的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。RHAMM的物种变体包括但不限于小鼠(SEQ ID NO:307)和大鼠(SEQ ID NO:308)。用于所提供的方法的RHAMM的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的RHAMM相比表现出改变如改良的活性的变体。这类变体包括包含 氨基酸修饰的那些变体，所述氨基酸修饰增加RHAMM对HA的结合亲和力，增加RHAMM对HA的特异性，和/或增加RHAMM的溶解性。
d.其他
可以用于本文提供的方法的结合HA的其他HABP(其中一些包含乙酰透明质酸结合结构域)包括但不限于IαI(SEQ ID NOS:243-245)、CDC37(SEQ ID NO:250)、PHBP(SEQ IDNO:251)、SPACR(SEQ ID NO:246)、SPACERCAN(SEQ ID NO:247)、CD38(SEQ ID NO:248)、IHABP4(SEQ ID NO:249)和PEP-1(SEQ ID NO:241)，或者它们足以结合HA的HA结合结构域或部分。本文还提供变体用于本文的方法，包括等位基因变体、物种变体以及包含氨基酸修饰的其他变体，只要所述变体保留其结合HA的能力。物种变体包括但不限于来自小鼠(SEQID NO:309-311)和牛(SEQ ID NO:312-314)的IαI，来自面包酵母(SEQ ID NO:326)、果蝇(SEQ ID NO:327)、大鼠(SEQ ID NO:328)、小鼠(SEQ ID NO:329)、裂殖酵母(SEQ ID NO:330)、果蝇(SEQ ID NO:331)、鸡(SEQ ID NO:332)、牛(SEQ ID NO:333)、白色念珠菌(Candida albicans)(SEQ ID NO:334)、线虫(SEQ ID NO:335)和绿河魨(SEQ ID NO:336)的CDC37，来自鸡(SEQ ID NO:315)和小鼠(SEQ ID NO:316)的SPACR，来自小鼠(SEQ ID NO:317)、大鼠(SEQ ID NO:318)和鸡(SEQ ID NO:319)的SPACRCAN，来自小鼠(SEQ ID NO:320)、大鼠(SEQ ID NO:321)和兔(SEQ ID NO:322)的CD38，来自小鼠(SEQ ID NO:324)和鸡(SEQ ID NO:325)的IHABP4，以及来自小鼠(SEQ ID NO:337)、大鼠(SEQ ID NO:338)和牛(SEQ ID NO:339)的PHBP。用于所提供的方法的HABP的变体或其HA结合片段包括具有氨基酸修饰并且与不含所述修饰的HABP相比表现出改变如改良的活性的变体。这类变体包括包含氨基酸修饰的那些变体，所述氨基酸修饰增加HABP对HA的结合亲和力，增加HABP对HA的特异性，和/或增加HABP的溶解性，例如IαI、CDC37、PHBP、SPACR、SPACRCAN、CD38、IHABP4和PEP-1，或者它们的HA结合片段。
3.HA结合蛋白的修饰
本文提供修饰的HABP以改良HABP的一种或多种特性用于本文提供 的方法。这类特性包括修饰增加哺乳动物表达系统中的蛋白表达，改良生物物理特性如稳定性和溶解性，改良蛋白纯化和检测和/或通过融合蛋白的二聚化增加对HA的亲和力。
a.HABP的多聚体
提供用于本文的方法的HABP可以直接或间接连接至多聚化结构域。多聚化结构域的存在可以产生HABP或其HA结合结构域的多聚体以增加分子上的HA结合位点。这可以导致HABP对HA的亲和力增加。例如，与不含多聚化结构域的HABP多肽相比，HABP多聚体的亲和力可以增加2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍或更多倍。当表示为解离常数(Kd)时，HABP多聚体对HA的亲和力一般至少少于或少于或1x10-8M-1x10-10M，例如至少少于或少于或9x10-9M、8x10-9M、7x10-9M、6x10-9M、5x10-9M、4x10-9M、3x10-9M、2x10-9M、1x10-9M、9x10-10M、8x10-10M、7x10-10M、6x10-10M、5x10-10M、4x10-10M、3x10-10M、2x10-10M、1x10-10M或更低的Kd。
本文提供包括第一HABP的HA结合结构域或其足以结合HA的部分以及第二HABP的HA结合结构域或其足以结合HA的部分的多聚体，其中所述第一和第二HA结合结构域直接或通过接头连接至多聚化结构域。所述第一和第二HA结合结构域可以来自相同的HABP或来自不同的HABP。例如，如果所述HA结合结构域相同，则可以产生同源二聚体或同源三聚体。如果所述HA结合结构域不同，则可以产生异源二聚体或异源三聚体。例如，HABP的HA结合结构域如连接结构域或模块可以共价连接、非共价连接或化学连接以形成两个或更多个HA结合结构域的多聚体。连接模块可以连接以形成二聚体、三聚体或更高的多聚体。在某些情况下，可以通过两个或更多个HABP多肽(每个包含HA结合结构域)的二聚化形成多聚体。
包括HA结合结构域的HABP的任何部分可以用作多聚体配对物。例如，上文所述的任何HABP，或者SEQ ID NO:206-207、222-340、407-414中任一个所示的那些HABP，或者HABP的任何部分，包括HA结合结构域，例如连接结构域或模块及其变体，包括SEQ ID NO:341和371-394中 任一个所示的任何HA结合结构域可以用来产生嵌合HABP多肽，其中全部或部分HABP多肽连接至多聚化结构域。通常，HABP部分的至少一个，但是有时候两个是连接至多聚化结构域的足以结合HA的HABP的全部或部分。用作多聚化配对物的HABP或其部分的实例在上文中描述，并且如SEQ ID NO:206-207、222-341、371-394、407-414、416-418或423-426中任一个所示。在一些实例中，至少一个多聚体配对物是包括HA结合结构域的HABP的全部或部分。例如，多聚化HABP多肽的实例为聚集蛋白聚糖、多能聚糖、神经聚糖、短小蛋白聚糖、磷酸蛋白聚糖、HAPLN1、HAPLN2、HAPLN3、HAPLN4、稳定素-1、稳定素-2、CAB61358、KIAA0527或TSG-6蛋白的HA结合结构域(例如连接结构域或连接模块)或其部分之间形成的多聚体。此外，用于形成HABP多聚体的嵌合HABP多肽可以包括连接至多聚化结构域的杂交HABP多肽。本文提供的多聚体的实例是通过TSG-6的连接模块(LM)或其足以结合HA的部分的多聚化产生的多聚体如二聚体。两个HABP多肽之间的多聚化可以是自发的，或者可以由于两个或更多个多肽的强迫连接而发生。在一实例中，多聚体可以通过不同HABP多肽或结构域或其足以结合HA的部分上的半胱氨酸残基之间形成的二硫键来连接。在另一实例中，多聚体可以包括通过共价或非共价相互作用连接至肽部分的HABP多肽或结构域或其足以结合HA的部分，所述肽部分融合至每个多肽。这类肽可以是肽接头(例如间隔物)，或者是具有促进多聚化的特性的肽。在另一的实例中，多聚体可以在两个多肽之间通过化学键形成，例如通过使用异双功能接头。
i.肽接头
肽接头可以用来制备HABP多肽多聚体，例如其中至少一个多聚化配对物包含HA结合结构域(例如，连接结构域或模块)的多聚体。在一实例中，肽接头可以融合至第一多肽的C-末端和第二多肽的N-末端。这个结构可以重复多次，从而至少1个，优选2、3、4个或更多个多肽通过在它们各自末端的肽接头互相连接。例如，多聚体多肽可以具有序列Z1-X-Z2，其中Z1和Z2各自为包括HA结合结构域的HABP的全部或部分序列，并且其中X为肽接头序列。在某些情况下，Z1和/或Z2是包括HA结合结构域的HABP 的全部。在其他情况下，Z1和/或Z2是包括HA结合结构域的HABP的部分。Z1和Z2相同或它们不同。在另一实例中，所述多肽具有Z1-X-Z2(-X-Z)n序列，其中“n”为任何整数，即一般为1或2。
通常，肽接头具有足够的长度以允许一个或两个HA结合结构域结合乙酰透明质酸底物，或者允许HA结合结构域之间的相互作用(例如C型HABP的G1HA结合结构域的两个Ig模块的相互作用)。肽接头的实例包括但不限于__Gly-Gly__、GGGGG(SEQ ID NO:342)、GGGGS或(GGGGS)n(SEQ ID NO:343)、SSSSG或(SSSSG)n(SEQ ID NO:344)、GKSSGSGSESKS(SEQ IDNO:345)、GGSTSGSGKSSEGKG(SEQ ID NO:346)、GSTSGSGKSSSEGSGSTKG(SEQ ID NO:347)、GSTSGSGKPGSGEGSTKG(SEQ ID NO:348)、EGKSSGSGSESKEF(SEQ ID NO:349)、或者AlaAlaProAla或(AlaAlaProAla)n(SEQ ID NO:350)，其中n为1-6，例如1、2、3或4。示例性接头包括：
(1)具有NcoI末端的Gly4Ser(SEQ ID NO:351)
CCATGGGCGG CGGCGGCTCT GCCATGG
(2)具有NcoI末端的(Gly4Ser)2(SEQ ID NO:352)
CCATGGGCGG CGGCGGCTCT GGCGGCGGCG GCTCTGCCAT GG
(3)具有NcoI末端的(Ser4Gly)4(SEQ ID NO:353)
CCATGGCCTC GTCGTCGTCG GGCTCGTCGT CGTCGGGCTCGTCGTCGTCG GGCTCGTCGTCGTCGGGCGC CATGG
(4)具有NcoI末端的(Ser4Gly)2(SEQ ID NO:354)
CCATGGCCTC GTCGTCGTCG GGCTCGTCGT CGTCGGGCGCCATGG
连接部分描述于例如Huston et al.(1988)PNAS85:5879-5883,Whitlow et al.(1993)Protein Engineering6:989-995，和Newton et al.,(1996)Biochemistry35:545-553。其他合适的肽接头包括美国专利第4,751,180号或第4,935,233号所述的任何肽接头，这些文献援引加入本文。可以利用任何合适的常规技术将编码期望的肽接头的多核苷酸以相同阅读框插入编码包括HA结合结构域的HABP的全部或部分的多核苷酸之间。在一实例中，融合多肽具有通过肽接头分开的2-4个HABP多肽，包括是包括HA结合 结构域的HABP多肽的全部或部分的HABP多肽。
ii.异双功能连接剂
HABP多肽连接至另一HABP多肽以产生异源多聚体融合多肽可以是直接或间接的。例如，两个或更多个HABP多肽的连接可以通过化学连接实现或者通过异双功能接头来促进，例如本领域已知或本文提供的任何异双功能接头。
用来形成氨基与硫醇基之间的共价键以及将硫醇基引入蛋白的许多异双功能交联剂是本领域技术人员已知的(参见，例如，the PIERCE CATALOG,ImmunoTechnologyCatalog & Handbook,1992-1993，其描述这类试剂的制备和用途，并且提供这类试剂的商业来源；还参见，例如，Cumber et al.(1992)Bioconjugate Chem.3:397-401；Thorpe etal.(1987)Cancer Res.47:5924-5931；Gordon et al.(1987)Proc.Natl.Acad Sci.84:308-312；Walden et al.(1986)J.Mol.Cell Immunol.2:191-197；Carlsson et al.(1978)Biochem.J.173:723-737；Mahan et al.(1987)Anal.Biochem.162:163-170；Wawrzynczaket al.(1992)Br.J.Cancer66:361-366；Fattom et al.(1992)Infection & Immun.60:584-589)。这些试剂可以用来形成包括HA结合结构域的HABP多肽的N-末端部分与包括HA结合结构域的另一HABP多肽的C-末端部分之间的共价键，或者这些部分中的每一个与接头之间的共价键。这些试剂包括但不限于：N-琥珀酰亚胺基-3-(2-吡啶二硫代)丙酸酯(SPDP；二硫键接头)；磺基琥珀酰亚胺基6-[3-(2-吡啶二硫代)丙酰胺基]己酸酯(磺基-LC-SPDP)；琥珀酰亚胺基氧基羰基-α-甲基苄基硫代硫酸酯(SMBT，受阻焦硫酸盐接头)；琥珀酰亚胺基6-[3-(2-吡啶二硫代)丙酰胺基]己酸酯(LC-SPDP)；磺基琥珀酰亚胺基4-(N-马来酰亚胺基甲基)环己烷-1-羧酸酯(磺基-SMCC)；琥珀酰亚胺基3-(2-吡啶二硫代)丁酸酯(SPDB；受阻二硫键接头)；磺基琥珀酰亚胺基2-(7-叠氮基-4-甲基香豆素-3-乙酰胺)乙基-1,3'-二硫代丙酸酯(SAED)；磺基-琥珀酰亚胺基7-叠氮基-4-甲基香豆素-3-乙酸酯(SAMCA)；磺基琥珀酰亚胺基-6-[α-甲基-α-(2-吡啶二硫代)甲苯甲酰胺基]-己酸酯(磺基-LC-SMPT)；1,4-二-[3'-(2'-吡啶二硫代)3-丙酰胺基]丁烷(DPDPB)；4-琥珀酰亚胺基氧基羰基-α-甲基-α-(2-吡啶硫代)甲苯(SMPT，受阻焦硫酸盐接头)； 磺基琥珀酰亚胺基-6-[α-甲基-α-(2-嘧啶基二-硫代)甲苯甲酰胺基]己酸酯(磺基-LC-SMPT)；间-马来酰亚胺基苯甲酰基-N-羟基-琥珀酰亚胺酯(MBS)；间-马来酰亚胺基苯甲酰基-N-羟基磺基-琥珀酰亚胺酯(磺基-MBS)；N-琥珀酰亚胺基(4-碘乙酰基)氨基苯甲酸酯(SIAB；硫代酸酯接头)；磺基琥珀酰亚胺基-(4-碘乙酰基)氨基苯甲酸酯(磺基-SIAB)；琥珀酰亚胺基-4-(对-马来酰亚胺基苯基)丁酸酯(SMPB)；磺基琥珀酰亚胺基-4-(对-马来酰亚胺基-苯基)丁酸酯(磺基-SMPB)；叠氮苯甲酰基酰肼(ABH)。例如，这些接头可以与肽接头组合使用，例如增加柔性或溶解性或者提供或消除空间位阻的肽接头。可以采用本领域技术人员已知的将多肽分子连接至另一分子的任何其他接头。一般特性是从而所得的分子结合HA。对于HABP试剂的体内诊断用途，一般接头必须对于给药至包括人在内的动物是生物相容的。
iii.多肽多聚化结构域
两个或更多个HABP多肽的相互作用可以通过将它们直接或间接连接至本身能够相互作用以形成稳定结构的任何部分或其他多肽来促进。例如，分别编码的HABP多肽链可以通过多聚化连接，其中所述多肽的多聚化由多聚化结构域介导。通常，所述多聚化结构域提供第一HABP多肽与第二HABP多肽之间稳定的蛋白-蛋白相互作用的形成。HABP多肽包括例如编码HABP的HA结合结构域(例如连接结构域或模块)的核酸与编码多聚化结构域的核酸的连接(直接或间接)。通常，至少一个多聚化配对物是编码直接或间接连接至多聚化结构域的包括HA结合结构域的HABP的全部或部分的核酸，因此形成嵌合分子。同源或异源多聚体多肽可以产生自不同HABP多肽的共表达。所述第一和第二HABP多肽可以相同或不同。
一般来说，多聚化结构域包括能够形成稳定的蛋白-蛋白相互作用的任何结构域。多聚化结构域可以通过免疫球蛋白序列(例如Fc结构域；参见例如，国际专利公开号WO93/10151和WO2005/063816US；美国公开第2006/0024298号；美国专利第5,457,035号)、亮氨酸拉链(例如来自核转换蛋白fos和jun或者原癌基因c-myc，或者来自总氮控制(GCN4))、疏水区、亲水区、或者在同源或异源多聚体的嵌合分子之间形成分子间二硫键的游离硫醇。此外，多聚化结构域可以包括与包含洞的氨基酸序列互补的包含 突起的氨基酸序列，例如美国专利第5,731,168号；国际专利公开号WO98/50431和WO2005/063816；Ridgway et al.(1996)Protein Engineering,9:617-621所述。可以将这样的多聚化区工程化，从而空间相互作用不仅促进稳定的相互作用，而且进一步促进从嵌合单体的混合物形成异源二聚体超过同源二聚体。一般来说，通过用较大的侧链(例如酪氨酸或色氨酸)从第一多肽的界面代替小氨基酸侧链来构建突起。任选地通过用较小的氨基酸侧链(例如，丙氨酸或苏氨酸)代替大氨基酸侧链在第二多肽的界面上产生与突起相同或相似大小的补偿腔。示例性多聚化结构域在下文中描述。
HABP多肽，例如本文提供的任何HABP多肽，包括HABP的任何HA结合结构域(例如，连接结构域或模块)，可以在任何地方连接，但是通常通过其N-或C-末端连接至多聚化结构域的N-或C-末端以形成嵌合多肽。连接可以是直接的，或者是通过接头间接的。而且，所述嵌合多肽可以是融合蛋白，或者可以通过化学连接形成，例如通过共价或非共价相互作用。例如，当制备包含多聚化结构域的嵌合多肽时，编码包括HA结合结构域的HABP的全部或部分的核酸可以可操作地连接至编码所述多聚化结构域序列的核酸，直接或间接或任选通过接头结构域。通常，所述构建体编码嵌合蛋白，其中HABP多肽的C-末端连接至多聚化结构域的N-末端。在某些情况下，构建体可以编码嵌合蛋白，其中HABP多肽的N-末端连接至多聚化结构域的N-或C-末端。
多肽多聚体包含通过将两个相同或不同的HABP多肽直接或间接连接至多聚化结构域产生的两个嵌合蛋白。在一些实例中，当多聚化结构域为多肽时，将编码HABP-多聚化结构域嵌合多肽的基因融合物插入适当的表达载体。所得的HABP-多聚化结构域嵌合蛋白可以在用重组表达载体转化的宿主细胞中表达，并且允许装配为多聚体，其中所述多聚化结构域相互作用以形成多价多肽。多聚化结构域化学连接至HABP多肽可以利用如上文所述的异双功能接头来实现。
所得嵌合多肽以及由其形成的多聚体可以通过任何合适的方法纯化，例如，通过在A蛋白或G蛋白柱上亲和色谱。当将编码不同HABP嵌合多肽的两个核酸分子转化入细胞时，同源二聚体和异源二聚体的形成会发生。可以调整表达条件，从而异源二聚体的形成优于同源二聚体的形成。
(1)免疫球蛋白结构域
多聚化结构域包括包含游离硫醇部分的多聚化结构域，所述游离硫醇部分能够与具有其他氨基酸序列的多聚化结构域反应以形成分子间二硫键。例如，多聚化结构域可以包括免疫球蛋白分子的部分，例如来自IgG1、IgG2、IgG3、IgG4、IgA、IgD、IgM或IgE。一般来说，这样的部分为免疫球蛋白恒定区(Fc)。已描述包含融合至抗体来源多肽的各种部分(包括Fc结构域)的多肽的融合蛋白的制备，参见例如，Ashkenazi et al.(1991)PNAS88:10535；Byrn et al.(1990)Nature,344:667；和Hollenbaugh and Aruffo,(1992)“Construction of Immunoglobulin Fusion Proteins,”in Current Protocols inImmunology,Ch.10,pp.10.19.1-10.19.11。
抗体结合特异性抗原，并且包含通过二硫键共价连接的两条相同的重链和两条相同的轻链。重链和轻链均包含结合抗原的可变区和恒定(C)区。在每条链中，一个结构域(V)具有取决于分子的抗体特异性的可变氨基酸序列。另一结构域(C)具有在相同类别的分子之间常见的相当恒定的序列。结构域以从氨基-末端的顺序计数。例如，IgG轻链由以VL-CL顺序从N-至C-末端连接的两个免疫球蛋白结构域组成，分别称为轻链可变结构域和轻链恒定结构域。IgG重链由以VH-CH1-CH2-CH3顺序从N-至C-末端连接的4个免疫球蛋白结构域组成，分别称为可变重链结构域，恒定重链结构域1、恒定重链结构域2和恒定重链结构域3。所得的抗体分子为4条链的分子，其中每条重链通过二硫键连接至轻链，并且两条重链通过二硫键互相连接。重链的连接是通过称为铰链区的重链的柔性区介导的。抗体分子的片段可以例如通过酶促切割产生。例如，当通过木瓜蛋白酶来蛋白酶切割时，重链恒定区的二聚体Fc结构域从两个Fab区(即包含可变区的部分)切下。
在人中，有基于它们的重链分类的5个抗体同种型，表示为δ、γ、μ和α和ε，分别产生抗体的IgD、IgG、IgM、IgA和IgE类别。IgA和IgG类别包含亚类IgA1、IgA2、IgG1、IgG2、IgG3和IgG4。免疫球蛋白重链之间的序列差异导致不同同种型的差别在于例如C结构域的数目、铰链区的存在以及链间二硫键的数目和位置。例如，IgM和IgE重链包含代替铰链区的额外的C结构域(C4)。IgG、IgD和IgA的Fc区通过它们的Cγ3、 Cδ3和Cα3结构域互相配对，而IgM和IgE的Fc区通过它们的Cμ4和Cε4结构域二聚化。IgM和IgA分别形成具有10个和4个抗原结合位点的多聚体结构。
本文提供的HABP免疫球蛋白嵌合多肽包括全长免疫球蛋白多肽。或者，所述免疫球蛋白多肽少于全长，即包含重链、轻链、Fab、Fab2、Fv或Fc。在一实例中，HABP免疫球蛋白嵌合多肽装配为单体或者异源或同源多聚体，特别是二聚体或四聚体。链或者改变结构的基本单元可以用来装配单体以及异源或同源多聚体。例如，可以将HABP多肽与免疫球蛋白分子的全部或部分融合，包括免疫球蛋白分子的CH、CL、VH或VL结构域的全部或部分(参见例如，美国专利第5,116,964号)。嵌合HABP多肽可以通过用适当核酸分子转化的哺乳动物细胞容易地产生和分泌。分泌形式包括那些形式，其中HABP多肽存在于重链二聚体中；轻链单体或二聚体中；以及重链和轻链异源四聚体中，其中HABP多肽融合至一条或多条轻链或重链，包括其中多达且包括全部4个可变区类似物被取代的异源四聚体。在一些实例中，可以将一个或一个以上核酸融合分子转化入宿主细胞以产生多聚体，其中多聚体的HABP部分相同或不同。在一些实例中，存在非HABP多肽轻-重链可变样结构域，从而产生异双功能抗体。在一些实例中，可以使嵌合多肽融合至缺少铰链二硫化物的免疫球蛋白分子的部分，其中两个HABP多肽部分的非共价或共价相互作用将分子联合为同源或异源二聚体。
(a)Fc结构域
通常，HABP嵌合蛋白的免疫球蛋白部分包括免疫球蛋白多肽的重链，最通常是重链的恒定结构域。人IgG亚型的重链恒定区的示例性序列如SEQ ID NO:355(IgG1)、SEQ IDNO:356(IgG2)、SEQ ID NO:357(IgG3)和SEQ ID NO:358(IgG4)所示。例如，对于SEQ ID NO:355所示的示例性重链恒定区，CH1结构域对应氨基酸1-98，铰链区对应氨基酸99-110，CH2结构域对应氨基酸111-223，而CH3结构域对应氨基酸224-330。
在一实例中，免疫球蛋白多肽嵌合蛋白可以包括免疫球蛋白多肽的Fc区。通常，这样的融合物至少保留免疫球蛋白重链恒定区的功能活性铰链、 CH2和CH3结构域。例如，IgG1的全长Fc序列包括SEQ ID NO:355所示序列的氨基酸99-330。hIgG1的示例性Fc序列如SEQID NO:359所示，并且包含对应于SEQ ID NO:355的氨基酸100-110的几乎全部铰链序列，以及如SEQ ID NO:355所示的CH2和CH3结构域的完整序列。另一示例性Fc多肽为SEQ ID NO:212所示的Fc多肽。另一示例性Fc多肽如PCT申请WO93/10151所示，并且是从N-末端铰链区延伸至人IgG1抗体Fc区的天然C-末端的单链多肽(SEQ ID NO:359)。进行连接的精确位点不是关键：具体位点是公知的，并且可以选择以便优化HABP多肽的生物学活性、分泌或结合特征。例如，其他示例性Fc多肽序列开始于SEQ ID NO:355所示序列的氨基酸C109或P113(参见例如，美国公开第2006/0024298号)。
除了hIgG1Fc，其他Fc区也可以包括在本文提供的HABP嵌合多肽内。例如，当最小化Fc/FcγR相互作用所介导的效应子功能时，可以考虑与难以募集补体或效应细胞的IgG同种型，例如IgG2或IgG4的Fc融合。此外，Fc融合物可以包含基本上由属于任何抗体类别的免疫球蛋白基因编码的免疫球蛋白序列，所述抗体类别包括但不限于抗体的IgG(包括人亚类IgG1、IgG2、IgG3或IgG4)、IgA(包括人亚类IgA1和IgA2)、IgD、IgE和IgM类别。此外，接头可以用来将Fc共价连接至另一多肽以产生Fc嵌合体。
本文还考虑修饰的Fc结构域用于与HABP多肽的嵌合体。在一些实例中，修饰Fc区，从而其表现出改变的结合FcR，以便导致与野生型免疫球蛋白重链的Fc区的效应子功能相比改变(更多或更少)的效应子功能。因此，修饰的Fc结构域可以具有改变的对Fc受体的亲和力，包括但不限于增加的或低的或无亲和力。例如，不同的IgG亚类具有不同的对FcγR的亲和力，IgG1和IgG3通常基本上比IgG2和IgG4更好地结合受体。此外，不同的FcγR介导不同的效应子功能。FcγR1、FcγRIIa/c和FcγRIIIa是免疫复合物触发活化的正调节物，其特征在于具有细胞内结构域，所述细胞内结构域具有基于免疫受体酪氨酸的活化基序(ITAM)。然而，FcγRIIb具有基于免疫受体酪氨酸的抑制基序(ITIM)，并且因此是抑制的。在某些情况下，可以修饰本文提供的HABP多肽Fc嵌合蛋白以增加结合补体蛋白C1q。此外，可以修饰Fc以改变其结合FcRn，从而改善HABP-Fc嵌合多肽的药物动力学。因此，改变Fc区对受体的亲和力可以调节Fc结构域相联的效应子功 能和/或药物动力学特性。修饰的Fc结构域是本领域技术人员已知的，并且描述于文献，对于示例性修饰，参见例如美国专利第5,457,035号；美国专利公开第US2006/0024298号；以及国际专利公开第WO2005/063816号。
通常，多肽多聚体是通过将两个相同或不同的HABP多肽直接或间接连接至Fc多肽所产生的两个嵌合蛋白的二聚体。在一些实例中，将编码HABP-Fc嵌合蛋白的基因融合物插入适当的表达载体。所得的HABP-Fc嵌合蛋白可以在用重组表达载体转化的宿主细胞中表达，并且允许很像抗体分子样装配，其中Fc部分之间形成链间二硫键以产生二价HABP多肽。
所得的包含Fc部分的嵌合多肽以及由其形成的多聚体可以在A蛋白或G蛋白柱上通过亲和色谱容易地纯化。对于异源二聚体的产生，纯化的额外步骤可以是必需的。例如，当将编码不同HABP嵌合多肽的两个核酸转化入细胞时，异源二聚体的形成必须生化实现，因为携带Fc-结构域的HABP嵌合分子还会表达为二硫键连接的同源二聚体。因此，可以在有利于破坏链间二硫键但不影响链内二硫键的条件下减少同源二聚体。通常，将具有不同HA结合结构域部分的嵌合单体以等摩尔量混合并氧化以形成同源和异源二聚体的混合物。通过色谱技术分离这种混合物的组分。或者，可以通过遗传工程化和表达HABP融合分子，其包含HABP多肽，随后为hIgG的Fc-结构域，随后为c-jun或c-fos亮氨酸拉链，来倾向于形成这种类型的异源二聚体(见下文)。因为亮氨酸拉链主要形成异源二聚体，当需要时它们可以用来驱动异源二聚体的形成。
还可以将包含Fc区的HABP嵌合多肽工程化以包括具有金属螯合物或其他表位的标签。标记的结构域可以用于通过金属螯合色谱和/或通过抗体快速纯化，允许在生物测定中蛋白印迹、免疫沉淀或活性消耗/阻断检测。
示例性HABP-Fc嵌合多肽包括TSG-6连接模块(TSG-6-LM)和Fc的融合蛋白。示例性TSG-6-LM-Fc如SEQ ID NO:212所示，并且由SEQ ID NO:211所示的核苷酸序列编码。此外，HABP-Fc分子，包括例如示例性TSG-6-Fc分子，可以任选地包含表达和分泌的表位标签或信号。例如，如SEQ ID NO:212所示的示例性TSG-6-LM-Fc嵌合多肽包含人免疫球蛋白轻链κ前导信号肽序列(SEQ ID NO:210)、人IgG1重链的Fc片段(SEQ ID NO:204)和人TSG-6连接模块(SEQ ID NO:207)。编码TSG-6-LM-Fc嵌合多 肽的cDNA序列如SEQ ID NO:211所示。编码人IgG1重链和人TSG-6连接模块区的DNA与6bp AgeI限制性酶切割位点和编码4个额外的氨基酸(DKTH；SEQ ID NO:209)的12bp序列，GACAAAACTCAC(SEQ ID NO:208)相连。
(2)亮氨酸拉链
制备用于本文提供的方法的HABP多肽多聚体的另一方法包括使用亮氨酸拉链结构域。亮氨酸拉链是促进其中发现它们的蛋白的多聚化的肽。通常，亮氨酸拉链是用来指在几种蛋白中作为保守结构域存在的包含4-5个亮氨酸残基的重复七肽基序的术语。亮氨酸拉链折叠为短的平行卷曲螺旋，并且据信负责它们形成结构域的蛋白的寡聚化。通过亮氨酸拉链结构域形成的二聚体通过命名为(abcdefg)n的七肽重复来稳定(参见例如，McLachlan and Stewart(1978)J.Mol.Biol.98:293)，其中残基a和d一般为疏水残基，d为亮氨酸，其在螺旋的面上对齐。带相反电荷的残基通常存在于位置g和e。因此，在从两个螺旋亮氨酸拉链结构域形成的平行卷曲螺旋中，由第一螺旋的疏水侧链形成的“突起”包装入第二螺旋的侧链之间形成的“洞”。
用作本文的多聚化结构域的示例性亮氨酸拉链源自表现出亮氨酸拉链结构域的两个核转换蛋白fos和jun中的任一个，或者小鼠原癌基因c-myc的产物。亮氨酸拉链结构域对于这些蛋白中的生物学活性(DNA结合)是必需的。核癌基因fos和jun的产物包含优选形成异源二聚体的亮氨酸拉链结构域(O’Shea et al.(1989)Science,245:646；Turner andTijian(1989)Science,243:1689)。例如，已显示人转录因子c-jun和c-fos的亮氨酸拉链形成具有1:1化学计量比的稳定异源二聚体(参见例如，Busch and Sassone-Corsi(1990)Trends Genetics,6:36-40；Gentz et al.,(1989)Science,243:1695-1699)。虽然已显示还形成jun-jun同源二聚体，但是它们比jun-fos异源二聚体不稳定约1000倍。
因此，通常利用jun-fos组合产生本文提供的HABP多肽多聚体。一般来说，通过遗传工程化融合基因将c-jun或c-fos的亮氨酸拉链结构域符合读框地融合在多肽的HABP的C-末端。c-jun和c-fos亮氨酸拉链的示例性 氨基酸序列分别如SEQ ID NO:362和363所示。在某些情况下，可以修饰亮氨酸拉链序列，例如通过添加半胱氨酸残基以允许形成二硫键，或者在C-末端添加酪氨酸残基以促进肽浓度的测量。所编码的修饰的c-jun和c-fos亮氨酸拉链的氨基酸的这类示例性序列分别如SEQ ID NO:362和363所示。此外，HABP多肽与亮氨酸拉链的连接可以是直接的，或者可以采用柔性接头结构域，例如IgG的铰链区，或者各种长度和组合的小氨基酸如甘氨酸、丝氨酸、苏氨酸或丙氨酸的其他多肽接头。在某些情况下，可以通过与编码蛋白酶切割位点如凝血酶切割位点的序列融合来实现从编码的多肽的C-末端分离亮氨酸拉链。此外，可以例如通过6XHis标签标记嵌合蛋白以允许通过金属螯合色谱和/或通过抗体可用的表位如myc标签快速纯化，允许在蛋白印迹、免疫沉淀或活性消耗/阻断生物测定上检测。
用作多聚化结构域的另一示例性亮氨酸拉链结构域源自功能为参与酿酒酵母(S.cerevisiae)中总氮控制(GCN4)代谢的基因家族的转录激活物的核蛋白。所述蛋白能够二聚化并结合包含GCN4的识别序列的启动子序列，从而在氮缺乏时激活转录。能够形成二聚体复合物的GCN4亮氨酸拉链的示例性序列如SEQ ID NO:364所示。已发现代表GCN4亮氨酸拉链结构域的合成肽的a和d残基中的氨基酸取代(即如SEQ ID NO:364所示的序列中的氨基酸取代)改变亮氨酸拉链结构域的寡聚化特性。例如，当将位置a处的所有残基改变为异亮氨酸时，亮氨酸拉链仍形成平行的二聚体。除了这个改变，当将位置d处的所有亮氨酸残基改变为异亮氨酸时，所得的肽在溶液中自发地形成三聚体平行卷曲螺旋。这样的能够形成三聚体的GCN4亮氨酸拉链结构域的示例性序列如SEQ ID NO:365所示。用异亮氨酸取代位置d处的所有氨基酸且用亮氨酸取代位置a处的所有氨基酸导致四聚化的肽。这样的能够形成四聚体的GCN4的亮氨酸拉链结构域的示例性序列如SEQ ID NO:366所示。包含这些取代的肽仍称作亮氨酸拉链结构域，因为据信寡聚体形成的机制与传统的亮氨酸拉链结构域如上文所述和SEQ ID NO:364所示的GCN4相同。
(3)亚基之间的蛋白-蛋白相互作用
用于修饰提供用于本文的方法的HABP的多聚化结构域的另一类型的 实例是其中通过不同亚基多肽之间的蛋白-蛋白相互作用促进多聚化的多聚化结构域。这样的多聚化结构域的实例源自cAMP依赖性蛋白激酶(PKA)与其A激酶锚蛋白(AKAP)的锚定结构域(AD)的机制。因此，可以通过将编码HABP多肽如HABP多肽的HA结合结构域的核酸与编码PKA的R亚基序列(即SEQ ID NO:367)的核酸(直接或间接)连接来产生异源多聚体HABP多肽。由于R亚基引起的二聚体的自发形成，这导致同源二聚体分子。同时，可以通过将编码另一HABP多肽的核酸连接至编码AKAP的AD序列(即SEQ ID NO:368)的核酸序列来产生另一HABP多肽融合物。当两个组分共表达时，例如在宿主细胞中共转染HABP嵌合组分时，二聚体R亚基提供结合AD序列的停靠位点，导致异源多聚体分子。这个结合事件可以通过共价连接如二硫键进一步稳定。在一些实例中，可以在编码HABP多肽和多聚化结构域的核酸之间融合柔性接头残基。在另一实例中，编码HABP多肽的核酸可以融合至编码包含半胱氨酸残基的R亚基的核酸，所述半胱氨酸残基邻近R亚基的氨基-末端掺入以促进共价连接(参见例如，SEQ IDNO:369)。相似地，编码配对物HABP多肽的核酸可以融合至编码也包含半胱氨酸残基的AD亚基的核酸，所述半胱氨酸残基掺入至AD的氨基-和羧基-末端(参见例如，SEQ ID NO:370)。
iv.其他多聚化结构域
可以用来多聚化提供用于本文的方法的HABP的其他多聚化结构域是本领域技术人员已知的，并且是促进分别产生并表达为HABP融合物的两个或更多个多肽的蛋白-蛋白相互作用的任何多聚化结构域。可以用来提供两个嵌合多肽之间的蛋白-蛋白相互作用的其他多聚化结构域的实例包括但不限于barnase-barstar模块(参见例如，Deyev et al.,(2003)Nat.Biotechnol.21:1486-1492)；使用特定蛋白结构域(参见例如，Terskikh etal.,(1997)Proc Natl Acad Sci USA94:1663-1668和Muller et al.,(1998)FEBSLett.422:259-264)；使用特定肽基序(参见例如，de Kruif et al.,(1996)J.Biol.Chem.271:7630-7634和Muller et al.,(1998)FEBS Lett.432:45-49)；以及使用二硫键以增加稳定性(de Kruif et al.,(1996)J.Biol.Chem.271:7630-7634和Schmiedlet al.,(2000)Protein Eng.13:725-734)。
b.提高HA结合的突变
在另一实例中，本文提供例如通过氨基酸置换而进行修饰的HABP用于本文的方法，以便表现出与其他GAG相比增加的对乙酰透明质酸的特异性。例如，本文提供突变的TSG-6-LM，其在氨基酸残基20、34、41、54、56、72和/或84处，特别是氨基酸残基20、34、41和/或54处(对应于SEQ ID NO:360所示的氨基酸残基)包含氨基酸置换。置换氨基酸可以是任何其他氨基酸残基，并且一般为非碱性氨基酸残基。例如，氨基酸置换可以置换为Asp(D)、Glu(E)、Ser(S)、Thr(T)、Asn(N)、Gln(Q)、Ala(A)、Val(V)、Ile(I)、Leu(L)、Met(M)、Phe(F)、Tyr(Y)或Trp(W)。氨基酸置换或多个置换赋予减少的对肝素的结合。与不含氨基酸置换的TSG-6-LM对肝素的结合相比，结合可以减少至少1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。用作本文提供的方法中的试剂的TSG-6-LM突变体的实例为K20A/K34A/K41A。因此，例如，对肝素的结合减少，从而对乙酰透明质酸的特异性增加。突变的TSG-6-LM可以直接或间接缀合至多聚化结构域以产生多聚体。例如，用于本文的方法的试剂的实例为TSG-6-LM(K20A/K34A/K41A)-Fc。
c.修饰HA结合蛋白用于检测
为了用于本文提供的诊断方法，可以修饰HA结合蛋白以包含可检测的蛋白或部分以促进检测。
i.缀合至可检测的蛋白或部分
可以通过缀合至可检测的部分来修饰用于本文提供的诊断方法的HA结合蛋白，所述可检测的部分包括但不限于肽标签、放射性标记、荧光分子、化学发光分子、生物发光分子、Fc结构域、生物素、催化可检测的反应或催化形成可检测的产物的酶以及结合可检测的化合物的蛋白。可检测的部分是本领域技术人员已知的，包括蛋白和化合物，或者促进检测的部分。可检测的部分可以用来促进HABP的检测和/或纯化。
在一实例中，通过缀合至可检测的蛋白或诱导可检测的信号的蛋白来修饰HA结合蛋白。可检测的蛋白或诱导可检测的信号的蛋白可以选自萤光素酶、荧光蛋白、生物发光蛋白、结合和/或转运造影剂的受体或转运蛋白、发色团、可以检测的化合物或配体。例如，可检测的蛋白或诱导可检测的信号的蛋白为绿色荧光蛋白(GFP)或红色荧光蛋白(RFP)。
可检测的标记可以用于本文提供的任何诊断方法。示例性可检测的标记包括例如化学发光部分、生物发光部分、荧光部分、放射性核素和金属。检测标记的方法是本领域公知的。这样的标记可以例如通过肉眼观察、通过荧光光谱学、通过反射测量、通过流式细胞术、通过X-射线、通过各种磁共振方法如磁共振成像(MRI)和磁共振波谱(MRS)来检测。检测的方法还包括各种断层扫描方法中的任一种，包括计算机断层扫描(CT)、计算机轴向断层扫描(CAT)、电子束计算机断层扫描(EBCT)、高解析度计算机断层扫描(HRCT)、内摆线体层摄影、正电子发射断层扫描(PET)、单光子发射计算机断层扫描(SPECT)、螺旋计算机断层扫描和超声断层扫描。
这类蛋白的实例是可以催化可检测的反应或催化形成可检测的产物的酶，例如萤光素酶，如叩头虫萤光素酶、海肾(Renilla)萤光素酶、萤火虫萤光素酶或β-葡糖醛酸酶(GusA)。这类蛋白的实例还有发出可检测的信号的蛋白，包括荧光蛋白，例如绿色荧光蛋白(GFP)或红色荧光蛋白(RFP)。编码可以发出可检测的信号或可以催化可检测的反应的蛋白如发光或荧光蛋白的各种DNA序列是已知的，并且可以用于本文提供的方法。编码发光蛋白的示例性基因包括例如来自哈氏弧菌(Vibrio harveyi)的细菌萤光素酶(Belas et al.,(1982)Science218:791-793)、来自费氏弧菌的细菌萤光素酶(Foran and Brown,(1988)Nucleic acids Res.16:777)、萤火虫萤光素酶(de Wet et al.,(1987)Mol.Cell.Biol.7:725-737)、来自维多利亚多管发光水母的水母发光蛋白(Aequorea victoria)(Prasher etal.,(1987)Biochem.26:1326-1332)、来自海肾(Renilla renformis)的海肾萤光素酶(Lorenz et al,(1991)Proc Natl Acad Sci USA88:4438-4442)以及来自维多利亚多管发光水母的绿色荧光蛋白(Prasher et al.,(1987)Gene111:229-233)的基因。可以将细菌萤光素酶的luxA和luxB基因融合以产生融合基因(Fab2)，可以将其表达以产生完整功能的萤光素酶(Escher et al.,(1989)PNAS86:6528-6532)。
可以缀合至用于本文提供的诊断方法的HA结合蛋白的示例性可检测的蛋白还包括可以结合造影剂、发色团的蛋白，或者可以检测的化合物或配体如转铁蛋白受体或铁蛋白；以及报道蛋白，例如大肠杆菌(E.coli)β-半乳糖苷酶、β-葡糖醛酸酶、黄嘌呤-鸟嘌呤磷酸核糖转移酶(gpt)和碱性磷酸酶。可检测的蛋白的实例还有可以特异性结合可检测的化合物的蛋白，包括但不限于受体、金属结合蛋白(例如，铁载体、铁蛋白、转铁蛋白受体)、配体结合蛋白和抗体。
还可以将HABP缀合至蛋白或肽标签。在一实例中，将HA结合蛋白缀合至Fc结构域。蛋白和肽标签还包括但不限于HexaHis标签(SEQ ID NO:54)、血凝素标签(SEQ ID NO:420)、FLAG标签(SEQ ID NO:55)、c-myc标签(SEQ ID NO:419)、VSV-G标签(SEQ ID NO:421)、HSV标签(SEQ ID NO:422)和V5标签(SEQ ID NO:415)、几丁质结合蛋白(CBP)、麦芽糖结合蛋白(MBP)以及谷胱甘肽s-转移酶(GST)。
可以通过重组方法或通过化学方法将可检测的标记偶联或缀合至HABP。例如，可以通过将蛋白直接或间接连接至接头如肽接头或化学接头来实现缀合。接头可以是多肽序列，例如约5-200个氨基酸的聚甘氨酸序列。可以将脯氨酸残基掺入多肽接头以防止接头形成大量的二级结构元件，即α-螺旋/β-折叠。柔性接头的实例是包括具有中间脯氨酸的甘氨酸链的多肽。在另一实例中，化学接头用来连接合成或重组产生的结合和随后的标记结构域。这类柔性接头是本领域技术人员已知的。例如，聚(乙二醇)接头可获得自ShearwaterPolymers,Inc.Huntsville,Ala。这些接头任选地具有酰胺键、巯基键或杂功能键。
4.选择HA结合蛋白用于诊断用途
适合用作诊断剂的HA结合蛋白可以基于一种或多种期望特性或活性来选择，包括但不限于对HA的特异性或亲和力、溶解性、肽稳定性、同质性、容易表达和纯化、表达的肽中最小的批次变化以及HA结合和检测中的低样品可变性。在一些实例中，考虑单一多肽诊断剂优于具有多种多肽组分的诊断剂。例如，在完整连接蛋白不存在下结合HA的连接模块。本文提供的HABP结合乙酰透明质酸的能力可以通过本领域公知的方法来 评价，所述方法包括但不限于基于ELISA的测定，与HA、肝素和其他糖胺聚糖如硫酸软骨素A或C、硫酸乙酰肝素或硫酸皮肤素的竞争结合测定。本文在D节和实施例中提供评价HA结合活性的示例性测定。
D.测定和分类
本文提供的方法是基于测定样品或多个样品如组织样品或体液样品中乙酰透明质酸(HA)的表达或水平。本文的方法是基于利用乙酰透明质酸结合蛋白同伴诊断剂(HABP，例如TSG-6-LM，其多聚体或变体)的结合方法用于评估、评价、确定、定量和/或特异性地检测样品中的乙酰透明质酸表达或水平。测定可以在体外或体内进行。通过与对照或参考样品比较或者基于预定水平分类，这类值可以用于乙酰透明质酸相关疾病或疾病状况的诊断或预后，预测患有乙酰透明质酸相关疾病或疾病状况的对象对乙酰透明质酸降解酶疗法的反应性，和/或监测或预测已用乙酰透明质酸降解酶疗法治疗的患有乙酰透明质酸相关疾病或疾病状况的对象的治疗的效力。例如，如本文所述，据发现HA水平和程度与对用乙酰透明质酸降解酶如透明质酸酶或修饰的透明质酸酶(例如聚乙二醇化的透明质酸酶如PEGPH20)治疗的反应性特异性地相关。
在任何上述实例中，所述乙酰透明质酸相关疾病或疾病状况是其中作为疾病或疾病状况的原因、结果或观察到乙酰透明质酸水平升高的疾病和疾病状况。示例性乙酰透明质酸相关疾病或疾病状况包括但不限于与高组织间隙液压相关的疾病或疾病状况，癌症且特别是乙酰透明质酸丰富的癌症，水肿，椎间盘压力，炎性疾病以及与乙酰透明质酸相关的其他疾病。在某些情况下，乙酰透明质酸相关疾病和疾病状况与升高的组织间隙液压、减少的血管容积和/或组织如肿瘤中增加的水含量有关。具体地，乙酰透明质酸相关疾病和疾病状况包括但不限于乙酰透明质酸丰富的癌症，例如肿瘤，包括实体瘤如晚期癌症、转移癌、未分化癌、卵巢癌、原位癌(ISC)、鳞状细胞癌(SCC)、前列腺癌、胰腺癌、非小细胞肺癌、乳腺癌、结肠癌和其他癌症。
在一实例中，基于乙酰透明质酸的水平或表达，可以选择患者或对象用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)进行治疗。例如，可以使来 自对象的样品与乙酰透明质酸结合蛋白(HABP)同伴诊断剂如TSG-6-LM、其多聚体或变体接触，并且可以检测HABP对样品的结合以确定样品中乙酰透明质酸的量。基于如本文所述的预定的选择或分类标准，可以诊断患者患有乙酰透明质酸相关疾病或疾病状况，因此选择疾病或疾病状况的治疗。而且，基于如本文所述的预定的选择或分类标准，本文的方法可以用于对象的预后。根据疾病或疾病状况的进程，可以相应地优化和调整剂量、治疗方案和/或治疗剂(例如乙酰透明质酸降解酶)的剂量给药方案。在本文的具体实例中，基于如本文所得的预定的选择或分类标准，可以选择患者或对象进行治疗，预测其对用抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如透明质酸酶或修饰的透明质酸酶(例如聚乙二醇化的透明质酸酶如PEGPH20)治疗有反应。因此，所述方法可以用来预测通过抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗的效力。
在本文的方法的实例中，可以通过在治疗过程中监测乙酰透明质酸的表达或水平来确定通过抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗的效力。因此，所述方法是监测疾病状态和/或解决的治疗后方法，其信息可以用来根据个性化的状态信息改变对象的治疗过程。例如，可以使来自对象的样品与乙酰透明质酸结合蛋白(HABP)同伴诊断剂如TSG-6-LM、其多聚体或变体接触，并且可以检测HABP对样品的结合以确定样品中乙酰透明质酸的量。可以将样品中乙酰透明质酸的表达或水平与参考或对照样品比较以评价乙酰透明质酸水平或表达的差异。例如，与健康或正常对象相比，患病对象中升高或积累的乙酰透明质酸水平是乙酰透明质酸相关疾病或疾病状况(例如肿瘤或癌症)的指示，并且乙酰透明质酸表达或水平的程度与疾病侵袭性相关。在这类方法中，所述对照或参考样品是来自健康对象的样品，是来自用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗之前的对象的基线样品(治疗前参考)，或者是来自抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的最后剂量之前的对象的样品。例如，为了监测患者反应，可以在治疗开始时进行测定以建立样品(例如组织或体液)中乙酰透明质酸的基线(或预定)水平。然后利用相同的测定采样相同的样品(例如组织或体液)，并且将乙酰透明质酸的水平与基线或预定水平进行比较。
1.测量乙酰透明质酸的测定
利用如本文所述的HABP同伴诊断剂如TSG-6-LM、其多聚体(例如TSG-6LM-Fc)或变体评价、定量、确定和/或检测样品中的乙酰透明质酸在本领域技术人员的水平之内。测定包括体外或体内测定。可以用来评估、评价、确定、定量和/或特异性地检测样品中的乙酰透明质酸表达或水平的示例性结合测定包括但不限于固相结合测定(例如酶联免疫吸附测定(ELISA))、放射免疫测定(RIA)、免疫放射测定、荧光测定、化学发光测定、生物发光测定、蛋白印迹以及组织化学方法如免疫组织化学(IHC)或利用非抗体结合剂的假免疫组织化学。在固相结合测定方法如ELISA方法中，例如，测定可以为夹心形式或竞争性抑制形式。在其他实例中，可以使用体内成像方法。
a.组织化学和免疫组织化学方法
评价乙酰透明质酸积累的方法是基于HABP同伴诊断剂结合样品如组织或细胞样品中的HA的能力，从而结合的HABP同伴诊断剂的量与所述样品中HA的量相关。本文提供的任何HABP同伴诊断剂可以用来检测HA，利用本领域技术人员已知的组织染色方法，包括但不限于细胞化学或组织化学方法，例如免疫组织化学(IHC)或利用非抗体结合剂的组织化学(例如假免疫组织化学)。这类组织化学方法允许定量或半定量检测结合样品如肿瘤组织样品中的HA的HABP的量。在这类方法中，可以使组织样品与本文提供的HABP试剂在允许结合组织或细胞相关HA的条件下接触，特别是可检测地标记或能够检测的HABP试剂。
用于本文提供的方法的通过组织化学确定的样品可以是分析其HA水平的任何生物学样品，例如组织或细胞样品。例如，组织样品可以为实体组织，包括新鲜、冷冻和/或保存的器官或组织样品或活组织检查或抽吸物，或者细胞。在一些实例中，组织样品是获得自实体瘤的组织或细胞，例如原发性和转移性肿瘤，包括但不限于乳腺、结肠、直肠、肺、胃、卵巢、宫颈、子宫、睾丸、膀胱、前列腺、甲状腺和肺癌肿瘤。在具体实例中，样品是来自癌症的组织样品，所述癌症为晚期癌症、转移癌、未分化癌、卵巢癌、原位癌(ISC)、鳞状细胞癌(SCC)、前列腺癌、胰腺癌、非小细胞肺癌、乳腺癌、结肠癌。在其他实例中，组织样品包含来自原代或培养细 胞或细胞系的细胞。细胞可以具有各种分化状态，并且可以是正常的、癌前的或癌性的，可以是新鲜组织、分散的细胞、包括干细胞在内的未成熟的细胞在、中间成熟的细胞以及完全成熟的细胞。通常，选择用于本文提供的方法的细胞为癌细胞。
当肿瘤为实体瘤时，分离肿瘤细胞通常通过手术活组织检查来完成。可以用来从对象收获肿瘤细胞的活组织检查技术包括但不限于细针活组织检查、CT指导的细针活组织检查、穿刺活组织检查、内窥镜活组织检查、支气管镜活组织检查、支气管灌洗、切取活组织检查、切除活组织检查、钻取活组织检查、刮削活组织检查、皮肤活组织检查、骨髓活组织检查以及电圈切除术(LEEP)。通常，获得非坏死的无菌的活组织检查或样本，其大于100mg，但是其可以更小，例如少于100mg、50mg或更少、10mg或更少或者5mg或更少；或者更大，例如多于100mg、200mg或更多、或者500mg或更多、1gm或更多、2gm或更多、3gm或更多、4gm或更多或者5gm。提取用于测定的样品大小可以取决于许多因素，包括但不限于待进行的测定数目、组织样品的健康、癌症类型以及对象的状况。将肿瘤组织置于无菌容器如无菌管或培养板中，并且可以任选地浸没在适当的培养基中。
通常通过福尔马林(甲醛)或戊二醛，例如，或者通过醇浸没来固定活组织检查之后获得自患者的组织。对于组织化学方法，可以利用已知的技术加工肿瘤样品，例如脱水和将肿瘤组织包埋在石蜡或本领域技术人员已知的其他固体支持物中(参见Plenat et al.,(2001)Ann Pathol January21(1):29-47)，将组织切成适合染色的切片，以及根据所选的组织化学染色方法加工切片用于染色，包括例如通过有机溶剂去除包埋的固体支持物和保存组织的复水。因此，用于本文的方法的样品可以包含组织或细胞样品中天然不存在的化合物，包括例如防腐剂、抗凝剂、缓冲剂、固定剂、营养物和抗生素。
在选择对象用乙酰透明质酸降解酶进行治疗的示例性方法中，收获肿瘤组织一般在用乙酰透明质酸降解酶治疗对象之前进行。在监测用乙酰透明质酸降解酶的肿瘤疗法的示例性方法中，从对象收获肿瘤组织可以在对象接受用乙酰透明质酸降解酶一次或多次治疗之前、期间或之后进行。
用于本文提供的方法的测定是其中利用组织化学或免疫组织化学检测样品中存在的HA的测定。组织化学(HC)是基于酶促反应利用结合配对物如抗体(例如单克隆或多克隆抗体)或其他结合配对物检测细胞或特异性蛋白如组织抗原或生物标记如HA的染色方法。例如，用于本文的方法的组织化学测定包括其中HABP用作结合配对物检测与细胞或组织相关的HA的组织化学测定。通常，组织化学方案包括检测系统，其使得标记的存在对人眼或自动化扫描系统可见，用于定性或定量分析。在直接HC测定中，由于使用标记的试剂，在结合配对物(例如一抗)结合组织或生物标记时直接确定结合。在间接HC测定中，二抗或第二结合配对物对于检测第一结合配对物的结合是必需的，因为第一结合配对物未标记。
在这类方法中，一般利用常见的组织化学技术将玻片固定的组织样品用标记的结合试剂(例如标记的HABP)染色。因此，在本文提供的示例性HC方法中，修饰HABP同伴诊断剂以包含能够检测的部分(如上文3C节所述)。在一些实例中，将HABP同伴诊断剂缀合至通过标记的结合配对物或抗体检测的小分子如生物素。在一些实例中，IHC方法是基于用HABP蛋白染色，通过用辣根过氧化物酶酶促染色检测所述HABP蛋白。例如，可以将HABP生物素化并用缀合至可检测的蛋白的抗生物素蛋白或链霉抗生物素蛋白如链霉抗生物素蛋白-辣根过氧化物酶检测(参见下文实施例6)。在其他实例中，可以将HABP同伴诊断剂缀合至允许直接检测的可检测的蛋白，例如缀合至荧光蛋白、生物发光蛋白或酶的HABP同伴诊断剂。本领域已知各种酶促染色方法用于检测所关注的蛋白。例如，可以利用不同的酶如过氧化物酶、碱性磷酸酶或者不同的色素原如DAB、AEC或固红使酶促相互作用可见。在其他实例中，将HABP同伴诊断剂缀合至可以通过标记的结合配对物或抗体检测的肽或蛋白。
在其他实例中，通过HC方法利用本文提供的HABP同伴诊断剂检测HA，其中通过标记的第二试剂检测HABP同伴诊断剂，例如识别HABP、HABP连接结构域或其HA结合片段的一个或多个表位的标记的抗体。在其他实例中，利用抗HABP抗体检测HABP同伴诊断剂。为了检测HABP，可以使用任何抗HABP抗体，只要其结合用来检测HA的HABP、HABP连接结构域或其HA结合片段。例如，为了检测TSG-6或TSG-6-LM，可 以使用抗TSG-6连接模块单克隆抗体，例如命名为A38和Q75的抗体(参见，Lesley et al.(2002)J Biol Chem277:26600-26608)。可以标记抗HABP抗体用于检测，或者可以用结合一抗的二抗检测。选择适当的抗HABP抗体在本领域技术人员的水平之内。
利用查看可检测的信号并获取图像如染色的数字图像的系统将所得的染色的样本各自成像。图像获取的方法是本领域技术人员公知的。例如，一旦样品已染色，任何光学或非光学成像装置可以用来检测染色或生物标记，例如直立或倒置光学显微镜、扫描共聚焦显微镜、照相机、扫描或隧道电子显微镜、扫描探针显微镜以及红外成像探测器。在一些实例中，可以数字捕获图像。然后所得的图像可以用于定量或半定量确定样品中HA的量。本领域可获得适合用于免疫组织化学的各种自动化样品加工、扫描和分析系统。这类系统可以包括自动化染色和显微镜扫描、计算机图像分析、连续切片比较(以控制样品的方向和大小的变化)、数字报告生成以及样品(例如放置组织切片的玻片)的存档和追踪。细胞成像系统可商购，其组合常规的光学显微镜与数字图像加工系统以对细胞和组织(包括免疫染色的样品)进行定量分析。参见，例如，CAS-200系统(Becton,Dickinson&Co.)。具体地，检测可以手动进行，或者通过包括计算机处理器和软件的图像加工技术进行。利用这类软件，例如，利用本领域技术人员已知的方法，基于包括例如染色质量或染色强度在内的因素，可以配置、校准、标准化和/或验证图像(参见例如公开的美国专利申请第US20100136549号)。
图像可以基于样品的染色强度定量或半定量分析和评分。定量或半定量组织化学指扫描和评分已进行组织化学的样品以鉴定和定量指定生物标记如抗原或其他蛋白(例如HA)的存在的方法。定量或半定量方法可以采用成像软件以检测染色密度或染色的量，或者采用通过人眼检测染色的方法，其中经过培训的操作者用数字排列结果。例如，可以利用像素计数算法定量分析图像(例如Aperio谱软件，自动化定量分析平台(platform)，以及测量或定量或半定量染色程度的其他标准方法；参见例如美国专利第8,023,714号；美国专利第7,257,268号；美国专利第7,219,016号；美国专利第7,646,905号；公开的美国专利申请号US20100136549和20110111435；Camp et al.(2002)NatureMedicine,8:1323-1327；Bacus,et al.(1997)Analyt Quant Cytol Histol,19:316-328)。可以计算和评分强阳性染色(例如褐色染色)比总染色区域的总和的比值。
利用组织化学如免疫组织化学或假免疫组织化学方法，将检测的HA的量定量并给出为HA阳性像素的百分比和/或评分。例如，可以将样品中检测的HA的量定量为HA阳性像素的百分比。在一些实例中，将样品中存在的HA的量定量为染色区域的百分比，例如HA阳性像素的百分比。例如，与总染色区域相比，样品可以具有至少或约至少或约0、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％或更多的HA阳性像素。
在一些实例中，对样品给出评分，其为样品的组织化学染色的强度或量的数值表示，并且代表样品中存在的靶生物标记(例如，HA)的量。光学强度或百分比区域值可以给出标准分，例如以整数计，如0-10、0-5或0-3。在具体实例中，将样品中乙酰透明质酸的量分类为0-3的范围，例如0、HA+1、HA+2和HA+3。存在的HA的量是相对于HA像素的百分比，即低HA像素百分比表示低水平的HA，而高HA像素百分比表示高水平的HA。评分可以与HA阳性像素的百分比相关，从而将染色的百分比区域评分为0、HA+1、HA+2和HA+3，分别代表无染色、少于10％染色、10-25％染色或超过25％染色。例如，如果比例(例如强像素染色比总染色区域)超过25％，则将肿瘤组织评分为HA+3；如果比例为10-25％的强阳性染色比总染色，则将肿瘤组织评分为HA+2；如果比例少于10％的强阳性染色比总染色，则将肿瘤组织评分为HA+1；并且如果强阳性染色比总染色的比例为0，则将肿瘤组织评分为0。0或HA+1的评分表示受试样品中低水平的HA，而HA+2或HA+3的评分表示受试样品中较高水平的HA。
b.固相结合测定
评价乙酰透明质酸积累的方法是基于HABP同伴诊断剂结合样品中的HA的能力，从而结合的HABP同伴诊断剂的量与所述样品中HA的量相关。具体地，可以使用固相结合测定。可以用来评估、评价、确定、定量 和/或特异性地检测样品中乙酰透明质酸表达或水平的结合测定的实例包括但不限于酶联免疫吸附测定(ELISA)、放射免疫测定(RIA)、荧光放射测定、荧光测定(fluroassay)、化学发光测定、生物发光测定。例如，利用本领域技术人员已知的任何结合测定，本文提供的HABP同伴诊断剂可以检测HA，所述结合测定包括但不限于酶联免疫吸附测定(ELISA)或其他相似的免疫测定，包括夹心ELISA或竞争ELISA测定。本文提供的示例性方法包括基于ELISA的方法用于定量或半定量检测结合样品中的HA的HABP的量，所述样品例如来自患有肿瘤或怀疑患有肿瘤的对象的肿瘤组织样品或流体样品。当在体液中检测HA时可以使用固相结合测定。
如本文所述，表现出肿瘤组织中高水平的乙酰透明质酸生成的患者还表现出血液中高水平的乙酰透明质酸。因此，本文提供的方法涵盖预测对象对用乙酰透明质酸降解酶治疗的反应性、选择对象用乙酰透明质酸降解酶进行治疗或监测用乙酰透明质酸降解酶治疗的方法，包括评价来自患有肿瘤的患者或怀疑患有肿瘤的患者的流体样品中乙酰透明质酸的积累。
用于分析HA相关疾病如癌症中HA生成的流体样品包括但不限于血清、尿、血浆、脑脊液和淋巴。对象可以患有或怀疑患有癌症，例如原发性和转移性肿瘤，如乳腺癌、结肠癌、直肠癌、肺癌、胃癌、卵巢癌、宫颈癌、子宫癌、睾丸癌、膀胱癌、前列腺癌、甲状腺癌、肺癌。在具体实例中，所述癌症为晚期癌症、转移癌、未分化癌、卵巢癌、原位癌(ISC)、鳞状细胞癌(SCC)、前列腺癌、胰腺癌、非小细胞肺癌、乳腺癌或结肠癌。
在预测对象对用乙酰透明质酸降解酶治疗的反应性或选择对象用乙酰透明质酸降解酶进行治疗的示例性方法中，采集来自对象的流体样品一般在用乙酰透明质酸降解酶治疗所述对象之前进行。在监测用乙酰透明质酸降解酶的肿瘤疗法的示例性方法中，从对象采集流体样品可以在所述对象接受用乙酰透明质酸降解酶一次或多次治疗之前、期间或之后进行。收获流体样品还可以在所述对象进行一轮或多轮抗癌疗法如放射和/或化疗治疗之前、期间或之后进行。
然后可以利用固相结合测定评价流体样品中HA的存在或量。固相结合测定可以通过底物结合固着或固定至固体表面的结合剂来检测流体样品中的底物(例如HA)。应用偶联至可检测的标记(例如酶)的底物特异性抗体 或结合蛋白(例如本文提供的HABP)并允许其结合底物。然后检测并定量抗体或结合蛋白的存在。检测和定量方法包括但不限于比色、荧光、发光或放射性方法。检测方法的选择取决于使用的可检测的标记。在一些实例中，比色反应采用偶联至抗体的酶。例如，常用于这种方法的酶包括辣根过氧化物酶和碱性磷酸酶。样品中存在的底物的量与产生的颜色的量成比例。底物标准品一般用来提高定量准确性。可以通过将数据插入标准曲线来计算样品中HA的浓度。HA量可以表示为流体样品的浓度。
在示例性方法中，首先将一般未标记的HABP试剂固定在固体支持物上(例如包被至微量滴定板的空)，然后与包含HA的流体样品(例如血清或血浆)温育以捕获HA。用适当的缓冲液洗涤流体样品之后，可以检测结合的HA。在检测结合的HA的一些实例中，与固定的HABP相同或不同且标记的第二HABP(标记的HABP)如生物素化的HABP用来结合平板上的HA。去除未结合的标记的HABP之后，利用检测试剂检测结合的标记的HABP。例如，可以利用抗生物素蛋白检测试剂检测生物素。在一些实例中，结合平板的HABP与用于检测的HABP不同。在其他实例中，结合平板的HABP与用于检测的HABP相同。在检测结合的HA的其他实例中，通过添加HABP，随后添加抗HABP抗体来检测结合的HA。例如，为了检测TSG-6或TSG-6-LM，可以使用抗TSG-6连接模块单克隆抗体，例如命名为A38和Q75的抗体(参见，Lesley et al.(2002)J Biol Chem277:26600-26608)。可以标记抗HABP抗体用于检测，或者可以用结合一抗的二抗检测。在检测结合的HA的其他实例中，用抗HA抗体直接检测结合的HA。抗HA抗体是本领域技术人员公知的，并且包括例如羊抗透明质酸多克隆抗体(例如，Abcam#53842或#93321)。
c.体内成像测定
在本文的一些实例中，利用体内成像方法检测HA的量。在这类方法中，将HABP如TSG-6-LM、其多聚体(例如TSG-6LLM-Fc)或变体缀合至可检测的部分或能够通过成像方法检测的部分。示例性成像方法包括但不限于荧光成像，X-射线，磁共振方法如磁共振成像(MRI)和磁共振波谱(MRS)，以及断层扫描方法，包括计算机断层扫描(CT)、计算机轴向断层扫 描(CAT)、电子束计算机断层扫描(EBCT)、高解析度计算机断层扫描(HRCT)、内摆线体层摄影、正电子发射断层扫描(PET)、单光子发射计算机断层扫描(SPECT)、螺旋计算机断层扫描和超声断层扫描。例如，对于荧光成像，可以利用荧光显微镜或荧光立体显微镜分析荧光信号。而且，还可以使用微光成像照相机。
具体地，将HABP如TSG-6-LM、其多聚体(例如TSG-6LLM-Fc)或变体用在成像时提供体内可检测的信号或诱导体内可检测的信号的部分标记或缀合，例如但不限于磁共振成像(MRI)、单光子发射计算机断层扫描(SPECT)、正电子发射断层扫描(PET)、闪烁扫描法、γ照相机、β+检测器、γ检测器、荧光成像和生物发光成像。示例性成像/监测方法包括各种磁共振方法中的任一种如磁共振成像(MRI)和磁共振波谱(MRS)，并且还包括各种断层扫描方法中的任一种，包括计算机断层扫描(CT)、计算机轴向断层扫描(CAT)、电子束计算机断层扫描(EBCT)、高解析度计算机断层扫描(HRCT)、内摆线体层摄影、正电子发射断层扫描(PET)、γ射线(PET扫描中正电子和电子湮没之后)、单光子发射计算机断层扫描(SPECT)、螺旋计算机断层扫描和超声断层扫描。其他示例性成像方法包括微光成像、X-射线、超声信号、荧光吸收和生物发光。此外，可以用发光或发射其他电磁波谱的化合物如荧光化合物或分子标记蛋白。可以通过检测发出的光或其他发射的电磁辐射来进行检测。
可检测的标记包括具有可直接检测的元件的试剂(例如放射性标记)以及具有可间接检测的元件的标记(例如反应产物)。C.3.c节也描述了可检测的标记。可检测的标记的实例包括放射性同位素、生物发光化合物、化学发光化合物、荧光化合物、金属螯合物和酶。可以通过化学或重组方法将可检测的标记掺入HABP。
适合X-射线成像的标记是本领域已知的，并且包括例如铋(III)、金(III)、镧(III)或铅(II)；放射性离子，例如67铜、67镓、68镓、111铟、113铟、123碘、125碘、131碘、197汞、203汞、186铼、188铼、97铷、103铷、99锝或90钇；核磁自旋-共振同位素，例如钴(II)、铜(II)、铬(III)、镝(III)、铒(III)、钆(III)、钬(III)、铁(II)、铁(III)、锰(II)、钕(III)、镍(II)、钐(III)、铽(III)、钒(II)或镱(III)；或者罗丹明或荧光素。
造影剂用于磁共振成像。示例性造影剂包括铁、金、钆和镓。适合磁共振成像的标记是本领域已知的，并且包括例如氟，钆螯合物，金属和金属氧化物如镓、金、钆、镁，1H、19F、13C和15N标记的化合物。在造影剂中使用螯合物是本领域已知的。适合断层扫描成像方法的标记是本领域已知的，并且包括例如β-辐射源如1lC、13N、15O或64Cu或者(b)γ-辐射源如123I。可以用作例如PET的示踪剂的其他示例性放射性核素包括55Co、67Ga、 68Ga、60Cu(II)、67Cu(II)、99Tc、57Ni、52Fe和18F。可以将试剂如TSG-6或其FC部分缀合至合适的标记和/或蛋白可以在其组成分子中包括放射性标记。
可用于本文提供的成像方法的放射性核素的示例性清单包括例如11碳、11氟、13碳、13氮、15氮、15氧、18氟、19氟、24钠、32磷、42钾、51铬、 55铁、59铁、57钴、60钴、64铜、67镓、68镓、75硒、81氰、82铷、89锶、92锶、90钇、99锝、103钯、106钌、111铟、117镥、123碘、125碘、131碘、133氙、 137铯、153钐、153钆、165镝、166钬、169镱、177Leutium186铼、188铼、192铱、 198金、201铊、211砹、212铋和213铋。本领域技术人员可以改变用于不同成像方法(例如MRI)的参数以使不同放射性核素/金属可见。
还可以使用荧光标记。这些包括荧光蛋白、荧光探针或荧光底物。例如，荧光蛋白可以包括但不限于荧光蛋白如绿色荧光蛋白(GFP)或其同系物或者RFP；荧光染料(例如，荧光素和衍生物如异硫氰酸荧光素(FITC)和Oregon罗丹明和衍生物(例如，德克萨斯红和四甲基罗丹明异硫氰酸盐(TRITC))、生物素、藻红蛋白、AMCA、Alexa 或Fluors)；tdTomato、mCherry、mPlum、Neptune、TagRFP、mKate2、TurboRFP和TurboFP635(Katushka)。可以基于使用者期望的激发和发射谱选择荧光试剂。还可以使用荧光底物，其导致荧光切割产物。
体内成像方法可以用于HA相关肿瘤或癌症的诊断。这样的技术允许诊断而不使用活组织检查。基于HABP结合肿瘤的程度或水平的体内成像方法还可以用于癌症患者的预后。体内成像方法还可以用来检测身体其他部分中的转移癌或循环肿瘤细胞(CTC)。确定除肿瘤以外的组织中乙酰透明质酸的背景水平在本领域技术人员的水平之内。表达乙酰透明质酸的肿瘤 会具有比背景组织高的信号水平。在一些实例中，可以通过与正常或健康对象中检测的信号比较来确定阈值标准。
2.对象的分类
一旦确定样品中乙酰透明质酸的量，可以将该量与对照或阈值水平比较。对照或阈值水平一般是指示乙酰透明质酸相关疾病或疾病状况(例如肿瘤或癌症)的预定的阈值水平或量。这类水平或量可以由本领域技术人员凭经验确定。应当理解本文的方法的特定的预定选择或分类标准取决于用于检测乙酰透明质酸的特定测定和测试的特定样品。确定测定是否与测试特定样品相容在本领域技术人员的水平之内。一般来说，体外固相测定用于测试体液样品。固相测定如组织化学或免疫组织化学一般用于测试组织样品。还应当理解在涉及与预定水平或量比较或者与对照或参考样品比较的方法中，参考用相同类型的样品制备并使用相同的测定和HABP试剂(包括相同的可检测的部分和检测方法)。
例如，可以基于参考或对照样品中标记的水平或量，例如对象的群体中标记的中值或平均水平或量来确定预定的阈值水平，以便评价水平或表达的差异。在一实例中，预定的阈值水平可以代表来自健康对象或已知患有乙酰透明质酸相关疾病或疾病状况(例如肿瘤或癌症)的对象的样品中乙酰透明质酸的平均或中值水平或量。在一实施方案中，来自正常组织或体液样品的乙酰透明质酸的预定水平或量是在正常样品(例如，所有分析的正常样品)中观察到的平均水平或量。在另一实施方案中，来自正常组织或体液样品的乙酰透明质酸的水平或量是在正常样品中观察到的水平或量的中值。预定的阈值水平还可以基于细胞系或其他对照样品(例如肿瘤细胞系)中乙酰透明质酸的水平或量。如下文所述，可以通过相同的检测测定和使用相同的HABP试剂所确定的相应正常样品中HA水平的比较或知识来确定这些预定值。
参考或对照样品可以是另一组织、细胞或体液，如正常组织、细胞或体液，例如与测试的样品类似但分离自不同对象的组织、细胞或体液。对照或参考对象可以是正常(即没有疾病或疾病状况)的对象或对象的群体，患有疾病但没有受试对象患有或怀疑患有的疾病或疾病状况类型的对象，例 如没有乙酰透明质酸相关疾病或疾病状况(例如肿瘤或癌症)的个体，或者来自患有相似疾病或疾病状况的另一对象的类似组织，但是所述对象的疾病不严重和/或表达相对较少的乙酰透明质酸。例如，当测试的细胞、组织或流体是患有癌症的对象或对象的群体时，可以将标记的水平或量与来自患有较不严重的癌症如早期、分化或其他类型的癌症的对象的组织、细胞或流体中标记的水平或量进行比较。在另一实例中，对照或参考样品为流体、组织、提取物(例如细胞或核提取物)、核酸或肽制品、细胞系、活组织检查、标准品或其他样品，具有已知量或相对量的乙酰透明质酸，例如已知表达相对低水平的HA的样品如肿瘤细胞系，例如表达低水平的HA的示例性肿瘤细胞系，例如HCT116细胞系、HT29细胞系、NCI H460细胞系、DU145细胞系、Capan-1细胞系以及来自利用这类细胞系产生的肿瘤模型的肿瘤。
在任何本文的方法中，可以在确定参考或正常组织中乙酰透明质酸的水平的同时确定来自怀疑或已知患有乙酰透明质酸相关疾病或疾病状况(例如，癌症)的对象的样品中乙酰透明质酸的水平。或者，可以将来自怀疑或已知患有乙酰透明质酸相关疾病或疾病状况(例如癌症)的对象的样品中乙酰透明质酸的水平与以前确定的正常组织或体液中乙酰透明质酸的水平进行比较。因此，任何检测、比较、确定或评价中采用的正常或健康样品或者其他参考样品中乙酰透明质酸的水平可以是在任何检测、确定或评价来自人患者的样品中乙酰透明质酸的水平或量之前确定的水平或量。
确定和/或评分乙酰透明质酸的水平或量，并且将其与疾病相关的乙酰透明质酸的预定表型进行比较。根据特定疾病、用于检测乙酰透明质酸的测定和/或使用的HABP检测试剂确定疾病诊断的阈值水平在本领域技术人员的水平之内。确定分类对用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的反应性的乙酰透明质酸的阈值水平在本领域技术人员的水平之内。本文提供分层肿瘤样品或体液样品用于治疗的对象的诊断、预后或选择的示例性方法。
应当理解特定改变，例如乙酰透明质酸的增加或减少取决于使用的测定。在ELISA中，在特定波长处的吸光度或蛋白的量(例如通过使用标准曲线确定)的倍数增加或减少可以相对于对照来表示。在PCR测定如RT-PCR中，可以利用本领域技术人员已知的方法如利用标准品将表达水平与对照 表达水平进行比较(例如表示为倍数改变)。
在本文的方法的具体实例中，如果确定样品中乙酰透明质酸的量升高，则选择对象作为用抗乙酰透明质酸剂治疗的候选。例如，与健康或正常对象相比，患病的对象中升高或积累的乙酰透明质酸水平是乙酰透明质酸相关疾病或疾病状况(例如肿瘤或癌症)的指示。乙酰透明质酸可以升高0.5倍、1倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍或更多倍。因此，在本文的方法的实例中，当测试来自对象的样品中乙酰透明质酸的量时，标记的检测可以确定来自对象的样品(例如癌细胞、组织或流体)中HA的量与预定水平或量或对照样品相比升高。在一实例中，如果组织、细胞或流体中HA的量与预定水平或量或对照样品相比升高或约升高0.5倍、1倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、11倍、12倍、13倍、14倍、15倍、20倍或更多倍，则确定对象患有乙酰透明质酸相关疾病或疾病状况。
可以基于来自对象的样品(例如体液或其他流体)中乙酰透明质酸的水平或量选择对象作为用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的候选。大于0.010μg/mL、0.015μg/mL，一般大于0.02μg/mL、0.03μg/mL、0.04μg/mL、0.05μg/mL、0.06μg/mL或更高的HA与肿瘤或癌症的存在相关。利用这类方法，在本文提供的示例性方法中，如果流体样品如血清样品中HA的浓度包含大于0.010μg/mL、0.015μg/mL，一般大于0.02μg/mL、0.03μg/mL、0.04μg/mL、0.05μg/mL、0.06μg/mL或更高的HA水平，则可以选择对象用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)进行治疗。
可以基于细胞或组织样品中乙酰透明质酸的水平或量来选择对象作为用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的候选。在这样的实例中，如果水平是疾病的指示，则诊断患者患有乙酰透明质酸相关疾病或疾病状况。例如，利用肿瘤组织的免疫组织化学方法，HA+2或HA+3的评分可以确定为疾病。例如，大于10％，例如10-25％的HA染色比总肿瘤面积的百分比是疾病的指示。在本文的方法中，如果样品的比例得分为HA+2或HA+3样品，则选择对象用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)进行治疗。例如，高评分如HA+3表示对象具有HA丰富的肿瘤指示，存在会受益于用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的肿瘤，因此 是用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的候选。在其他实例中，基于染色的百分比，例如，如果HA染色的程度为总染色面积的10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％或更多，并且一般至少25％或更多，则选择对象用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)进行治疗。
通过随时间比较对象中乙酰透明质酸的水平或量还可以监测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的效力或对治疗的反应性。乙酰透明质酸的水平或量的改变可以用来优化用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的剂量给药或时间安排。在所述方法中，将来自治疗的对象的样品中HA表达的水平，特别是肿瘤组织中评价的HA表达的水平(例如通过免疫组织化学或其他相似的方法)与HA表达的预定水平进行比较。为了监测治疗的目的，给药乙酰透明质酸降解酶，特别是具有延长的半衰期的乙酰透明质酸降解酶(例如PEGPH20)之后，监测的样品不是其中可以存在酶的全身水平的体液。
为了监测治疗的目的，HA的预定水平可以来自正常或健康对象，治疗之前的基线HA值，之前测量的在治疗之后较早时间相同对象中的HA水平，或者已知与疾病发展或消退相关的HA水平的分类或分层。例如，如果乙酰透明质酸水平与比较的参考或对照样品大约相同或低于比较的参考或对照样品(或减少)，则治疗可能有效，并且可以继续或停止或改变治疗。例如，HA的预定水平可以是来自正常或健康组织样品的HA水平，并且如果治疗之后对象中测量的HA水平高于正常HA水平，则治疗恢复或继续。例如，HA的预定水平可以是从治疗之前的基线HA值确定的HA水平，并且相应地确定治疗进程。例如，如果HA的水平与基线HA相同，则继续或恢复治疗；如果HA的水平高于基线HA，则继续或恢复治疗，或者加速或增加治疗(例如通过增加乙酰透明质酸降解酶的剂量或增加剂量方案周期中的剂量计划)；如果HA的水平低于基线HA，则继续或恢复、终止或者降低或减少治疗(例如通过减少乙酰透明质酸降解酶的剂量或者减少剂量方案周期中的剂量计划)。在另一实例中，HA的预定水平可以是在相同对象的较早治疗过程中的先前测量中确定的HA水平。例如，如果HA的水平与较早测量的HA相同，则继续或恢复治疗；如果HA的水平高于较 早测量的HA，则继续或恢复治疗，或者加速或增加治疗(例如通过增加乙酰透明质酸降解酶的剂量或增加剂量方案周期中的剂量计划)；如果HA的水平低于较早测量的HA，则继续或恢复、终止或者降低或减少治疗(例如通过减少乙酰透明质酸降解酶的剂量或者减少剂量方案周期中的剂量计划)。
在监测方法或确定治疗的效力的方法中，可以在治疗过程中改变具体疗法以最大化个体反应。可以对改变水平反应，修改治疗的剂量给药和时间安排。在这类治疗方法中还可以采用使用其他抗癌剂的组合疗法。确定治疗的确切过程在治疗医生的技术水平之内。例如，可以改变治疗，从而相应地调整剂量给药量、计划(例如给药频率)或方案，例如停止、减少或较不频繁，或者与疾病或疾病状况的另一治疗组合。另一方面，如果乙酰透明质酸水平在比较的参考或对照样品之上，则患者可能不对治疗反应。在这类情况下，可以修改或改变抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的特定性质和类型或者组合疗法。在其他情况下，可以相应地调整剂量给药、量、计划和/或方案，例如增加或更频繁。确定治疗的确切过程在治疗医生的水平之内。
为了监测治疗的效力的目的，可以凭经验确定乙酰透明质酸的预定水平或量，从而水平或量指示治疗是有效的。可以通过相同的检测测定和使用相同的HABP试剂所确定的相应正常样品或疾病对象的样品中HA水平的比较或知识来确定这些预定值。例如，利用定量评分方案通过免疫组织化学方法评价的高水平的HA(例如HA+3)或大于25％的乙酰透明质酸的肿瘤染色百分比与跨越一定范围的癌症类型的恶性疾病的存在相关，并且指示患者对治疗不反应。在另一实例中，大于0.015μg/mL，一般大于0.02μg/mL，如0.03μg/mL、0.04μg/mL、0.05μg/mL或0.06μg/mL HA的体液如血浆中的HA水平与晚期疾病阶段相关。在另一方面，如果样品的比例得分少于HA+2或HA+3，或者HA染色的百分比少于25％、20％、15％、10％、9％、8％、7％、6％、5％、4％、3％、2％或更少，则对象可能对治疗反应。如果体液如血浆中的HA水平少于0.03μg/mL、0.02μg/mL、0.01μg/mL或更少，则对象可能对治疗反应。
在本文的方法中，可以通过本领域技术人员已知的任何方法确定与预 定水平或者与对照或参考样品的水平的比较。例如，可以通过自动化系统进行乙酰透明质酸水平与参考、对照或预定水平的比较，例如软件程序或智能系统，其为进行测定的设备(例如计算机平台)的部分或者与进行测定的设备相容。或者，可以由医生或者其他经过培训或有经验的专业人士或技术员进行这种比较。
E.用抗乙酰透明质酸剂治疗所选的对象
本文提供的方法包括用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗具有肿瘤的对象的方法，其中已基于肿瘤中检测的HA的水平选择所述对象用于治疗。治疗的方法还包括评价用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗的效果的方法，例如治疗的效力，如肿瘤抑制或消退，或者治疗的副作用，如肌肉骨骼副作用。还提供与一种或多种额外的抗癌剂或另一种物质的组合疗法以治疗用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的疗法的一种或多种副作用。
1.抗乙酰透明质酸剂
抗乙酰透明质酸剂包括抑制乙酰透明质酸合成或降解乙酰透明质酸的物质。抗乙酰透明质酸剂如乙酰透明质酸降解酶可以用来治疗乙酰透明质酸相关疾病或疾病状况，包括肿瘤或癌症或者炎性疾病或疾病状况。例如，通过改变的乙酰透明质酸代谢、分布和功能，HA积累与关节炎、免疫和炎性病症、肺部和血管疾病以及癌症相关(Morohashi et al.(2006)Biochem.Biophys.Res.Comm.,345:1454-1459)。这类疾病可以通过抑制HA合成或降解HA来治疗(参见例如Morohashi2006；美国公开申请第20100003238号和国际公开PCT申请第WO2009/128917号)。在一些实例中，降低细胞或组织上的乙酰透明质酸水平的这类治疗可以与有害副作用如肌肉骨骼副作用相关。因此，用抗乙酰透明质酸剂治疗可以进一步包括用皮质类固醇治疗以改善或减少这类副作用。
a.抑制乙酰透明质酸合成的物质
HA可以通过3种酶合成，所述酶是鉴定为HA合成酶，命名为has-1、 has-2和has-3的3个相关的哺乳动物基因的产物。不同的细胞类型表达不同的HAS酶，并且HAS mRNA的表达与HA生物合成相关。已知在肿瘤细胞中沉默HAS基因抑制肿瘤生长和转移。抗乙酰透明质酸剂包括抑制、减少或下调HA合成酶的表达或水平的任何物质。这类物质是本领域技术人员已知的，或者可以鉴定。
例如，HAS的下调可以通过提供与编码HAS的一种或多种核酸分子特异性杂交或相互作用的寡核苷酸来完成。例如，抑制乙酰透明质酸合成的抗乙酰透明质酸剂包括针对has基因的反义或正义分子。这类反义或正义抑制通常是基于寡核苷酸链或片段的基于氢键的杂交，从而至少一条链或片段被切割、降解或不可操作。在其他实例中，可以采用转录后基因沉默(PTGS)、RNAi、核糖核酸酶和DNA酶。基于HAS1(在SEQ ID NO:219中示出)、HAS2(在SEQ ID NO:220中示出)或HAS3(在SEQ ID NO:221中示出)的序列产生这类构建体在本领域技术人员的水平之内。在本领域中应当理解反义或正义化合物的序列不必与其可特异性杂交的靶核酸的序列100％互补。此外，寡核苷酸可以在一个或多个片段上杂交，从而干预或相邻片段不参与杂交事件(例如环结构或发夹结构)。一般来说，反义或正义化合物与靶核酸内的靶区域具有至少70％序列互补性，例如75％-100％互补性，如75％、80％、85％、90％、95％或100％。示例性正义或反义分子是本领域已知的(参见例如Chao et al.(2005)J.Biol.Chem.,280:27513-27522；Simpson et al.(2002)J.Biol.Chem.,277:10050-10057；Simpson et al.(2002)Am.J Path.,161:849；Nishida et al.(1999)J.Biol.Chem.,274:21893-21899；Edward et al.(2010)British J Dermatology,162:1224-1232；Udabage et al.(2005)Cancer Res.,65:6139；和公开的美国专利申请第US20070286856号)。
是HA合成抑制物的另一示例性抗乙酰透明质酸剂为4-甲基伞形酮(4-MU；7-羟基-4-甲基香豆素)或其衍生物。4-MU通过减少HA合成所需要的UDP-GlcUA前体池来发挥作用。例如，在哺乳动物细胞中，通过HAS利用UDP-葡糖醛酸(UGA)和UDP-N-乙酰基-D-葡糖胺前体合成HA。4-MU干扰产生UGA的过程，从而消耗UGA的细胞内池并导致HA合成的抑制。已知4-MU具有抗肿瘤活性(参见例如Lokeshwar et al.(2010)Cancer Res.,70:2613-23；Nakazawaet al.(2006)Cancer Chemother.Pharmacol., 57:165-170；Morohashi et al.(2006)Biochem.Biophys.Res.Comm.,345-1454-1459)。在B16黑素瘤模型中以600mg/kg/d口服给药4-MU减少转移64％(Yoshihara et al.(2005)FEBS Lett.,579:2722-6)。4-MU的结构如下文所示。而且，4-MU的衍生物表现出抗癌活性，特别是6,7-二羟基-4-甲基香豆素和5,7-二羟基-4-甲基香豆素(参见例如Morohashi et al.(2006)Biochem.Biophys.Res.Comm.,345-1454-1459)。
4-甲基伞形酮(4-MU；C10H8O3)
其他示例性抗乙酰透明质酸剂为酪氨酸激酶抑制剂，例如来氟米特(爱若华)、染料木素或erbstatin。来氟米特还是嘧啶合成抑制剂。来氟米特是已知的用于治疗类风湿性关节炎(RA)的药物，并且还在治疗同种异体移植以及异种移植的排斥中有效。已知HA直接或间接有助于RA(参见例如Stuhlmeier(2005)J Immunol.,174:7376-7382)。酪氨酸激酶抑制剂抑制HAS1基因表达(Stuhlmeier2005)。
在一实例中，来氟米特或其衍生物一般可获得为包含1-100mg活性药物的片剂，例如1、5、10、20、30、40、50、60、70、80、90或100mg药物。为了治疗乙酰透明质酸相关疾病和疾病状况，例如类风湿性关节炎或者肿瘤或癌症，将其以10-500mg/天给药，通常100mg/天。如治疗疾病或疾病状况需要，剂量可以继续，或者可以逐渐减少或降低至连续的较低剂量。例如，为了治疗类风湿性关节炎，来氟米特可以以100mg/天的初始负荷剂量给药3天，然后以20mg/天的持续剂量给药。
b.乙酰透明质酸降解酶
乙酰透明质酸是胞外基质的必要组分和间质屏障的主要成分。通过催化乙酰透明质酸的水解，乙酰透明质酸降解酶降低乙酰透明质酸的粘度，从而增加组织通透性并增加肠胃外给药的流体的吸收率。因此，乙酰透明质酸降解酶如透明质酸酶已与其他物质、药物和蛋白联合用作例如铺展剂或分散剂以增加它们的分散和递送。
乙酰透明质酸降解酶通过切割乙酰透明质酸聚合物来作用以降解乙酰 透明质酸，所述乙酰透明质酸聚合物由通过交替的β-1→4和β-1→3糖苷键连接的重复二糖单元D-葡糖醛酸(GlcA)和N-乙酰基-D-葡糖胺(GlcNAc)组成。乙酰透明质酸链的长度可以达到约25,000个二糖重复或更长，并且乙酰透明质酸聚合物在体内的大小可以为约5,000-20,000,000Da。因此，用于所提供的用途和方法的乙酰透明质酸降解酶包括具有催化乙酰透明质酸二糖链或聚合物的切割的能力的任何酶。在一些实例中，乙酰透明质酸降解酶切割乙酰透明质酸链或聚合物中的β-1→4糖苷键。在其他实例中，乙酰透明质酸降解酶催化乙酰透明质酸链或聚合物中的β-1→3糖苷键的切割。
因此，乙酰透明质酸降解酶如透明质酸酶是降解透明质酸的酶家族，透明质酸是胞外基质的必要组分和间质屏障的主要成分。通过催化间质屏障的主要成分透明质酸的水解，乙酰透明质酸降解酶降低透明质酸的粘度，从而增加组织通透性。因此，乙酰透明质酸降解酶如透明质酸酶已与其他物质、药物和蛋白联合用作例如铺展剂或分散剂以增加它们的分散和递送。乙酰透明质酸降解酶还用作佐剂以增加用于皮下灌注术(皮下流体给药)的其它注射药物的吸收和分散，并且用作皮下尿路造影术的添加剂用于提高造影剂(radiopaque agent)的吸收。乙酰透明质酸降解酶如透明质酸酶可以用于眼科手术的应用中，例如在眼科手术之前局部麻醉中的球周和Tenon下阻断(peribulbar and sub-Tenon’sblock)。透明质酸酶还可以用于其它治疗和化妆用途，例如在整容手术如眼睑成形术和拉皮中促进运动不能。
已制备包括透明质酸酶在内的各种形式的乙酰透明质酸降解酶并批准用于包括人的对象中的治疗用途。通过这些和其它治疗用途，所提供的组合物和方法可以用来治疗乙酰透明质酸相关疾病和疾病状况。例如，动物来源的透明质酸酶制品包括Vitrase(ISTAPharmaceuticals)，其为纯化的绵羊睾丸透明质酸酶；Amphadase(AmphastarPharmaceuticals)，其为牛睾丸透明质酸酶；以及Hydase(Prima Pharm Inc.)，其为牛睾丸透明质酸酶。应当理解任何动物来源的透明质酸酶制品可以用于本文提供的方法和用途(参见，例如，美国专利号2,488,564、2,488,565、2,676,139、2,795,529、2,806,815、2,808,362、5,747,027和5,827,721以及国际PCT申请第WO2005/118799号)。Hylenex(HalozymeTherapeutics)是由遗传工程化的中国仓鼠卵巢(CHO)细胞产生的人重组透明质酸酶，所述细胞包含编码命名 为rHuPH20的可溶形式的PH20的核酸。
本文提供的组合物和方法中的乙酰透明质酸降解酶的实例是可溶性透明质酸酶。其它示例性乙酰透明质酸降解酶包括但不限于具有切割乙酰透明质酸的能力的特定软骨素酶和裂解酶。
如下文所述，乙酰透明质酸降解酶以膜结合或分泌自细胞的可溶形式存在。为了本文的目的，提供可溶性乙酰透明质酸降解酶用于本文的方法、用途、组合物或组合。因此，当乙酰透明质酸降解酶包括糖基磷脂酰肌醇(GPI)锚和/或膜锚定或不溶时，本文通过截短或缺失GPI锚以使该酶分泌和可溶来以可溶形式提供这类乙酰透明质酸降解酶。因此，乙酰透明质酸降解酶包括截短的变体，例如截短以去除所有或部分GPI锚。本文提供的乙酰透明质酸降解酶还包括可溶性乙酰透明质酸降解酶的等位基因或物种变体或者其他变体。例如，乙酰透明质酸降解酶在其一级序列中可以含有一个或多个变异，如氨基酸取代、添加和/或缺失。乙酰透明质酸降解酶的变体与不含变异的乙酰透明质酸降解酶相比一般表现出至少或约60％、70％、80％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多的序列相同性。任何变异可以包括在乙酰透明质酸降解酶中用于本文的目的，只要该酶保留透明质酸酶活性，如至少或约5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％或更多的不含变异的乙酰透明质酸降解酶的活性(如通过本领域公知和本文所述的体外和/或体内测定测量的)。
当本文提供的方法和用途描述可溶性透明质酸酶的用途时，相应地可以使用任何乙酰透明质酸降解酶，一般为可溶性乙酰透明质酸降解酶。应当理解任何透明质酸酶均可以用于本文提供的方法和用途(参见，例如，美国专利第7,767,429号和美国公开第US20040268425号和第US20100143457号)。
i.透明质酸酶
透明质酸酶是乙酰透明质酸降解酶大家族的成员。有三种普通类别的透明质酸酶：哺乳动物型透明质酸酶，细菌透明质酸酶，以及来自水蛭、 其它寄生虫和甲壳动物的透明质酸酶。这类酶可以用于本文提供的组合物、组合和方法。
(1)哺乳动物型透明质酸酶
哺乳动物型透明质酸酶(EC3.2.1.35)是内-β-N-乙酰基-氨基己糖苷酶，其将乙酰透明质酸的β-1→4糖苷键水解为各种寡糖长度，如四糖和己糖。这些酶具有水解和转糖苷酶活性，并且可以降解乙酰透明质酸和硫酸软骨素(CS)，一般为C4-S和C6-S。这种类型的透明质酸酶包括但不限于来自如下来源的透明质酸酶：牛(牛的)(SEQ ID NO:10、11和64以及BH55(美国专利第5,747,027号和第5,827,721号)SEQ ID NO:190-192所示的核酸分子)、绵羊(Ovis aries)(SEQ ID NO:26、27、63和65，SEQ ID NO:66和193-194所示的核酸分子)、黄蜂(SEQ ID NO:12和13)、蜜蜂(SEQ ID NO:14)、白脸大黄蜂(SEQ ID NO:15)、胡蜂(SEQ IDNO:16)、小鼠(SEQ ID NO:17-19、32)、猪(SEQ ID NO:20-21)、大鼠(SEQ ID NO:22-24、31)、兔(SEQ ID NO:25)、猩猩(SEQ ID NO:28)、食蟹猴(SEQ ID NO:29)、豚鼠(SEQ ID NO:30)、黑猩猩(SEQ ID NO:101)、猕猴(SEQ ID NO:102)和人透明质酸酶(SEQ ID NO:1-2、36-39)。本文提供的组合物、组合和方法中的透明质酸酶的实例是可溶性透明质酸酶。
哺乳动物透明质酸酶可以进一步细分为以下类型：在中性条件下有活性，主要在睾丸提取物中发现；以及在酸性条件下有活性，主要在器官如肝中发现。示例性在中性条件下有活性的透明质酸酶包括PH20，包括但不限于源自不同物种如绵羊(SEQ ID NOS:27、63和65)、牛(SEQ ID NO:11和64)和人(SEQ ID NO:1)的PH20。人PH20(也称作SPAM1或者精子表面蛋白PH20)一般通过糖基磷脂酰肌醇(GPI)锚附着至质膜。其天然参与精-卵粘附，并且通过消化透明质酸来辅助精子穿透卵丘细胞层。
除了人PH20(也称作SPAM1)，在人基因组中还已鉴定了5个透明质酸酶-样基因，HYAL1、HYAL2、HYAL3、HYAL4和HYALP1。HYALP1为假基因，而HYAL3(SEQ ID NO:38)尚未显示对任何已知底物具有酶活性。HYAL4(SEQ ID NO:39所示的前体多肽)为软骨素酶，并且对乙酰透明质酸表现出很少活性。HYAL1(SEQ ID NO:36所示的前体多肽)为原型酸活 性酶，而PH20(SEQ ID NO:1所示的前体多肽)为原型在中性条件下有活性的酶。酸活性透明质酸酶如HYAL1和HYAL2(SEQ ID NO:37所示的前体多肽)一般在中性pH(即pH7)下缺少催化活性。例如，HYAL1在体外于pH4.5以上具有很少的催化活性(Frost et al.(1997)Anal.Biochem.251:263-269)。HYAL2为酸活性酶，在体外具有非常低的特异性活性。所述透明质酸酶样酶还可以通过以下特点表征：其一般通过糖基磷脂酰肌醇锚附着至质膜，如人HYAL2和人PH20(Danilkovitch-Miagkova et al.(2003)Proc Natl Acad Sci USA100(8):4580-5)，并且其一般是可溶的，如人HYAL1(Frost et al.(1997)Biochem Biophys ResCommun.236(1):10-5)。
(a)PH20
像其他哺乳动物透明质酸酶，PH20为内-β-N-乙酰-氨基己糖苷酶，将透明质酸的β1→4糖苷键水解为各种寡糖长度，如四糖和己糖。其具有水解和转糖苷酶活性，并且可以降解透明质酸和硫酸软骨素，如C4-S和C6-S。PH20天然参与精-卵粘附，并且通过消化透明质酸来辅助精子穿透卵丘细胞层。PH20位于精子表面和溶酶体衍生的顶体，其中PH-20结合顶体内膜。质膜PH20仅在中性pH下具有透明质酸酶活性，而顶体内膜PH20在中性和酸性pH下均具有活性。除了作为透明质酸酶，据报道PH20是HA诱导的细胞信号传导的受体和卵母细胞周围的透明带的受体。
示例性PH20蛋白包括但不限于人(SEQ ID NO:1所示的前体多肽，SEQ ID NO:2所示的成熟多肽)、黑猩猩(SEQ ID NO:101)、猕猴(SEQ ID NO:102)、牛(SEQ ID NOS:11和64)、兔(SEQ ID NO:25)、绵羊PH20(SEQ ID NOS:27、63和65)、食蟹猴(SEQ ID NO:29)、豚鼠(SEQ ID NO:30)、大鼠(SEQ ID NO:31)和小鼠(SEQ ID NO:32)PH20多肽。
牛PH20是553个氨基酸的前体多肽(SEQ ID NO:11)。牛PH20与人PH20的对比显示仅微弱的同源性，从氨基酸470至各羧基末端存在多个缺口，这是由于牛多肽中不存在GPI锚(参见例如，Frost GI(2007)Expert Opin.Drug.Deliv.4:427-440)。事实上，在除人以外的许多其他PH20中，未预测明显的GPI锚。因此，制备自绵羊和牛的PH20多肽以可溶形式天然存在。虽然牛PH20非常松散地粘附至质膜而存在，但是其不是通过磷脂酶敏感 性锚锚定的(Lalancette et al.(2001)Biol Reprod.65(2):628-36)。牛透明质酸酶的这种独特特征使得可以将作为提取物的可溶性牛睾丸透明质酸酶用于临床应用
人PH20mRNA转录物通常翻译产生509个氨基酸的前体多肽(SEQ ID NO:1)，其包含N-末端的35个氨基酸的信号序列(氨基酸残基位置1-35)以及C末端的19个氨基酸的糖基磷脂酰肌醇(GPI)锚附着信号序列(氨基酸残基位置491-509)。因此，成熟的PH20为SEQ IDNO:2所示的474个氨基酸的多肽。将前体多肽转运至ER并去除信号肽之后，将C-末端GPI附着信号肽切割以促进GPI锚在对应于SEQ ID NO:1所示的前体多肽的位置490的氨基酸位置共价附着至新形成的C-末端氨基酸。因此，产生具有SEQ ID NO:2所示的氨基酸序列的474个氨基酸的GPI锚定的成熟多肽。
人PH20在中性和酸性pH均表现出透明质酸酶活性。在一方面，人PH20为原型在中性条件下有活性的透明质酸酶，其一般通过GPI锚锁定至质膜。在另一方面，PH20在顶体内膜上表达，在此其在中性和酸性pH下均具有透明质酸酶活性。PH20在多肽不同区域包含两个催化位点：肽1和肽3区(Cherr et al.(2001)Matrix Biology20:515-525)。证据显示对应于SEQ ID NO:2所示的成熟多肽的氨基酸位置107-137和SEQ ID NO:1所示的前体多肽的位置142-172的PH20的肽1区是在中性pH下酶活性所需的。据报道在这个区域内的位置111和113的氨基酸(对应于SEQ ID NO:2所示的成熟PH20多肽)对于活性很重要，因为通过氨基酸置换进行诱变导致与野生型PH20相比分别具有3％透明质酸酶活性或不可检测的透明质酸酶活性的PH20多肽(Arming et al.,(1997)Eur.J.Biochem.247:810-814)。
据报道对应于SEQ ID NO:2所示的成熟多肽的氨基酸位置242-262和SEQ ID NO:1所示的前体多肽的位置277-297的肽3区对于在酸性pH下的酶活性很重要。在这个区域内，据报道在成熟PH20多肽的位置249和252处的氨基酸对活性至关重要，因为诱变任一个均导致产生基本上丧失活性的多肽(Arming et al.,(1997)Eur.J.Biochem.247:810-814)。
除了催化位点，PH20还包含乙酰透明质酸结合位点。实验证据显示这个位点位于肽2区，肽2区对应于SEQ ID NO:1所示的前体多肽的氨基酸位置205-235和SEQ ID NO:2所示的成熟多肽的位置170-200。这个区域在 透明质酸酶中高度保守并且与肝素结合基序相似。在位置176处(对应于SEQ ID NO:2所示的成熟PH20多肽)的精氨酸残基突变为甘氨酸导致具有仅约1％野生型多肽的透明质酸酶活性的多肽(Arming et al.,(1997)Eur.J.Biochem.247:810-814)。
在SEQ ID NO:1示例的多肽的N82、N166、N235、N254、N368、N393、S490处，人PH20有7个潜在的糖基化位点，包括N-联糖基化位点。因为据报道SEQ ID NO:1的氨基酸36-464包含最小活性人PH20透明质酸酶结构域，糖基化位点S-490不是适当的透明质酸酶活性所需要的。人PH20中有6个二硫键。SEQ ID NO：1示例的多肽的半胱氨酸残基C60和C351之间以及C224和C238之间(分别对应于SEQ ID NO：2所示的成熟多肽的残基C25和C316，以及C189和C203)的两个二硫键。另外4个二硫键在SEQ ID NO：1示例的多肽的半胱氨酸残基C376和C387之间；C381和C435之间；C437和C443之间；以及C458和C464之间形成(分别对应于SEQID NO：2所示的成熟多肽的残基C341和C352之间；C346和C400之间；C402和C408之间；以及C423和C429之间)。
(2)其他透明质酸酶
细菌透明质酸酶(EC4.2.2.1或EC4.2.99.1)降解乙酰透明质酸，并且不同程度地降解硫酸软骨素和硫酸皮肤素。分离自细菌的乙酰透明质酸裂解酶在它们的作用方式方面不同于透明质酸酶(来自其他来源，例如透明质酸氨基葡糖苷酶(hyaluronoglucosaminidase)，EC3.2.1.35)。它们是催化乙酰透明质酸中N-乙酰基-β-D-葡糖胺和D-葡糖醛酸残基之间的β1→4-糖苷键的消除反应而不是水解的内-β-N-乙酰氨基己糖苷酶，产生3-(4-脱氧-β-D-gluc-4-enuronosyl)-N-乙酰基-D-葡糖胺四糖和己糖，以及二糖终产物。反应导致在它们的非还原末端具有不饱和的己糖醛酸残基的寡糖的形成。
用于所提供的组合物、组合和方法的来自细菌的示例性透明质酸酶包括但不限于微生物中的乙酰透明质酸降解酶，包括节杆菌(Arthrobacter)、蛭弧菌(Bdellovibrio)、梭菌(Clostridium)、微球菌(Micrococcus)、链球菌、消化球菌(Peptococcus)、丙酸杆菌(Propionibacterium)、类杆菌(Bacteroides)和链霉菌(Streptomyces)的菌株。这类菌株和酶的具体实例包括但不限于节 杆菌(菌株FB24(SEQ ID NO:67))、噬菌蛭弧菌(SEQ IDNO:68)、痤疮丙酸杆菌(SEQ ID NO:69)、无乳链球菌((SEQ ID NO:70)；18RS21(SEQ ID NO:71)；血清型Ia(SEQ ID NO:72)；血清型III(SEQ ID NO:73))、金黄色葡萄球菌(菌株COL(SEQ ID NO:74)；菌株MRSA252(SEQ ID NOS:75和76)；菌株MSSA476(SEQ ID NO:77)；菌株NCTC8325(SEQ ID NO:78)；菌株牛RF122(SEQ ID NO:79和80)；菌株USA300(SEQ ID NO:81))、肺炎链球菌((SEQ ID NO:82)；菌株ATCC BAA-255/R6(SEQ ID NO:83)；血清型2、菌株D39/NCTC7466(SEQ ID NO:84))、化脓性链球菌(血清型M1(SEQ ID NO:85)；血清型M2、菌株MGAS10270(SEQ ID NO:86)；血清型M4、菌株MGAS10750(SEQ ID NO:87)；血清型M6(SEQ IDNO:88)；血清型M12、菌株MGAS2096(SEQ ID NO:89和90)；血清型M12、菌株MGAS9429(SEQ IDNO:91)；血清型M28(SEQ ID NO:92))、猪链球菌(SEQ ID NO:93-95)；费氏弧菌(菌株ATCC700601/ES114(SEQ ID NO:96))，以及Streptomyces hyaluronolyticus透明质酸酶，其对透明质酸特异性且不切割软骨素或硫酸软骨素(Ohya,T.and Kaneko,Y.(1970)Biochim.Biophys.Acta198:607)。来自水蛭、其他寄生虫和甲壳动物的透明质酸酶(EC3.2.1.36)是产生四糖和己糖终产物的内-β-葡糖醛酸酶。这些酶催化透明质酸盐中β-D-葡糖醛酸盐和N-乙酰基-D-葡糖胺残基之间的1→3-键的水解。来自水蛭的示例性透明质酸酶包括但不限于来自以下的透明质酸酶：医蛭科(例如欧洲医蛭(Hirudomedicinalis))、石蛭科(例如，Nephelopsis obscura和Erpobdella punctata,)、舌蛭科(例如，Desserobdella picta、静泽蛭(Helobdella stagnalis)、平扁舌蛭(Glossiphoniacomplanata)、润饰盾蛭(Placobdella ornata)和Theromyzon sp.)和黄蛭科(Haemopismarmorata)(Hovingh et al.(1999)Comp Biochem Physiol B Biochem Mol Biol.124(3):319-26)。具有与水蛭透明质酸酶相同的作用机制的来自细菌的示例性透明质酸酶是来自蓝细菌，聚球藻(Synechococcus sp.)的透明质酸酶(菌株RCC307,SEQ ID NO:97)。
(3)其他乙酰透明质酸降解酶
除了透明质酸酶家族，其他乙酰透明质酸降解酶可以用于所提供的组合物、组合和方法。例如，可以采用具有切割乙酰透明质酸的能力的酶， 包括特定软骨素酶和裂解酶。可以降解乙酰透明质酸的示例性软骨素酶包括但不限于软骨素ABC裂解酶(也称作软骨素酶ABC)、软骨素AC裂解酶(也称作硫酸软骨素裂解酶或硫酸软骨素消除酶)和软骨素C裂解酶。制备和纯化用于所提供的组合物、组合和方法的这类酶的方法是本领域已知的(例如美国专利第6,054,569号；Yamagata,et al.(1968)J.Biol.Chem.243(7):1523-1535；Yang etal.(1985)J.Biol.Chem.160(30):1849-1857)。
软骨素ABC裂解酶包含两种酶，硫酸软骨素-ABC内切裂合酶(endolyase)(EC4.2.2.20)和硫酸软骨素-ABC外切裂合酶(exolyase)(EC4.2.2.21)(Hamai et al.(1997)J Biol Chem.272(14):9123-30)，它们降解各种硫酸软骨素和硫酸皮肤素类型的糖胺聚糖。硫酸软骨素、硫酸软骨素蛋白聚糖和硫酸皮肤素是硫酸软骨素-ABC内切裂合酶的优选底物，但是该酶还可以以较低速率作用于乙酰透明质酸。硫酸软骨素-ABC内切裂合酶降解各种硫酸软骨素和硫酸皮肤素类型的糖胺聚糖，产生不同大小的Δ4-不饱和寡糖的混合物，它们最终被降解为Δ4不饱和四糖和二糖。硫酸软骨素-ABC外切裂合酶具有相同的底物特异性，但是从聚合的硫酸软骨素和它们的由硫酸软骨素-ABC内切裂合酶产生的寡糖片段的非还原端去除二糖残基(Hamai,A.et al.(1997)J.Biol.Chem.272:9123-9130)。示例性硫酸软骨素-ABC内切裂合酶和硫酸软骨素-ABC外切裂合酶包括但不限于来自普通变形杆菌和Pedobacter heparinus的那些(普通变形杆菌硫酸软骨素-ABC内切裂合酶在SEQ IDNO:98中示出(Sato et al.(1994)Appl.Microbiol.Biotechnol.41(1):39-46)。
软骨素AC裂解酶(EC4.2.2.5)对硫酸软骨素A和C、软骨素和透明质酸有活性，但是对硫酸皮肤素(硫酸软骨素B)没有活性。来自细菌的示例性软骨素酶AC包括但不限于来自Pedobacter heparinus和Victivallis vadensis(分别在SEQ ID NO:99和100中示出)和金黄节杆菌的那些(Tkalec et al.(2000)Applied and Environmental Microbiology66(1):29-35；Ernst et al.(1995)Critical Reviews in Biochemistry and MolecularBiology30(5):387-444)。
软骨素酶C切割硫酸软骨素C，产生四糖加上不饱和的6-硫酸化二糖(δDi-6S)。其还切割透明质酸，产生不饱和的未硫酸化的二糖(δDi-OS)。来自细菌的示例性软骨素酶C酶包括但不限于来自链球菌和黄杆菌的那些(Hibi et al.(1989)FEMS-Microbiol-Lett.48(2):121-4；Michelacci et al.(1976)J.Biol.Chem.251:1154-8；Tsuda et al.(1999)Eur.J.Biochem.262:127-133)。
ii.可溶性乙酰透明质酸降解酶
本文的组合物、组合、用途和方法中提供可溶性乙酰透明质酸降解酶，包括可溶性透明质酸酶。可溶性乙酰透明质酸降解酶包括在表达时从细胞(例如CHO细胞)分泌并以可溶形式存在的任何乙酰透明质酸降解酶。这类酶包括但不限于可溶性透明质酸酶，包括非人可溶性透明质酸酶，包括非人动物可溶性透明质酸酶，细菌可溶性透明质酸酶和人透明质酸酶，Hyal1，牛PH20和绵羊PH20，它们的等位基因变体以及它们的其他变体。例如，可溶性乙酰透明质酸降解酶中包括已修饰为可溶性的任何乙酰透明质酸降解酶。例如，可以通过截短和除去全部或部分GPI锚来使得包含GPI锚的乙酰透明质酸降解酶可溶。在一个实例中，可以通过截短或者除去C-末端的全部或部分GPI锚来使通常通过GPI锚膜锚定的人透明质酸酶PH20可溶。
可溶性乙酰透明质酸降解酶还包括在中性条件下有活性和酸活性的透明质酸酶。根据各种因素，例如但不限于给药之后和/或给药部位的酶活性的期望水平，可以选择在中性条件下有活性和酸活性的透明质酸酶。在一具体实例中，用于本文的组合物、组合和方法的乙酰透明质酸降解酶是可溶性的在中性条件下有活性的透明质酸酶。
可溶性透明质酸酶的实例是来自任何物种的PH20，如SEQ ID NO:1、2、11、25、27、29-32、63-65和101-102中任一个所示的PH20，或者是其缺少全部或部分C-末端GPI锚的截短形式，只要所述透明质酸酶是可溶的(在表达时分泌)且保留透明质酸酶活性。可溶性透明质酸酶中还包括SEQ ID NO:1、2、11、25、27、29-32、63-65和101-102中任一个的等位基因变体或其他变体，或者它们的截短形式。等位基因变体和其他变体是本领域技术人员已知的，并且包括与SEQ ID NO:1、2、11、25、27、29-32、63-65和101-102中任一个具有60％、70％、80％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性的多肽，或者它们的截短形式。氨基酸变体包括保守和非保守突变。应当理解对透明质酸 酶的活性很重要或需要的残基，如上文所述和本领域技术人员已知的任何残基，一般是不变的，并且不可以改变。这些包括例如活性位点残基。因此，例如，人PH20多肽或其可溶形式的氨基酸残基111、113和176(对应于SEQ ID NO:2所示的成熟PH20多肽的残基)一般是不变的，并且不改变。赋予糖基化和正确折叠所需的二硫键形成的其他残基也可以是不变的。
在某些情况下，可溶性乙酰透明质酸降解酶通常是GPI锚定的(例如人PH20)，并且通过C-末端截短是其可溶。这类截短可以去除全部GPI锚附着信号序列，或者可以仅去除一些GPI锚附着信号序列。但是，所得的多肽是可溶的。在其中可溶性乙酰透明质酸降解酶保留部分GPI锚附着信号序列的情况下，可以保留GPI锚附着信号序列中的1、2、3、4、5、6、7或更多个氨基酸残基，只要多肽是可溶的。包含GPI锚的一个或多个氨基酸的多肽称为延长的可溶性乙酰透明质酸降解酶。本领域技术人员可以利用本领域公知的方法确定多肽是否是GPI锚定的。这类方法包括但不限于利用已知的算法预测GPI锚附着信号序列和ω-位点的存在和位置，以及在用磷脂酰肌醇特异性的磷脂酶C(PI-PLC)或D(PI-PLD)消化之前和之后进行溶解性分析。
延长的可溶性乙酰透明质酸降解酶可以通过对任何天然的GPI锚定的乙酰透明质酸降解酶进行C-末端截短来制备，从而所得的多肽是可溶的，并且包含来自GPI锚附着信号序列的一个或多个氨基酸残基(参见，例如，美国公开专利申请第US20100143457号)。C-末端截短但保留部分GPI锚附着信号序列的示例性延长的可溶性乙酰透明质酸降解酶包括但不限于灵长类来源的延长的可溶性PH20(esPH20)多肽，例如人和黑猩猩esPH20多肽。例如，esPH20多肽可以通过SEQ ID NO:1、2或101所示的任何成熟或前体多肽，或者它们的等位基因或其它变异，包括它们的活性片段的C-末端截短来制备，其中所得的多肽是可溶的，并且保留来自GPI-锚附着信号序列的一个或多个氨基酸残基。等位基因变体和其他变体是本领域技术人员已知的，并且包括与SEQ ID NO:1或2中任一个具有60％、70％、80％、90％、91％、92％、93％、94％、95％或更多序列相同性的多肽。本文提供的esPH20多肽与野生型多肽如具有SEQ ID NO:1、2或101所示的序列的多肽相比，可以C-末端截短1、2、3、4、5、6、7、8、9、10或更多个 氨基酸，只要所得的esPH20多肽是可溶的，并且保留来自GPI-锚附着信号序列的1个或多个氨基酸残基。
通常，为了用于本文的组合物、组合和方法，使用可溶性人乙酰透明质酸降解酶，如可溶性人PH20。尽管可以利用来自其他动物的乙酰透明质酸降解酶如PH20，但是这类制品具有潜在的免疫原性，因为它们是动物蛋白。例如，大部分患者证实继发于摄入的食物的优先致敏作用，因为这些是动物蛋白，所有患者均具有随后致敏作用的危险。因此，非人制品可能不适于长期使用。如果期望非人制品，则本文考虑可以制备这类多肽以具有降低的免疫原性。这类修饰在本领域技术人员的水平之内，并且可以包括例如去除和/或置换分子上的一个或多个抗原表位。
本文的方法中使用的乙酰透明质酸降解酶，包括透明质酸酶(例如，PH20)可以重组产生或者可以纯化或部分纯化自天然来源，例如来自睾丸提取物。制备重组蛋白，包括重组乙酰透明质酸降解酶的方法在本文的其他地方提供，并且是本领域公知的。
(1)可溶性人PH20
可溶性透明质酸酶的实例为可溶性人PH20。可溶形式的重组人PH20已经产生，并且可以用于本文所述的组合物、组合和方法。这类可溶形式的PH20的制备描述于美国公开专利申请号US20040268425；US20050260186、US20060104968、US20100143457以及国际PCT申请第WO2009111066号。例如，可溶性PH20多肽，包括C-末端截短的变体多肽，其包括SEQID NO:1中的氨基酸序列，或者与SEQ ID NO:1中包括的氨基酸序列具有至少91％、92％、93％、94％、95％、95％、97％、98％序列相同性，保留透明质酸酶活性并且是可溶的。这些多肽中包括完全缺少全部或部分GPI-锚附着信号序列的可溶性PH20多肽。
还包括包含GPI锚的至少一个氨基酸的延长的可溶性PH20(esPH20)多肽。因此，代替具有共价附着于ER中的蛋白的C-末端的GPI锚并锚定至质膜的胞外小叶，这些多肽是分泌和可溶的。C-末端截短的PH20多肽可以与全长野生型多肽如具有SEQ ID NO:1或2所示的序列的全长野生型多肽或者它们的等位基因或物种变体或其他变体相比，C-末端截短1、2、3、 4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、45、50、55、60个或更多个氨基酸。
例如，可溶形式包括但不限于SEQ ID NO:1所示的人PH20的C-末端截短多肽，其具有SEQ ID NO:1所示的氨基酸序列的C-氨基酸残基467、468、469、470、471、472、473、474、475、476、477、478、479、480、481、482和483、484、485、486、487、488、489、490、491、492、493、494、495、496、497、498、499或500，或者与其表现出至少85％相同性的多肽。可溶形式的人PH20一般包括包含SEQ ID NO:1所示的氨基酸36-464的人PH20。例如，当在哺乳动物细胞中表达时，加工期间35个氨基酸的N-末端信号序列被切割，并且分泌蛋白的成熟形式。因此，成熟的可溶性多肽包含SEQ ID NO:1的氨基酸36至467、468、469、470、471、472、473、474、475、476、477、478、479、480、481、482和483。表3提供示例性C-末端截短的PH20多肽的非限制性实例，包括C-末端截短的可溶性PH20多肽。在下文表3中，提供了前体和成熟多肽的长度(以氨基酸计)以及序列标识符(SEQ ID NO)，其中示出了C-末端截短的PH20蛋白的前体和成熟多肽的示例性氨基酸序列。表3中还包括野生型PH20多肽用于比较。具体地，可溶性透明质酸酶的实例为可溶性人PH20多肽，其长度为442、443、444、445、446或447个氨基酸，如SEQ ID NO:4-9中任一个所示，或者它们的等位基因或物种变体或其他变体。
例如，表现出透明质酸酶活性的示例性C-末端截短的PH20多肽分泌自细胞，并且是可溶的，包括表3所示的截短的人PH20的任何成熟形式，或者其表现出透明质酸酶活性的变体。例如，PH20或其截短形式包含SEQ ID NO:4-9、47、48、150-170和183-189中任一个所示的氨基酸序列，或者表现出与SEQ ID NO:4-9、47、48、150-170和183-189中任一个的至少85％序列相同性的氨基酸序列。例如，PH20多肽可以表现出与SEQ ID NO:4-9、47、48、150-170和183-189中任一个的至少85％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更多序列相同性。
一般利用蛋白表达系统制备可溶形式的PH20，所述蛋白表达系统促进正确的N-糖基化以确保多肽保留活性，因为糖基化对于透明质酸酶的催化活性和稳定性非常重要。这类细胞包括例如中国仓鼠卵巢(CHO)细胞(例如DG44CHO细胞)。
(2)rHuPH20
重组的可溶形式的人PH20已经产生，并且可以用于本文提供的组合物、组合和方法。这类可溶形式的重组人PH20的制备描述于例如美国公开专利申请号US20040268425；US20050260186；US20060104968； US20100143457以及国际PCT申请第WO2009111066号。这类多肽的实例是通过表达编码氨基酸1-482(在SEQ ID NO:3中示出)的核酸分子而产生的那些多肽。这样的示例性核酸分子如SEQ ID NO:49所示。翻译后加工去除35个氨基酸的信号序列，留下447个氨基酸的可溶性重组人PH20(SEQ ID NO:4)。由于在培养基中产生，因此在C-末端有异质性，从而命名为rHuPH20的产物包括混合物，其可以包括各种丰度的SEQ IDNO:4-9中的任一个或多个。通常，rHuPH20在促进正确的N-糖基化以保留活性的细胞中产生，例如CHO细胞(例如DG44CHO细胞)。
iii.乙酰透明质酸降解酶的糖基化
包括透明质酸酶在内的一些乙酰透明质酸降解酶的糖基化对于它们的催化活性和稳定性可以是非常重要的，所述糖基化包括N-和O-联糖基化。虽然改变修饰糖蛋白的聚糖类型可以对蛋白的抗原性、结构折叠、溶解性和稳定性有巨大影响，但是并不认为大多数酶为了最佳酶活性而需要糖基化。对于一些透明质酸酶，去除N-联糖基化可以导致透明质酸酶活性的几乎完全失活。因此，对于这类透明质酸酶，N-联聚糖的存在对于产生活性酶是必需的。
N-联寡糖分为几个主要类型(甘露低聚糖、复杂、杂合、硫酸化)，全部具有通过属于-Asn-Xaa-Thr/Ser-序列(其中Xaa不是Pro)的Asn残基的酰胺氮来连接的(Man)3-GlcNAc-GlcNAc-核心。对于凝固蛋白C已报道在-Asn-Xaa-Cys-位点的糖基化。在某些情况下，乙酰透明质酸降解酶如透明质酸酶可以包含N-糖苷键和O-糖苷键。例如，PH20具有O-联寡糖以及N-联寡糖。在SEQ ID NO:1示例的人PH20的N82、N166、N235、N254、N368、N393、N490处有7个潜在的N-联糖基化位点。氨基酸残基N82、N166和N254被复杂型聚糖占据，而氨基酸残基N368和N393被高甘露糖型聚糖占据。氨基酸残基N235约80％被高甘露糖型聚糖且20％被复杂型聚糖占据。如上文所述，在N490处的N-联糖基化不是透明质酸酶活性所必需的。
在一些实例中，用于所提供的组合物、组合和/或方法的乙酰透明质酸降解酶在一个或全部糖基化位点糖基化。例如，对于人PH20或其可溶形 式，对应于SEQ ID NO:1的氨基酸N82、N166、N235、N254、N368和N393的N-糖基化位点中的2、3、4、5或6个糖基化。在一些实例中，乙酰透明质酸降解酶在一个或多个天然糖基化位点糖基化。在其他实例中，在一个或多个非天然糖基化位点修饰乙酰透明质酸降解酶以在一个或多个额外的位点赋予多肽的糖基化。在这类实例中，额外的糖部分的附着可以增强分子的药物动力学特性，如改善的半衰期和/或改善的活性。
在其他实例中，用于本文提供的组合物、组合和/或方法的乙酰透明质酸降解酶部分去糖基化(或N-部分糖基化的多肽)。例如，保留完全糖基化的透明质酸酶的全部或部分透明质酸酶活性的部分去糖基化的可溶性PH20多肽可以用于本文提供的组合物、组合和/或方法。示例性部分去糖基化的透明质酸酶包括来自任何物种的部分去糖基化的PH20多肽的可溶形式，例如SEQ ID NO:1、2、11、25、27、29-32、63、65和101-102中任一个所示的任何多肽，或者它们的等位基因变体、截短变体或其他变体。这类变体是本领域技术人员已知的，并且包括与SEQ ID NO:1、2、11、25、27、29-32、63、65和101-102中任一个具有60％、70％、80％、90％、91％、92％、93％、94％、95％或更多序列相同性的多肽，或者它们的截短形式。本文提供的部分去糖基化的透明质酸酶还包括杂合、融合和嵌合的部分去糖基化的透明质酸酶以及部分去糖基化的透明质酸酶缀合物。
糖苷酶或糖苷水解酶是催化糖苷键的水解以产生两个较小的糖的酶。脊椎动物中N-聚糖的主要类型包括高甘露糖聚糖、杂合聚糖和复杂聚糖。有几种导致仅部分蛋白去糖基化的糖苷酶，包括：EndoF1，其切割高甘露糖和杂合型聚糖；EndoF2，其切割二分支的复杂型聚糖；EndoF3，其切割二分支和更多分支的复杂聚糖；以及EndoH，其切割高甘露糖和杂合型聚糖。用这些糖苷酶的一种或全部来处理乙酰透明质酸降解酶，如可溶性透明质酸酶，如可溶性PH20，可以导致仅部分去糖基化并因此保留透明质酸酶活性。
部分去糖基化的乙酰透明质酸降解酶如部分去糖基化的可溶性透明质酸酶可以通过用一种或多种糖苷酶消化来制备，所述糖苷酶一般是不去除全部N-聚糖而仅使蛋白质部分去糖基化的糖苷酶。例如，用上述糖苷酶中的一种或全部(例如EndoF1、EndoF2和/或EndoF3)处理PH20(例如命名为 rHuPH20的重组PH20)导致部分去糖基化。这些部分去糖基化的PH20多肽可以表现出与完全糖基化的多肽可比的透明质酸酶酶促活性。相比之下，用切割所有N-聚糖的糖苷酶PNGaseF处理PH20导致完全去除所有N-聚糖，从而使得PH20酶促失活。因此，尽管所有N-联糖基化位点(例如在SEQ ID NO:1示例的人PH20的氨基酸N82、N166、N235、N254、N368和N393处的那些位点)均可以糖基化，但是用一种或多种糖苷酶处理可以使得与未用一种或多种糖苷酶消化的透明质酸酶相比，糖基化程度降低。
部分去糖基化的乙酰透明质酸降解酶，包括部分去糖基化的可溶性PH20多肽可以具有完全糖基化的多肽的糖基化水平的10％、20％、30％、40％、50％、60％、70％或80％。在一实例中，对应于SEQ ID NO:1的氨基酸N82、N166、N235、N254、N368和N393的N-糖基化位点中的1、2、3、4、5或6个部分糖基化，从而它们不再包含高甘露糖或复杂型聚糖，而是包含至少一个N-乙酰葡糖胺部分。在一些实例中，对应于SEQ ID NO:1的氨基酸N82、N166和N254的N-糖基化位点中的1、2或3个去糖基化，即它们不含糖部分。在其他实例中，对应于SEQ IDNO:1的氨基酸N82、N166、N235、N254、N368和N393的N-糖基化位点中的3、4、5或6个糖基化。糖基化的氨基酸残基最少包含N-乙酰葡糖胺部分。通常，部分去糖基化的乙酰透明质酸降解酶，包括部分去糖基化的可溶性PH20多肽表现出是完全糖基化的多肽所表现的透明质酸酶活性的10％、20％、30％、40％、50％、60％、70％、80％、90％、100％、110％、120％、130％、140％、150％、200％、300％、400％、500％、1000％或更多的透明质酸酶活性。
iv.修饰的(聚合物-缀合的)乙酰透明质酸降解酶
在一实例中，所提供的组合物和组合包含已通过缀合于一个或多个聚合物分子(聚合物)而修饰的乙酰透明质酸降解酶，特别是可溶性透明质酸酶，通常以便增加乙酰透明质酸降解酶的半衰期，例如以便促进对象中延长/持续的治疗效果。
将聚合物分子如聚乙二醇(聚乙二醇化部分(PEG))共价或其他稳定方式附着至乙酰透明质酸降解酶如透明质酸酶，赋予所得的乙酰透明质酸降解 酶-聚合物组合物有益特性。这类特性包括改善的生物相容性、蛋白(和酶促活性)在对象内的血液、细胞和/或组织中的半衰期延长、有效保护蛋白免于蛋白酶和水解、改善的生物分布、增强的药物动力学和/或药效学以及增加的水溶性。
因此，在本文的具体实例中，将乙酰透明质酸降解酶缀合至聚合物。聚合物的实例例如多元醇(即poly-OH)、聚胺(即poly-NH2)和聚羧酸(即poly-COOH)；以及其他杂聚物，即包含一种或多种不同的偶联基团如羟基和氨基的聚合物。合适的聚合物分子的实例包括选自以下分子的聚合物分子：聚亚烷基氧化物(PAO)，如聚亚烷基二醇(PAG)，包括聚乙二醇(PEG)、甲氧基聚乙二醇(mPEG)和聚丙二醇；PEG-缩水甘油醚(Epox-PEG)；PEG-氧羰基咪唑(CDI-PEG)；支化聚乙二醇(PEG)；聚乙烯醇(PVA)；聚羧酸酯；聚乙烯吡咯烷酮；聚-D,L-氨基酸；聚乙烯-共-马来酸酐(polyethylene-co-maleic acid anhydride)；聚苯乙烯-共-马来酸酐(polystyrene-co-maleic acid anhydride)；葡聚糖，包括羧甲基-葡聚糖；肝素；同源白蛋白；纤维素，包括甲基纤维素、羧甲基纤维素、乙基纤维素、羟乙基纤维素、羧乙基纤维素和羟丙基纤维素；壳聚糖的水解产物；淀粉，如羟乙基-淀粉和羟丙基-淀粉；糖原；琼脂糖及其衍生物；瓜耳胶；支链淀粉；菊粉；黄原胶；鹿角菜胶；果胶；海藻酸水解产物；以及生物聚合物。
具体地，聚合物为聚乙二醇(PEG)。附着至乙酰透明质酸降解酶的合适的聚合物分子包括但不限于聚乙二醇(PEG)和PEG衍生物，如甲氧基-聚乙二醇(mPEG)、PEG-缩水甘油醚(Epox-PEG)、PEG-氧羰基咪唑(CDI-PEG)、支化PEG和聚环氧乙烷(PEO)(参见例如Robertset al.,Advanced Drug Delivery Review(2002)54:459-476；Harris and Zalipsky,S(eds.)"Poly(ethy1ene glycol),Chemistry and Biological Applications"ACSSymposium Series680,1997；Mehvar et al.,J.Pharm.Pharmaceut.Sci.,3(1):125-136,2000；Harris,(2003)Nature Reviews Drug Discovery2:214-221；和Tsubery,(2004)J Biol.Chem279(37):38118-24)。聚合物分子的分子量通常可以为约3kDa至约60kDa。在一些实施方案中，缀合至蛋白如rHuPH20的聚合物分子具有5、10、15、20、25、30、35、40、45、50、55、60或大于60kDa的分子量。
通过共价附着(缀合)PEG或PEG衍生物而修饰多肽(即“聚乙二醇化”)的各种方法是本领域已知的(参见例如，U.S.2006/0104968；U.S.5,672,662；U.S.6,737,505；和U.S.2004/0235734)。这类技术在本文其他地方描述。
2.药物组合物和制剂
本文提供抗乙酰透明质酸剂如乙酰透明质酸降解酶或其修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如聚乙二醇化的透明质酸酶)的药物组合物用于所提供的治疗方法。本文还提供包含用来治疗与乙酰透明质酸相关疾病或疾病状况相关的疾病或病症如癌症的第二物质。这类物质的实例包括但不限于抗癌剂，包括药物、多肽、核酸、抗体、肽、小分子、基因治疗载体、病毒和其他治疗剂。抗乙酰透明质酸剂如乙酰透明质酸降解酶或其修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如聚乙二醇化的透明质酸酶或PEGPH20)可以与这类第二物质的药物制剂共同配制或共给药以增加它们递送至与过量或积累的乙酰透明质酸相关的体内的期望部位或组织。
鉴于监管机构或其他机构的批准根据公认的药典制备药学可接受的组合物用于动物和人。化合物可以配制为任何合适的药物制剂用于任何口服或静脉内给药，例如溶液剂、混悬剂、散剂或缓释制剂。通常，利用本领域公知的技术和方法将化合物配制为药物组合物(参见例如，Ansel Introduction to Pharmaceutical Dosage Forms,FourthEdition,1985,126)。所述制剂应当适合给药模式。
在一实例中，药物制剂可以为液体形式，例如溶液剂、糖浆剂或混悬剂。如果以液体形式提供，所述药物制剂可以提供为浓缩制剂，在使用之前稀释至治疗有效浓度。这类液体制剂可以通过常规方法用药学可接受的添加剂制备，如悬浮剂(例如，山梨醇糖浆、纤维素衍生物或氢化食用脂肪)；乳化剂(例如，卵磷脂或阿拉伯胶)；非水性媒介物(例如，杏仁油、油酯或分馏植物油)；和防腐剂(例如，甲基或丙基对羟基苯甲酸酯或山梨酸)。在另一实例中，药物制剂可以以冻干形式存在，在使用之前用水或其他合适的媒介物还原。
药物组合物可以包含与组合物(例如皮质类固醇或抗乙酰透明质酸剂， 如聚乙二醇化的乙酰透明质酸降解酶)一起给药的载体，如稀释剂、佐剂、赋形剂或媒介物。合适的药物载体的实例在E.W.Martin的"Remington's Pharmaceutical Sciences"中描述。这类组合物包含一般为纯化形式或部分纯化形式的治疗有效量的化合物或物质，连同适量的载体以便提供适合给药至患者的形式。这类药物载体可以为无菌液体，如水和油，包括石油、动物、植物或合成来源的油，如花生油、大豆油、矿物油和芝麻油。水是典型的载体。盐水溶液以及葡萄糖和甘油水溶液也可以用作液体载体，特别是用于可注射溶液。除活性成分以外，组合物可以包含：稀释剂，如乳糖、蔗糖、磷酸二钙或羧甲基纤维素；润滑剂，如硬脂酸镁、硬脂酸钙和滑石；以及粘合剂，如淀粉、诸如阿拉伯树胶的天然树胶、明胶、葡萄糖、糖蜜、聚乙烯吡咯烷酮、纤维素及其衍生物、聚维酮、交聚维酮以及本领域技术人员已知的其他此类粘合剂。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酰酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇(propylene,glycol)、水和乙醇。例如，合适的赋形剂为水、盐水、葡萄糖、甘油或乙醇。如果期望，组合物还可以包含其他少量的无毒辅助物质如湿润或乳化剂、pH缓冲剂、稳定剂、增溶剂以及其他这样的物质，例如乙酸钠、失水山梨糖醇单月桂酸酯、油酸三乙醇胺和环糊精。
用于肠胃外制剂的药学可接受的载体包括水性媒介物、非水性媒介物、抗微生物剂、等渗剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮和分散剂、乳化剂、多价螯合或螯合剂以及其他药学可接受的物质。水性媒介物的实例包括氯化钠注射液、林格氏注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖和乳酸盐林格氏注射液。非水性肠胃外媒介物包括植物来源的不挥发性油、棉子油、玉米油、芝麻油和花生油。包装在多剂量容器中的肠胃外制剂中可以添加抑制细菌或抑制真菌浓度的抗微生物剂，包括酚或甲酚、汞制剂、苯甲醇、氯代丁醇、甲基和丙基对羟基苯甲酸酯、硫柳汞、苯扎氯铵和苄索氯铵。等渗剂包括氯化钠和葡萄糖。缓冲剂包括磷酸盐和柠檬酸盐。抗氧化剂包括硫酸氢钠。局部麻醉剂包括盐酸普鲁卡因。悬浮和分散剂包括羧甲基纤维素钠、羟丙基甲基纤维素和聚乙烯吡咯烷酮。乳化剂包括聚山梨酯80(TWEEN80)。金属离子的多价螯合或螯合剂包括EDTA。 药物载体还包括用于水混溶的媒介物的乙醇、聚乙二醇和丙二醇以及用于pH调整的氢氧化钠、盐酸、柠檬酸或乳酸。
注射剂(injectable)可以制备为液体溶液剂或混悬剂的常规形式，适合在注射前溶解或悬浮于液体中的固体形式，或者乳剂。用于前列腺内给药的制剂包括准备注射用的无菌溶液，无菌干可溶产物如冻干粉，准备在使用之前与溶剂组合，包括皮下注射用片剂，准备注射用的无菌混悬剂，准备在使用之前与媒介物组合的无菌干不可溶产物，无菌乳剂。溶液剂可以是水性或非水性的。
3.剂量和给药
通常，抗乙酰透明质酸剂如乙酰透明质酸降解酶的剂量是在治疗乙酰透明质酸相关疾病或疾病状况如癌症中还获得疗效的剂量。因此，抗乙酰透明质酸剂如乙酰透明质酸降解酶的组合物包括足以发挥治疗有用效果的量。包含活性剂的组合物可以包括药学可接受的载体。抗乙酰透明质酸剂的组合物还可以包括第二治疗剂。
抗乙酰透明质酸剂如乙酰透明质酸降解酶的治疗有效浓度可以通过在已知的体外和体内系统中测试化合物来凭经验确定，如本文提供的测定。例如，抗乙酰透明质酸剂如乙酰透明质酸降解酶或其修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如聚乙二醇化的透明质酸酶)的浓度取决于吸收、失活和排泄速率，物理化学特征，剂量方案，给药的量以及本领域技术人员已知的其他因素。例如，应当理解精确剂量和治疗持续时间是治疗的组织、治疗的疾病或疾病状况、给药途径、患者或对象以及特定抗乙酰透明质酸剂的函数，并且可以利用已知的测试方案凭经验确定或者通过从体内或体外测试数据外推和/或可以从特定物质的已知剂量给药方案确定。给药用于治疗疾病或疾病状况，例如乙酰透明质酸相关疾病或疾病状况如HA丰富的肿瘤的抗乙酰透明质酸剂如乙酰透明质酸降解酶或其修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如聚乙二醇化的透明质酸酶)的量可以通过标准临床技术来确定。此外，体外测定和动物模型可以用来帮助鉴定最佳剂量范围。可以凭经验确定的精确剂量可以取决于特定的酶、给药途径、治疗的疾病类型和疾病的严重程度。
例如，利用抗乙酰透明质酸剂如乙酰透明质酸降解酶或其修饰形式(例如聚乙二醇化形式)治疗乙酰透明质酸相关疾病和疾病状况的方法是本领域公知的(参见例如美国公开申请第20100003238号和国际公开PCT申请第WO2009/128917号)。因此，抗乙酰透明质酸剂如乙酰透明质酸降解酶，例如透明质酸酶的剂量可以基于在给定给药路线下该物质的标准剂量给药方案来选择。
用于治疗乙酰透明质酸相关疾病或疾病状况的抗乙酰透明质酸剂的有效剂量的实例为0.01μg-100g/kg体重的剂量。例如，抗乙酰透明质酸剂的有效量为0.01μg-100mg/kg体重的剂量，例如0.01μg-1mg/kg体重、1μg-100μg/kg体重、1μg-10μg/kg体重或0.01mg-100mg/kg体重。例如，有效量包括至少或约至少或约或0.01μg、0.05、0.1、0.5、1、2、3、4、5、6、7、8、9、10、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、200、300、400、500、600、700、800、900或1000μg/kg体重。有效量的其他实例包括0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、2、3、4、5、6、7、8、9、10、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100g/kg体重。例如，抗乙酰透明质酸剂如乙酰透明质酸降解酶，例如透明质酸酶(例如聚乙二醇化的透明质酸酶如PEGPH20)可以以0.1μg/kg-1mg/kg或约0.1μg/kg-1mg/kg给药，例如0.5μg/kg-100μg/kg、0.75μg/kg-15μg/kg、0.75μg/kg-7.5μg/kg或1.0μg/kg-3.0μg/kg。在其他实例中，抗乙酰透明质酸剂如乙酰透明质酸降解酶，例如透明质酸酶(例如聚乙二醇化的透明质酸酶如PEGPH20)可以以或1mg/kg-500mg/kg给药，例如100mg/kg-400mg/kg，如200mg/kg。例如，组合物包含0.5mg-100克抗乙酰透明质酸剂，例如20μg-1mg，如100μg-0.5mg，或者可以包含1mg-1克，例如5mg-500mg。
例如，治疗乙酰透明质酸相关疾病或疾病状况的物质和治疗如抗癌剂是本领域公知的(参见例如美国公开申请第20100003238号和国际公开PCT申请第WO2009/128917号)。因此，乙酰透明质酸降解酶如透明质酸酶的剂量或者组合物中的其他第二物质可以基于在给定给药途径下该物质的标准剂量给药方案来选择。
乙酰透明质酸降解酶的有效量的实例为0.01μg-100g/kg体重的剂量。例如，乙酰透明质酸降解酶的有效量为0.01μg-100mg/kg体重的剂量，例如0.01μg-1mg/kg体重、1μg-100μg/kg体重、1μg-10μg/kg体重或0.01mg-100mg/kg体重。例如，有效量包括至少或约至少或约或0.01μg、0.05、0.1、0.5、1、2、3、4、5、6、7、8、9、10、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、200、300、400、500、600、700、800、900或1000μg/kg体重。有效量的其他实例包括0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、2、3、4、5、6、7、8、9、10、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100g/kg体重。例如，乙酰透明质酸降解酶如透明质酸酶(例如聚乙二醇化的透明质酸酶如PEGPH20)可以以0.1μg/kg-1mg/kg或约0.1μg/kg-1mg/kg给药，例如0.5μg/kg-100μg/kg、0.75μg/kg-15μg/kg、0.75μg/kg-7.5μg/kg或1.0μg/kg-3.0μg/kg。在其他实例中，乙酰透明质酸降解酶如透明质酸酶(例如聚乙二醇化的透明质酸酶如PEGPH20)可以以或1mg/kg-500mg/kg给药，例如100mg/kg-400mg/kg，如200mg/kg。一般来说，组合物包含0.5mg-100克乙酰透明质酸降解酶，例如20μg-1mg，如100μg-0.5mg，或者可以包含1mg-1克，例如5mg-500mg。
剂量或组合物可以用于单一剂量给药或用于多剂量给药。剂量或组合物可以一次，每周几次，每周两次，每15天、16天、17、18、19、20、21、22、23、24、25、26、27、28、29或30天，每月一次，每年几次或每年以单一给药来给药。在其他实例中，剂量或组合物可以分开，并且一次，每周几次，每周两次，每15天、16天、17、18、19、20、21、22、23、24、25、26、27、28、29或30天，每月一次，每年几次或每年给药。乙酰透明质酸降解酶组合物可以配制为液体组合物，或者可以冻干。所述组合物还可以配制为片剂或胶囊剂。
下文提供用于本文的方法的缀合至聚合物(例如聚乙二醇化)的示例性乙酰透明质酸降解酶的剂量和剂量方案的描述。乙酰透明质酸降解酶可以在单一物质疗法中单独使用，或者与其他物质组合用于治疗HA相关疾病或疾病状况如癌症。如本文其他地方所讨论的，特别是本文的方法和用途 的实例，所述物质可以与皮质类固醇组合给药以减轻与抗乙酰透明质酸剂治疗相关的副作用。
a.聚乙二醇化的乙酰透明质酸降解酶的给药
乙酰透明质酸降解酶如聚乙二醇化的乙酰透明质酸降解酶(例如透明质酸酶)可以全身给药，例如静脉内(IV)、肌肉内或通过任何其他全身途径。在特定实例中，可以局部给予较低剂量。例如，乙酰透明质酸降解酶如聚乙二醇化的乙酰透明质酸降解酶，例如聚乙二醇化的透明质酸酶(例如PH20)的局部给药包括肿瘤内给药、动脉注射(例如肝动脉)、腹腔内给药、膀胱内给药以及用于癌症治疗的可以增加较低绝对剂量的局部作用的其他局部途径。
示例性剂量范围为或约为0.3单位/kg-320,000单位/kg，例如10单位/kg-320,000单位/kg的聚乙二醇化的透明质酸酶，或者功能等同量的另一聚乙二醇化的乙酰透明质酸降解酶。在本文中应当理解将活性单位归一化至标准活性，例如，在测定透明质酸酶活性的微浊度(microturbidity)测定中测量的活性。与没有这样缀合的天然可溶性透明质酸酶相比，聚乙二醇化的可溶性透明质酸酶可以表现出较低的活性每mg总蛋白，即表现出较低的特异性活性。例如，示例性rHuPH20制品表现出120,000单位/mg的特异性活性，而rHuPH20的聚乙二醇化形式表现出为或约为32,000单位/mg的特异性活性。通常，乙酰透明质酸降解酶如透明质酸酶，例如rHuPH20的聚乙二醇化的形式表现出为或约为18,000至为或约为45,000U/mg之间的范围内的特异性活性。在一实例中，PEG-乙酰透明质酸降解酶可以提供为3.5mg/mL112,000U/mL(～32,000U/mg)的储备溶液，PEG比蛋白摩尔比在5:1和9:1之间，例如7:1，或者可以以较不浓缩的形式提供。为了本文的目的，剂量可以参考单位。
例如，聚乙二醇化的乙酰透明质酸降解酶如透明质酸酶，例如PEGPH20可以每周两次、每周一次或每21天一次静脉内给药。通常，聚乙二醇化的乙酰透明质酸降解酶每周两次给药。给药周期可以为一定时期，一般为3周或4周。给药周期在剂量方案中可以重复超过1个月、2个月、3个月、4个月、5个月、6个月、7个月、8个月、9个月、10个月、11 个月、1年或更久。一般来说，给药周期由治疗医生自行决定重复，并且可以取决于许多因素，例如疾病或疾病状况的缓解、疾病或疾病状况的严重程度、不良事件和其他因素。在其他实例中，在随后的给药周期中，乙酰透明质酸降解酶可以较不频繁地给药。例如，在第一周期中，乙酰透明质酸降解酶每周两次给药，持续4周，而在随后的给药周期中，乙酰透明质酸降解酶每周一次或每两周一次、每3周一次(例如每21天一次)或每4周一次给药。如本文所述，皮质类固醇的剂量或剂量给药方案取决于乙酰透明质酸降解酶的剂量给药方案。
虽然剂量可以根据疾病和患者变化，但是乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶一般以为或约为0.01μg/kg如0.0005mg/kg(0.5μg/kg)至10mg/kg(320,000U/kg)的范围，例如0.02mg/kg-1.5mg/kg，例如0.05mg/kg的量给药。聚乙二醇化的透明质酸酶可以以为或约为0.0005mg/kg(的对象)、0.0006mg/kg、0.0007mg/kg、0.0008mg/kg、0.0009mg/kg、0.001mg/kg、0.0016mg/kg、0.002mg/kg、0.003mg/kg、0.004mg/kg、0.005mg/kg、0.006mg/kg、0.007mg/kg、0.008mg/kg、0.009mg/kg、0.01mg/kg、0.016mg/kg、0.02mg/kg、0.03mg/kg、0.04mg/kg、0.05mg/kg、0.06mg/kg、0.07mg/kg、0.08mg/kg、0.09mg/kg、0.1mg/kg、0.15mg/kg、0.2mg/kg、0.25mg/kg、0.30mg/kg、0.35mg/kg、0.40mg/kg、0.45mg/kg、0.5mg/kg、0.55mg.kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.1mg/kg、1.2mg/kg、1.3mg/kg、1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2mg/kg、2.5mg/kg、3mg/kg、3.5mg/kg、4mg/kg、4.5mg/kg、5mg/kg、5.5mg/kg、6mg/kg、6.5mg/kg、7mg/kg、7.5mg/kg、8mg/kg、8.5mg/kg、9mg/kg、9.5mg/kg、10mg/kg、11mg/kg、12mg/kg、13mg/kg、14mg/kg、15mg/kg、16mg/kg、17mg/kg、18mg/kg、19mg/kg、20mg/kg、21mg/kg、22mg/kg、23mg/kg、24mg/kg、25mg/kg的剂量给药，或者更多给药至平均成年人对象，通常体重约70kg-75kg。在具体实例中，乙酰透明质酸降解酶以较低的量给药，如少于20μg/kg，例如0.01μg/kg-15μg/kg、0.05μg/kg-10μg/kg、0.75μg/kg-7.5μg/kg或1.0μg/kg-3.0μg/kg。
本文提供的乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶(例如PH20)，例如PEGPH20可以以为或约为1单位/kg-800,000单位/kg给药的 对象的体重给药，例如10-800,000单位/kg、10-750,000单位/kg、10-700,000单位/kg、10-650,000单位/kg、10-600,000单位/kg、10-550,000单位/kg、10-500,000单位/kg、10-450,000单位/kg、10-400,000单位/kg、10-350,000单位/kg、10-320,000单位/kg、10-300,000单位/kg、10-280,000单位/kg、10-260,000单位/kg、10-240,000单位/kg、10-220,000单位/kg、10-200,000单位/kg、10-180,000单位/kg、10-160,000单位/kg、10-140,000单位/kg、10-120,000单位/kg、10-100,000单位/kg、10-80,000单位/kg、10-70,000单位/kg、10-60,000单位/kg、10-50,000单位/kg、10-40,000单位/kg、10-30,000单位/kg、10-20,000单位/kg、10-15,000单位/kg、10-12,800单位/kg、10-10,000单位/kg、10-9,000单位/kg、10-8,000单位/kg、10-7,000单位/kg、10-6,000单位/kg、10-5,000单位/kg、10-4,000单位/kg、10-3,000单位/kg、10-2,000单位/kg、10-1,000单位/kg、10-900单位/kg、10-800单位/kg、10-700单位/kg、10-500单位/kg、10-400单位/kg、10-300单位/kg、10-200单位/kg、10-100单位/kg、16-600,000单位/kg、16-500,000单位/kg、16-400,000单位/kg、16-350,000单位/kg、16-320,000单位/kg、16-160,000单位/kg、16-80,000单位/kg、16-40,000单位/kg、16-20,000单位/kg、16-16,000单位/kg、16-12,800单位/kg、16-10,000单位/kg、16-5,000单位/kg、16-4,000单位/kg、16-3,000单位/kg、16-2,000单位/kg、16-1,000单位/kg、16-900单位/kg、16-800单位/kg、16-700单位/kg、16-500单位/kg、16-400单位/kg、16-300单位/kg、16-200单位/kg、16-100单位/kg、160-12,800单位/kg、160-8,000单位/kg、160-6,000单位/kg、160-4,000单位/kg、160-2,000单位/kg、160-1,000单位/kg、160-500单位/kg、500-5000单位/kg、1000-100,000单位/kg或1000-10,000单位/kg。在一些实例中，本文提供的乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶(例如PH20)，例如PEGPH20可以以为或约为1单位/kg-1000单位/kg、1单位/kg-500单位/kg或10单位/kg-50单位/kg给药。
一般来说，当聚乙二醇化的透明质酸酶的特异性活性为或约为18,000U/mg-45,000U/mg时，一般为或约为1单位/kg(U/kg)、2U/kg、3U/kg、4U/kg、5U/kg、6U/kg、7U/kg、8U/kg、8U/kg、10U/kg、16U/kg、32U/kg、64U/kg、100U/kg、200U/kg、300U/kg、400U/kg、500U/kg、600U/kg、700U/kg、800U/kg、900U/kg、1,000U/kg、2,000U/kg、3,000U/kg、4,000 U/kg、5,000U/kg、6,000U/kg、7,000U/kg、8,000U/kg、9,000U/kg、10,000U/kg、12,800U/kg、20,000U/kg、32,000U/kg、40,000U/kg、50,000U/kg、60,000U/kg、70,000U/kg、80,000U/kg、90,000U/kg、100,000U/kg、120,000U/kg、140,000U/kg、160,000U/kg、180,000U/kg、200,000U/kg、220,000U/kg、240,000U/kg、260,000U/kg、280,000U/kg、300,000U/kg、320,000U/kg、350,000U/kg、400,000U/kg、450,000U/kg、500,000U/kg、550,000U/kg、600,000U/kg、650,000U/kg、700,000U/kg、750,000U/kg、800,000U/kg或更多，每对象体重，将其给药。
在一些方面，将聚乙二醇化的乙酰透明质酸降解酶配制并剂量给药以维持血浆中至少3U/mL的聚乙二醇化的透明质酸酶(参见例如公开的美国专利申请第US20100003238号和公开的国际专利申请第WO2009128917号)。例如，以足量配制聚乙二醇化的可溶性透明质酸酶用于全身给药以维持血浆中至少或约3U/mL，一般3U/mL-12U/mL或更多，例如至少或约或在4U/mL、5U/mL、6U/mL、7U/mL、8U/mL、9U/mL、10U/mL、11U/mL、12U/mL、13U/mL、14U/mL、15U/mL、16U/mL、17U/mL、18U/mL、19U/mL、20U/mL、25U/mL、30U/mL、35U/mL、40U/mL、45U/mL、50U/mL或更多的水平。一般来说，为了本文维持血浆中至少3U/mL的透明质酸酶的目的，给药为或约为0.02mg/kg(对象)、0.03mg/kg、0.04mg/kg、0.05mg/kg、0.06mg/kg、0.07mg/kg、0.08mg/kg、0.09mg/kg、0.1mg/kg、0.15mg/kg、0.2mg/kg、0.25mg/kg、0.30mg/kg、0.35mg/kg、0.40mg/kg、0.45mg/kg、0.5mg/kg、0.55mg.kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.1mg/kg、1.2mg/kg、1.3mg/kg、1.4mg/kg、1.5mg/kg或更多。一般来说，当修饰的透明质酸酶的特异性活性为或约为20,000U/mg-60,000U/mg时，一般给药为或约为35,000U/mg、60,000U；70,000U；80,000U；90,000U；100,000U；200,000U；300,000U；400,000U；500,000U；600,000U；700,000U；800,000U；900,000U；1,000,000U；1,500,000U；2,000,000U；2,500,000U；3,000,000U；3,500,000U；4,000,000U或更多。为了维持这样的水平，给药可以每天、每周几次、每周两次、每周或每个月。
确定聚乙二醇化的乙酰透明质酸降解酶如聚乙二醇化的PH20的量以 维持血液中至少3U/mL的透明质酸酶在本领域技术人员的水平之内。可以随时间监测血液中的透明质酸酶水平以确保血液中存在足量的透明质酸酶。可以进行本领域技术人员已知的测量血浆中的透明质酸酶的任何测定。例如，可以对血浆中的蛋白进行本文实施例中描述的微浊度测定或酶促测定。应当理解血浆通常包含透明质酸酶。这类血浆透明质酸酶通常在酸性pH下具有活性(美国专利第7,105,330号)。因此，在用修饰的酶治疗之前，应当确定透明质酸酶的血浆水平并用作基线。随后治疗之后血浆透明质酸酶水平的测量可以与治疗之前的水平进行比较。或者，可以在抑制通常在酸性条件下表现出活性的血浆中的内源性溶酶体透明质酸酶活性的pH条件下进行测定。因此，当修饰的可溶性透明质酸酶在中性pH下有活性时(例如人PH20)，仅测量修饰的在中性条件下有活性的可溶性透明质酸酶的活性。
在其他实例中，将聚乙二醇化的乙酰透明质酸降解酶以较低剂量配制并给药，本文发现这对治疗在血液中没有维持的可检测水平的透明质酸酶的乙酰透明质酸相关疾病或疾病状况具有疗效。例如，将聚乙二醇化的可溶性透明质酸酶以少于20μg/kg的量给药，例如0.01μg/kg-15μg/kg、0.05μg/kg-10μg/kg、0.75μg/kg-7.5μg/kg或1.0μg/kg-3.0μg/kg，如为或约为0.01μg/kg(对象)、0.02μg/kg、0.03μg/kg、0.04μg/kg、0.05μg/kg、1.0μg/kg、1.5μg/kg、2.0μg/kg、2.5μg/kg、3.0μg/kg、3.5μg/kg、4.0μg/kg、4.5μg/kg、5.0μg/kg、5.5μg/kg、6.0μg/kg、7.0μg/kg、7.5μg/kg、8.0μg/kg、9.0μg/kg、10.0μg/kg、12.5μg/kg或15μg/kg。一般来说，当修饰的透明质酸酶的特异性活性为或约为20,000U/mg-60,000U/mg时，一般为或约为35,000U/mg，给药200单位-50,000(U)，例如给药200U、300U；400U；500U；600U；700U；800U；900U；1,000U；1250U；1500U；2000U；3000U；4000U；5,000U；6,000U；7,000U；8,000U；9,000U；10,000U；20,000U；30,000U；40,000U；或50,000U。为了维持这样的水平，给药可以每天、每周几次、每周两次、每周或每个月。
通常，本文考虑的聚乙二醇化的透明质酸酶的注射或输液体积为或约为0.5mL、1mL、2mL、3mL、4mL、5mL、6mL、7mL、8mL、9mL、10mL、15mL、20mL、30mL、40mL、50mL或更多。聚乙二醇化的乙 酰透明质酸降解酶如聚乙二醇化的透明质酸酶可以提供为或约为50U/mL、100U/mL、150U/mL、200U/mL、400U/mL或500U/mL(或者功能等同量)的储备溶液，或者可以以更浓缩的形式提供，例如为或约为1000U/mL、2000单位/mL、3000U/mL、4000U/mL、5000U/mL、6000U/mL、7000U/mL、8000U/mL、9000U/mL、10,000U/mL、11,000U/mL、12,000U/mL或12,800U/mL，直接使用或在使用之前稀释至有效浓度。给药的聚乙二醇化的乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶的体积是所需要的剂量的函数，但是可以根据乙酰透明质酸降解酶如可溶性透明质酸酶的浓度、可用的储备制剂变化。例如，本文考虑聚乙二醇化的乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶不以大于约50mL的体积给药，并且通常以5-30mL的体积给药，一般以不大于约10mL的体积给药。聚乙二醇化的乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶可以提供为液体或冻干制剂。冻干制剂对于储存大单位剂量的聚乙二醇化的乙酰透明质酸降解酶是理想的。
4.组合治疗
抗乙酰透明质酸剂如乙酰透明质酸降解酶或其修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶或聚乙二醇化的透明质酸酶如PEGPH20)可以在组织治疗中给药，例如用于治疗乙酰透明质酸相关疾病或疾病状况如癌症。抗乙酰透明质酸剂的组合物可以与其他治疗剂或药剂或者治疗如程序，例如治疗乙酰透明质酸相关疾病或疾病状况如乙酰透明质酸相关癌症的物质或治疗，共配制或者在一起、在其之前、间歇或随后共给药。这类物质包括但不限于其他生物制品、抗癌剂、小分子化合物、分散剂、麻醉剂、血管收缩剂和手术，以及它们的组合。可用于治疗疾病或疾病状况的这类其他物质和治疗，包括所有本文示例的那些，是本领域技术人员已知的或者可以凭经验确定。
第二物质或多种物质或者治疗或多种治疗的制剂可以一次给药，或者可以分为以时间间隔给药的许多较小剂量。所选的物质/治疗制剂可以在治疗时间的过程中，例如在几小时、几天、几周或几个月中以一个或多个剂量给药。在某些情况下，连续给药是有用的。应当理解精确剂量和给药过 程取决于适应症和患者的耐受性。一般来说，本文的第二物质/治疗的剂量给药方案是本领域技术人员已知的。
在一实例中，将抗乙酰透明质酸剂如乙酰透明质酸降解酶或其缀合至聚合物的修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如聚乙二醇化的透明质酸酶)与第二物质或治疗一起给药用于治疗疾病或疾病状况。在一实例中，抗乙酰透明质酸剂如乙酰透明质酸降解酶或其缀合至聚合物的修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶)以及第二物质或治疗可以共配制并一起给药。在另一实例中，将抗乙酰透明质酸剂如乙酰透明质酸降解酶或其缀合至聚合物的修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如聚乙二醇化的透明质酸酶)在第二物质或治疗制剂之后、间歇或同时给药。一般来说，在给药第二物质或治疗制剂之前给药抗乙酰透明质酸剂如乙酰透明质酸降解酶(例如聚乙二醇化的乙酰透明质酸降解酶)以允许所述药剂降低组织或细胞相关的乙酰透明质酸的水平或量。例如，在第二物质或治疗之前给药乙酰透明质酸降解酶如聚乙二醇化的乙酰透明质酸降解酶以允许该酶减少或降解对象的细胞、组织或流体如细胞间隙、胞外基质、肿瘤组织、血液或其他组织中的透明质酸。例如，抗乙酰透明质酸剂如乙酰透明质酸降解酶或其缀合至聚合物的修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如可溶性透明质酸酶)可以在给药第二物质制剂之前0.5分钟、1分钟、2分钟、3分钟、4分钟、5分钟、6分钟、7分钟、8分钟、9分钟、10分钟、20分钟、30分钟、1小时或更久给药。在一些实例中，将抗乙酰透明质酸剂如乙酰透明质酸降解酶或其缀合至聚合物的修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶)与第二物质制剂一起给药。本领域技术人员会理解，共给药的期望接近主要取决于所述物质在特定组织设置中的有效半衰期，以及治疗的特定疾病，并且可以通过在合适的模型如合适的动物模型中与不同时间测试给药所述物质的效果容易地优化。在某些情况下，给药抗乙酰透明质酸剂如乙酰透明质酸降解酶或其缀合至聚合物的修饰形式(例如聚乙二醇化的乙酰透明质酸降解酶，如聚乙二醇化的透明质酸酶)的最佳时间会超过60分钟。
例如，抗乙酰透明质酸剂如乙酰透明质酸降解酶可以与抗癌剂联合给药(参见例如美国公开第US2010-0003238号)。与乙酰透明质酸降解酶组合 使用的抗癌剂或治疗包括但不限于手术、辐射、药物、化疗剂、多肽、抗体、肽、小分子或基因治疗载体、病毒或DNA。
在其他实例中，本文提供的治疗方法包括除了乙酰透明质酸降解酶，给药一种或多种额外的抗乙酰透明质酸剂用于治疗的方法。抗乙酰透明质酸剂包括减少或消除肿瘤中HA的积累的任何物质。这类物质包括但不限于本文所述的乙酰透明质酸降解酶还有抑制HA合成的物质。例如，抑制乙酰透明质酸合成的抗乙酰透明质酸剂包括针对has基因的反义或正义分子。这类反义或正义抑制通常是基于寡核苷酸链或片段的基于氢键的杂交，从而至少一条链或片段被切割、降解或不可操作。在其他实例中，可以采用转录后基因沉默(PTGS)、RNAi、核糖核酸酶和DNA酶。基于HAS1(在SEQ ID NO:195中示出)、HAS2(在SEQ IDNO:196中示出)或HAS3(在SEQ ID NO:197或198中示出)的序列产生这类构建体在本领域技术人员的水平之内。在本领域中应当理解反义或正义化合物的序列不必与其可特异性杂交的靶核酸的序列100％互补。寡核苷酸可以在一个或多个片段上杂交，从而干预或相邻片段不参与杂交事件(例如环结构或发夹结构)。一般来说，反义或正义化合物与靶核酸内的靶区域具有至少70％序列互补性，例如75％-100％互补性，如75％、80％、85％、90％、95％或100％。示例性正义或反义分子是本领域已知的(参见例如Chao et al.(2005)J.Biol.Chem.280:27513-27522；Simpson et al.(2002)J.Biol.Chem.277:10050-10057；Simpson et al.(2002)Am.J Path.161:849；Nishida et al.(1999)J.Biol.Chem.274:21893-21899；Edward et al.(2010)British J Dermatology162:1224-1232；Udabage etal.(2005)Cancer Res.65:6139；和公开的美国专利申请第US20070286856号)。是HA合成抑制物的另一示例性抗乙酰透明质酸剂为4-甲基伞形酮(4-MU；7-羟基-4-甲基香豆素)或其衍生物。4-MU通过减少HA合成所需要的UDP-GlcUA前体池来发挥作用。其他示例性抗乙酰透明质酸剂为酪氨酸激酶抑制剂，例如来氟米特(爱若华)、染料木素或erbstatin。
在一些实例中，可以给药皮质类固醇以改善组合疗法中乙酰透明质酸降解酶的副作用或不良事件(参见例如美国专利申请第13/135,817号)。在一些实例中，糖皮质激素选自可的松、地塞米松、氢化可的松、甲泼尼龙、泼尼松龙和泼尼松。在一具体实例中，糖皮质激素为地塞米松。通常，皮 质类固醇口服给药，虽然考虑给药皮质类固醇的任何方法。通常，糖皮质激素以为或约为0.4-20mg的量给药，例如，为或约为0.4mg、0.5mg、0.6mg、0.7mg、0.75mg、0.8mg、0.9mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg或20mg/剂量。
F.制备乙酰透明质酸结合蛋白和乙酰透明质酸降解酶的核酸和所编码的多肽的方法
用于所提供的组合物和方法的乙酰透明质酸结合蛋白的多肽或者用于本文所示的治疗的乙酰透明质酸降解酶如可溶性透明质酸酶可以通过本领域公知的用于蛋白纯化和重组蛋白表达的方法获得。可以使用本领域技术人员已知的鉴别编码期望基因的核酸的任何方法。本领域可用的任何方法均可以用来例如从细胞或组织来源获得编码乙酰透明质酸结合蛋白或透明质酸酶的全长(即涵盖整个编码区)cDNA或者基因组DNA克隆。修饰或变异的乙酰透明质酸结合蛋白或透明质酸酶可以例如通过定向诱变从野生型多肽工程化。
利用本领域已知的用于克隆和分离核酸分子的任何可用方法可以克隆或分离多肽。这类方法包括核酸的PCR扩增和文库的筛选，包括核酸杂交筛选、基于抗体的筛选和基于活性的筛选。
用于核酸扩增的方法可以用来分离编码期望多肽的核酸分子，包括例如聚合酶链式反应(PCR)方法。包含原料的核酸可以用作起始原料，可以从其分离编码期望多肽的核酸分子。例如，DNA和mRNA制品、细胞提取物、组织提取物、流体样品(例如血液、血清、唾液)、来自健康和/或患病对象的样品可以用于扩增方法。核酸文库也可以用作起始原料的来源。引物可以设计为扩增期望多肽。例如，引物可以基于产生期望多肽的表达序列来设计。引物可以基于多肽氨基酸序列的回译来设计。通过扩增产生的核酸分子可以进行测序并确认编码期望多肽。
可以将额外的核苷酸序列加入编码多肽的核酸分子，包括为了将合成的基因克隆入载体的包含限制性内切核酸酶位点的接头序列，所述载体例如蛋白表达载体或为扩增编码核心蛋白的DNA序列而设计的载体。此外， 可以将指定功能DNA原件的额外的核苷酸序列可操作地连接至编码多肽的核酸分子。这类序列的实例包括但不限于设计为促进细胞内蛋白表达的启动子序列以及设计为促进蛋白分泌的分泌序列，例如异源信号序列。这类序列是本领域技术人员已知的。还可以将额外的核苷酸残基序列如指定蛋白结合区域的碱基序列连接至编码酶的核酸分子。这类区域包括但不限于促进或编码蛋白的残基序列，所述蛋白促进酶吸收入特定靶细胞或者改变合成基因的产物的药物动力学。例如，可以将酶连接至PEG部分。
此外，可以添加标签或其他部分，例如以辅助多肽的检测或亲和纯化。例如，还可以将额外的核苷酸残基序列如指定表位标签或其他可检测的标记的碱基序列连接至编码酶的核酸分子。这类序列的实例包括编码His标签(例如，6xHis,HHHHHH；SEQ ID NO:54)或Flag标签(DYKDDDDK；SEQ ID NO:55)的核酸序列。
然后可以将鉴定和分离的核酸插入适当的克隆载体。可以使用本领域已知的大量载体-宿主系统。可能的载体包括但不限于质粒或修饰的病毒，但是载体系统必须与所用的宿主细胞相容。这类载体包括但不限于噬菌体如λ衍生物，或者质粒如pCMV4、pBR322或pUC质粒衍生物，或者Bluescript载体(Stratagene,La Jolla,CA)。其他表达载体包括本文例示的HZ24表达载体。插入克隆载体可以，例如通过将DNA片段连接入具有互补粘性末端的克隆载体来完成。插入可以利用TOPO克隆载体(Invitrogen,Carlsbad,CA)来进行。如果克隆载体中不存在用来片段化DNA的互补限制性位点，则可以酶促修饰DNA分子的末端。或者，可以通过将核苷酸序列(接头)连接至DNA末端来产生期望的任何位点；这些连接的接头可以包含特定的化学合成的寡核苷酸，其编码限制性内切酶识别序列。在一可选方法中，可以通过同聚物加尾来修饰切割的载体和蛋白基因。可以将重组分子引入宿主细胞，通过例如转化、转染、感染、电穿孔和超声穿孔，从而产生基因序列的许多拷贝。
在具体实施方案中，用并入分离的蛋白基因的重组DNA分子、cDNA或合成的DNA序列转化宿主细胞使得能够产生基因的多个拷贝。因此，通过使转化子生长、从转化子分离重组DNA分子以及在必要时从分离的重组DNA回收插入的基因可以获得大量基因。
1.载体和细胞
为了重组表达一种或多种期望蛋白，例如本文所述的乙酰透明质酸结合蛋白或乙酰透明质酸降解酶，可以将包含全部或部分编码所述蛋白的核苷酸序列的核酸插入适当的表达载体，即包含对插入的蛋白编码序列的转录和翻译必需的元件的载体。必需的转录和翻译信号还可以通过酶基因和/或它们的侧翼区的天然启动子来提供。
本文还提供包含编码酶的核酸的载体。本文还提供包含所述载体的细胞。所述细胞包括真核和原核细胞，并且所述载体是适合在其中使用的任何载体。
本文提供包含载体的原核和真核细胞，包括内皮细胞。这类细胞包括细菌细胞、酵母细胞、真菌细胞、古细菌(Archea)、植物细胞、昆虫细胞和动物细胞。通过使上述细胞在细胞表达编码的蛋白的条件下生长并回收表达的蛋白来将细胞用于产生其蛋白。为了本文的目的，例如，酶可以分泌入培养基。
本文提供载体及其多个拷贝，所述载体包含偶联至天然或异源信号序列的编码乙酰透明质酸降解酶多肽(在一些实例中，可溶性透明质酸酶多肽)的核苷酸序列。可以选择载体用于在细胞中表达酶蛋白或者从而酶蛋白作为分泌蛋白表达。
各种宿主-载体系统可以用来表达蛋白编码序列。这些系统包括但不限于病毒(例如痘苗病毒、腺病毒和其他病毒)感染的哺乳动物细胞系统；病毒(例如杆状病毒)感染的昆虫细胞系统；微生物，如包含酵母载体的酵母；或者用噬菌体、DNA、质粒DNA或粘粒DNA转化的细菌。载体的表达元件的长度和特异性可以变化。根据使用的宿主-载体系统，可以使用许多合适的转录和翻译元件中的任一种。
本领域技术人员已知的用于将DNA片段插入载体的任何方法可以用来构建包含嵌合基因的表达载体，所述嵌合基因包含适当的转录/翻译控制信号和蛋白编码序列。这些方法可以包括体外重组DNA和合成技术以及体内重组(遗传重组)。编码蛋白或者其结构域、衍生物、片段或同系物的核酸序列的表达可以通过第二核酸序列来调节，从而基因或其片段在用重组DNA分子转化的宿主中表达。例如，蛋白的表达可以通过本领域已知的任 何启动子/增强子控制。在一具体实施方案中，启动子对于期望蛋白的基因不是天然的。可以使用的启动子包括但不限于SV40早期启动子(Bernoist and Chambon,Nature290:304-310(1981))，劳斯肉瘤病毒的3’长末端重复序列所含的启动子(Yamamoto et al.Cell22:787-797(1980))，疱疹胸苷激酶启动子(Wagner et al.,Proc.Natl.Acad.Sci.USA78:1441-1445(1981))，金属硫蛋白基因的调节序列(Brinster et al.,Nature296:39-42(1982))；原核表达载体如β-内酰胺酶启动子(Jay et al.,(1981)Proc.Natl.Acad.Sci.USA78:5543)或tac启动子(DeBoer et al.,Proc.Natl.Acad.Sci.USA80:21-25(1983))；还参见Gilbert and Villa-Komaroff“Useful Proteins from Recombinant Bacteria”Scientific American242:74-94(1980))；包含胭脂氨酸合成酶启动子(Herrera-Estrellaet al.,Nature303:209-213(1984))或花椰菜花叶病毒35SRNA启动子(Gardner et al.,Nucleic Acids Res.9:2871(1981))的植物表达载体，和光合酶核酮糖二磷酸羧化酶的启动子(Herrera-Estrella et al.,Nature310:115-120(1984))；来自酵母和其他真菌的启动子元件如Gal4启动子，乙醇脱氢酶启动子，磷酸甘油激酶启动子，碱性磷酸酶启动子，以及以下表现出组织特异性并已用于转基因动物的动物转录控制区：在胰腺腺泡细胞中活跃的弹性蛋白酶I基因控制区(Swift et al.,Cell38:639-646(1984)；Ornitz et al.,ColdSpring Harbor Symp.Quant.Biol.50:399-409(1986)；MacDonald,Hepatology7:425-515(1987))；在胰腺β细胞中活跃的胰岛素基因控制区(Hanahan et al.,Nature315:115-122(1985))，在淋巴样细胞中活跃的免疫球蛋白基因控制区(Grosschedl et al.,Cell38:647-658(1984)；Adams et al.,Nature318:533-538(1985)；Alexander et al.,Mol.CellBiol.7:1436-1444(1987))，在睾丸细胞、乳腺细胞、淋巴样细胞和肥大细胞中活跃的小鼠乳癌病毒控制区(Leder et al.,Cell45:485-495(1986))，在肝中活跃的白蛋白基因控制区(Pinkert et al.,Genes and Devel.1:268-276(1987))，在肝中活跃的甲胎蛋白基因控制区(Krumlauf et al.,Mol.Cell.Biol.5:1639-1648(1985)；Hammer et al.,Science235:53-581987)),，在肝中活跃的α-1抗胰蛋白酶基因控制区(Kelsey et al.,Genes and Devel.1:161-171(1987))，在髓样细胞中活跃的β珠蛋白基因控制区(Magramet al.,Nature315:338-340(1985)；Kollias et al.,Cell46:89-94(1986))，在脑的少突胶质细胞中活跃的髓鞘碱性蛋白基因 控制区(Readhead et al.,Cell48:703-712(1987))，在骨骼肌中活跃的肌球蛋白轻链-2基因控制区(Shani,Nature314:283-286(1985))，以及在下丘脑的促性腺激素细胞中活跃的促性腺激素释放激素基因控制区(Mason et al.,Science234:1372-1378(1986))。
在一具体实施方案中，使用载体，其包含可操作地连接至编码期望蛋白或者其结构域、片段、衍生物或同系物的核酸的启动子，一个或多个复制起点，以及任选存在的一个或多个选择标记(例如，抗生素抗性基因)。用于大肠杆菌细胞转化的示例性质粒载体包括例如pQE表达载体(可获得自Qiagen,Valencia,CA；还参见Qiagen公开的描述该系统的文献)。pQE载体具有噬菌体T5启动子(被大肠杆菌RNA聚合酶识别)和双lac操纵基因阻遏模块以提供大肠杆菌中重组蛋白的紧密调控、高水平的表达，用于有效翻译的合成核糖体结合位点(RBS II)，6XHis标签编码序列，t0和T1转录终止子，ColE1复制起点，以及用于赋予氨苄青霉素抗性的β-内酰胺酶基因。pQE载体允许在重组蛋白的N-或C-末端放置6xHis标签。这类质粒包括pQE32、pQE30和pQE31，其提供用于所有三个阅读框的多克隆位点，并且提供N-末端6xHis-标记的蛋白的表达。用于大肠杆菌细胞转化的其他示例性质粒载体包括例如pET表达载体(参见，美国专利4,952,496；可获得自Novagen,Madison,WI；还参见Novagen公开的描述该系统的文献)。这类质粒包括pET11a，其包含T7lac启动子、T7终止子、可诱导的大肠杆菌lac操纵基因和lac阻遏基因；pET12a-c，其包含T7启动子、T7终止子和大肠杆菌ompT分泌信号；以及pET15b和pET19b(Novagen,Madison,WI)，其包含在用His柱纯化中使用的His-TagTM前导序列和允许用柱纯化之后切割的凝血酶切割位点、T7-lac启动区和T7终止子。
用于哺乳动物细胞表达的载体的实例为HZ24表达载体。HZ24表达载体源自pCI载体骨架(Promega)。其包含编码β-内酰胺酶抗性基因(AmpR)的DNA、F1复制起点、巨细胞病毒即时早期增强子/启动区(CMV)和SV40晚期加A信号(SV40)。表达载体还具有来自ECMV病毒(Clontech)的内部核糖体进入位点(IRES)和小鼠二氢叶酸还原酶(DHFR)基因。
2.表达
乙酰透明质酸结合蛋白和乙酰透明质酸降解酶多肽，包括可溶性透明质酸酶多肽可以通过本领域技术人员已知的任何方法产生，包括体内和体外方法。期望蛋白可以在适合产生所需的蛋白量和形式的任何生物体中表达，例如给药和治疗所需的量和形式。表达宿主包括原核和真核生物体，如大肠杆菌、酵母、植物、昆虫细胞、哺乳动物细胞，包括人细胞系和转基因动物。表达宿主的蛋白生产水平以及对表达蛋白的翻译后修饰的类型可以不同。表达宿主的选择可以基于这些和其他因素，例如监管和安全考虑、生产成本以及纯化的需求和方法。
许多表达载体是可用的且为本领域技术人员已知，并且可以用于蛋白的表达。表达载体的选择会受到宿主表达系统的选择的影响。一般来说，表达载体可以包含转录启动子和任选存在的增强子、翻译信号以及转录和翻译终止信号。用于稳定转化的表达载体通常具有选择标记，其允许选择和维持转化的细胞。在某些情况下，复制起点可以用来扩增载体的拷贝数。
乙酰透明质酸结合蛋白和乙酰透明质酸降解酶多肽如可溶性透明质酸酶多肽还可以作为蛋白融合物来利用或表达。例如，可以产生酶融合物以将额外的功能性加入酶。酶融合蛋白的实例包括但不限于信号序列融合物；标签融合物，如用于定位，例如his6标签或myc标签，或者用于纯化的标签，例如GST融合物；以及用于指导蛋白分泌和/或膜关联的序列融合物。
a.原核细胞
原核生物，特别是大肠杆菌提供产生大量蛋白的系统。大肠杆菌的转化是本领域技术人员公知的简单且快速的技术。大肠杆菌的表达载体可以包含诱导型启动子，这类启动子可用于诱导高水平的蛋白表达和用于表达对宿主细胞表现出一些毒性的蛋白。诱导型启动子的实例包括lac启动子、trp启动子、杂合tac启动子、T7和SP6RNA启动子以及温度调控的λPL启动子。
蛋白如本文提供的任何蛋白可以在大肠杆菌的细胞质环境中表达。细胞质为还原环境，并且对于一些分子这可以导致不可溶性包含体的形成。还原剂如二硫苏糖醇和β-巯基乙醇以及变性剂如胍-HCl和尿素可以用来重溶解蛋白。可选的方法是在细菌的周质间隙中表达蛋白，细菌的周质间隙 提供氧化环境以及伴侣蛋白样蛋白(chaperonin-like)和二硫键异构酶，并且可以导致可溶性蛋白的产生。通常，将前导序列融合至待表达的蛋白，其将蛋白引导至周质。然后前导序列被周质中的信号肽酶去除。靶向周质的前导序列的实例包括来自果胶酸裂合酶基因的pelB前导序列以及源自碱性磷酸酶基因的前导序列。在某些情况下，周质表达允许表达的蛋白渗漏至培养基。蛋白的分泌允许从培养上清液快速且简单的纯化。不分泌的蛋白可以通过渗透裂解从周质获得。与细胞质表达相似，在一些情况下蛋白可以变为不溶的，并且变性剂和还原剂可以用来促进溶解和重折叠。诱导和生长的温度也可以影响表达水平和溶解性，通常使用25℃-37℃的温度。通常，细菌产生非糖基化(aglycosylated)的蛋白。因此，如果蛋白的功能需要糖基化，则可以在从宿主细胞纯化后体外加入糖基化。
b.酵母细胞
酵母如酿酒酵母(Saccharomyces cerevisae)、粟酒裂殖酵母(Schizosaccharomyces pombe)、解脂耶氏酵母(Yarrowia lipolytica)、乳酸克鲁维酵母(Kluyveromyces lactis)和毕赤酵母(Pichia pastoris)是公知的酵母表达宿主，可以用于蛋白的产生，如本文所述的任何蛋白。酵母可以用游离型复制载体转化或者通过同源重组进行稳定染色体整合。通常，诱导型启动子用于调控基因表达。这类启动子的实例包括GAL1、GAL7和GAL5以及金属硫蛋白启动子，如CUP1、AOX1，或者其他毕赤酵母(Pichia)或其他酵母启动子。表达载体常包含用于选择和维持转化DNA的选择标记，如LEU2、TRP1、HIS3和URA3。在酵母中表达的蛋白通常是可溶的。与伴侣蛋白如Bip和蛋白二硫键异构酶共表达可以提高表达水平和溶解性。此外，在酵母中表达的蛋白可以被引导分泌，利用分泌信号肽融合如来自酿酒酵母的酵母交配型α-因子分泌信号以及与酵母细胞表面蛋白如Aga2p交配粘附受体或Arxula adeninivorans葡糖淀粉酶融合。可以工程化蛋白酶切割位点如Kex-2蛋白酶以在表达的多肽离开分泌途径时从表达的多肽去除融合序列。酵母还能够在Asn-X-Ser/Thr基序处糖基化。
c.昆虫细胞
昆虫细胞，特别是利用杆状病毒表达，可用于表达多肽，包括乙酰透明质酸结合蛋白和乙酰透明质酸降解酶多肽如可溶性透明质酸酶多肽。昆虫细胞表达高水平的蛋白，并且能够进行高等真核生物所用的大多数翻译后修饰。杆状病毒具有有限的宿主范围，这提高了安全性并且减少了真核表达的监管问题。典型的表达载体为了高水平表达使用启动子，如杆状病毒的多角体蛋白启动子。常用的杆状病毒系统包括杆状病毒和昆虫细胞系，杆状病毒如苜蓿银纹夜蛾(Autographa californica)核型多角体病毒(AcNPV)和家蚕(bombyx mori)核型多角体病毒(BmNPV)，昆虫细胞系如来源于草地夜蛾(Spodopterafrugiperda)的Sf9、美洲粘虫(Pseudaletia unipuncta)(A7S)和黑脉金斑蝶(Danausplexippus)(DpN1)。为了高水平表达，将待表达的分子的核苷酸序列直接融合至病毒多角体蛋白起始密码子的下游。哺乳动物分泌信号在昆虫细胞中被准确加工并且可以用来将表达蛋白分泌入培养基。此外，细胞系美洲粘虫(A7S)和黑脉金斑蝶(DpN1)产生具有与哺乳动物细胞系统相似的糖基化模式的蛋白。
昆虫细胞中可选的表达系统是使用稳定转化的细胞。细胞系如Schneider2(S2)和Kc细胞(果蝇(Drosophila melanogaster))以及C7细胞(白纹伊蚊(Aedes albopictus))可以用于表达。果蝇(Drosophila)金属硫蛋白启动子可以用来在镉或铜的重金属诱导的存在下诱导高水平表达。表达载体通常通过使用选择标记如新霉素和潮霉素来保持。
d.哺乳动物细胞
哺乳动物表达系统可以用来表达蛋白，包括乙酰透明质酸结合蛋白和乙酰透明质酸降解酶多肽如可溶性透明质酸酶多肽。表达构建体可以通过病毒感染如腺病毒或者通过直接DNA转移来转移至哺乳动物细胞，所述直接DNA转移如脂质体、磷酸钙、DEAE-葡聚糖以及通过物理方式如电穿孔和显微注射。用于哺乳动物细胞的表达载体通常包含mRNA帽位点、TATA框、翻译起始序列(Kozak共有序列)和聚腺苷酸化元件。还可以添加IRES元件以允许与另一基因如选择标记双顺反子表达。这类载体常包含用于高水平表达的转录启动子-增强子，例如SV40启动子-增强子、人巨细胞病毒(CMV)启动子和劳斯肉瘤病毒(RSV)的长末端重复序列(RSV)。这些启动子- 增强子在许多细胞类型中活跃。组织和细胞类型启动子和增强子区也可以用于表达。示例性启动子/增强子区包括但不限于来自诸如弹性蛋白酶I、胰岛素、免疫球蛋白、小鼠乳癌病毒、白蛋白、甲胎蛋白、α1抗胰蛋白酶、β珠蛋白、髓鞘碱性蛋白、肌球蛋白轻链2和促性腺激素释放激素基因调控的基因的启动子/增强子区。选择标记可以用来选择和保持具有表达构建体的细胞。选择标记基因的实例包括但不限于潮霉素B磷酸转移酶、腺苷脱氨酶、黄嘌呤鸟嘌呤磷酸核糖转移酶、氨基糖苷磷酸转移酶、二氢叶酸还原酶(DHFR)和胸苷激酶。例如，表达可以在甲氨蝶呤的存在下进行以仅选择表达DHFR基因的那些细胞。与细胞表面信号分子如TCR-ζ和FcεRI-γ的融合可以引导蛋白在细胞表面上以活性状态表达。
许多细胞系可用于哺乳动物表达，包括小鼠、大鼠、人、猴、鸡和仓鼠细胞。示例性细胞系包括但不限于CHO、Balb/3T3、HeLa、MT2、小鼠NS0(非分泌)和其他骨髓瘤细胞系、杂交瘤和异种杂交瘤细胞系、淋巴细胞、成纤维细胞、Sp2/0、COS、NIH3T3、HEK293、293S、2B8和HKB细胞。还可以使细胞系适应无血清培养基，其促进从细胞培养基纯化分泌的蛋白。实例包括CHO-S细胞(Invitrogen,Carlsbad,CA,cat#11619-012)和无血清EBNA-1细胞系(Phamet al.,(2003)Biotechnol.Bioeng.84:332-342)。还可以使细胞系适应在优化最大表达的特殊培养基中生长。例如，DG44CHO细胞适应在化学成分确定、无动物产物的培养基中悬浮培养生长。
e.植物
转基因植物细胞和植物可以用来表达蛋白，如本文所述的任何蛋白。通常利用直接DNA转移如微粒轰击和PEG-介导的转移入原生质体以及用农杆菌-介导的转化来将表达构建体转移至植物。表达载体可以包含启动子和增强子序列、转录终止元件以及翻译控制元件。在双子叶植物宿主如拟南芥(Arabidopsis)和烟草以及单子叶植物宿主如玉米和水稻之间通常划分表达载体和转化技术。用于表达的植物启动子的实例包括花椰菜花叶病毒启动子、胭脂氨酸合成酶启动子、核糖二磷酸羧化酶启动子以及泛素和UBQ3启动子。选择标记如潮霉素、磷酸甘露糖异构酶和新霉素磷酸转移酶常用来促进转化细胞的选择和维持。转化的植物细胞可以在培养中保持 为细胞、团聚体(愈伤组织)或再生为整个植物。转基因植物细胞还可以包括工程化以产生透明质酸酶多肽的藻类。因为植物具有与哺乳动物细胞不同的糖基化模式，所以这可以影响这些宿主中产生的蛋白的选择。
3.纯化技术
从宿主细胞纯化多肽，包括乙酰透明质酸结合蛋白和乙酰透明质酸降解酶多肽(例如可溶性透明质酸酶多肽)或其他蛋白的方法取决于所选的宿主细胞和表达系统。对于分泌的分子，蛋白一般在去除细胞后从培养基纯化。对于细胞内表达，可以将细胞裂解并从提取物纯化蛋白。当转基因生物体如转基因植物和动物用于表达时，组织或器官可以用作起始原料以产生裂解的细胞提取物。此外，转基因动物产品可以包括乳汁或卵中的多肽产品，可以将其收集，并且如有必要可以利用本领域的标准方法提取和进一步纯化蛋白。
可以利用本领域已知的标准蛋白纯化技术纯化蛋白，所述标准蛋白纯化技术包括但不限于SDS-PAGE、大小分级和大小排阻层析、硫酸铵沉淀以及离子交换层析如阴离子交换。亲和纯化技术也可以用来提高制品的效率和纯度。例如，抗体、受体以及结合乙酰透明质酸结合蛋白或透明质酸酶的其他分子可以用于亲和纯化。还可以将表达构建体工程化以将亲和标签如myc表位、GST融合或His6加入蛋白，并且分别用myc抗体、谷胱甘肽树脂和Ni-树脂亲和纯化。可以通过本领域已知的任何方法评价纯度，包括凝胶电泳以及染色和分光光度技术。如本文提供的纯化的rHuPH20组合物通常具有至少70,000-100,000单位/mg，例如约120,000单位/mg的特异性活性。特异性活性可以根据修饰如用聚合物修饰而变化。
4.乙酰透明质酸降解酶多肽的聚乙二醇化
聚乙二醇(PEG)已广泛用于生物材料、生物技术和药物，主要是因为PEG是生物相容的无毒的水溶性聚合物，其通常没有免疫原性(Zhao and Harris,ACS SymposiumSeries680:458-72,1997)。在药物递送领域，PEG衍生物已广泛用于共价附着(即“聚乙二醇化”)至蛋白质以减少免疫原性、蛋白水解和肾清除并增加溶解性(Zalipsky,Adv.DrugDel.Rev.16:157-82,1995)。 相似地，PEG已附着至低分子量的相对疏水的药物以增加溶解性，减少毒性并改变生物分布。通常，聚乙二醇化的药物以溶液注射。
一种密切相关的应用是合成交联的可降解的PEG网络或制剂用于药物递送，因为许多用于设计可降解的可溶性药物载体的相同化学也可以用于设计可降解的凝胶(Sawhney et al.,Macromolecules26:581-87,1993)。还已知大分子间复合物可以通过混合两种互补聚合物的溶液而形成。这类复合物一般通过所涉及的聚合物之间的静电相互作用(聚阴离子-聚阳离子)和/或氢键(多酸-多碱)和/或水性环境中聚合物之间的疏水相互作用来稳定(Krupers et al.,Eur.Polym J.32:785-790,1996)。例如，在适当条件下混合聚丙烯酸(PAAc)和聚环氧乙烷(PEO)的溶液导致形成主要基于氢键的复合物。这些复合物在生理条件下的解离已用于递送游离药物(即非聚乙二醇化的)。此外，互补聚合物的复合物已从均聚物和共聚物形成。
本领域已描述许多聚乙二醇化的试剂。这类试剂包括但不限于N-羟基琥珀酰亚氨基(NHS)活化的PEG、琥珀酰亚氨基mPEG、mPEG2-N-羟基琥珀酰亚胺、mPEG琥珀酰亚氨基α-甲基丁酸酯、mPEG琥珀酰亚氨基丙酸酯、mPEG琥珀酰亚氨基丁酸酯、mPEG羧甲基3-羟基丁酸琥珀酰亚氨基酯、同双功能PEG-琥珀酰亚氨基丙酸酯、同双功能PEG丙醛、同双功能PEG丁醛、PEG马来酰亚胺、PEG酰肼、对硝基苯基-碳酸酯PEG、mPEG-苯并三唑碳酸酯、丙醛PEG、mPEG丁醛、支化的mPEG2丁醛、mPEG乙酰基、mPEG哌啶酮、mPEG甲基酮、mPEG“无接头”马来酰亚胺、mPEG乙烯基砜、mPEG硫醇、mPEG邻吡啶基硫酯(orthopyridylthioester)、mPEG邻吡啶基二硫化物(orthopyridyl disulfide)、Fmoc-PEG-NHS、Boc-PEG-NHS、乙烯基砜PEG-NHS、丙烯酸PEG-NHS、荧光素PEG-NHS和生物素PEG-NHS(参见例如Monfardini et al.,BioconjugateChem.6:62-69,1995；Veronese et al.,J.Bioactive Compatible Polymers12:197-207,1997；U.S.5,672,662；U.S.5,932,462；U.S.6,495,659；U.S.6,737,505；U.S.4,002,531；U.S.4,179,337；U.S.5,122,614；U.S.5,324,844；U.S.5,446,090；U.S.5,612,460；U.S.5,643,575；U.S.5,766,581；U.S.5,795,569；U.S.5,808,096；U.S.5,900,461；U.S.5,919,455；U.S.5,985,263；U.S.5,990,237；U.S.6,113,906；U.S.6,214,966；U.S.6,258,351；U.S.6,340,742；U.S.6,413,507；U.S. 6,420,339；U.S.6,437,025；U.S.6,448,369；U.S.6,461,802；U.S.6,828,401；U.S.6,858,736；U.S.2001/0021763；U.S.2001/0044526；U.S.2001/0046481；U.S.2002/0052430；U.S.2002/0072573；U.S.2002/0156047；U.S.2003/0114647；U.S.2003/0143596；U.S.2003/0158333；U.S.2003/0220447；U.S.2004/0013637；US2004/0235734；WO05000360；U.S.2005/0114037；U.S.2005/0171328；U.S.2005/0209416；EP1064951；EP0822199；WO01076640；WO0002017；WO0249673；WO9428024；和WO0187925)。
在一实例中，聚乙二醇具有约3kD-约50kD的分子量，并且通常为约5kD-约30kD。PEG共价附着至药物(已知为“聚乙二醇化”)可以通过已知的化学合成技术来完成。例如，蛋白的聚乙二醇化可以通过使NHS-活化的PEG与蛋白在合适反应条件下反应来完成。
虽然已描述许多聚乙二醇化的反应，但是一般最适用的那些反应赋予方向性，使用温和反应条件并且不需要深入的下游加工以去除有毒催化剂或副产物。例如，单甲氧基PEG(mPEG)仅具有一个反应性末端羟基，因此其使用限制所得PEG-蛋白产物混合物的一些异质性。聚合物末端的与末端甲氧基相反的羟基基团的活化一般是完成有效的蛋白聚乙二醇化所必需的，目的在于使衍生化的PEG对亲核攻击更敏感。攻击亲核体通常为赖氨酰残基的ε-氨基，但是如果局部条件是有利的，则其它胺也可以反应(例如N末端α-胺或组氨酸的环胺)。在包含单个赖氨酸或半胱氨酸的蛋白中更定向的附着是可能的。后一种残基可以通过PEG-马来酰亚胺靶向硫醇特异性修饰。或者，PEG酰肼可以与高碘酸盐氧化的乙酰透明质酸降解酶反应并在NaCNBH3的存在下还原。更具体地，聚乙二醇化的CMP糖可以与乙酰透明质酸降解酶在适当的糖基-转移酶的存在下反应。一种技术是“聚乙二醇化”技术，其中将许多聚合物分子偶联至所关注的多肽。当使用这种技术时，免疫系统对识别多肽表面上负责抗体形成的表位有困难，从而减少免疫应答。对于直接引入人体循环系统以提供特定生理学作用的多肽(即药物)，典型的潜在免疫应答是IgG和/或IgM应答，而通过呼吸系统吸入的多肽(即工业多肽)潜在地可以引起IgE应答(即变态反应)。一种解释减少的免疫应答的理论是聚合物分子屏蔽多肽表面上负责导致抗体形成的免疫应答的表位。另一理论或至少部分因素是缀合物越重，则获得的免疫应答越 少。
通常，为了制备本文提供的聚乙二醇化的乙酰透明质酸降解酶，包括聚乙二醇化的透明质酸酶，将PEG部分通过共价附着缀合至多肽。聚乙二醇化的技术包括但不限于专门的接头和偶联化学(参见例如Roberts,Adv.Drug Deliv.Rev.54:459-476,2002)、多个PEG部分附着至单个缀合位点(例如通过使用支化的PEG；参见例如，Guiotto et al.,Bioorg.Med.Chem.Lett.12:177-180,2002)、位点特异性聚乙二醇化和/或单聚乙二醇化(参见例如，Chapman et al.,Nature Biotech.17:780-783,1999)以及位点定向酶促聚乙二醇化(参见例如，Sato,Adv.Drug Deliv.Rev.,54:487-504,2002)。本领域所述的方法和技术可以产生具有附着至单个蛋白分子的1、2、3、4、5、6、7、8、9、10或超过10个PEG或PEG衍生物的蛋白(参见例如，U.S.2006/0104968)。
作为制备聚乙二醇化的乙酰透明质酸降解酶如聚乙二醇化的透明质酸酶的示例性说明方法，PEG醛、琥珀酰亚胺和碳酸酯已各自用来将PEG部分，通常为琥珀酰亚氨基PEG缀合于rHuPH20。例如，rHuPH20已与示例性琥珀酰亚氨基单PEG(mPEG)试剂缀合，包括mPEG-琥珀酰亚氨基丙酸酯(mPEG-SPA)、mPEG-琥珀酰亚氨基丁酸酯(mPEG-SBA)和(用于附着“支化的”PEG的)mPEG2-N-羟基琥珀酰亚胺。这些聚乙二醇化的琥珀酰亚氨基酯在PEG基团和活化的交联接头与单个或支化的PEG基团之间包含不同长度的碳骨架。这些差异可以用来例如提供不同的反应动力学以及在缀合过程中可供PEG附着至rHuPH20的潜在限制位点。
可以将包含线性或支化的PEG的琥珀酰亚氨基PEG(如上)缀合至rHuPH20。PEG可以用来可重复地产生包含分子的rHuPH20，所述分子每透明质酸酶具有平均约3-6个或3-6个PEG分子。这类聚乙二醇化的rHuPH20组合物可以容易地纯化以获得具有约25,000或30,000单位/mg蛋白透明质酸酶活性的比活性的组合物，并且基本上不含非聚乙二醇化的rHuPH20(少于5％非聚乙二醇化的)。
利用各种PEG试剂，可以例如利用mPEG-SBA(30kD)、mPEG-SMB(30kD)以及基于mPEG2-NHS(40kD)和mPEG2-NHS(60kD)的支化形式制备乙酰透明质酸降解酶的示例性形式，特别是可溶性人重组透明质酸酶(例如 rHuPH20)。已利用NHS化学以及碳酸酯和醛产生rHuPH20的聚乙二醇化形式，利用以下每种试剂：mPEG2-NHS-40K支化的、mPEG-NHS-10K支化的、mPEG-NHS-20K支化的、mPEG2-NHS-60K支化的；mPEG-SBA-5K、mPEG-SBA-20K、mPEG-SBA-30K；mPEG-SMB-20K、mPEG-SMB-30K；mPEG-丁醛；mPEG-SPA-20K、mPEG-SPA-30K；以及PEG-NHS-5K-生物素。还已利用可获得自Dow Chemical Corporation的分公司Dowpharma的PEG试剂制备聚乙二醇化的透明质酸酶；包括用Dowpharma的对硝基苯基-碳酸酯PEG(30kDa)以及用丙醛PEG(30kDa)聚乙二醇化的透明质酸酶。
在一实例中，聚乙二醇化包括将mPEG-SBA如mPEG-SBA-30K(具有约30kDa的分子量)或PEG丁酸衍生物的另一琥珀酰亚氨基酯缀合至可溶性透明质酸酶。PEG丁酸衍生物的琥珀酰亚氨基酯如mPEG-SBA-30K容易地偶联至蛋白的氨基。例如，如下述方案1所示，m-PEG-SBA-30K和rHuPH20(其大小为约60KDa)的共价缀合提供rHuPH20和mPEG之间的稳定酰胺键。
方案1
通常，将mPEG-SBA-30K或其他PEG以10:1的PEG:多肽摩尔比在合适缓冲液如pH6.8的130mM NaCl/10mM HEPES或70mM磷酸盐缓冲液，pH7中添加至乙酰透明质酸降解酶，在某些情况中为透明质酸酶，然后灭菌，例如过滤灭菌，并且例如在搅拌下于冷室中在4℃下持续缀合过夜。在一个实例中，将缀合的PEG-乙酰透明质酸降解酶浓缩并进行缓冲液交换。
偶联PEG丁酸衍生物的琥珀酰亚氨基酯如mPEG-SBA-30K的其他方法是本领域已知的(参见例如，U.S.5,672,662；U.S.6,737,505；和U.S.2004/0235734)。例如，可以通过在硼酸盐缓冲液(0.1M,pH8.0)中于4℃下反应1小时来将多肽如乙酰透明质酸降解酶(例如透明质酸酶)偶联至NHS活化的PEG衍生物。可以通过超滤纯化所得的聚乙二醇化的蛋白。或者，牛碱性磷酸酶的聚乙二醇化可以通过将磷酸酶与mPEG-SBA在包含0.2M磷酸钠和0.5M NaCl(pH7.5)的缓冲液中于4℃下混合30分钟来完成。可以通过超滤去除未反应的PEG。另一方法使多肽与mPEG-SBA在去离子水中反应，向其三乙胺以将pH提高至7.2-9。将所得的混合物在室温下搅拌几小时以完成聚乙二醇化。
乙酰透明质酸降解多肽，包括例如动物来源的透明质酸酶和细菌乙酰透明质酸降解酶的聚乙二醇化的方法是本领域技术人员已知的。参见，例如，欧洲专利第EP0400472号，其描述牛睾丸透明质酸酶和软骨素ABC裂解酶的聚乙二醇化。而且，美国公开第2006014968号描述衍生自人PH20的人透明质酸酶的聚乙二醇化。例如，聚乙二醇化的乙酰透明质酸降解酶一般包含至少3个PEG部分/分子。例如，乙酰透明质酸降解酶可以具有5:1-9:1的PEG比蛋白摩尔比，例如7:1。
G.抗乙酰透明质酸剂的评价活性和监测效果的方法
抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如透明质酸酶或修饰的透明质酸酶(例如PH20或PEGPH20)单独或与第二物质如化疗药物组合作为治疗剂发挥作用，用于治疗乙酰透明质酸相关疾病和疾病状况，特别是癌症(参见例如，US2010/0003238和WO09/128917)。此外，如本文其他地方所述，用抗乙酰透明质酸剂如乙酰透明质酸降解酶治疗可以伴随有用皮质类固醇治疗以最小化聚乙二醇化的透明质酸酶的全身性副作用，例如肌肉骨骼副作用。本文提供的HABP同伴诊断剂如TSG-6-LM或TSG-6-LM:Fc或者它们的变体可以与抗乙酰透明质酸剂疗法如乙酰透明质酸降解酶疗法联用，用于治疗乙酰透明质酸相关疾病或疾病状况如癌症，以便监测用所述物质(例如乙酰透明质酸降解酶)治疗的反应性和效力。此外，辅助或补充方法也可以用来评价抗乙酰透明质酸剂(例如乙酰透明质酸 降解酶)在单独或与皮质类固醇组合治疗中的效果。评价通过皮质类固醇改善副作用以及包括乙酰透明质酸降解酶疗法在内的抗乙酰透明质酸剂疗法的效力、耐受性和药物动力学研究在本领域技术人员的水平之内。这节提供可以用来评价乙酰透明质酸降解酶疗法的效力、反应性、耐受性和/或药物动力学的辅助或补充方法的描述。
1.评价副作用的方法
体内测定可以用来评价皮质类固醇对改善或消除可以由抗乙酰透明质酸剂引起的肌肉骨骼副作用的效力，所述抗乙酰透明质酸剂例如乙酰透明质酸降解酶，如透明质酸酶或修饰以表现出增加的全身半衰期的透明质酸酶(例如PH20或PEGPH20)。可以评价的副作用包括例如肌肉和关节疼痛、上肢和下肢僵硬、痉挛、肌炎、整个身体的肌肉酸痛和压痛、虚弱、疲劳和/或膝和肘关节运动范围的减少。评价副作用的测定可以包括动物模型，其中可以观察动物减少的运动、行为或姿势改变、影像学发现、组织病理学改变以及其他值得注意的临床观察。其他测定可以包括人对象中的临床试验，其中可以询问患者有关症状、通过身体检查进行评价、成像(例如通过MRI或PET)或通过放射性评价。当与其不存在时相比，在皮质类固醇的存在下副作用改善、消除、减轻或降低时，观察到给药抗乙酰透明质酸剂(例如乙酰透明质酸降解酶剂)所引起的副作用的改善。
在这类实例中，可以改变抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)和/或皮质类固醇的剂量以鉴定获得活性同时改善副作用所需的最佳或最小剂量。这类研究在本领域技术人员的水平之内。此外，可以改变剂量方案。例如，可以利用乙酰透明质酸降解酶的剂量方案每个月、每两周、每周一次、每周两次、每周3次、每周4次或更多进行研究。此外，皮质类固醇可以在给药抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)之前、同时和/或随后给药。
例如，体内动物模型可以用来评价皮质类固醇如地塞米松改善或消除与抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)给药相关的副作用的能力。动物模型可以包括非人灵长类如食蟹猴或猕猴，犬如比格犬，或者表现出对用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶，如聚乙二醇化的透明质 酸酶，例如PEGPH20)治疗治疗反应的不良副作用的任何其他动物。动物模型可以在皮质类固醇的存在或不存在下用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)剂量给药，并且观察或测量肌肉骨骼影响。
例如，可以将能够观察或测量肌肉骨骼事件的动物如食蟹猴、比格犬或其他相似的动物模型在皮质类固醇的存在或不存在下用乙酰透明质酸降解酶处理。在一实例中，将一组动物如食蟹猴或比格犬例如通过静脉内给药单独用抗乙酰透明质酸剂如乙酰透明质酸降解酶，例如聚乙二醇化的透明质酸酶给药。例如，给药可以每周两次。治疗可以继续，直至在膝和肘关节观察到四肢关节运动范围的改变，或者观察到僵硬或减少的活动性。然后，可以将另一组动物用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)以及例如通过口服剂量的地塞米松或其他皮质类固醇给药的皮质类固醇处理，所述皮质类固醇在抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)给药的同一天给予。然后可以将动物的组例如通过关节活动范围或其他减少的活动性的身体检测、关节的组织病理学、僵硬的触诊或者本领域技术人员已知的成像进行比较，以便评价皮质类固醇如地塞米松改善抗乙酰透明质酸剂介导的，如乙酰透明质酸降解酶介导的肌肉骨骼副作用的能力。可以改变皮质类固醇如地塞米松的剂量、剂量给药频率、给药途径和剂量给药时间以优化皮质类固醇的效果。
在另一实例中，可以在具有实体瘤的人患者中评价皮质类固醇如地塞米松对改善或消除与抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)给药相关的不良副作用的效力。例如，可以向人患者剂量给药以检测皮质类固醇改善和/或消除抗乙酰透明质酸剂介导的(例如乙酰透明质酸降解酶介导的)不良事件的能力，所述不良事件包括但不限于以下任一种或多种：肌肉和关节疼痛/上肢和下肢僵硬、痉挛、肌肉肌炎、整个身体肌肉酸痛和触痛、虚弱以及疲劳。患者可以用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗，用或不用皮质类固醇如地塞米松共治疗。在给药抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)期间和之后，可以评价两个治疗组的副作用。医生可以通过对象的身体检查确定症状的严重程度，所述身体检查包括例如患者陈述、生命特征、体重的改变、12-导联ECG、超声心动图、临床化学或成像(MRI、PET或放射性评价)。然后可以利用不良事件的NCI常用术 语标准(CTCAE)分级系统定量症状的严重程度。CTCAE是用于不良事件(AE)报道的描述性术语。为每个AE术语提供分级(严重程度)等级。CTCAE显示等级1-5，具有基于以下一般准则的每个不良事件的严重程度的临床描述：等级1(轻度AE)；等级2(中度AE)；等级3(严重AE)；等级4(威胁生命或致残的AE)；和等级5(与AE相关的死亡)。皮质类固醇改善与给药抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)相关的不良副作用的能力可以通过以下观察来测量：与单独用相同的抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的对象相比，用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)和皮质类固醇治疗的对象中一种或多种不良副作用的CTCAE等级的分级或严重程度降低，即副作用的严重程度从等级3降低至等级1或等级2。
在另一实例中，可以向人患者剂量给药以通过逐步升高抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的剂量来评价耐受性，并且如通过副作用的严重程度所测量的评价剂量限制性毒性。在这样的实例中，可以确定在改善剂如皮质类固醇的存在下可以耐受的抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的最大耐受剂量。治疗方案可以包括剂量递增，其中每个患者在相同剂量水平的皮质类固醇下接受较高剂量的乙酰透明质酸降解酶。可以监测患者的不良事件以确定在不再耐受副作用之前可以与皮质类固醇一起给药的最高剂量的乙酰透明质酸降解酶。可以基于治疗期间和之后出现的症状的严重程度测量耐受性。抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的剂量可以逐步升高，直至副作用达到预定水平，例如等级3。剂量给药方案还可以包括逐步减少给药的皮质类固醇的量以检测对皮质类固醇的持续需求以及在所得的副作用方面适应抗乙酰透明质酸剂的可能性。
2.评价与抗乙酰透明质酸剂的活性(例如乙酰透明质酸降解酶活性)相关的生物标记
如本文所述，HA表型的程度和水平是与抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的效力和活性相关且关联的生物标记。例如，对于具有肿瘤如晚期实体瘤的癌症患者，减少的肿瘤和基质相关是给药的乙酰透明质酸降解酶的活性的生物标记。可以进行如本文其他地方所述的检测组织(例如肿瘤活组织检查)或体液(例如血浆)中存在的HA的HABP结合测定以评 价和监测抗乙酰透明质酸(例如乙酰透明质酸降解酶)的疗效。
此外，可以单独或与本文所述的用来检测组织(例如肿瘤活组织检查)或体液(例如血浆)中的HA的HABP测定联合进行测定以进一步评价抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)对乙酰透明质酸抑制或降解活性的影响。具体地，对于治疗乙酰透明质酸相关疾病或疾病状况如癌症，与抗乙酰透明质酸剂如乙酰透明质酸降解酶的活性相关的临床量度或生物标记包括但不限于减少的肿瘤代谢活性、增加的表观扩散和增强的肿瘤灌注和/或HA分解代谢物的增加。测量这类生物标记的额外的测定可以包括但不限于测量血液或尿中的乙酰透明质酸分解代谢物，测量血浆中的透明质酸酶活性，或者测量肿瘤中的组织间隙液压、血管容积或水含量。进行这类测定在本领域技术人员的水平之内。
这些测定可以在用乙酰透明质酸降解酶处理的动物模型或人患者中进行。例如，乙酰透明质酸相关疾病、病症或疾病状况的动物模型可以用来评价给药抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如透明质酸酶或修饰以表现出增加的半衰期的透明质酸酶(例如PH20或PEGPH20)的体内影响。另一物质如化疗剂也可以包括在活性的评价中。可以利用适当的动物模型的示例性乙酰透明质酸相关疾病包括实体瘤，例如晚期癌症、转移癌、未分化癌、卵巢癌、原位癌(ISC)、鳞状细胞癌(SCC)、前列腺癌、胰腺癌、非小细胞肺癌、乳腺癌、结肠癌和其他癌症。乙酰透明质酸相关疾病和病症的实例还有炎性疾病、椎间盘压力、癌症和水肿，例如器官移植、中风、脑外伤或其他损伤引起的水肿。
动物模型可以包括但不限于小鼠、大鼠、兔、犬、豚鼠和非人灵长类模型，例如食蟹猴或猕猴。在一些实例中，将免疫缺陷小鼠如裸鼠或SCID小鼠用来自乙酰透明质酸相关癌症的肿瘤细胞系移植以建立该癌症的动物模型。来自乙酰透明质酸相关癌症的示例性细胞系包括但不限于PC3前列腺癌细胞、BxPC-3胰腺癌细胞、MDA-MB-231乳腺癌细胞、MCF-7乳腺肿瘤细胞、BT474乳腺肿瘤细胞、Tramp C2前列腺肿瘤细胞和Mat-LyLu前列腺癌细胞，以及本文所述的乙酰透明质酸相关(例如包含升高水平的乙酰透明质酸)的其他细胞系。然后可以将抗乙酰透明质酸剂如乙酰透明质酸降解酶给药至动物，有或无皮质类固醇如地塞米松，以便通过测量例如乙 酰透明质酸水平或含量来评价皮质类固醇对抗乙酰透明质酸活性的影响。可以通过染色肿瘤组织样品的乙酰透明质酸或者通过测量血浆中的可溶性乙酰透明质酸水平来测量乙酰透明质酸含量。抗乙酰透明质酸活性的其他测量包括评价肿瘤体积、晕的形成或大小、组织间隙液压、水含量和/或血管容积。
在其他实例中，可以将犬如比格犬在皮质类固醇如地塞米松的存在或不存在下用抗乙酰透明质酸剂处理。将组织如皮肤或骨骼肌组织活组织检查，染色乙酰透明质酸并视觉评价。然后将来自单独用抗乙酰透明质酸剂处理的动物的组织与来自用抗乙酰透明质酸剂和皮质类固醇处理的动物的组织进行比较以测量皮质类固醇对抗乙酰透明质酸活性的影响。
抗乙酰透明质酸剂如乙酰透明质酸降解酶活性的测定还可以在人对象中进行。例如，测量与抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)活性相关的生物标记的测定可以对已知或怀疑患有乙酰透明质酸相关疾病或疾病状况(例如癌症)并已用乙酰透明质酸降解酶(例如PEGPH20)治疗的人对象进行。
a.评价乙酰透明质酸降解酶活性的测定
可以利用本领域公知的方法评价乙酰透明质酸降解酶的活性。例如，透明质酸酶的USP XXII测定通过未降解的透明质酸或乙酰透明质酸的量来间接确定活性，使酶切(enzyme)后剩余的(HA)底物与HA在37℃下反应30min(USP XXII-NF XVII(1990)644-645United States Pharmacopeia Convention,Inc,Rockville,MD)。透明质酸酶参考标准(USP)或国家药品集(NF)标准透明质酸酶溶液可以在测定中用来确定任何透明质酸酶的活性，以单位计。在一实例中，利用微浊度测定测量活性。这是基于当透明质酸与血清白蛋白结合时形成不溶性沉淀。通过将透明质酸酶或者包含透明质酸酶的样品如血液或血浆与透明质酸钠(透明质酸)温育一段时间(例如10分钟)，然后通过添加酸化血清白蛋白沉淀未消化的透明质酸钠。额外的显影期之后在640nm处测量所得的样品的浊度。透明质酸酶对透明质酸钠底物的活性所致的浊度减少是透明质酸酶酶促活性的量度。
在另一实例中，利用微量滴定测定测量透明质酸酶活性，其中与透明 质酸酶或者包含透明质酸酶的样品如血液或血浆温育之后测量残余的生物素化的透明质酸(参见例如Frost and Stern(1997)Anal.Biochem.251:263-269,美国专利公开第20050260186号)。将透明质酸的葡糖醛酸残基上的游离羧基生物素化，并且将生物素化的透明质酸底物共价偶联至微量滴定板。与透明质酸酶温育之后，利用抗生物素蛋白-过氧化物酶反应检测残余的生物素化的透明质酸底物并与已知活性的透明质酸酶标准品反应之后获得的残余的生物素化的透明质酸底物进行比较。测量透明质酸酶活性的其他测定也是本领域已知的，并且可以用于本文的方法(参见例如Delpech et al.,(1995)Anal.Biochem.229:35-41；Takahashi et al.,(2003)Anal.Biochem.322:257-263)。
还可以评价活性乙酰透明质酸降解酶如修饰的可溶性透明质酸酶(例如聚乙二醇化的PH20)作为化疗剂的铺展剂或扩散剂发挥作用的能力。例如，可以将台盼蓝染料如皮下或皮内注射入裸鼠每侧的皮肤，有或无乙酰透明质酸降解酶。然后例如用测微计测量染料区域以确定透明质酸降解酶作为铺展剂发挥作用的能力(参见例如美国公开专利第20060104968号)。
b.HA分解代谢物的测量
在另一实例中，可以在患者治疗的不同时间点收集血液和尿并测定乙酰透明质酸的分解代谢物。分解代谢物的存在是乙酰透明质酸降解的指示，因此是透明质酸酶活性的量度。还可以在给药之后随时间评价和测量血浆酶。例如，可以利用高效液相色谱(HPLC)评价是HA-二糖分解产物的HA分解代谢物以分离和测量糖峰面积。实施例15示例这个测定。
c.肿瘤代谢活性
肿瘤代谢活性的减少与抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)活性相关。可以利用本领域已知的标准方法评价肿瘤代谢活性。例如，可以使用[18F]-氟脱氧葡萄糖正电子发射断层扫描(FDG-PET)。PET为非侵入性诊断，其提供组织的灌注、细胞成活力、增殖和/或代谢活性的图像和定量参数。图像由使用正电子发射放射性同位素标记的不同生物物质(例如糖、氨基酸、代谢前体、激素)产生。例如，FDG为葡萄糖的类似物，并且 通过正常葡萄糖途径的第一步被活细胞吸收。在癌症中，存在增加的糖酵解活性，导致癌细胞中FDG的截留。FDG截留的减少与减少的肿瘤代谢活性和抗肿瘤发生活性相关。PET成像的指导是本领域技术人员已知的，并且任何治疗医生或技术员都应当遵从。
d.增加的表观扩散和增强的肿瘤灌注
额外的评价抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)活性的方法包括评价组织中水的扩散的测定。如本文其他地方所讨论的，积累乙酰透明质酸的组织一般具有比正常组织高的组织间隙液压，这是由于水的伴随积累。因此，积累HA的组织如肿瘤具有高组织间隙液压，这可以通过本领域已知的各种方法进行测量。例如，可以使用扩散MRI如ADCMRI或DCE MRI。水的扩散可以通过这些方法评价，并且与乙酰透明质酸丰富的组织如实体瘤的存在直接相关(参见例如Chenevert et al.(1997)Clinical Cancer Research,3:1457-1466)。例如，因为增加的灌注，积累乙酰透明质酸的肿瘤的ADC MRI或DCE MRI具有明显增加。这类测定可以在乙酰透明质酸降解酶的存在或不存在下进行，并且将结果进行比较。测量扩散的方法是评价这类疗法后细胞变化的可用量度。
3.肿瘤大小和体积
抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的活性与肿瘤大小和/或体积的减少有关。肿瘤大小和体积可以基于本领域技术人员已知的技术来进行监测。例如，肿瘤大小和体积可以通过放射线照相术、超声成像、尸检、通过使用卡尺、通过microCT或通过18F-FDG-PET来进行监测。肿瘤大小还可以目测评价。在具体实例中，利用卡尺直接测量肿瘤大小(直径)。
在其他实例中，可以利用通过卡尺或超声评价获得的测量肿瘤直径(D)的平均值测量肿瘤体积。例如，可以利用VisualSonics Vevo770高分辨率超声或其他相似的超声确定肿瘤体积。体积可以从式V＝D3xπ/6(对于利用卡尺测量的直径)或V＝D2x d xπ/6(对于利用超声测量的直径，其中d为深度或厚度)确定。例如，卡尺测量可以由肿瘤长度(l)和宽度(w)组成，并且肿瘤体积计算为长度x宽度2x0.52。在另一实例中，microCT扫描可以 用来测量肿瘤体积(参见例如Huang et al.(2009)PNAS,106:3426-3430)。作为实例，可以将小鼠用Optiray Pharmacy碘佛醇注射74％造影剂(例如741mg碘佛醇/mL)注射，将小鼠麻醉，并且利用MicroCat1A扫描仪或其他相似的扫描仪(例如IMTek)(40kV、600μA、196旋转步、总角或旋转＝196)进行CT扫描。可以利用软件(例如RVA3软件程序；ImTek)重建图像。可以通过利用可用的软件(例如Amira3.1软件；Mercury计算机系统)确定肿瘤体积。还可以基于肿瘤的大小或重量确定肿瘤体积或大小。
可以利用等式：％TGI＝[1–(Tn-T0)÷(Cn-C0)]x100％基于体积计算肿瘤生长抑制的百分比，其中“Tn”为乙酰透明质酸降解酶的最后剂量之后第“n”天治疗组的平均肿瘤体积；“T0”为治疗之前，在第0天该治疗组中的平均肿瘤体积；“Cn”为第“n”天相应的对照组的平均肿瘤体积；并且“C0”为治疗之前，在第0天对照组中的平均肿瘤体积。可以确定肿瘤体积的统计分析。
4.药物动力学和药效学测定
药物动力学或药效学研究可以利用动物模型进行，或者可以在研究期间用患者进行，以便评价抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如透明质酸酶或修饰的透明质酸酶(例如PEGPH20)的药物动力学特性。动物模型包括但不限于小鼠、大鼠、兔、犬、豚鼠和非人灵长类模型，例如食蟹猴或猕猴。在某些情况下，利用健康动物进行药物动力学或药效学研究。在其他实例中，利用考虑用乙酰透明质酸治疗的疾病的动物模型进行研究，如任何乙酰透明质酸相关疾病或病症的动物模型，例如肿瘤模型。
可以通过给药之后测量这类参数如最大(峰)浓度(Cmax)、峰时间(即最大浓度出现的时间；Tmax)、最小浓度(即剂量之间的最小浓度；Cmin)、消除半衰期(T1/2)和曲线下面积(即通过作图时间对浓度产生的曲线下面积；AUC)来评价抗乙酰透明质酸剂(例如乙酰透明质酸降解酶，如修饰的透明质酸酶)的药物动力学特性。可以通过比较皮下递送之后的曲线下面积(AUCsc)与静脉内递送之后的AUC(AUCiv)来确定所述物质或酶(例如透明质酸酶)的绝对生物利用度。可以利用式：F＝([AUC]sc×剂量sc)/([AUC]iv×剂量iv)计算绝对生物利用度(F)。一系列剂量和剂量给药的不同剂量给药频率可以 在药物动力学研究中给药以评价增加或减少剂量中抗乙酰透明质酸剂，例如乙酰透明质酸降解酶，如透明质酸酶或修饰的透明质酸酶(例如聚乙二醇化的PH20)的浓度的影响。
H.试剂盒和制成品
本文提供试剂盒用于选择患者用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)进行治疗，预测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的效力，确定患有HA相关疾病的患者的预后，或者监测用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗HA相关疾病，特别是癌症的效力。本文提供的试剂盒包含本文提供的HABP试剂用于检测或定量样品中的乙酰透明质酸，以及任选存在的试剂用于进行所述方法。例如，试剂盒可以额外地包含用于收集组织、制备和加工组织的试剂，以及用于定量样品中HA的量的试剂，例如但不限于检测试剂，如抗体、缓冲液、酶促染色的底物、色素原或其他材料，例如玻片、容器、微量滴定板以及任选存在的进行所述方法的说明书。本领域技术人员会认识可以用于接触各种材料的许多其他可能的容器和板和试剂。试剂盒还可以包含代表具有不同水平的HA的组织的对照样品或者染色HA含量的参考样品用于受试样品的比较和分类。所提供的HABP诊断剂可以在诊断剂的冻干或其他稳定制剂中提供。在一些实例中，试剂盒包括用于测定检测的装置，例如自动化细胞成像系统(ACIS)、荧光计、发光计或分光光度计。
本文还提供本文提供的HABP试剂的组合，包括所提供的改良的HABP试剂和乙酰透明质酸降解酶。如本文所述，HABP可以用作同伴诊断剂用于乙酰透明质酸降解酶治疗。这类组合可以任选地包装为试剂盒用于选择患者用抗乙酰透明质酸剂(例如酰透明质酸降解酶)进行治疗和用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗这类患者，预测在患者中用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗的效力和用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗这类患者，确定患有HA相关疾病的患者的预后和用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗这类患者，或者监测对于治疗HA相关疾病，特别是癌症，用抗乙酰透明质酸降解酶(例如乙酰透明质酸降解酶)治疗患者的效力和基于治疗的效力用抗乙酰透明质 酸剂(例如乙酰透明质酸降解酶)治疗这类患者。可以包装为试剂盒的组合可以包括一种或多种额外的物质用于疗法，例如抗癌剂，或者用于疗法的治疗或副作用，包括皮质类固醇用于治疗与用抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)治疗相关的骨骼肌肉副作用。试剂盒可以包括用于包装抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)的包装材料或者一种或多种额外的治疗剂。例如，试剂盒可以包含容器，包括单室和双室容器。容器可以包括但不限于管、瓶和注射器。容器还可以包括给药的材料，例如皮下给药的针。抗乙酰透明质酸剂(例如乙酰透明质酸降解酶)或者一种或多种额外的治疗剂可以一起或单独提供。试剂盒可以任选地包括给药说明，包括剂量、剂量给药方案和给药模式的说明。
本文提供的试剂盒还可以包括用于检测样品中一种或多种额外的蛋白或编码RNA的表达的试剂，例如一种或多种额外的癌症标记，例如但不限于癌胚抗原(CEA)、甲胎蛋白(AFP)、CA125、CA19-9、前列腺特异性抗原(PSA)、人绒毛膜促性腺激素(HCG)、HER2/neu抗原、CA27.29、CYFRA21-2、LASA-P、CA15-3、TPA、S-100和CA-125。
I.实施例
以下实施例仅用于说明目的而不意图限制本发明的范围。
实施例1rHuPH20表达细胞系
A.初始可溶性rHuPH20-表达细胞系的产生
将中国仓鼠卵巢(CHO)细胞用HZ24质粒(如SEQ ID NO:52所示)转染。用于表达可溶性rHuPH20的HZ24质粒载体包含pCI载体骨架(Promega)、编码人PH20透明质酸酶的氨基酸1-482的DNA(SEQ ID NO:49)、来自ECMV病毒的内部核糖体进入位点(IRES)(Clontech)以及小鼠二氢叶酸还原酶(DHFR)基因。pCI载体骨架还包括编码β-内酰胺酶抗性基因(AmpR)的DNA、f1复制起点、巨细胞病毒即时早期增强子/启动子区(CMV)、嵌合内含子以及SV40晚期多腺苷酸化信号(SV40)。编码可溶性rHuPH20构建体的DNA包含NheI位点和Kozak共有序列(其在编码人PH20的天然35个氨基酸信号序列的氨基酸位置1的甲硫氨酸的DNA之前)，以及终止密 码子(其在编码对应于SEQ ID NO:1所示的人PH20透明质酸酶的氨基酸位置482的酪氨酸的DNA之后)，然后是BamHI限制位点。因此，构建体pCI-PH20-IRES-DHFR-SV40pa(HZ24)导致CMV启动子驱动的单一mRNA种类，其编码人PH20的氨基酸1-482(如SEQ ID NO:3所示)和小鼠二氢叶酸还原酶的氨基酸1-186(如SEQ ID NO:53所示),所述氨基酸序列由内部核糖体进入位点(IRES)分离。
将在补充了4mM谷氨酰胺和18ml/L Pluronic F68/L(Gibco)的用于DHFR(-)细胞的GIBCO改良的CD-CHO培养基中生长的未转染的CHO细胞以0.5x106个细胞/ml接种于摇瓶中准备用于转染。使细胞在加湿保温箱中于37℃和5％CO2下生长，以120rpm振荡。转染之前检测指数生长的未转染的CHO细胞的成活力。
将未转染的CHO细胞培养物的6,000,000个活细胞沉淀并在0.7mL的2x转染缓冲液(2x HeBS:40mM Hepes,pH7.0,274mM NaCl,10mM KCl,1.4mM Na2HPO4,12mM葡聚糖)中重悬至2×107个细胞的密度。向每等分试样的重悬细胞添加0.09mL(250μg)的线性HZ24质粒(通过用Cla I(New England Biolabs)消化过夜来线性化)，并且在室温下将细胞/DNA溶液转移入0.4cm gap BTX(Gentronics)细胞电击管。没有质粒DNA与细胞混合来进行阴性对照电穿孔。将细胞/质粒混合物用330V和960μF或者350V和960μF的电容器放电进行电穿孔。
电穿孔之后将细胞从电击管移出并转移入5mL补充了4mM谷氨酰胺和18ml/LPluronic F68/L(Gibco)的用于DHFR(-)细胞的改良的CD-CHO培养基，并且允许所述细胞在6孔组织培养板的孔中在湿化保温箱中于37℃和5％CO2下生长2天而没有选择。
电穿孔后2天，从每个孔去除0.5mL组织培养基，并且利用实施例3所述的微浊度测定检测透明质酸酶活性的存在。从组织培养孔收集表达最高水平的透明质酸酶活性的细胞，计数并稀释至1×104-2×104活细胞/mL。将0.1mL等分试样的细胞悬浮液转移至5个96孔圆底组织培养板的每个孔。将100微升包含4mM GlutaMAXTM-1补充物(GIBCOTM,InvitrogenCorporation)且不含次黄嘌呤和胸苷补充物的CD-CHO培养基(GIBCO)添加至包含细胞的孔(终体积0.2mL)。
从在无甲氨蝶呤条件下生长的5个板鉴定了10个克隆。将这些HZ24克隆中的6个扩大培养并转移入摇瓶作为单一细胞悬浮液。利用二维无限稀释策略将克隆3D3，3E5，2G8，2D9，1E11和4D10平板接种入96-孔圆底组织培养板，其中将细胞沿板向下(down theplate)1:2稀释，并且横跨板(across the plate)1:3稀释，从左上角的孔中的5000个细胞开始。使稀释的克隆在500个未转染的DG44CHO细胞/孔的背景中生长，y以便为培养初期提供必要的生长因子。每个亚克隆制备10个板，5个板包含50nM甲氨蝶呤，而5个板没有甲氨蝶呤。
克隆3D3产生24个可见的亚克隆(13个来自无甲氨蝶呤处理，而11个来自50nM甲氨蝶呤处理)。在来自24个亚克隆中的8个的上清中测量到显著的透明质酸酶活性(>50单位/mL)，并且将这8个亚克隆扩大至T-25组织培养瓶中。将分离自甲氨蝶呤处理方案的克隆在50nM甲氨蝶呤的存在下扩大。将克隆3D35M在摇瓶中于500nM甲氨蝶呤中进一步扩大，得到产生超过1,000单位/ml透明质酸酶活性的克隆(克隆3D35M；或Gen13D35M)。然后制备3D35M细胞的主细胞库(MCB)。
B.表达可溶性rHuPH20的第二代细胞系的产生
使实施例1所述的Gen13D35M细胞系适应较高的甲氨蝶呤水平以产生第2代(Gen2)克隆。将3D35M细胞从建立的包含甲氨蝶呤的培养物接种入包含4mM GlutaMAX-1TM和1.0μM甲氨蝶呤的CD CHO培养基。通过生长并在46天的时间中于37℃、7％CO2加湿培养箱中传代9次来使所述细胞适应较高的甲氨蝶呤水平。通过在包含具有2.0μM甲氨蝶呤的培养基的96-孔组织培养板中有限稀释来克隆出扩增的细胞群体。大约4周之后，鉴定克隆并选择克隆3E10B扩大。使3E10B细胞在包含4mMGlutaMAX-1TM和2.0μM甲氨蝶呤的CD CHO培养基中生长20代。产生3E10B细胞系的主细胞库(MCB)，将其冷冻并用于随后的研究。
通过在包含4mM GlutaMAX-1TM和4.0μM甲氨蝶呤的CD CHO培养基中培养3E10B细胞来继续细胞系的扩增。第12代之后，将细胞在小瓶中冷冻作为研究细胞库(RCB)。将一小瓶的RCB解冻并在包含8.0μM甲氨蝶呤的培养基中培养。5天之后，将培养基中的甲氨蝶呤浓度增加至16.0 μM，然后18天后为20.0μM。通过在包含CD CHO培养基的96-孔组织培养板中有限稀释来克隆出来自包含20.0μM甲氨蝶呤的培养基中的第8代的细胞，所述CD CHO培养基包含4mM GlutaMAX-1TM和20.0μM甲氨蝶呤。5-6周后鉴定克隆并选择克隆2B2在包含20.0μM甲氨蝶呤的培养基中扩大。第11代之后，将2B2细胞在小瓶中冷冻作为研究细胞库(RCB)。
所得的2B2细胞为二氢叶酸还原酶缺陷(dhfr-)的DG44CHO细胞，其表达可溶性重组人PH20(rHuPH)。可溶性PH20以约206个拷贝/细胞的拷贝数存在于2B2细胞中。利用rHuPH20特异性探针的Spe I-、Xba I-和BamH I/Hind III-消化的基因组2B2细胞DNA的DNA印迹分析显示以下限制性消化谱：用Spe I消化的DNA的～7.7kb的一条主要杂交带和四条次要杂交带(～13.9,～6.6,～5.7和～4.6kb)；用Xba I消化的DNA的～5.0kb的一条主要杂交带和二条次要杂交带(～13.9和～6.5kb)；利用BamH I/Hind III消化的2B2DNA观察到的～1.4kb的单一杂交带。mRNA转录物的序列分析显示衍生的cDNA(SEQ ID NO:56)与参考序列(SEQ ID NO:49)相同，除了在位置1131处的一个碱基对差异，据观察其为胸苷(T)代替预期的胞嘧啶(C)。这是沉默突变，对氨基酸序列没有影响。
实施例2rHuPH20的制备和纯化
A.在300L生物反应器细胞培养中制备Gen2可溶性rHuPH20
将小瓶的HZ24-2B2细胞(实施例1B)解冻并且在补充了20μM甲氨蝶呤和GlutaMAX-1TM(Invitrogen)的CD-CHO培养基(Invitrogen,Carlsbad,CA)中从摇瓶扩大至36L转瓶。简单地说，将小瓶细胞在37℃水浴中解冻，添加培养基并将细胞离心。用20mL新鲜培养基将细胞重悬于125mL摇瓶中并放置在37℃、7％CO2的培养箱中。在125mL摇瓶中将细胞扩大至40mL。当细胞密度达到大于1.5x106个细胞/mL时，将培养物扩大至125mL转瓶，培养体积为100mL。将瓶在37℃、7％CO2下培养。当细胞密度达到大于1.5x106个细胞/mL时，将培养物扩大至250mL转瓶，培养体积为200mL，并且将瓶在37℃、7％CO2下培养。当细胞密度达到大于1.5x106个细胞/mL时，将培养物扩大至1L转瓶，培养体积为800mL，并且在37℃、7％CO2下培养。当细胞密度达到大于1.5x106个细胞/mL时，将 培养物扩大至6L转瓶，培养体积为5000mL，并且在37℃、7％CO2下培养。当细胞密度达到大于1.5x106个细胞/mL时，将培养物扩大至36L转瓶，培养体积为32L，并且在37℃、7％CO2下培养。
将400L反应器灭菌并添加230mL的CD-CHO培养基。使用之前，检查反应器的污染。将约30L细胞从36L转瓶转移至400L生物反应器(Braun)，接种密度为4.0×105个活细胞/ml，并且总体积为260L。参数为温度设定值，37℃；叶轮转速40-55RPM；容器压力：3psi；空气喷雾0.5-1.5L/Min；空气覆盖：3L/min。反应器每天取样用于细胞计数、pH校准、培养基分析、蛋白生产和保留。而且，在运行期间添加营养补料。在120hr(第5天)，添加10.4L补料#1培养基(4×CD-CHO+33g/L葡萄糖+160mL/LGlutamax-1TM+83mL/L酵母粉(Yeastolate)+33mg/L重组人胰岛素(rHuInsulin))。在168小时(第7天)，添加10.8L补料#2(2×CD-CHO+33g/L葡萄糖+80mL/L Glutamax-1TM+167mL/L酵母粉+0.92g/L丁酸钠)，并且将培养温度变为36.5℃。在216小时(第9天)，添加10.8L补料#3(1×CD-CHO+50g/L葡萄糖+50mL/LGlutamax-1TM+250mL/L酵母粉+1.80g/L丁酸钠)，并且将培养温度变为36℃。在264小时(第11天)，添加10.8L补料#4(1×CD-CHO+33g/L葡萄糖+33mL/L Glutamax-1TM+250mL/L酵母粉+0.92g/L丁酸钠)，并且将培养温度变为35.5℃。观察到补料培养基的添加在生产的最后阶段显著增加了可溶性rHuPH20的产生。在第14或15天或者当细胞成活力降至低于40％时收获反应器。所述方法导致17,000单位/ml的最终生产力与1.2×107个细胞/mL的最大细胞密度。在收获时，将培养物取样用于体外和体内支原体、生物负荷、内毒素和病毒，透射电镜术(TEM)以及酶活性。
通过蠕动泵将培养物泵过4个平行的Millistak过滤系统模块(Millipore)，每个包含一层分级至4-8μm的硅藻土和一层分级至1.4-1.1μm的硅藻土，随后为纤维素膜；然后通过第二单一Millistak过滤系统(Millipore)，其包含一层分级至0.4-0.11μm的硅藻土和一层分级至<0.1μm的硅藻土，随后为纤维素膜；然后通过0.22μm最终滤器至容量为350L的单次使用无菌软袋。向收获的细胞培养液补充10mM EDTA和10mM Tris至pH为7.5。利用4个Sartoslice TFF30kDa分子量截止(MWCO)聚醚 砜(PES)滤器(Sartorious)，用切向流过过滤(TFF)装置，将培养物浓缩10×，然后与10mM Tris、20mM Na2SO4，pH7.5进行10×缓冲液交换至0.22μm最终滤器并进入50L无菌储存袋。
将浓缩、渗滤的收获物灭活病毒。在病毒灭活之前，准备10％TritonX-100、3％磷酸三(正丁)酯(TNBP)的溶液。就在Q柱上的纯化之前，将浓缩、渗滤的收获物在36L玻璃反应容器中暴露于1％Triton X-100、0.3％TNBP1小时。
B.Gen2可溶性rHuPH20的纯化
准备Q琼脂糖(Pharmacia)离子交换柱(9L树脂，H＝29cm，D＝20cm)。收集洗涤样品用于pH、电导率的确定和内毒素(LAL)测定。用5个柱体积的10mM Tris、20mM Na2SO4，pH7.5平衡柱。病毒灭活之后，将浓缩、渗滤的收获物(实施例2A)以100cm/hr的流速装至Q柱。用5个柱体积的10mM Tris、20mM Na2SO4，pH7.5和10mM Hepes、50mM NaCl，pH7.0洗涤柱。用10mM Hepes、400mM NaCl，pH7.0将蛋白洗脱至0.22μm最终滤器并进入无菌袋。测试洗脱物样品的生物负荷、蛋白浓度和透明质酸酶活性。在交换的开始和结束读取A280吸光度读数。
然后进行苯基-琼脂糖(Pharmacia)疏水相互作用色谱。准备苯基-琼脂糖(PS)柱(19-21L树脂，H＝29cm，D＝30cm)。收集洗涤液并采样pH、电导率和内毒素(LAL测定)。用5个柱体积的5mM磷酸钾、0.5M硫酸铵、0.1mM CaCl2，pH7.0平衡柱。向来自Q琼脂糖柱的蛋白洗脱物补充2M硫酸铵、1M磷酸钾和1M CaCl2贮存液以分别获得5mM、0.5M和0.1mM的终浓度。将蛋白以100cm/hr的流速装至PS柱并收集柱流穿液(flow thru)。用5mM磷酸钾、0.5M硫酸铵和0.1mM CaCl2pH7.0以100cm/hr洗涤柱，然后将洗涤液添加至收集的流穿液。与柱洗涤液合并，使流穿液通过0.22μm最终滤器进入无菌袋。采样流穿液的生物负荷、蛋白浓度和酶活性。
准备氨基苯基硼酸酯柱(ProMedics)。收集洗涤液并采样pH、电导率和内毒素(LAL测定)。用5个柱体积的5mM磷酸钾、0.5M硫酸铵平衡柱。将包含纯化的蛋白的PS流穿液以100cm/hr的流速装至氨基苯基硼酸酯柱。用5mM磷酸钾、0.5M硫酸铵，pH7.0洗涤柱。用20mMN-二甘氨酸、 0.5M硫酸铵，pH9.0洗涤柱。用20mM N-二甘氨酸、100mM氯化钠，pH9.0洗涤柱。用50mM Hepes、100mM NaCl，pH6.9洗脱蛋白并通过无菌滤器进入无菌袋。测试洗脱样品的生物负荷、蛋白浓度和酶活性。
准备羟基磷灰石(HAP)柱(Biorad)。收集洗涤液并测试pH、电导率和内毒素(LAL测定)。用5mM磷酸钾、100mM NaCl、0.1mM CaCl2，pH7.0平衡柱。向氨基苯基硼酸酯纯化的蛋白补充至终浓度为5mM磷酸钾和0.1mM CaCl2，并且以100cm/hr的流速装至HAP柱。用5mM磷酸钾，pH7、100mM NaCl、0.1mM CaCl2洗涤柱。然后用10mM磷酸钾，pH7，100mMNaCl，0.1mM CaCl2洗涤柱。用70mM磷酸钾，pH7.0洗脱蛋白并通过0.22μm无菌滤器进入无菌袋。测试洗脱样品的生物负荷、蛋白浓度和酶活性。
然后使HAP纯化的蛋白通过病毒去除滤器。首先通过用2L的70mM磷酸钾，pH7.0洗涤来准备无菌的Viosart滤器(Sartorius)。使用之前，采样过滤的缓冲液的pH和电导率。通过蠕动泵将HAP纯化的蛋白泵过20nM病毒去除滤器。使70mM磷酸钾，pH7.0中的过滤的蛋白通过0.22μm最终滤器进入无菌袋。测试病毒过滤的样品的蛋白浓度，酶活性，寡糖、单糖和唾液酸谱。还测试样品的方法相关的杂质。
实施例3可溶性rHuPH20的透明质酸酶活性的确定
利用比浊法或生物素化-透明质酸底物测定确定样品如细胞培养物、血浆、纯化级分和纯化的溶液中可溶性rHuPH20的透明质酸酶活性，所述比浊法是基于当透明质酸与血清白蛋白结合时不溶性沉淀的形成，而所述生物素化-透明质酸底物测定通过消化非共价地结合塑料多孔微量滴定板的生物素化的透明质酸(b-HA)底物来测量酶促活性的rHuPH20或PEGPH20的量。
A.微浊度测定
通过将可溶性rHuPH20与透明质酸钠(透明质酸)温育一段时间(10分钟)，然后添加酸化血清白蛋白沉淀未消化的透明质酸钠来测量可溶性rHuPH20的透明质酸酶活性。30分钟显影期之后在640nm处测量所得的样品的浊度。对透明质酸钠底物的酶活性所致的浊度减少是可溶性 rHuPH20透明质酸酶活性的量度。利用可溶性rHuPH20测定工作参照标准品的稀释物产生的校准曲线进行所述方法，并且相对于该校准曲线进行样品活性测量。
在酶稀释剂溶液中制备样品的稀释物。通过将33.0±0.05mg水解明胶溶于25.0mL的50mM PIPES反应缓冲液(140mM NaCl,50mM PIPES,pH5.5)和25.0mL的无菌注射用水(SWFI)中，并且将0.2mL的25％正常人血清白蛋白(Buminate)溶液稀释于混合物中并涡旋30秒来制备酶稀释剂溶液。这在使用前2小时之内进行，并且在冰上保存直至需要。将样品稀释至估计为1-2U/mL。一般来说，每步的最大稀释度不超过1:100，并且第一稀释的初始样品大小不少于20μL。进行测定所需的最小样品体积如下：过程中样品，FPLC级分：80μL；组织培养上清：1mL；浓缩物质：80μL；纯化或最终步骤物质：80μL。在低蛋白结合的96孔板中一式三份进行稀释，并且将30μL的每种稀释物转移至Optilux黑色/透明底板(BDBioSciences)。
在酶稀释剂溶液中制备浓度为2.5U/mL的已知可溶性rHuPH20的稀释物以产生标准曲线，并且将其一式三份添加至Optilux板。稀释物包括0U/mL、0.25U/mL、0.5U/mL、1.0U/mL、1.5U/mL、2.0U/mL和2.5U/mL。在板中包括含有60μL酶稀释剂溶液的“试剂空白”孔作为阴性对照。然后盖上板并且在加热块上于37℃下加热5分钟。去除盖并将板摇动10秒。摇动之后，将板放回加热块，并且向MULTIDROP384液体处理装置注入热的0.25mg/mL透明质酸钠溶液(通过将100mg透明质酸钠(LifeCore Biomedical)溶于20.0mL的SWFI来制备。通过在2-8℃下轻轻旋转和/或摆动2-4小时来混合，或者直至完全溶解)。将反应板转移至MULTIDROP384并且通过按下启动键将30μL透明质酸钠分入每孔来起始反应。然后将板从MULTIDROP384取出并摇动10秒，再转移至加热块并更换板盖。将板在37℃下温育10分钟。
通过向机器注入血清工作液并将体积设置变为240μL来使MULTIDROP384终止反应。(75mL的500mM乙酸缓冲液中的25mL血清贮存液[用9体积的500mM乙酸缓冲液稀释1体积的马血清(Sigma)并用盐酸将pH调至3.1])。将板从加热块取出并放置在MULTIDROP384上，并且将240μL血清工作液分入孔中。将板取出并且在酶标仪上摇动10秒。在另外的15分钟之后，在640nm处测量样品的浊度，并且通过拟合至标准曲线来确定每个样品的透明质酸酶活性(以U/mL计)。
通过用透明质酸酶活性(U/ml)除以蛋白浓度(mg/mL)来计算特异性活性(单位/mg)。
B.生物素化的乙酰透明质酸测定
生物素化-透明质酸测定通过消化非共价地结合塑料多孔微量滴定板的大分子量(～1.2兆道尔顿)生物素化的透明质酸(b-HA)底物来测量生物样品中酶促活化的rHuPH20或PEGPH20的量。将标准品和样品中的rHuPH20或PEGPH20在用b-HA包被的板中于37℃下温育。一系列洗涤之后，将剩余的未切割/结合的b-HA用链霉抗生物素蛋白辣根过氧化物酶缀合物(SA-HRP)处理。固定的SA-HRP与生色底物3,3’,5,5’-四甲基联苯胺(TMB)之间的反应产生蓝色溶液。用酸终止反应之后，通过利用微量滴定板分光光度计在450nm处读取吸光度来确定可溶性黄色反应产物的形成。对生物素化的透明质酸(b-HA)底物的酶活性所致的在450nm处吸光度减少是可溶性rHuPH20透明质酸酶活性的量度。利用可溶性rHuPH20或PEGPH20参照标准品的稀释物产生的校准曲线进行所述方法，并且相对于该校准曲线进行样品活性测量。
在测定稀释剂中制备样品和校准品的稀释物。通过将1％v/v汇集的血浆(来自适当的物种)添加至HEPES,pH7.4中的0.1％(w/v)BSA来制备测定稀释剂。其每天制备并储存在2-8℃下。根据物种类型以及预期的透明质酸酶水平，制备单个或多个稀释物以确保至少一个样品稀释物落在校准曲线的范围内。为了指导测试样品稀释物的选择，已知关于给药的透明质酸酶的剂量、给药途径、物种的大约血浆体积和时间点的信息用来估计透明质酸酶活性水平。在制备时通过短暂的脉冲-涡旋混合每个样品稀释物，并且在每个稀释物之间更换枪头。一般来说，稀释开始为初始50或100倍稀释，然后额外的系列稀释。制备rHuPH20或PEGPH20的7-点校准曲线(取决于给药的治疗)，对于rHuPH20，范围在0.004-3.0U/mL的浓度中，而对于PEGPH20，范围在0.037-27U/mL的浓度中。将一百微升(100μL)的每个 测试样品稀释物和校准曲线点应用于96-孔微量滴定板(Immulon4HBX,Thermo)的一式三份的孔，所述96-孔微量滴定板先前已用100μL/孔的0.1mg/mL的b-HA包被，并且用250μL的PBS中的1.0％(w/v)牛血清白蛋白封闭。将板用粘性板封条盖上，并且在37℃下温育约90分钟。在温育时间结束时，从板去除粘性封条，将样品吸出，并且利用自动化板洗涤器(BioTekELx405Select CW,Program‘4HBX1’)将板用300μL/孔洗涤缓冲液(10mM磷酸盐缓冲液，2.7mM氯化钾，137mM氯化钠，pH7.4，具有0.05％(v/v)Tween20，PBST)洗涤五(5)次。每孔添加100微升的链霉抗生物素蛋白-HRP缀合物工作液(20mM Tris-HCl、137mM氯化钠、0.025％(v/v)Tween20、0.1％(w/v)牛血清白蛋白中的链霉抗生物素蛋白-HRP缀合物(1:5,000v/v))。将板密封并在环境温度下温育约60分钟，不振荡且避光。在温育时间结束时，从板去除粘性封条，将样品吸出，并且如上文所述将板用300μL/孔洗涤缓冲液洗涤五(5)次。将TMB溶液(在环境温度下)添加至每孔，并且在室温下避光温育约五(5)分钟。然后以100μL/孔添加TMB终止液(KPL,目录#50-85-06)。利用微量滴定板分光光度计确定在450nm处每孔的吸光度。利用4-参数logistic曲线拟合建模每个板上校准曲线的反应。通过从校准曲线插入计算每个未知的透明质酸酶活性，对样品稀释因子校正，并且以U/mL报道。
实施例4聚乙二醇化的rHuPH20的制备
在这个实施例中，通过酶与甲氧基聚(乙二醇)丁酸的线性N-羟基琥珀酰亚胺基酯(mPEG-SBA-30K)的反应来将rHuPH20聚乙二醇化。
A.mPEG-SBA-30K的制备
为了产生PEGPH20，将rHuPH20(大小约60kDa)共价缀合至甲氧基聚(乙二醇)丁酸的线性N-羟基琥珀酰亚胺酯(mPEG-SBA-30K)，其具有30kD的近似分子量。mPEG-SBA的结构如下所示，其中n≈681。
用来制备用于聚乙二醇化rHuPH20的mPEG-SBA-30K的方法描述于例如美国专利第5,672,662号。简单地说，根据以下方法制备mPEG-SBA-30K：
在氮气气氛下将溶于二噁烷的丙二酸乙酯(2当量)溶液逐滴添加至氢化钠(2当量)和甲苯。将mPEG甲磺酸酯(1当量，MW30kDa，Shearwater)溶于甲苯，并且添加至上述混合物。将所得的混合物回流约18小时。将反应混合物浓缩至其原体积的一半，用10％的NaCl水溶液萃取，用1％盐酸水溶液萃取，并且合并水性萃取物。将收集的水层用二氯甲烷萃取(3x)，并且将有机层用硫酸镁干燥，过滤并蒸发干燥。将所得的残余物溶于包含氯化钠的1N氢氧化钠，并且将混合物搅拌1小时。通过添加6N盐酸来将混合物的pH值调整至约3。将混合物用二氯甲烷萃取(2x)。
将有机层在硫酸镁上干燥，过滤，浓缩并倒入冷的二乙醚中。通过过滤和真空干燥收集沉淀。将所得的化合物溶于二噁烷并回流8小时，然后浓缩干燥。将所得的残余物溶于水，用二氯甲烷萃取(2x)，在硫酸镁上干燥，并且将溶液通过旋转蒸发浓缩，然后倒入冷的二乙醚中。通过过滤和真空干燥收集沉淀。将所得的化合物(1当量)溶于二氯甲烷，并且添加N-羟基琥珀酰亚胺(2.1当量)。将溶液冷却至0℃，并且逐滴添加二环己基碳二亚胺(2.1当量)在二氯甲烷中的溶液。将溶液在室温下搅拌约18小时。将反应混合物过滤，浓缩并在二乙醚中沉淀。通过过滤和真空干燥收集沉淀以提供粉末mPEG-SBA-30K，然后将其在≤-15℃下冷冻。
B.mPEG-SBA-30K缀合至rHuPH20
为了制备PEGPH20，将mPEG-SBA-30K偶联至rHuPH20的氨基，提供rHuPH20和mPEG之间的稳定酰胺键，如下所示，其中n≈681。
缀合之前，利用具有0.2m2过滤面积的10kDa聚醚砜(PES)切向流过滤(TFF)盒(Sartorius)将实施例2B中制备的rHuPH20纯化的大量蛋白浓缩至10mg/mL，并且对pH7.2的70mM磷酸钾进行缓冲液交换。然后将浓缩的蛋白储存在2-8℃下直至使用。
为了缀合rHuPH20，将mPEG-SBA-30K(Nektar)在室温下于黑暗中解冻不超过2小时。根据批次大小，将无菌的3”搅拌棒置于1或3升Erlenmeyer瓶中，并且添加缓冲液交换的rHuPH20蛋白。在真空罩下将5克mPEG-SBA-30K干粉/克rHuPH20(10:1摩尔比的mPEG-SBA-30K:rHuPH20)添加至瓶中，并且将混合物混合10分钟或直至mPEG-SBA-30K完全溶解。设置搅拌速率，从而涡旋不发生起泡。
然后在100级罩下通过蠕动泵将溶液泵过0.22μm聚苯乙烯、醋酸纤维素滤器胶囊(Corning50mL Tubetop滤器)进入新的包含无菌3”搅拌棒的1或3升Erlenmeyer瓶来过滤溶液。通过质量确定PEGPH20反应混合物的体积(1g/mL密度)，并且在使用后完整性测试中检查用于过滤的0.22μm滤器。
然后将混合物在2-8℃下置于搅拌板上，并且在黑暗中混合20±1小时。再次设置搅拌速率，从而涡旋不发生起泡。将整个Erlenmeyer容器包在箔中以使溶液避光。混合之后，通过添加1M甘氨酸至25mM的终浓度来终止反应。从容器取出样品以测试pH和电导率。然后通过添加至5mMTris碱(5.65L/L)和5mM Tris,10mM NaCl,pH8.0(13.35L/L)的溶液来调整pH和电导率以进行Q琼脂糖纯化。
通过用5个柱体积(36L)的5mM Tris,10mM NaCl,pH8.0平衡来准备QFF琼脂糖(GEHealthcare)离子交换柱(高度＝21.5-24.0cm，直径＝20cm)。将缀合的产物以95cm/hr的流速装至QFF柱。然后将柱用11L平衡缓冲液(5mM Tris,10mM NaCl,pH8.0)以95cm/hr的流速洗涤，随后用25L平衡缓冲液以268cm/hr的流速洗涤。然后用5mM Tris,130mM NaCl,pH8.0以268cm/hr的流速洗脱蛋白产物。利用具有0.2m2过滤面积的30kDa聚醚砜(PES)切向流过滤(TFF)盒(Sartorius)将所得的纯化的PEGPH20浓缩至3.5mg/mL，并且对pH6.5的10mM组氨酸、130mM NaCl进行缓冲液交换。如实施例3所述测试所得的物质的酶活性。将3mL体积的浓度为3.5mg/mL(最终酶活性140,000U/mL)的聚乙二醇化的rHuPH20物质装入具有硅化溴丁基橡胶塞和铝易拉盖(flip-off seal)的5mL玻璃小瓶并冷冻(在-20℃冰箱中冷冻过夜，然后置于-80℃冰箱长期保存)。聚乙二醇化的rHuHP20包含约4.5摩尔PEG/摩尔rHuPH20。
B.聚乙二醇化的rHuPH20的分析
通过凝胶电泳测定聚乙二醇化的rHuPH20。如上文实施例4A所述制备的3批PEGPH20显示多条带的相同模式，代表未反应的PEG和多种PEGPH20缀合物，其以不同距离迁移。基于与分子量标记迁移的比较，所述条带代表约90kDa至300kDa的种类，其具有3条迁移高于240kDa标记的暗带。这些数据表明通过mPEG-SBA-30K的共价缀合产生的PEGPH20包含PEGPH20种类的异源混合物，可能包括单-、二-和三-聚乙二醇化的蛋白。缺少在60kDa处的可见带表明所有蛋白均已与PEG反应，并且混合物中不存在可检测的天然rHuPH20。
实施例5肿瘤细胞形成细胞周围基质的能力以及与肿瘤细胞乙酰透明质酸(HA)含量、乙酰透明质酸合成酶(HAS)水平和透明质酸酶(Hyal)表达的关系
A.肿瘤细胞HA含量的比较，HAS1、2、3以及Hyal1和2的表达，以及细胞周围基质形成
在这个实施例中，比较内源HA合成酶，乙酰透明质酸合成酶(HAS)1、2和3，透明质酸酶(Hyal)1和(Hyal)2的量以及肿瘤细胞中乙酰透明质酸 (HA)积累的量以显示各自与肿瘤细胞的细胞周围基质形成相关。
1.用于研究的细胞系
在该研究中检测来自各种组织来源(例如，前列腺、乳房、卵巢、胰腺和肺)和物种来源(例如，人、小鼠和大鼠)的肿瘤的10个细胞系。以下细胞系获得自美国典型培养物保藏中心(ATCC)：4T1小鼠乳腺肿瘤(ATCC CRL-2539)、PC-3人前列腺癌(ATCC CRL-1435)、BxPC-3人胰腺癌(ATCC CRL-1687)、MDA MB231人乳腺癌(ATCC HTB-26)、Mat-Lylu大鼠恶性前列腺癌(ATCC JHU-92)、AsPc-1人胰腺癌(ATCC CRL-1682)、DU-145人前列腺癌(ATCC HTB-81)和MIA PaCa2人胰腺癌(ATCC CRL-1420)。使ATCC细胞系在包含10％FBS的推荐培养基中于37℃下在提供5％CO2/95％空气的加湿培养箱中生长。表达北美萤火虫萤光素酶基因的MDA-MB-231-Luc(Cat.No.D3H2LN)细胞购自Caliper Life Sciences Inc.并使其在包含10％FBS的RPMI中生长。
通过用编码乙酰透明质酸合成酶2(HAS2)(SEQ ID NO:195)的逆转录病毒转导DU-145和MDA-MB-231-Luc细胞系产生DU-145/HAS2和MDA-MB-231-Luc/HAS2细胞系。为了产生HAS2逆转录病毒，将N-末端His6-标记的hHAS2cDNA(SEQ ID NO:196)插入包括新霉素抗性基因的载体pLXRN(SEQ ID NO:197；Clontech,Cat.No.631512)的AvrII和NotI位点以产生pLXRN-hHAS2(SEQ ID NO:201)。然后利用Lipofectamine2000试剂(Life Technologies)将pLXRN-hHAS2His质粒与pVSV-G包膜载体(SEQ ID NO:198Clontech，Cat.No.631530的部分)共转染入GP-293细胞。还通过空pLXRN质粒和pVSV-G包膜载体的共转染产生DU-145模拟细胞系。
通过定量PCR方法(Retro-XTMqRT-PCR滴定试剂盒；Clontech，目录号631453)利用以下引物(Clontech目录号#K1060-E)确定病毒滴度：
pLXSN5’引物(1398-1420):5’-CCCTTGAACCTCCTCGTTCGACC-3’(SEQ ID NO:199)；
pLXSN3’引物(1537-1515):5’-GAGCCTGGGGACTTTCCACACCC-3’(SEQ ID NO:200)。
为了建立HAS2表达细胞系，将70％汇合的癌细胞、DU-145或MDA MB231Luc与包含10％FBS的DMEM(Mediatech)中的60:1至6:1比例的逆转录病毒温育72小时。将培养物维持在包含200μg/mL的G418的选择培养基中。2周的G418条件培养基选择之后产生稳定的HAS2-表达癌细胞。
2.透明质酸的定量
基于乙酰透明质酸结合蛋白(HABP)的测定用来确定肿瘤细胞产生的乙酰透明质酸的量。对于测量HA作为肿瘤微环境(TME)生物标记的化学方法，优选基于HABP的测定，因为HABP优选检测由至少15个(n-乙酰基葡萄糖-葡糖醛酸)二糖组成的HA，其能够结合透明质酸粘素(HA结合蛋白)(参见，例如，Haserodt S,et al.(2011)Glycobiology21:175-183)。
将肿瘤细胞以1x106个细胞接种于75cm2瓶中并培养24小时。收获组织培养上清用于HA的定量，利用酶联HABP夹心测定(R&D Systems，目录号DY3614)，其使用重组人聚集蛋白聚糖作为HA捕获和检测试剂(重组人聚集蛋白聚糖G1-IGD-G2结构域，登录号NP_037359的Val20-Gly676(SEQ ID NO:202)，具有C-末端10-HIS标签，R&D Systems，目录号1220-PG)。根据制造商的说明书进行HA检测的测定。简单地说，将测定板用重组人聚集蛋白聚糖包被，并且将包含HA的样品(即组织培养上清)添加至所述板(测试每个细胞系的3个独立重复)。将板洗涤，并且利用生物素化的重组聚集蛋白聚糖检测结合的HA。去除未结合的探针之后，添加缀合至辣根过氧化物酶(HRP)的链霉抗生物素蛋白作为第二检测试剂。洗涤板之后，通过与1:1H2O2/四甲基联苯胺底物溶液(R&D Systems)来检测结合的HRP，并且通过利用SpectraMax M3多模式酶标仪(Molecular Devices,CA)在450nm处光密度检测来定量。每个肿瘤细胞类型的培养基中的HA浓度表示为培养基中的平均HA浓度(ng/mL)(表5)。
3.HAS1、HAS2、HAS3、HYAL1和HYAL2mRNA表达的定量
利用Mini试剂盒(Qiagen GmbH)根据制造商的说明书从细胞沉淀提取RNA。然后利用NanoDrop分光光度计(NanoDrop Technologies,Wilmington,DE)定量提取的RNA。使用基因特异性引物的定量实时PCR(qRT-PCR)用来定量每种乙酰透明质酸合成酶和透明质酸酶的相对mRNA 水平。qRT-PCR引物购自Bio Applied Technologies Joint,Inc,(San Diego,CA)。用于各PCR反应的引物的DNA序列如下：
对于PCR反应，将样品与iQ SYBR绿色预混液(Bio-Rad)和每个基因的指定引物对混合。在Bio-Rad Chromo4qPCR装置上进行PCR反应。在以下条件下进行第一链合成：42℃维持2分钟用于DNA消除反应，42℃维持15分钟用于逆转录，并且在95℃下3分钟用于逆转录酶的灭活。对于扩增，使用以下条件：在95℃下3分钟初始变性，15秒变性和在58℃下1分钟退火延伸的45个循环。通过用内部看家基因GAPDH归一化来计算来自每个样品的基因表达CT值，并且作图相对值。表5列出了测定的每个基因的每个肿瘤细胞类型的CT值。
4.细胞周围基质形成的测定
使10个细胞系的单层培养物生长并测试聚集蛋白聚糖促进的细胞周围基质形成。为了使聚集蛋白聚糖介导的HA细胞周围基质在体外可见，如 Thompson CB,et al.(2010)Mol Cancer Ther9:3052-3064以前所述使用颗粒排阻测定，进行一些修改。简单地说，将细胞以1x105个细胞/孔接种于6-孔板中24小时，然后用单独的细胞培养基或包含1000U/mLrHuPH20的培养基在37℃下处理1小时。用rHuPH20预处理抑制细胞周围基质的形成；因此，其用作每个细胞类型的细胞周围基质形成的阴性对照。然后将细胞与0.5mg/mL牛聚集蛋白聚糖(Sigma-Aldrich)在37℃下温育1小时。随后，去除培养基并用PBS,pH7.4中的2％戊二醛固定的分离自Balb/c小鼠(Taconic,Hudson,NY)的小鼠红细胞(RBC)的108/mL悬浮液代替。允许颗粒沉降15分钟。然后将培养物用连接有照相扫描仪和成像程序的相差显微镜(Diagnostic Instruments)成像。利用SPOT Advance程序(Diagnostic Instruments,Inc.,Sterling Heights,MI)测量颗粒排阻面积和细胞面积。细胞周围基质面积计算为基质面积减去细胞面积，并且表示为μm2(表5)。
5.结果：肿瘤细胞HA含量，以及HAS和HYAL表达与细胞周围基质形成的比较
据发现如通过基于HABP的检测测定确定的条件培养基中的HA浓度与单层培养中肿瘤细胞形成的聚集蛋白聚糖介导的细胞周围基质面积相关(表5，P<0.0029)。此外，工程化以表达乙酰透明质酸合成酶2(HAS2)、DU-145/HAS2和MDA-MB-231/HAS2的细胞系与各自的亲代细胞系相比在体外表现出增加的HA产量和增强的细胞周围基质形成。相比之下，在细胞周围基质形成与HAS1、2或3或Hyal1或2mRNA表达的相对水平之间未发现相关性。这些发现表明直接测量肿瘤细胞相关的HA特异性地提供细胞周围基质形成的预测。
NE：未评价
1通过颗粒排阻测定评价的细胞周围基质面积(μm3)。
2培养基中的平均HA浓度(ng/mL)(n＝3，独立的培养物)。
3,4通过实时RT-PCR确定的乙酰透明质酸合成酶(HAS)和透明质酸酶(Hyal)表达。通过GAPDH mRNA归一化Ct值，并且倍数差异是相对于BxPC3表达。
实施例6肿瘤细胞乙酰透明质酸浓度的测量以及与PEGPH20的抗肿瘤活性的关系
在这个实施例中，通过免疫组织化学分析评价不同肿瘤细胞系中的乙酰透明质酸浓度，并且比较PEGPH20抑制从肿瘤细胞系产生的异种移植肿瘤的肿瘤生长的能力以及HA丰富的肿瘤细胞系的肿瘤集落生长。
A.各种异种移植模型中HA含量与PEGPH20效力的比较
1.异种移植肿瘤模型
从以下肿瘤细胞系产生14种肿瘤细胞系衍生的异种移植肿瘤：DU-145人前列腺癌(用空pLXRN质粒转染的ATCC HTB-81模拟物，参见实施例5.A.1)、DU-145HAS2(参见5.A.1)、MDA MB231人乳腺癌(ATCC HTB-26)、MDA-MB-231\Luc(D3H2LN,Caliper Life Sciences)、MDA MB231Luc/HAS2(参见实施例5.A.1)、SKOV3人卵巢癌(ATCC HTB-77)、AsPc-1人胰腺癌(ATCC CRL-1682)、MIA PaCa2人胰腺癌(ATCC CRL-1420)、4T1小鼠乳腺肿瘤(ATCC CRL-2539)、BxPC-3人胰腺癌(ATCC CRL-1687)、Mat-Lylu大鼠恶性前列腺癌(ATCC JHU-92)以及PC-3人前列腺癌(ATCC CRL-1435)。如实施例5所述维持肿瘤细胞系。LUM697和LUM330人肿瘤外植体获得自Crown Bioscience,Beijing China。
将6-8周龄的nu/nu(Ncr)无胸腺的裸鼠(Taconic)或Balb/c(Harlan)或Balb/c裸鼠(Shanghai Laboratory Animal Center,CAS(SLACCAS)；参见实施例7)关在小分离(micro-isolator)笼中，在12-小时光照/12-小时黑暗循环的环境控制室中，并且随意接受无菌的食物和水。所有动物研究均按照批准的IACUC方案进行。
对于肿瘤的产生，根据下文的表6将小鼠用肿瘤细胞胫骨周围(邻近右胫骨骨膜肌肉内注射)、皮下(s.c.，右后腿)或在乳腺脂肪垫中接种。
表6.动物肿瘤模型
H：人；M：小鼠；R：大鼠
对于胫骨周围肿瘤，利用VisualSonics Vevo770高分辨率超声确定肿瘤体积。对于皮下和乳腺脂肪垫肿瘤，通过实体瘤块的长度(L)和宽度(W)的卡尺测量计算肿瘤体积。肿瘤体积(TV)计算为：(L×W2)/2。当肿瘤体积达到～400-500mm3时，选择动物用于PEGPH20处理。然后将动物随机分入处理组和对照组(n≥6只小鼠/组)。
用PEGPH20处理和肿瘤生长抑制(TGI)的分析如(Thompson et al.)所述进行。根据表7所示的安排将小鼠用媒介物(10mM组氨酸，pH6.5，130mMNaCl)或PEGPH20处理2-3周。每周2次测量肿瘤体积。当肿瘤大小超过2,000mm3时，将动物从研究中去除并人道安乐死。
基于来自如表7所示的研究终止日的体积计算每个肿瘤模型的TGI。利用以下等式计算每个肿瘤模型的肿瘤生长抑制百分比(TGI)：
％TGI＝[1–(Tn-T0)÷(Cn-C0)]x100％
其中“Tn”是在聚乙二醇化的rHuPH20的最终剂量后的第“n”天，处理组 (接受聚乙二醇化的rHuPH20的动物)的平均肿瘤体积；“T0”是在处理之前的第0天，该处理组中的平均肿瘤体积；“Cn”在第“n”天，相应对照组的平均肿瘤体积；而“C0”是在处理之前的第0天，对照组中的平均肿瘤体积。利用单向ANOVA测试进行对照组和处理组之间肿瘤体积的统计分析，P≤0.05的P值定义为统计显著。
2.肿瘤组织中HA的组织化学染色以及HA含量的半定量
在肿瘤生长抑制研究终止时，通过组织化学分析所产生的14种异种移植肿瘤中每一种的HA含量，利用生物素化的乙酰透明质酸结合蛋白(B-HABP)作为探针用于HA和数字定量。
收获肿瘤组织，在10％中性缓冲的福尔马林溶液(NBF)中固定，包埋在石蜡中，并且切为5μm切片。对于组织化学分析，将切片脱蜡并再水合。用于peroxo-封闭液(Invitrogen,CA,USA)封闭内源性过氧化物酶2分钟。在室温(RT)下利用2％正常山羊血清PBS中的2％BSA封闭非特异性染色1小时，然后在37℃下与2.5μg/ml生物素化的HA-结合蛋白(B-HABP，目录号400763,Seikagaku,Tokyo,Japan)温育1小时。为了证实染色的特异性，在添加B-HABP之前将切片的一个子集用PIPES缓冲液(25mM PIPES,70mM NaCl,0.1％BSA,pH5.5)中的rHuPH20(1000U/mL)在37℃下预处理1h。洗涤以去除第一试剂之后，将样品与链霉抗生物素蛋白-辣根过氧化物酶溶液(BD Pharmingen，目录号550946)在RT下温育30分钟并用3,3’-二氨基联苯胺(DAB；Dako,目录号K3467)检测。然后将切片在Gill’s苏木精(Vector Labs，目录号H-3401)中复染，脱水并封固在Cytoseal60介质中(AmericanMasterTech)。
Aperio T2Scanscope(Aperio)用来产生组织切片的高分辨率图像。用Aperio谱软件定量分析图像，利用像素计数算法用于褐色(HA)计数。对于评价，排除切片中具有少于10％肿瘤细胞或超过50％坏死组织的组织核心。PC3(HA+3)异种移植肿瘤组织用作阳性对照。计算强阳性(褐色)染色面积比总染色面积的总和的比例，并且在该比例为超过25％、10-25％、少于10％或0时分别评分为+3、+2、+1或0。
Spearman秩相关系数用来评价HA表达与对PEGPH20处理的反应之 间的关系。
3.结果：PEGPH20处理之后肿瘤HA含量和肿瘤生长抑制的比较
表8所示的结果比较了采自异种移植肿瘤的组织切片中测量的HA水平和通过PEGPH20的肿瘤生长抑制(TGI)百分比。结果来自用至少1mg/kgPEGPH20处理的肿瘤。高于1mg/kg的剂量不增加肿瘤生长抑制。在PC-3(HA+3)和BxPC3(HA+2)动物模型中，分别在高于10μg/kg和100μg/kg的剂量下未观察到效力的显著增加。
尽管肿瘤细胞的多样性(人、小鼠和大鼠来源)，增加B-HABP介导的HA染色强度与PEGPH20的体内抗肿瘤活性之间有显著相关性(P<0.001,Spearman’s r＝8,n＝14)(表8)。
H：人；M：小鼠；R：大鼠
B.HAS2过量表达的异种移植肿瘤模型中HA含量与PEGPH20效力的比较
在表达外源性乙酰透明质酸合成酶2(HAS2)的肿瘤异种移植物中进一步检测增加肿瘤细胞中HA产量对增加肿瘤对用PEGPH20处理的敏感性的影响。如实施例5所示，DU-145肿瘤细胞系的HA产量可以通过用编码HAS2的基因转导细胞来增加，这在体外导致增强的细胞周围基质形成。此外，在上文所述的异种移植模型中，DU142-HAS2表现出增加的HA染色和增加的通过PEGPH20的肿瘤抑制。在这个实施例中，在DU-145对DU-145-HAS2异种移植物中比较PEGPG20处理随时间的效力。
如上文实施例6A所述制备小鼠异种移植模型。简单地说，如表6所示将小鼠用DU-145/载体对照或DU-145/HAS2细胞接种。当肿瘤大小达到约500mm3时，将小鼠分入处理组(n＝8)并且用单独是媒介物或PEGPH20处理。对于PEGPH20处理，将小鼠通过尾静脉以4.5mg/kg的剂量注射，每周2次，维持3周。如上文所述通过卡尺测量监测肿瘤体积。用PEGPH20最后处理24小时之后，如上文所述通过组织化学利用生物素化的乙酰透明质酸结合蛋白(B-HABP)分析异种移植肿瘤的HA含量。
HAS2过量表达的DU-145前列腺肿瘤异种移植物在裸鼠中比用空载体转染的亲代细胞系(DU-145模拟)更侵袭性地生长，与以前的报道相似(表7)(Thompson et al.(2010))。PEGPH20在DU-145-HAS2肿瘤中抑制肿瘤生长(TGI＝50％,P<0.001,n＝8)，但是在DU-145载体对照肿瘤中不抑制肿瘤生长(TGI＝0.7％,P>0.05,n＝8)。此外，用B-HABP组织化学染色PEGPH20处理的肿瘤显示与对照肿瘤相比，肿瘤样品中HA去除。这些数据表明ECM中HA的积累促进肿瘤发展，并且增加的肿瘤相关的HA积累与PEGPH20的抗肿瘤活性相关。
C.乙酰透明质酸丰富的肿瘤中PEGPH20处理的剂量相关效应
在这个实验中，检测PEGPH20对HA丰富的肿瘤的肿瘤生长抑制的剂量依赖性效应。如上文实施例6A所述制备小鼠异种移植模型。简单地说，根据表6将小鼠用BxPC-3人胰腺癌(ATCC CRL-1687)或PC-3人前列腺癌(ATCC CRL-1435)接种。当肿瘤大小达到约500mm3时，将小鼠分入处理 组(n＝10)并且用单独是媒介物或PEGPH20处理。对于PEGPH20处理，将小鼠以0.01、0.1、1、4.5和15mg/kg(分别为350、3,500、35,000、157,500和500,000U/kg)的剂量尾静脉全身注射，每周2次，维持2周。如上文所述通过卡尺测量监测肿瘤体积。
观察到PEGPH20的最大有效剂量低于1mg/kg。在PC-3异种移植模型中对所有剂量的PEGPH20均观察到显著的肿瘤抑制(对于0.1、1、4.5、15mg/kg剂量，P<0.001；与媒介物相比，对于0.01mg/kg剂量，P<0.01)，而在BxPC-3异种移植模型中对大于0.01的所有剂量均观察到显著的肿瘤抑制(与媒介物相比，对于0.1、1、4.5、15mg/kg剂量，P<0.001)。在大于0.01μg/kg(PC3,HA+3)或0.1mg/kg(BxPC3,HA+2)的剂量未观察到效力的显著增加。
D.聚乙二醇化的rHuPH20对体外乙酰透明质酸丰富的肿瘤细胞的集落生长的影响
为了确定PEGPH20是否可以在体外抑制乙酰透明质酸丰富的前列腺肿瘤细胞(PC3)的贴壁依赖性生长和增殖，对细胞进行三维集落形成测定(clonogenic assay)。将约80％汇合的PC3细胞胰蛋白酶消化、收获并在完全培养基中洗涤一次。将细胞密度调整至8x104/mL细胞并在冰上悬浮于 (BD Biosciences,San Jose,CA)中。将0.025mL这种细胞/混合物接种于48孔细胞培养板上，所述48孔细胞培养板已用0.1mL/孔的预包被并在37℃下固化1小时。为了在17天中连续暴露于对照API缓冲液和各种浓度的PEGPH20，将0.6mL/孔的包含API缓冲液，1、3、10和100U/mL的PEGPH20的完全培养基添加至适当空的顶部。将孔在37℃下于空气中具有5％CO2的加湿气氛中温育17天，在17天时间中每3-4天更换在适当处包括适当浓度的酶的新鲜处理培养基。
在第17天，通过用连接至Insight FireWire数码相机的Nikon Eclipse TE2000U倒置显微镜(Diagnostic Instruments,Michigan)捕捉图像来评价集落的生长。利用ImageJ软件(开源软件，用于展示和分析图像，用于计算面积和像素值的可公开获得的程序)和耦合的校准功能测量集落数量和以μm计的每个集落的直径(利用集落直径并利用式：4/3πr3计算集落体积。
确定每个条件的孔的平均集落体积，并且通过比较对照样品(没有酶的API(活性药物成分)缓冲液(10mM Hepes和130mM NaCl,pH7.0))与在聚乙二醇化的rHuPH20的存在下温育的样品中的平均集落体积来评价PEGPH20对集落体积影响。利用下式计算抑制比：
(对照的平均体积-处理的平均体积)/(对照的平均体积)*100。
通过与对照相比较低的集落体积证实，聚乙二醇化的rHuPH20诱导剂量依赖性的生长抑制。基于利用上式计算的抑制比，与对照缓冲液温育的培养物相比，在1、3、10和100U/mL的PEGPH20的存在下温育的培养物分别表现出39％、67％、73％和75％的平均集落体积减少(对于3U和10U样品，p<0.01；对于100U样品，p<0.001；n＝6)。利用Mann-Whitney检验分析统计差异。
利用Graphpad4程序(GraphPad Software,Inc.,La Jolla,CA)确定的PEGPH20在减少集落体积中的IC50为约1.67U/mL。在媒介物处理(对照)的培养物中，平均集落数为10.17±1.56/孔，而在用PEGPH20100U/mL处理的培养物中，平均集落数为11.50±0.89/孔。集落数的差异在对照和100U/mL培养物之间不显著(n＝6,p>0.05)。这些结果表明PEGPH20可以抑制乙酰透明质酸丰富的癌细胞的增殖和/或存活。
在独立的实验中，如上文所述将PC3细胞接种于重组基底膜(Matrigel)中并持续暴露于媒介物或者0.1、1、10、100和1000U/mL的PEGPH2019天。然后数字捕捉图像并利用ImageJ程序评价集落体积。与对照相比集落体积的抑制分别为22、45、63、73和74％(对于1U/ml，P<0.01，对于10U/mL及以上，与媒介物相比，P<0.001；n＝3)。
实施例7HA作为预测人NSCLC肿瘤对PEGPH20的反应的生物标记的评价
A.HA在NSCLC患者活组织检查中的表达
以前的工作已显示在非小细胞肺癌(NSCLC)中出现升高的HA积累(Hernández JR,et al.(1995)Int J Biol Markers10:149-155和Pirinen R,et al.(2001)Int JCancer95:12-17)。相比之下，NSCLC衍生的细胞系表现出低水平，表明NSCLC细胞系在体外传代期间丧失了HA表达。因此，检测原 发性肿瘤活组织检查中的HA表达。
检测190个NSCLC活组织检查的组织微阵列(TMA)组的组织型和HA积累。通过如实施例6所述的B-HABP组织化学染色确定HA含量。当强阳性(褐色)染色面积比总染色面积的总和的比例为超过25％、10-25％、少于10％或0时将样品分别评分为+3、+2、+1或0。在这个组中，分别以32％、51％和3％的频率观察到腺癌(ADC)、鳞状细胞癌(SCC)和大细胞癌(LCC)细胞类型，基于US Biomax提供的病理学诊断进行分类(表9)。其他未鉴定的亚型包含检测的190个样品的约11％。
肿瘤相关的HA积累的分析显示所有组织型均具有表达HA+3高HA表型的细胞子集，总比率为约27％(表9)。具体地，40％的SCC病例表现出HA+3表型，而11％的ADC和33％的LCC病例评分为HA+3。34％的SCC病例表现出HA+2表型，而48％的ADC和50％的LCC病例评分为HA+2。25％的SCC病例表现出HA+1表型，而36％的ADC和17％的LCC病例评分为HA+2。在这个数据集中，没有正常肺组织样品表达HA+3表型，虽然在正常肺组织的大多数样品中观察到可检测的HA。
1基于阳性HA染色强度的％定义HA评分
2ADC：腺癌
3SCC：鳞状细胞癌
4LCC：大细胞癌
B.NSCLC患者外植体中HA的表达以及PEGPH20效力的预测
为了前瞻性地测试HA过量表达和NSCLC对PEGPH20介导的HA消耗的抗肿瘤反应之间的关系，选择代表不同程度的HA积累的人NSCLC患者肿瘤外植体并在异种移植肿瘤模型中评价对PEGPH20处理的反应性。特征在于HA积累的原代外植体用于这个研究，因为外植体包含完整肿瘤的遗传多样性的更有代表性的采样，并且应当保留天然肿瘤样基质的方面。
肿瘤活组织检查获得自16个NSCLC患者，并且在裸鼠中以低传代数皮下维持(Crown Bioscience,Beijing,China)。从第1-4代筛选NSCLC肿瘤外植体的外植体组织中的HA积累，并且通过如上文所述的B-HABP组织化学染色指定HA表型(即，+1、+2或+3)。前瞻性地选择3个鳞状细胞类型(SCC)外植体用于异种移植，代表HA+3(LUM697)、HA+2(LUM330)和HA+1(LUM858)表型。
当所选肿瘤外植体的种子肿瘤大小达到500-700mm3时，将小鼠处死，提取肿瘤并切为3×3×3mm3片段。如表6所示将每个肿瘤的一个片段皮下植入雌性Balb/c裸鼠的右后侧(每组n＝10)。通过卡尺测量最大的纵径(长度(L))和最大的横径(宽度(W))来确定肿瘤体积并利用(L×W2)/2计算来估计。当平均肿瘤大小达到500mm3(范围300-600mm3)时，将动物随机分为两组。对于处理，如上文表7所示，将动物用媒介物或4.5mg/kg的PEGPH20处理，每周2次，持续5个剂量。如实施例6所述进行肿瘤生长抑制百分比(％TGI)和统计分析。
据发现如通过组织化学确定的HA表型的等级排序(即+1、+2或+3)预测通过PEGPH20的肿瘤生长抑制程度(表9)。例如，生长抑制百分比对于LUM697(HA+3)为97％，对于LUM330(HA+2)为44％，而对于LUM858(HA+1)为16％。此外，在LUM697(HA+3)肿瘤外植体组中观察到肿瘤退化，但是在LUM330(HA+2)和LUM858(HA+1)组中未观察到：与处理前相比，具有LUM697(HA+3)肿瘤的10只动物中的4只具有减少的肿瘤负荷。
实施例8PEGPH20处理对异种移植肿瘤细胞DNA合成和肿瘤微环境(TME)的影响
A.HA消耗对肿瘤细胞DNA合成的影响
为了测试在体内HA消耗是否对肿瘤细胞具有抗增殖效应，检测用 PEGPH20处理的PC-3(HA+3)肿瘤异种移植物的DNA合成水平。
如实施例6所述将6-8周龄的nu/nu(Ncr)无胸腺裸鼠胫骨内(intraperitibially)植入PC-3肿瘤细胞(每只小鼠0.05mL中的1×106个细胞)。通过卡尺测量监测肿瘤体积。当肿瘤达到～400mm3时，将小鼠用媒介物或PEGPH20处理(1mg/kg(35,000U/kg)或4.5mg/kg(157,500U/kg)；基于20g小鼠体重约700U/剂量或3150U/剂量)，100μL通过尾静脉注射，每周2次，维持2周。研究终止之前24小时，向小鼠腹腔内给药10mg/kg BrdU(0.2mL)(Invitrogen,Cat#00-0103)。将肿瘤从小鼠切除，在10％缓冲的福尔马林中固定并包埋在石蜡中。将组织切为5μm切片，并且在根据制造商的说明书用抗BrdU抗体(BrdU染色试剂盒；Invitrogen,Cat#93-3943)染色之后评价细胞增殖。
将用PEGPH20处理的动物与媒介物处理的动物进行比较。与媒介物处理的肿瘤相比，在PEGPH20处理的肿瘤中观察到合成活性的核减少58.3％(BrdU阳性核百分比从4.8％减少至2％)。这个结果与观察到的作为PEGPH20处理结果的前列腺PC3(HA+3)或胰腺BxPC3(HA+2)异种移植物的生长抑制一致(在1mg/kg或更多的剂量下～50％TGI)(参见实施例6)。
B.HA消耗对肿瘤微环境相关蛋白的表达的影响
以前的研究已显示用PEGPH20处理HA+3肿瘤对肿瘤组织间隙液压(IFP)具有显著效果，因此对肿瘤与其外部环境之间的液压差有显著效果(参见Thompson et al.(2010))。TME的物理变化可以对基因表达有影响(Shieh AC(2011)Ann Biomed Eng39:1379-1389)。为了测试去除HA是否对TME蛋白的转换或表达有影响，检测在活性重塑基质中发现的TME蛋白的表达，例如小鼠胶原蛋白I(Col1α1)、小鼠胶原蛋白V(Col5α1)和生腱蛋白C(TNC)。
1.肿瘤组织中胶原蛋白的定位和半定量
将来自实施例8A中产生的PC-3肿瘤的邻近皮肤的肿瘤组织在10％中性缓冲的福尔马林中固定48小时，利用组织处理机(TISSUE-TEKVIP,Sakura Finetek,CA)处理并包埋在石蜡块中。将石蜡包埋的组织样品切为 5μm切片、脱蜡并在去离子水中再水合。通过将玻片在pH8.0的EDTA缓冲液中100℃加热25min来进行抗原修复。将玻片在PBS-T中漂洗，用2％PBS/BSA中的2％正常山羊血清封闭30min，然后与兔多克隆抗1型胶原蛋白抗体(1:200,Abcam,Cat#ab34710)在室温下温育2小时。然后将切片在室温下于德克萨斯红标记的山羊抗兔IgG(1:200,Vector Laboratories,Cat#F1-1000)中温育1小时，并且用有DAPI的Gold antifade试剂(Invitrogen,CA)复染和封固。在配有RT3相机的ZeissAxioskop显微镜(Diagnostic Instruments,MI)下捕捉显微照片。利用Image-Pro plus程序分析来自每个切片的随机的5个视野的胶原蛋白阳性强度。
2.PC3异种移植肿瘤组织中基因表达的cDNA阵列分析
如实施例6A所述产生携带PC3肿瘤的NCR nu/nu小鼠并用媒介物或PEGPH20处理。在用媒介物或PEGPH20处理后8和48小时将动物安乐死。在无菌条件下切除肿瘤组织并在液氮中快速冷冻。根据Asuragen的标准操作方法从冷冻的组织分离总RNA。利用NanoDrop ND-1000UV分光光度计通过在260和280nm处的吸光度读数确定总RNA样品的纯度和量。总RNA的完整性通过Bioanalyzer2100微流控电泳来定性。用于mRNA谱研究的样品由Asuragen,Inc.利用Affymetrix Mouse4302.0和Human U133plus2.0阵列进行加工。
3.结果
通过用PEGPH20处理而HA消耗之后，观察到PC-3肿瘤中Col1α1的肿瘤特异性减少。观察到与媒介物处理的肿瘤相比，Col1α1染色减少80％(P<0.05t test)。但是，来自PEGPH20处理的小鼠的皮肤中的Col1α1染色保持稳定。此外，如通过mRNA表达阵列分析测量的，观察到Col1α1、Col5α1和TNC的小鼠(基质)mRNA的水平降低。TNC mRNA受到最显著的影响(66％减少)，然后是Col1α1(53％减少)和Col5α1(45％减少)。这些结果表明HA的消耗导致TME内蛋白表达的显著改变。
实施例9TSG-6连接模块IgG Fc融合蛋白的产生
产生包含TSG-6的连接模块和IgG的Fc结构域的融合蛋白TSG-6-LM-Fc。还产生其中TSG-6连接模块的肝素结合区突变的突变融合蛋白TSG-6-LM-Fc/ΔHep。
A.重组人TSG-6连接模块融合蛋白的载体构建
DNA从头合成(GenScript,NJ)用来产生编码TSG-6-LM-Fc融合蛋白的核酸。所述核酸包含编码人免疫球蛋白轻链κ前导信号肽序列(SEQ ID NO:210)的DNA、669bp长的人IgG1重链的cDNA片段(GI No.5031409；SEQ ID NO:203，编码SEQ ID NO:204所示的肽序列)和285bp长的人TSG-6连接模块区的cDNA片段(SEQ ID NO:216，编码SEQ ID NO:207所示的肽序列，其对应于TSG-6蛋白的氨基酸位置35-129，GI No.315139000，如SEQ ID NO:205(mRNA)和SEQ ID NO:206(蛋白)所示)。人IgG1重链和人TSG-6连接模块区与6bp AgeI限制性酶切割位点和12bp序列GACAAAACTCAC(SEQ ID NO:208)相连，所述12bp序列编码最初公开为IgG1Fc序列的部分的4个额外的氨基酸(DKTH；SEQ ID NO:209)(Nucleic AcidsResearch,1982,Vol.10,p4041)。在融合蛋白序列的两侧合成两个独特的限制性酶切割位点，NheI在5’端而BamHI在3’端。合成的片段具有SEQ ID NO:217所示的序列。将该片段密码子优化用于提高的蛋白表达并通过从头DNA合成来合成。密码子优化的片段具有SEQ IDNO:211所示的序列。所编码的TSG-6-LM-Fc融合蛋白的蛋白序列如SEQ ID NO:212所示。
利用公知的重组DNA方法将合成的密码子优化的片段通过NheI和BamHI切割位点插入pHZ24IRES双顺反子哺乳动物表达载体(SEQ ID NO:52)(限制性酶和连接试剂获得自New England Biolabs,Ipswich,MA)以产生pHZ24-TSG-6-LM-Fc构建体(SEQ ID NO:213)。通过CMV启动子驱动这个载体中的重组蛋白表达。
为了增加乙酰透明质酸(HA)结合特异性并减少对其他GAG链的结合，构建编码突变的融合蛋白TSG-6-LM-Fc/ΔHep的构建体，其在TSG-6连接模块的氨基酸位置55、69、76包含3个赖氨酸至丙氨酸突变。所述突变减少TSG-6连接模块的肝素结合活性，同时不影响HA结合活性(参见 Mahoney DJ et al.(2005)J Biol Chem.280:27044-27055，其报道三突变体的低10倍的肝素结合活性；肝素结合位点中的K20A/K34A/K41A)。通过编码TSG-6-LM-Fc融合蛋白的核酸片段的诱变产生TSG-6-LM-Fc/ΔHep，并且插入pHZ24IRES载体以产生HZ24-TSG-6-LM-Fc/ΔHep(SEQ ID NO:218)。TSG-6-LM-Fc/ΔHep片段的序列如SEQ ID NO:214所示，其编码SEQ ID NO:215所示的TSG-6-LM-Fc/ΔHep融合蛋白。
B.重组蛋白表达和纯化
FreeStyle CHO-S悬浮细胞(Invitrogen)用于TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep融合蛋白的表达。转染之前将FreeStyle CHO-S悬浮细胞系维持在CHO-S CD培养基(Invitrogen)中。为了制备用于转染和重组细胞表达的细胞，将FreeStyle CHO-S细胞在补充了8mM L-谷氨酰胺的FreeStyle CHO表达培养基(Invitrogen)中于摇瓶中在37℃下于空气中8％CO2的加湿气氛中在以125rpm旋转的定轨振荡器平台上培养，瓶盖松开以允许换气。
根据制造商的说明书进行悬浮细胞的瞬时转染。简单地说，转染之前24小时将细胞以密度6×105/ml分开，并且利用FreeStyle Max脂质用1:1的DNA/脂质比进行转染。转染后96小时之后，以4,000g维持20min收获细胞，并且收集上清。瞬时转染后期间的蛋白表达水平的时间过程分析显示转染后96小时之后蛋白表达水平达到平台期。因此，在转染后96小时收集重组蛋白。
根据制造商的说明书通过A蛋白树脂(Bio-Rad,Hercules,CA)亲和纯化收集的上清中表达的TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep融合蛋白。简单地说，将收集的上清用1MTris-HCl，pH7.4(Teknova目录号T1074)和5MNaCl(Sigma)调整至pH7.4，0.15M NaCl，并且在装至A蛋白柱之前用结合缓冲液稀释3倍。将洗脱的产物立即用1M Tris-HCl，pH8.5中和，在4℃对磷酸盐缓冲液(PBS,137mM NaCl,2.7mM KCl,8mM Na2HPO4,1.46mMKH2PO4和pH7.4)透析并储存在-20℃下。来自上清的通过单一步骤A蛋白亲和柱的纯化蛋白的收率为3-5mg/升。
C.表达的重组蛋白的SDS-PAGE和蛋白印迹分析
通过还原和非还原条件下的SDS-PAGE4-20％梯度凝胶和蛋白印迹分析确定纯化的融合蛋白的纯度、大小和性质。将60ng纯化的蛋白用于分析。纯化的融合蛋白的大小在还原条件下为约40kDa，而在非还原条件下为约80kDa，表明表达的蛋白通过IgG Fc的铰链区中的二硫键形成同源二聚体。蛋白样品的纯度大于95％。纯化的蛋白在4℃下于PBS中稳定至少一个月，没有任何可见的降解或丧失结合活性。
通过蛋白印迹用山羊抗人TSG-6IgG(R&D Systems,Inc.,Minneapolis,MN)然后兔抗山羊IgG-HRP(EMD,San Diego,CA)评价TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep中的TSG-6连接模块的性质。重组全长人TSG-6蛋白(R&D Systems,Inc.,Minneapolis,MN)用作阳性对照。在还原和非还原条件下通过蛋白印迹分析的检测蛋白的模式与SDS-PAGE分析的模式相同，除了在非还原条件下观察到的少量上带，基于它们的分子量大小，最可能代表重组蛋白的四聚体。
通过蛋白印迹分析用HRP-兔抗人IgGFc(Jackson ImmunoResearch,West Grove,PA)证实纯化的重组蛋白中的Fc部分的性质。检测的蛋白的模式与SDS-Page和抗TSG-6分析相同，表明纯化的蛋白包含TSG-6连接模块(LM)以及hIgGFc。
为了分析蛋白是否糖基化，将纯化的蛋白用糖苷酶PNGase F(0.5单位/ng蛋白)处理并通过SDS-PAGE和蛋白印迹进行分析，所述糖苷酶PNGase F从蛋白去除N-联寡糖。用PNGase F处理之前和之后之间观察到蛋白分子量的5kDa差异，表明表达的蛋白是糖基化的。
实施例10TSG-6结合乙酰透明质酸和肝素
两种形式用来测试TSG-6-LM-Fc及其突变体对HA和肝素的结合。在一种形式中，采用TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep结合微孔板上固定的HA或肝素。在第二种形式中，采用生物素化的HA和肝素结合微孔板上固定的重组TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep蛋白。
A.重组TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep结合固定的HA和肝素
利用HA或肝素包被的微孔板测试野生型和突变TSG-6-LM Fc融合同源二聚体的HA结合和肝素结合活性。简单地说，将0.5M碳酸钠缓冲液，pH9.6中的浓度为100μg/ml的具有约1000kDa的平均MW的乙酰透明质酸(Lifecore,Chaska,MN)或具有15kDa的平均MW的肝素(Calbiochem,San Diego,CA)一式两份分入96-孔板，100μl/孔，并且在4℃下温育过夜。将板用PBS中的1％BSA封闭以减少非特异性结合。
将TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep纯化的蛋白样品稀释以产生0.31-40ng/ml的浓度范围用于结合HA包被的板，0.78-100ng/ml的浓度范围用于结合肝素包被的板。对于每个样品，将一式两份100μl/孔添加至微孔板并在室温下温育1小时。将板用具有0.05％Tween20的PBS洗涤5次以去除未结合的蛋白。用兔抗人IgG Fc-HRP(JacksonImmunoResearch,West Grove,PA)然后TMB(3,3′,5,5′-四甲基联苯胺)底物(KPL,Gaithersburg,MD)检测乙酰透明质酸或肝素结合的TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep。将样品与兔抗人IgG Fc-HRP抗体温育60分钟。洗涤之后，用TMB溶液经过10-15分钟显影时间然后添加磷酸试剂以终止颜色显影来检测结合的HRP。利用Molecular Devices,SpectraM3分光光度计在OD450处测量吸光度。
TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep在HA包被的板上表现出相同的HA结合活性；并且它们的HA结合活性的滴定曲线几乎重叠，表明这两种表达的蛋白以高亲和力结合HA，这是基于来自HA结合的滴定曲线的EC50值。肝素结合位点中的三突变对其HA结合没有影响。相比之下，两种蛋白结合肝素包被的板表现出显著差异。野生型TSG-6-LM-Fc结合肝素，虽然与其结合HA相比具有相对低的结合活性，这可能是由于板上包被的两条GAG链的大小差异。与野生型相比，突变的TSG-6-LM-Fc蛋白表现出约10％的肝素结合活性，这与三突变的TSG-6-LM单体的报道结果一致(Mahoney DJ et al.(2005))。
B.生物素化的HA和肝素结合固定的重组TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep
通过用重组蛋白包被微孔板并评价它们对生物素化的HA和生物素化的肝素的结合来进一步检测野生型TGS6-LM-Fc和TSG-6-LM-Fc/ΔHep的 GAG结合特性。
对于微孔板的准备，将1x PBS缓冲液中的浓度为2μg/ml的TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep一式两份分入96-孔板，100μl/孔，并且在4℃下温育过夜。将板用PBS中的1％BSA封闭以减少非特异性结合。
将TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep纯化的蛋白样品稀释以产生0.31-40ng/ml的浓度范围用于结合HA包被的板，0.78-100ng/ml的浓度范围用于结合肝素包被的板。对于每个样品，将一式两份100μl/孔添加至微孔板并在室温下温育1小时。用抗人IgG Fc-HRP(Jackson ImmunoResearch,West Grove,PA)然后TMB(3,3′,5,5′-四甲基联苯胺)底物(KPL,Gaithersburg,MD)检测乙酰透明质酸或肝素结合的TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep。
对于HA的生物素化，HA上的羧基用于通过酰肼化学缀合。简单地说，将生物素-酰肼以25mM的浓度溶于DMSO，并且以6:100的体积比添加至HA溶液中，所述HA溶液包含0.1MMES，pH5.0中的1mg/ml的1000kDa或150kDa分子量HA(Lifecore Biomedical,LLC Chaska,MN)。在缀合反应中分别添加1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(ECD)和磺基-N-羟基琥珀酰亚胺(磺基-NHS)至40μM和850μM的浓度以介导生物素酰肼和HA的缀合。将反应在4℃下保持过夜，同时搅拌。通过透析从生物素化的HA去除过量的化学品。生物素化的肝素购自EMD,San Diego(Catalog No.375054)。
将生物素化的乙酰透明质酸或肝素在PBS中稀释，浓度范围0.78ng/ml-100ng/ml，分入100μl/孔，并且在室温下温育1小时。将板用具有0.05％Tween20的PBS洗涤5次以去除未结合的蛋白。如上文所述用抗链霉抗生物素蛋白-HRP(Jackson ImmunoResearch,WestGrove,PA)然后TMB底物(3,3′,5,5′-四甲基联苯胺)底物(KPL,Gaithersburg,MD)检测结合的生物素化的乙酰透明质酸和肝素。在OD450处测量吸光度。
观察到的结合结果与实施例10A中进行的使用固定的HA和肝素以及游离的TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep的结合测定相似。固定的TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep对生物素化的HA的结合活性或者TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep之间的结合滴定曲线没有差异，并且还观察到与野生型蛋白相比，突变TSG-6-LM-Fc/Δhep对生物素化的肝素的结合显著减少。因此，可以在GAG包被或重组蛋白包被的形式中评价野生型TSG-6-LM-Fc及其突变体的HA和肝素结合特性；并且两种形式显示相似的结合模式。
C.TSG-6-LM-Fc的结合亲和力的计算
利用Bio-Layer Interferometry(BLI)技术通过Octet QKe仪器(ForteBio,MenloPark,CA)测量TSG-6-LM-Fc的HA结合亲和力。全长TSG-6重组蛋白(R&D Systems,Inc.,Minneapolis,MN)用作对照。简单地说，将具有150kDa的平均分子量的生物素化的HA固定在链霉抗生物素蛋白包被的生物传感器上240秒。然后使TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep在pH6.0或pH7.4的PBS中以不同浓度与固定的HA结合180秒，随后在pH6.0或pH7.4的PBS中解离结合的蛋白240秒。通过制造商提供的软件分析结合动力学的结果。计算的结合亲和力的结果在表10中提供。
实施例11通过其他糖胺聚糖的TSG-6结合乙酰透明质酸和肝素的竞争抑制评价
TSG-6连接模块的HA和肝素GAG结合位点位于连接模块的不同区域。为了确定两个结合位点在与TSG-6连接模块相互作用期间或者在其他GAG链的存在下是否会相互干扰，进行竞争抑制测定以评价在其他GAG链的存在下HA或肝素的结合。
如实施例10A所述准备HA和肝素包被的96-孔微孔板。将TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep(对于HA包被的板，浓度为40ng/ml，而对于肝素包被的板，浓度为100ng/ml)与4种不同的GAG链在室温下预 温育10分钟：HA(Lifecore Biomedical,LLC Chaska,MN)、硫酸软骨素A(EMD,San Diego,CA,目录号230687)、硫酸软骨素C(EMD,San Diego,CA,目录号2307)和硫酸肝素(EMD,San Diego,CA,目录号375095)，3个不同浓度(0.11,0.33,1.0μg/ml)，或者没有GAG链作为对照。然后将样品一式两份分入(100μl)HA和肝素包被的96-孔微孔板，并且在室温下温育1小时。将板用具有0.05％Tween20的PBS洗涤5次以去除未结合的蛋白。如上文所述用抗人IgG Fc-HRP(Jackson ImmunoResearch,West Grove,PA)然后TMB(3,3′,5,5′-四甲基联苯胺)底物(KPL,Gaithersburg,MD)检测结合的TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep。在OD450处测量吸光度。
对于HA包被的板，TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep均显示相似的竞争抑制模式。TSG-6-LM-Fc结合固定的HA受到相同量的蛋白与不同剂量的游离HA的预温育的有效抑制(对于0.11、0.33、1.0μg/ml剂量，分别约68％、85％和93％抑制)，但是不受与不同剂量的游离肝素或硫酸软骨素C预温育的影响。对于与硫酸软骨素A预温育，观察到TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep的一些抑制，虽然其少于HA(对于0.11、0.33、1.0μg/ml剂量，约23％、43％和63％抑制)。因此，抑制需要高约10倍量的硫酸软骨素A。(在独立的实验中，与HA相比，抑制需要高达高30倍量的硫酸软骨素A)。因为关于与硫酸软骨素A预温育，TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep表现出相似的抑制，可能TSG-6连接模块中的HA结合位点负责硫酸软骨素A结合。
对于肝素包被的板，TSG-6-LM-Fc对肝素的结合不仅受到与肝素预温育的有效抑制，而且还受到与HA或硫酸软骨素A预温育的有效抑制。这个数据表明TSG-6-Fc-LM结合HA可以阻断其肝素结合活性。正如预期的，突变的TSG-6-LM-Fc/ΔHep不结合肝素，因此表现出与对照和预温育样品的背景接近的读数。
这个研究证实TSG-6的连接模块对HA的结合不受游离肝素或预先形成的TSG-6肝素复合物的存在的影响，但是其对肝素的结合受到游离HA或预先形成的TSG-6HA的显著抑制。基于这些观察，可以得出结论，TSG-6-LM同时结合HA和肝素或者TSG-6-LM结合HA强于其结合肝素。HA和TSG-6-LM复合物形成可以引起蛋白构象改变或者不利于其结合肝 素的蛋白的其他排列。
实施例12TSG-6-LM-Fc、TSG-6-LM-Fc/ΔHep和HABP的糖胺聚糖结合特性的比较
在这个实施例中，比较TSG-6-LM-Fc、TSG-6-LM-Fc/ΔHep和HA结合蛋白(HABP)对HA、肝素和其他GAG的特异性和结合活性。对于这个实验，产生生物素化的TSG-6-LM-Fc和生物素化的TSG-6-LM-Fc/ΔHep HA结合蛋白并与可商购的生物素化的HA结合蛋白(HABP)(Seikagaku,Tokyo,Japan)比较它们在GAG链包被的板上的结合活性。
A.TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep的生物素化
随机标记方法用来将生物素直接缀合至蛋白中包含伯胺的残基(Lys)而不与游离HA预温育，以便保护HA结合位点。对于TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep的生物素化，根据制造商的说明书进行伯胺活性剂NHS-PEG4-生物素(Thermo Fisher Scientific,Chicago,IL)的直接缀合。浓度为1mg/ml的PBS中的0.5mg蛋白和10μl的20mM生物素化试剂用于生物素化反应。NHS-PEG4-生物素的N-羟基琥珀酰亚胺酯(NHS)基团在pH7-9下特异性且高效地与赖氨酸和N-末端氨基反应以形成稳定的酰胺键。亲水的聚乙二醇(PEG)间隔臂赋予水溶性，这转移至生物素化的分子，因此减少溶液中储存的标记蛋白的积累。PEG间隔臂还向该试剂提供长和柔性的连接以最小化结合抗生物素蛋白分子所涉及的位阻。对1×PBS透析去除未反应的NHS-PEG4-生物素并储存在-20℃下。
为了比较，还利用导向标记方法将TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep蛋白生物素化，所述导向标记方法通过利用NaIO4然后生物素-酰肼氧化蛋白上的多糖链来将生物素单元缀合至蛋白上的糖链。简单地说，将0.1M磷酸盐缓冲液中的浓度为1mg/ml的1ml蛋白首先通过终浓度为5mg/ml的高碘酸钠(NaIO4)在4℃下氧化30分钟。该反应将糖上两个相邻的伯羟基转化为相应的醛反应基团。将氧化的蛋白对0.1M磷酸盐缓冲液，pH7.2透析。然后将透析的蛋白与制备于DMSO中的50mM酰肼-生物素以体积比9比1混合，导致该反应中5mM酰肼-生物素，并且在室温下温 育2小时以在醛基团和酰肼基团之间形成腙键。将标记的蛋白对1×PBS透析并储存在-20℃下。
缀合并去除游离生物素之后，利用如实施例10A所述的结合测定使用HA包被的板，与未标记的相应蛋白一起测试生物素-TSG-6-LM-Fc和生物素-TSG-6-LM-Fc/ΔHep的HA结合活性以检测标记是否会引起减少的HA结合活性。标记对未标记的蛋白之间未发现HA结合活性的差异。
B.生物素化的TSG-6-LM-Fc、生物素化的TSG-6-LM-Fc/ΔHep和生物素化的HABP结合GAG
为了制备GAG包被的微孔板，将0.5M碳酸钠缓冲液中的浓度为100μg/ml的HA、肝素、硫酸软骨素A或硫酸软骨素C以100μl/孔一式两份分入96-孔板，并且在4℃下温育过夜。将板用PBS中的1％BSA封闭以减少非特异性结合。将3种生物素化的蛋白，生物素化的TSG-6-LM-Fc、生物素化的TSG-6-LM-Fc/ΔHep和生物素化的HABP稀释至0.05-100ng/ml的浓度用于结合HA、硫酸软骨素A和硫酸软骨素C包被的板，并且稀释至0.23-500ng/ml的浓度用于结合肝素包被的板。将稀释的蛋白样品一式两份分在板上，100μl/孔，并且在室温下温育1小时。如上文所述用抗链霉抗生物素蛋白-HRP(Jackson ImmunoResearch,West Grove,PA)然后TMB(3,3′,5,5′-四甲基联苯胺)底物(KPL,Gaithersburg,MD)检测结合GAG包被的板的蛋白。在OD450处测量吸光度。
全部3种生物素化的GAG结合蛋白在HA包被的板上均表现出强HA结合活性。在代表低于对HA的最大结合浓度(即33.3ng/ml和100ng/ml)的一个稀释度的11.1ng/ml蛋白浓度下，生物素化的TSG-6-LM-Fc和生物素化的TSG-6-LM-Fc/ΔHep结合HA超过背景约14倍，而B-HABP结合HA超过背景约9倍。
生物素化的HABP和生物素化的TSG-6-LM-Fc/ΔHep对肝素包被的板均表现出很少的结合活性。生物素化的野生型TSG-6-LM-Fc在肝素结合活性中也表现为阴性，这表明用NHS-PEG4-生物素的随机标记方法导致肝素结合活性的丧失。当如上文所述将TSG-6-LM-Fc通过导向标记方法生物素化时，恢复结合肝素，并且蛋白表现出与未标记的TSG-6-LM-Fc相似的肝 素结合活性。因此，TSG-6-LM-Fc的肝素位点中的赖氨酸的生物素修饰应当废除其肝素结合活性。
全部3种蛋白均对硫酸软骨素C包被的板表现出无结合活性，但是证实对硫酸软骨素A包被的板的强结合。观察到生物素化的TSG-6-LM-Fc和生物素-TSG-6-LM-Fc/ΔHep表现出比生物素-HABP高数倍的结合活性。在11.1ng/ml蛋白浓度下，生物素化的TSG-6-LM-Fc和生物素化的TSG-6-LM-Fc/ΔHep结合HA分别超过背景约20倍和12倍，而B-HABP结合HA超过背景约6倍。尽管如此，如GAG竞争测定中证实的，TSG-6-LM-Fc和TSG-6-LM-Fc/ΔHep对结合HA有更强的偏好。如实施例11所示，需要多至少10倍的硫酸软骨素A以达到与HA相似的竞争抑制。此外，在单独的实验中，在GAG竞争测定中比较生物素化的HABP与生物素化的TSG-6-LM-Fc，并且观察到4种GAG链(HA、肝素、硫酸软骨素A&C)对生物素-HABP结合HA对TSG-6-LM-Fc结合HA相似的抑制模式。
实施例13通过聚集蛋白聚糖结合测定定量K3-EDTA人血浆中的乙酰透明质酸
利用夹心结合测定确定临床人血浆样品中乙酰透明质酸的浓度。血浆样品获得自19个对象，所述对象患有实体瘤和晚期阶段的各种肿瘤类型并且参与临床研究(1-101期和1-102期；参见表1)，其评价在地塞米松的存在或不存在下患者中PEGPH20的逐步升高的剂量。此外，血浆样品还获得自二十(20)个正常患者(获得自BioReclamation,Hicksville,NY)。在用PEGPH20治疗之前，如下确定HA的基线水平。
将Immulon4HBX96-孔平底微量滴定板(Immulon/Thermo；目录号3855)用重组人聚集蛋白聚糖(rHu-聚集蛋白聚糖)R&D Systems，目录号842162)包被作用捕获试剂。使用之前，通过将250μl试剂稀释剂添加至1个小瓶来重建rHu-聚集蛋白聚糖并在2-8℃下储存长达1个月。然后，为了产生rHu-聚集蛋白聚糖的0.5μg/mL溶液，制备储备液的240倍稀释液(例如41.7μL储备液至约10mL PBS)。稀释之后，立即将100μL分入4HBX板的每个孔，将板用板密封器盖上并在室温下温育过夜或长达3天。温育之后，利用ELx405Select CW洗板机将板中的每个孔用1XPBST洗涤缓冲 液(1X PBS,0.05％Tween20)洗涤五(5)次。然后通过将300μL封闭缓冲液添加至每个孔来将测定板用封闭缓冲液(PBS中的5％Tween20)封闭。将板用粘性板盖盖上，并且在环境温度下温育至少1小时不振荡。
将板与样品温育之前，制备血浆样品和标准曲线。简单地说，获得血浆测试样品并在≤60℃下储存直至分析。分析之前立即将测试样品在湿冰上解冻，并且在正要稀释之前通过涡旋短暂混合。然后，通过在试剂稀释剂(5％Tween-20PBS溶液，通过将6.5mL Tween-20(Sigma；目录号P7949)添加至123.5mL磷酸盐缓冲盐水(PBS；CellGro；Catalog No.21-031-CV)来制备)中稀释来制备血浆测试样品稀释液的几个系列稀释液以确保至少一个样品稀释液落在校准曲线的范围内。为了评价测定正确性，还稀释两个质量对照样品用于测定。对照是在K3-EDTA中采集的汇集的人血浆(汇集的人K3-EDTA血浆；“低质量对照”)和掺入外源性乙酰透明质酸(HA)的汇集的人K3-EDTA血浆(“高治疗对照”)。对于人K3-EDTA血浆(用作对照)，最小需要的稀释度(MRD)为1:4。稀释液在聚丙烯管(例如，BioRad Titertubes；BioRad,目录号223-9391)中，并且总体积(样品和稀释剂)为500μl。在其通过短暂的脉冲-涡旋制备时混合每个稀释液。在每个稀释液之间更换移液管。
对于标准曲线，通过在试剂稀释剂(PBS中的5％Tween20)中系列稀释来将乙酰透明质酸储备液(132kD,1800ng/mL；R&D Systems,目录号842164)稀释至500ng/mL、167ng/mL、55.6ng/mL、18.5ng/mL、6.2ng/mL、2.1ng/mL和0.68ng/mL的终浓度。包含试剂稀释剂的空白孔也包括在标准品中。
然后，在封闭步骤结束时，利用ELx405Select CW洗板机将每个孔用1XPBST洗涤缓冲液(1X PBS,0.05％Tween20)洗涤五(5)次。通过将每个100μL一式三份添加至板的孔来将测试样品、对照和标准曲线添加至包被和封闭的板。将板用粘性板封闭器盖上，并且在环境温度下温育约2小时。温育之后，利用ELx405Select CW洗板机将每个孔用1XPBST洗涤缓冲液(1X PBS,0.05％Tween20)洗涤五(5)次。
为了检测HA结合包被的rHu-聚集蛋白聚糖，将生物素化的rHu聚集蛋白聚糖检测试剂(72μg/mL；R&D Systems,目录号842163)添加至板。首 先，通过将储备液在试剂稀释剂(5％Tween/PBS)中稀释240倍来制备10mL的0.3μg/mL生物素化的聚集蛋白聚糖溶液。然后，将100μL检测试剂添加至每个孔。将板用粘性封闭器盖上，并且在环境温度下温育约2小时。利用ELx405Select CW洗板机将每个孔用1XPBST洗涤缓冲液(1X PBS,0.05％Tween20)洗涤五(5)次。然后，通过稀释储备液200倍来在试剂稀释剂中制备链霉抗生物素蛋白-HRP(SA-HRP；R&D Systems,目录号890803)工作液。然后，将100μL稀释的SA-HRP工作液添加至每个孔。将板用粘性封闭器盖上，并且在环境温度下温育约20分钟，同时以500rpm振荡。在SA-HRP温育期结束时，利用ELx405Select CW洗板机将每个孔用1XPBST洗涤缓冲液(1X PBS,0.05％Tween20)洗涤五(5)次。然后，将避光平衡至环境温度的100μL的TMB底物(KPL；目录号52-00-03)添加至每个孔，并且在环境温度下温育20分钟，同时以500rpm振荡。然后，将100μL的TMB终止溶液(KPL；目录号50-85-06)添加至每个孔维持至少5分钟但少于30分钟，然后利用微量滴定板分光光度计和SoftMax Pro软件确定在450nm(OD450nm)处的光密度。
基于OD450nm值，通过插入标准曲线来确定每个样品的完整乙酰透明质酸的浓度。将结果乘以样品稀释因子。数据报道为校准曲线的定量限度内的所有值的平均值，以ng/mL计。结果如表11和12所示。结果显示健康人中的中值血浆HA为0.015μg/mL，而在1期对象中其为0.06μg/mL。这代表具有p<0.0001的统计显著差异。
实施例14HA的组织化学检测
HA的组织化学检测获得自患者的活组织检查前肿瘤样本和治疗后转移性肝活组织检查样品，该患者用1.6μg/kg PEGPH20+地塞米松剂量给药4周。剂量给药前活组织检查(活组织检查前)为2007年获得的保存样品(用PEGPH20治疗前3.5年)。治疗后活组织检查样品在PEGPH20加地塞米 松治疗方案的最后一次剂量给药(第8次剂量)后3天获得自具有肝转移的女性结肠癌患者。具体地，患者治疗后活组织检查在与地塞米松共治疗的给药周期的每周两次方案的一个周期的1.6μg/kg PEGPH20治疗后获得。治疗周期定义为28天期，其中静脉内(IV)给药PEGPH20并且口服给药地塞米松。在每个剂量给药日，在PEGPH20前1小时口服给药4mg地塞米松的预给药方案，然后在PEGPH20剂量给药后8-12小时给药4mg地塞米松的第二剂量。
简单的说，将肿瘤活组织检查固定在中性缓冲的福尔马林(NBF)中，进行5μm切片，并用生物素标记的乙酰透明质酸结合蛋白(HABP-bio)(Seikagaku,Japan)进行染色。洗涤以去除第一试剂后，使用标记的第二试剂。用DAPI(4',6-二脒基-2-苯基吲哚)试剂复染细胞核。利用Nikon Eclipse TE2000U倒置荧光显微镜获取显微图像，该显微镜配有InsightFireWire数码相机(Diagnostic Instruments,Michigan)或具有相同成像系统的ZEISS顶置显微镜(overhead scope)(Carl Zeiss,Inc.)。
用生物素化的HA结合蛋白进行的样品的组织化学染色证实一个周期的PEGPH20治疗后细胞周围和基质HA水平降低。结果总结于表13。H评分表示细胞周围和基质HA的相对强度。如通过治疗后肿瘤活组织检查中HA染色的减少所证实的，数据证实了PEGPH20降解肿瘤相关HA的能力。
**肿瘤相关基质
实施例15用于估计血浆中的乙酰透明质酸(HA)水平的HPLC方法
这个实施例描述用于确定血浆中的HA-二糖含量作为HA分解代谢物的量度的方法，HA-二糖是PEGPH20的酶促活性后的分解产物。该方法用软骨素酶ABC水解HA以释放HA-二糖，将其用2-氨基吖啶酮(AMAC)衍 生化并在配有荧光检测的反向HPLC上进行分析。通过与HA-二糖标准品进行比较来完成HA-二糖的定量。这个测定通过监测患者血浆中的乙酰透明质酸分解代谢物浓度来测量PEGPH20的酶促活性，该患者从用PEGPH20治疗后的患者以计划时间选择。
1.工作标准品
在所述方法中，产生工作标准品溶液。首先，从HA-二糖储备液(SS)产生稀释的储备液(DSS)。通过将1mL水添加至包含2mg冻干粉末的一瓶HA-Disac(V-labs,Cat.No.C3209)以产生均匀的悬浮液来制备HA二糖SS。为了产生稀释的储备液，将5μl的SS溶液用125μl水稀释以产生DSS1溶液(包含200pmole/μl HA-Disac；200nmole/ml HA-Disac)。在水中进行5倍系列稀释以产生DSS2(包含40pmole/μl HA-Disac；40nmole/ml HA-Disac)，然后产生DSS3(包含8pmole/μl HA-Disac；8nmole/ml HA-Disac)。然后，如表14和15所示，如25％人血清白蛋白(HSA)(ABO Pharmaceuticals,Cat.No.1500233)或正常小鼠血浆(Bioreclamation,Cat.No.MSEPLEDTA2-BALB-M)所示产生工作标准品溶液。
2.样品的水解和衍生化
然后，将样品水解。通过取约100μg蛋白置于聚丙烯管中并用水将体积调至340μl来制备样品(如血浆)。还通过取与样品等体积的稀释缓冲液(1.59g HEPES,5.07g NaCl,1800mL水,pH7.0)并将体积调至340μl来制备基质空白。样品和基质空白的水解通过将60μl的TFA添加至样品管和基质空白管并且将内容物混合并在100℃下温育4小时来进行。使小瓶冷却至室温。利用真空离心蒸发浓缩器(speed vac)将小瓶蒸干。然后将300μl水添加至各管并涡旋以重悬浮样品。
对于水解样品的衍生化，将空白和工作样品，每个样品45μl(样品、空白或工作样品)在真空离心蒸发浓缩器中蒸干。然后，将10μl的SAS添加至干燥的样品、空白和工作标准品。然后，添加50μl的ABA/NaCNBH3标记溶液。将管短暂涡旋并离心。然后，添加440μl流动相A，并将管充分混合。流动相A如下制备：将132mL的1M乙酸铵缓冲液(Sigma,Cat.No.A7330)添加至1L容量瓶，并加水填满容量瓶。衍生化后，对于工作标准品，每20μl进样的标称柱上进样如表16所示。
3.HPLC
以1.0mL/min的流速，用如表17所示的初始流动相设定将HPLC柱平衡。使系统平衡直至基线稳定。用表17所示的仪器参数进行HPLC分析。
样品分析顺序如下：WSS5(1进样)，用于柱调节/平衡/检测器增益；水进样(1进样)；WSS3(3进样)；WSS1(1进样)；WSS2(1进样)；WSS4(1进样)；WSS5(1进样)；水(1进样)；基质空白(1进样)；样品1(1进样)；样品2(1进样)；WSS3(3进样)；水(1进样)。当分离质量可接受时认为系统合适；WSS1样品中较短单糖峰的信噪比等于或大于10；WSS3的6个进样的每个单糖标准品的峰面积的相对标准偏差(RSD)等于或小于4％；相关系数(r)为0.99(利用软件将每个工作标准品的峰面积对柱上进样(以pmol表示)作图来测量r，其使用WSS3标准品的前三个进样，并利用线性最小二乘回归模型计算工作标准品的斜率、截距和相关系数)；对应单糖的峰的峰面积不大于对WSS5测量的峰面积的2％；并且对应水进样中的单糖的峰的峰面积不大于对WSS5测量的峰面积的0.5％。
4.样品分析
确定每个样品制品中每种单糖的平均校正峰面积。谷差(valley-to-valley)积分用于GalN峰。为了确定这一点，从工作标准品产生的线性曲线用于计算每个样品制品进样的每种单糖的量。对于每种类型的单糖，计算每个样品的每蛋白分子的单糖平均摩尔比。然后，对于每个样品，确定所有5种单糖的平均摩尔比的总和。计算如下进行：未糖基化的透明质酸酶蛋白的分子量(MW)为51106g/mol；每个样品的总体积为500μl；样品稀释系数为0.15；每个进样的体积为20μl；并且从mg换算为pg的转换系数为109。对于每种单糖如下进行计算：
利用如下等式计算每个制品中单糖的量：
利用下式计算每蛋白分子的单糖的数目：
对于每个样品，每个样品的结果报道为每种单糖的单糖每蛋白比率以及5种单糖比率的总和。
5.结果
如上所述的二糖测定用于患者的测量HA及其分解代谢物，该患者参与接受有或无地塞米松的剂量方案周期的0.5μg/kg-50μg/kg剂量范围的PEGPH20的IV剂量给药的I期临床研究。对于研究中的所有患者，PEGPH20剂量给药之前的血浆HA浓度通常少于1μg/mL或低于定量水平(0.5μg/mL)。
收集自接受单次50μg/kg剂量的PEGPH20的患者的血浆在处理后随时间进行评价。结果表明，乙酰透明质酸的血浆浓度显著增加。在该患者中，虽然PEGPH20浓度随2天的终末半衰期而降低，但是HA分解代谢物的升高的浓度更缓慢地积累并在PEGPH20处理后持续长达2周，在PEGPH20剂量给药后约200小时观察到最大HA血浆浓度。
还在初始PEGPH20剂量给药后24小时开始从12个额外的患者收集血浆，该患者用0.5μg/kg PEGPH20，每周2次(1个患者)；0.5μg/kg，每21天(3个患者)；0.75μg/kg，每21天(4个患者)；1.0μg/kg，每21天(3个患者)；或1.5μg/kg，每21天(1个患者)处理。结果表明，单次或多次剂量给药0.5μg/kg-1.5μg/kg的PEGPH20后，HA分解代谢物水平在一周内以剂量依赖性的方式增加。对每个患者还确定最大HA浓度(Cmax)和一周曲线下面积估计值(AUC0-168h)以定量药效学反应。结果证实，如通过最大血浆浓度或曲线下面积所测量的，全身性暴露于HA分解代谢物随PEGPH20剂量的增加而增加。此外，给药PEGPH20的患者的血液样品，其中向剂量给药方案加入地塞米松作为预给药以消除或改善PEGPH20给药引起的肌肉骨骼效应。治疗周期定义为28天时间，其中静脉内(IV)给药PEGPH20并且口服给药地塞米松。PEGPH20和地塞米松的剂量给药在28天周期的第1、4、8、11、15、18、22和25天进行。在每个剂量给药日，在PEGPH20之前1小时口服给药4mg地塞米松的预给药方案，然后在PEGPH20剂量给药后8-12小时给药4mg地塞米松的第二剂量。在治疗的第一周期间，给药PEGPH20后在各个时间点取血浆。与上文所述的来自仅接受PH20的患者的样品中的观察一致，血浆HA浓度比时间数据在给药PEGPH20后增加。在剂量给药的第一周期间测量的血浆HA浓度随PEGPH20剂量增加而增加。在完成治疗的完整周期并接受8个剂量PEGPH20的3个患者中，结果 证实了在整个剂量给药期测量的所有3个患者的样品中持续增加的血浆HA浓度。
这些结果与预期的PEGPH20活性机制一致，并且支持HA作为PEGPH20药效学的生物标记的作用。
实施例16磁共振成像
利用单次激发快速自旋回波序列进行扩散加权MRI以消除表观扩散系数的像素间(pixel-by-pixel)值。动态对比增强磁共振成像(DCE-MRI)包括在灌注期间用造影剂成像。利用包括内管和冰/水混合物的两部分模型(two part phantom)来完成校正。在处理前和处理后进行扫描。
1.表观扩散系数磁共振成像(ADC-MRI)
表观扩散系数磁共振成像(ADC-MRI)基于源自处理前和处理后扫描的计算来测量通过细胞膜的水的体积。对于评价没有地塞米松预给药PEGPH20治疗的I期临床研究的总共14个患者中的10个以及评价用地塞米松预给药的PEGPH20治疗的I期临床研究的5个患者中的4完成ADC-MRI扫描。在Imaging Endpoints(Scottsdale,AZ)，通过放射学家进行获得自每个患者的图像的分析，并且在每个患者中计算组织的ADC的定量估计值。与肿瘤区域相关的ADC-MRI发现总结于表18。如表中所示，PEGPH20剂量给药后，在14个患者中的7个(50％)中观察到ADC-MRI增加。增加的ADC值与PEGPH20的作用机制一致。然而，ADC值在14个患者中的5个中没有改变，并且值在14个患者中的2个中降低。
2.动态造影剂增强的磁共振成像(DCE-MRI)
动态造影剂增强的磁共振成像(DCE-MRI)测量指示肿瘤血管分布改变的血流。在评价用地塞米松预给药的PEGPH20治疗的I期临床研究的4个患者中完成扫描。在ImagingEndpoints(Scottsdale,AZ)，由放射学家进行获得自每个患者的图像的分析，并且在每个患者中计算组织的容积转换系数(Ktrans)、血液容积(Vp)和细胞外容积分数(Ve)的定量估计值。与肿瘤区域相关的DCE-MRI发现总结于表19。在PEGPH20剂量给药的当天扫描的两个患者中观察到Ktrans参数的显著增加。剂量给药的数小时内Ktrans的增加与表明PEGPH20引起血管减压和增加的血流的临床前数据一致(Thompson et al.(2010)Mol.CancerTher.,9:3052-64)。
还对另一患者进行DCE-MRI成像，该患者患有胰腺肿瘤并且参与接受28天的给药周期的3.0μg/kg+地塞米松/wk的I期临床研究。成像在剂量给药前和剂量给药后进行，如下：周期1中第4个每周PEGPH20剂量给药后8小时(第1天)、24小时(第2天)和3天(周期1结束时)。结果示于表20。结果表明，PEGPH20增加通过系列DCE-MRI测量的肿瘤Ktrans。
3.FDG-PET成像
使用葡萄糖的类似物FDG进行正电子发射断层扫描(PET)以获得关于区域葡萄糖摄入的组织代谢活性。对患有转移性直肠癌的患者进行FDG-PET成像，该患者具有肺转移并参与接受28天的给药周期的3.0μg/kg+地塞米松；2x/wk的I期临床研究。成像在剂量给药前、剂量给药后8小时、剂量给药后24小时和周期1结束时(第8次剂量给药后1天)进行。利用标准方法确定FDG标准化摄入值(SUV)。结果示于表21。结果表明， 患者表现出重要的肺转移的PEGPH20治疗后的降低的肿瘤代谢活性。
4.总结
结果表明，各种肿瘤成像方式可以用于证实和监测肿瘤组织中的PEGPH20活性。
实施例17用于HA丰富的癌症诊断和治疗的TSG-6-Fc肿瘤靶向成像
向带有乙酰透明质酸丰富的肿瘤的小鼠或对照小鼠给药用DyLight755Fluor标记试剂标记的TSG-6-LM-Fc/ΔHep(TSG-6-LM-Fc/ΔHepDL755)，并且将小鼠成像以评价TSG-6-LM-Fc/ΔHepDL755的肿瘤结合和分布。还通过比较对IgGDL755对照的染色和分布来评价特异性。为了产生带有BxPC3胫骨周围(peritibial)肿瘤的小鼠，将小鼠用BxPC-3人胰腺癌(ATCCCRL-1687)肿瘤细胞以1x107个细胞/0.1mL皮下接种((s.c.，右后腿)。为了产生带有HA+3Du145-Has2和HA-DU145肿瘤的小鼠，将小鼠用Du145-Has2细胞(如上所述产生)和Du145细胞以5x106/0.05mL胫骨周围接种(在任意侧的右胫骨骨膜附近肌肉内注射)。
利用Thermo Scientific DyLight755Amine-Reactive Dye试剂盒(目录号84538，Thermo Scientific,Rockford,IL)，根据制造商的方案，通过用DyLight755荧光标记TSG-6-LM-Fc/ΔHep(如实施例9所述产生)来产生TSG-6-LM-Fc/ΔHepDL755。
A.用或不用PEGPH20预处理的TSG-6-LM-Fc/ΔHepDL755的分布
将带有直径约18-20mm的HA+2BxPC3胫骨周围肿瘤的小鼠静脉内注射1μg、5μg或10μg TSG-6-LM-Fc/ΔHepDL755。在一组小鼠中，在给药TSG-6-LM-Fc/ΔHepDL755前3小时，将小鼠用静脉内给药的4.5mg/kg的PEGPH20预处理。
荧光整体成像系统(IVIS Lumina XR,Caliper Life Sciences,Mountain View,CA)用于追踪动物内的荧光。利用D745nm带通(band-pass)滤波器进行DyLight755的选择性激发，并且通过长通(long-pass)D800nm滤波器收集发射的荧光。在TSG-6-LM-Fc/ΔHepDL755后的各个时间点(1小时、4小时、第1天、第2天、第3天、第4天、第5天和第6天)将3组小鼠成像(未注射、TSG-6-LM-Fc/ΔHepDL755和PEGPH20+TSG-6-LM-Fc/ΔHep DL755)。对于成像，还评价了未注射的对照小鼠。用超冷高灵敏性数码相机捕捉荧光图像。随后用Living Image(Caliper Life Sciences,Mountain View,CA)分析荧光图像。
结果显示，注射后1小时和4小时，检测到TSG-6-LM-Fc/ΔHepDL755在血流中循环，并且还检测到其开始结合肿瘤。对肿瘤的结合是剂量依赖性的，在10μg剂量观察到增加的染色强度。于所有的剂量和时间点，在用PEGPH20处理的小鼠中通过成像检测到较少的肿瘤结合。在注射后较晚的时间点(例如，第1天或第2天)，还检测到肝结合，虽然这在注射1μg低剂量的TSG-6-LM-Fc/ΔHepDL755小鼠中较少。如通过成像分析评价的，TSG-6-LM-Fc/ΔHepDL755在第1天和第2天之间达到峰值水平。在低剂量处理的小鼠中，TSG-6-LM-Fc/ΔHepDL755在注射后第3天消除。注射后5天，TSG-6-LM-Fc/ΔHepDL755仍然在高剂量处理的小鼠中循环，并且在注射后6天，所有对肿瘤的结合都减少。
总之，体内成像结果表明，TSG-6-LM-Fc/ΔHepDL755结合是剂量依赖性的，并且在注射后1-2天达到峰值水平。此外，通过PEGPH20去除HA导致较少的TSG-6-LM-Fc/ΔHepDL755结合。注射后6天，TSG-6-LM-Fc/ΔHepDL755结合从肿瘤消除。
B.Du145肿瘤+/-Has2之间TSG-6-LM-Fc/ΔHepDL755结合的比较
将带有HA+3Du145-Has2和HA-DU145肿瘤的小鼠静脉内注射5μgTSG-6-LM-Fc/ΔHepDL755。将小鼠在TSG-6-LM-Fc/ΔHepDL755注射后每天成像。虽然检测到低水平的HA-DU145肿瘤背景染色，但是如通过成像结果评价的，有多得多的TSG-6-LM-Fc/ΔHepDL755结合HA丰富的Du145-Has2。通过染色强度确定结合峰值在第1-2天。因此，结果表明，肿瘤中存在的HA越多，越多的TSG-6-LM-Fc/ΔHepDL755结合肿瘤。
C.TSG-6-LM-Fc/ΔHepDL755的靶向特异性
还通过比较TSG-6-LM-Fc/ΔHepDL755或IgGDL755对带有HA+2BxPC3胫骨周围肿瘤的小鼠的结合来进一步评价TSG-6-LM-Fc/ΔHepDL755对HA丰富的肿瘤的特异性。将带有HA++BxPC3胫骨周围肿瘤的小鼠静脉内注射5μg TSG-6-LM-Fc/ΔHepDL755或5μg IgGDL755。将小鼠在注射后每天成像。成像结果表明，有很少或没有可检测的IgGDL755对肿瘤的染色，因此TSG-6-LM-Fc/ΔHep DL755对PC3肿瘤的结合比IgGDL755更大。
由于修改对本领域技术人员是明显的，因此本发明仅受所附权利要求书范围的限制。
<110> 哈洛齐梅公司
P ·江
H · M ·谢泼德
L ·黄
<120> 抗乙酰透明质酸剂疗法的同伴诊断剂及其使用方法
<130> 33320.03096.WO01/3096PC
<140> Not yet assigned
<141> Herewith
<150> US 61/628,187
<151> 2011-10-24
<150> US 61/559,011
<151> 2011-11-11
<150> US 61/630,765
<151> 2011-12-16
<150> US 61/714,700
<151> 2012-10-16
<160> 426
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 509
<212> PRT
<213> Homo sapiens
<220>
<223> precursor human PH20
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 1
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
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354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
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100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
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130135140
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145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
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325330335
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340345350
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370375380
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<210> 2
<211> 474
<212> PRT
<213> Homo sapiens
<220>
<223> mature human PH20, amino acid residues 36-509
<400> 2
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
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354045
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859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
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Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile Ile Ser Ser Val Ala Ser Leu
465470
<210> 3
<211> 482
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-482
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 3
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
1 51015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr
<210> 4
<211> 447
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-482
<400> 4
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr
435440445
<210> 5
<211> 446
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-481
<400> 5
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe
435440445
<210> 6
<211> 445
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-480
<400> 6
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
15 1015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
435440445
<210> 7
<211> 444
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-479
<400> 7
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln
435440
<210> 8
<211> 443
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-478
<400> 8
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro
435440
<210> 9
<211> 442
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-477
<400> 9
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu
435440
<210> 10
<211> 450
<212> PRT
<213> Bos taurus
<220>
<223> cow hyaluronidase-1 precursor
<400> 10
Met Arg Pro Phe Ser Leu Glu Val Ser Leu His Leu Pro Trp Ala Met
151015
Ala Ala His Leu Leu Pro Val Cys Thr Leu Phe Leu Asn Leu Leu Ser
202530
Met Thr Gln Gly Ser Arg Asp Pro Val Val Pro Asn Gln Pro Phe Thr
354045
Thr Ile Trp Asn Ala Asn Thr Glu Trp Cys Met Lys Lys His Gly Val
505560
Asp Val Asp Ile Ser Ile Phe Asp Val Val Thr Asn Pro Gly Gln Thr
65707580
Phe Arg Gly Pro Asn Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly Thr
859095
Tyr Pro Tyr Tyr Thr Ser Ala Gly Glu Pro Val Phe Gly Gly Leu Pro
100105110
Gln Asn Ala Ser Leu Asn Ala His Leu Ala Arg Thr Phe Gln Asp Ile
115120125
Leu Ala Ala Met Pro Glu Pro Arg Phe Ser Gly Leu Ala Val Ile Asp
130135140
Trp Glu Ala Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys Asp
145150155160
Ile Tyr Arg Gln Arg Ser Arg Ala Leu Val Gln Lys Gln His Pro Asp
165170175
Trp Leu Ala Pro Arg Val Glu Ala Ala Ala Gln Asp Gln Phe Glu Gly
180185190
Ala Ala Glu Glu Trp Met Ala Gly Thr Leu Lys Leu Gly Gln Ala Leu
195200205
Arg Pro Gln Gly Leu Trp Gly Phe Tyr Asn Phe Pro Glu Cys Tyr Asn
210215220
Tyr Asp Phe Lys Ser Pro Asn Tyr Thr Gly Arg Cys Pro Leu Asn Ile
225230235240
Cys Ala Gln Asn Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg Ala
245250255
Leu Tyr Pro Ser Ile Tyr Leu Pro Ala Ala Leu Glu Gly Thr Lys Lys
260265270
Thr Gln Met Phe Val Gln His Arg Val Ala Glu Ala Phe Arg Val Ala
275280285
Ala Gly Ala Gly Asp Pro Lys Leu Pro Val Leu Pro Tyr Met Gln Leu
290295300
Phe Tyr Asp Met Thr Asn His Phe Leu Pro Ala Glu Glu Leu Glu His
305310315320
Ser Leu Gly Glu Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu Trp
325330335
Val Ser Trp Leu Ser Thr Ser Thr Lys Glu Ser Cys Gln Ala Ile Lys
340345350
Glu Tyr Val Asp Thr Thr Leu Gly Pro Ser Ile Leu Asn Val Thr Ser
355360365
Gly Ala Arg Leu Cys Ser Gln Val Leu Cys Ser Gly His Gly Arg Cys
370375380
Ala Arg Arg Pro Ser Tyr Pro Lys Ala Arg Leu Ile Leu Asn Ser Thr
385390395400
Ser Phe Ser Ile Lys Pro Thr Pro Gly Gly Gly Pro Leu Thr Leu Gln
405410415
Gly Ala Leu Ser Leu Glu Asp Arg Leu Arg Met Ala Val Glu Phe Glu
420425430
Cys Arg Cys Tyr Arg Gly Trp Arg Gly Thr Arg Cys Glu Gln Trp Gly
435440445
Met Trp
450
<210> 11
<211> 553
<212> PRT
<213> Bos taurus
<220>
<223> cow PH20 hyaluronidase precursor
<400> 11
Met Arg Met Leu Arg Arg His His Ile Ser Phe Arg Ser Phe Ala Gly
151015
Ser Ser Gly Thr Pro Gln Ala Val Phe Thr Phe Leu Leu Leu Pro Cys
202530
Cys Leu Ala Leu Asp Phe Arg Ala Pro Pro Leu Ile Ser Asn Thr Ser
354045
Phe Leu Trp Ala Trp Asn Ala Pro Val Glu Arg Cys Val Asn Arg Arg
505560
Phe Gln Leu Pro Pro Asp Leu Arg Leu Phe Ser Val Lys Gly Ser Pro
65707580
Gln Lys Ser Ala Thr Gly Gln Phe Ile Thr Leu Phe Tyr Ala Asp Arg
859095
Leu Gly Tyr Tyr Pro His Ile Asp Glu Lys Thr Gly Lys Thr Val Phe
100105110
Gly Gly Ile Pro Gln Leu Gly Asn Leu Lys Ser His Met Glu Lys Ala
115120125
Lys Asn Asp Ile Ala Tyr Tyr Ile Pro Asn Asp Ser Val Gly Leu Ala
130135140
Val Ile Asp Trp Glu Asn Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys
145150155160
Pro Lys Asp Val Tyr Arg Asp Glu Ser Val Glu Leu Val Leu Gln Lys
165170175
Asn Pro Gln Leu Ser Phe Pro Glu Ala Ser Lys Ile Ala Lys Val Asp
180185190
Phe Glu Thr Ala Gly Lys Ser Phe Met Gln Glu Thr Leu Lys Leu Gly
195200205
Lys Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp
210215220
Cys Tyr Asn His Asn His Asn Gln Pro Thr Tyr Asn Gly Asn Cys Pro
225230235240
Asp Val Glu Lys Arg Arg Asn Asp Asp Leu Glu Trp Leu Trp Lys Glu
245250255
Ser Thr Ala Leu Phe Pro Ser Val Tyr Leu Asn Ile Arg Leu Lys Ser
260265270
Thr Gln Asn Ala Ala Leu Tyr Val Arg Asn Arg Val Gln Glu Ala Ile
275280285
Arg Leu Ser Lys Ile Ala Ser Val Glu Ser Pro Leu Pro Val Phe Val
290295300
Tyr Ala Arg Pro Val Phe Thr Asp Gly Ser Ser Thr Tyr Leu Ser Gln
305310315320
Gly Asp Leu Val Asn Ser Val Gly Glu Ile Val Ser Leu Gly Ala Ser
325330335
Gly Ile Ile Met Trp Gly Ser Leu Asn Leu Ser Leu Ser Met Gln Ser
340345350
Cys Met Asn Leu Gly Thr Tyr Leu Asn Thr Thr Leu Asn Pro Tyr Ile
355360365
Ile Asn Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys His
370375380
Asn Glu Gly Val Cys Thr Arg Lys His Trp Asn Ser Ser Asp Tyr Leu
385390395400
His Leu Asn Pro Met Asn Phe Ala Ile Gln Thr Gly Glu Gly Gly Lys
405410415
Tyr Thr Val Pro Gly Thr Val Thr Leu Glu Asp Leu Gln Lys Phe Ser
420425430
Asp Thr Phe Tyr Cys Ser Cys Tyr Ala Asn Ile His Cys Lys Lys Arg
435440445
Val Asp Ile Lys Asn Val His Ser Val Asn Val Cys Met Ala Glu Asp
450455460
Ile Cys Ile Asp Ser Pro Val Lys Leu Gln Pro Ser Asp His Ser Ser
465470475480
Ser Gln Glu Ala Ser Thr Thr Thr Phe Ser Ser Ile Ser Pro Ser Thr
485490495
Thr Thr Ala Thr Val Ser Pro Cys Thr Pro Glu Lys His Ser Pro Glu
500505510
Cys Leu Lys Val Arg Cys Ser Glu Val Ile Pro Asn Val Thr Gln Lys
515520525
Ala Cys Gln Ser Val Lys Leu Lys Asn Ile Ser Tyr Gln Ser Pro Ile
530535540
Gln Asn Ile Lys Asn Gln Thr Thr Tyr
545550
<210> 12
<211> 331
<212> PRT
<213> Vespula vulgaris
<220>
<223> yellow jacket wasp hyaluronidase A
<400> 12
Ser Glu Arg Pro Lys Arg Val Phe Asn Ile Tyr Trp Asn Val Pro Thr
151015
Phe Met Cys His Gln Tyr Asp Leu Tyr Phe Asp Glu Val Thr Asn Phe
202530
Asn Ile Lys Arg Asn Ser Lys Asp Asp Phe Gln Gly Asp Lys Ile Ala
354045
Ile Phe Tyr Asp Pro Gly Glu Phe Pro Ala Leu Leu Ser Leu Lys Asp
5055 60
Gly Lys Tyr Lys Lys Arg Asn Gly Gly Val Pro Gln Glu Gly Asn Ile
65707580
Thr Ile His Leu Gln Lys Phe Ile Glu Asn Leu Asp Lys Ile Tyr Pro
859095
Asn Arg Asn Phe Ser Gly Ile Gly Val Ile Asp Phe Glu Arg Trp Arg
100105110
Pro Ile Phe Arg Gln Asn Trp Gly Asn Met Lys Ile His Lys Asn Phe
115120125
Ser Ile Asp Leu Val Arg Asn Glu His Pro Thr Trp Asn Lys Lys Met
130135140
Ile Glu Leu Glu Ala Ser Lys Arg Phe Glu Lys Tyr Ala Arg Phe Phe
145150155160
Met Glu Glu Thr Leu Lys Leu Ala Lys Lys Thr Arg Lys Gln Ala Asp
165170175
Trp Gly Tyr Tyr Gly Tyr Pro Tyr Cys Phe Asn Met Ser Pro Asn Asn
180185190
Leu Val Pro Glu Cys Asp Val Thr Ala Met His Glu Asn Asp Lys Met
195200205
Ser Trp Leu Phe Asn Asn Gln Asn Val Leu Leu Pro Ser Val Tyr Val
210215220
Arg Gln Glu Leu Thr Pro Asp Gln Arg Ile Gly Leu Val Gln Gly Arg
225230235240
Val Lys Glu Ala Val Arg Ile Ser Asn Asn Leu Lys His Ser Pro Lys
245250255
Val Leu Ser Tyr Trp Trp Tyr Val Tyr Gln Asp Glu Thr Asn Thr Phe
260265270
Leu Thr Glu Thr Asp Val Lys Lys Thr Phe Gln Glu Ile Val Ile Asn
275280285
Gly Gly Asp Gly Ile Ile Ile Trp Gly Ser Ser Ser Asp Val Asn Ser
290295300
Leu Ser Lys Cys Lys Arg Leu Gln Asp Tyr Leu Leu Thr Val Leu Gly
305310315320
Pro Ile Ala Ile Asn Val Thr Glu Ala Val Asn
325330
<210> 13
<211> 340
<212> PRT
<213> Vespula vulgaris
<220>
<223> yellow jacket wasp hyaluronidase B
<400> 13
Asp Arg Thr Ile Trp Pro Lys Lys Gly Phe Ser Ile Tyr Trp Asn Ile
151015
Pro Thr His Phe Cys His Asn Phe Gly Val Tyr Phe Lys Glu Leu Lys
202530
Gln Phe Asn Ile Lys Tyr Asn Ser Met Asn Asn Phe Arg Gly Glu Thr
354045
Ile Ser Leu Phe Tyr Asp Pro Gly Asn Phe Pro Ser Met Val Leu Leu
505560
Lys Asn Gly Thr Tyr Glu Ile Arg Asn Glu Gly Val Pro Gln Lys Gly
65707580
Asn Leu Thr Ile His Leu Glu Gln Phe Thr Lys Glu Leu Asp Glu Ile
859095
Tyr Pro Lys Lys Ile Ala Gly Gly Ile Gly Val Ile His Phe His Asn
100105110
Trp Arg Pro Ile Phe Arg Arg Asn Val Asp Asn Leu Lys Ile Asn Lys
115120125
Asp Ile Ser Ile Asp Leu Val Arg Lys Glu His Pro Lys Trp Asp Lys
130135140
Ser Met Ile Glu Lys Glu Ala Ser Asn Arg Phe Glu Thr Ser Ala Lys
145150155160
Ile Phe Met Glu Lys Thr Leu Lys Leu Ala Lys Glu Ile Arg Lys Lys
165170175
Thr Glu Trp Gly Tyr His Gly Tyr Pro His Cys Leu Ser Gly Ser Thr
180185190
Asp Lys Pro Ser Phe Asp Cys Asp Ala Leu Ser Met Ser Glu Asn Asp
195200205
Lys Met Ser Trp Leu Phe Asn Asn Gln Asn Val Leu Leu Pro Ser Ile
210215220
Tyr Leu Lys Asn Val Leu Lys Pro Asp Glu Lys Ile His Leu Val Gln
225230235240
Glu Arg Leu Lys Glu Ala Ile Arg Ile Ser Lys Asn Phe Lys His Leu
245250255
Pro Lys Val Leu Pro Tyr Trp Trp Tyr Thr Tyr Gln Asp Lys Glu Ser
260265270
Ile Phe Leu Thr Glu Ala Asp Val Lys Asn Thr Phe Lys Glu Ile Leu
275280285
Thr Asn Gly Ala Asp Gly Ile Ile Ile Trp Gly Val Ser Tyr Glu Leu
290295300
Thr Asp Arg Lys Arg Cys Glu Lys Leu Lys Glu Tyr Leu Met Lys Ile
305310 315320
Leu Gly Pro Ile Ala Phe Lys Val Thr Lys Ala Val Lys Glu Asn Thr
325330335
Pro Leu Asn Phe
340
<210> 14
<211> 382
<212> PRT
<213> Apis mellifera
<220>
<223> honey bee hyaluronidase precursor
<400> 14
Met Ser Arg Pro Leu Val Ile Thr Glu Gly Met Met Ile Gly Val Leu
151015
Leu Met Leu Ala Pro Ile Asn Ala Leu Leu Leu Gly Phe Val Gln Ser
202530
Thr Pro Asp Asn Asn Lys Thr Val Arg Glu Phe Asn Val Tyr Trp Asn
354045
Val Pro Thr Phe Met Cys His Lys Tyr Gly Leu Arg Phe Glu Glu Val
505560
Ser Glu Lys Tyr Gly Ile Leu Gln Asn Trp Met Asp Lys Phe Arg Gly
65707580
Glu Glu Ile Ala Ile Leu Tyr Asp Pro Gly Met Phe Pro Ala Leu Leu
859095
Lys Asp Pro Asn Gly Asn Val Val Ala Arg Asn Gly Gly Val Pro Gln
100105110
Leu Gly Asn Leu Thr Lys His Leu Gln Val Phe Arg Asp His Leu Ile
115120125
Asn Gln Ile Pro Asp Lys Ser Phe Pro Gly Val Gly Val Ile Asp Phe
130135140
Glu Ser Trp Arg Pro Ile Phe Arg Gln Asn Trp Ala Ser Leu Gln Pro
145150155160
Tyr Lys Lys Leu Ser Val Glu Val Val Arg Arg Glu His Pro Phe Trp
165170175
Asp Asp Gln Arg Val Glu Gln Glu Ala Lys Arg Arg Phe Glu Lys Tyr
180185190
Gly Gln Leu Phe Met Glu Glu Thr Leu Lys Ala Ala Lys Arg Met Arg
195200205
Pro Ala Ala Asn Trp Gly Tyr Tyr Ala Tyr Pro Tyr Cys Tyr Asn Leu
210215220
Thr Pro Asn Gln Pro Ser Ala Gln Cys Glu Ala Thr Thr Met Gln Glu
225230235240
Asn Asp Lys Met Ser Trp Leu Phe Glu Ser Glu Asp Val Leu Leu Pro
245250255
Ser Val Tyr Leu Arg Trp Asn Leu Thr Ser Gly Glu Arg Val Gly Leu
260265270
Val Gly Gly Arg Val Lys Glu Ala Leu Arg Ile Ala Arg Gln Met Thr
275280285
Thr Ser Arg Lys Lys Val Leu Pro Tyr Tyr Trp Tyr Lys Tyr Gln Asp
290295300
Arg Arg Asp Thr Asp Leu Ser Arg Ala Asp Leu Glu Ala Thr Leu Arg
305310315320
Lys Ile Thr Asp Leu Gly Ala Asp Gly Phe Ile Ile Trp Gly Ser Ser
325330335
Asp Asp Ile Asn Thr Lys Ala Lys Cys Leu Gln Phe Arg Glu Tyr Leu
340345350
Asn Asn Glu Leu Gly Pro Ala Val Lys Arg Ile Ala Leu Asn Asn Asn
355360365
Ala Asn Asp Arg Leu Thr Val Asp Val Ser Val Asp Gln Val
370375380
<210> 15
<211> 331
<212> PRT
<213> Dolichovespula maculata
<220>
<223> white-face hornet hyaluronidase
<400> 15
Ser Glu Arg Pro Lys Arg Val Phe Asn Ile Tyr Trp Asn Val Pro Thr
151015
Phe Met Cys His Gln Tyr Gly Leu Tyr Phe Asp Glu Val Thr Asn Phe
202530
Asn Ile Lys His Asn Ser Lys Asp Asp Phe Gln Gly Asp Lys Ile Ser
354045
Ile Phe Tyr Asp Pro Gly Glu Phe Pro Ala Leu Leu Pro Leu Lys Glu
505560
Gly Asn Tyr Lys Ile Arg Asn Gly Gly Val Pro Gln Glu Gly Asn Ile
65707580
Thr Ile His Leu Gln Arg Phe Ile Glu Asn Leu Asp Lys Thr Tyr Pro
859095
Asn Arg Asn Phe Asn Gly Ile Gly Val Ile Asp Phe Glu Arg Trp Arg
100105110
Pro Ile Phe Arg Gln Asn Trp Gly Asn Met Met Ile His Lys Lys Phe
115120125
Ser Ile Asp Leu Val Arg Asn Glu His Pro Phe Trp Asp Lys Lys Met
130135140
Ile Glu Leu Glu Ala Ser Lys Arg Phe Glu Lys Tyr Ala Arg Leu Phe
145150155160
Met Glu Glu Thr Leu Lys Leu Ala Lys Lys Thr Arg Lys Gln Ala Asp
165170175
Trp Gly Tyr Tyr Gly Tyr Pro Tyr Cys Phe Asn Met Ser Pro Asn Asn
180185190
Leu Val Pro Asp Cys Asp Ala Thr Ala Met Leu Glu Asn Asp Lys Met
195200205
Ser Trp Leu Phe Asn Asn Gln Asn Val Leu Leu Pro Ser Val Tyr Ile
210215220
Arg His Glu Leu Thr Pro Asp Gln Arg Val Gly Leu Val Gln Gly Arg
225230235240
Val Lys Glu Ala Val Arg Ile Ser Asn Asn Leu Lys His Ser Pro Lys
245250255
Val Leu Ser Tyr Trp Trp Tyr Val Tyr Gln Asp Asp Thr Asn Thr Phe
260265270
Leu Thr Glu Thr Asp Val Lys Lys Thr Phe Gln Glu Ile Ala Ile Asn
275280285
Gly Gly Asp Gly Ile Ile Ile Trp Gly Ser Ser Ser Asp Val Asn Ser
290295300
Leu Ser Lys Cys Lys Arg Leu Arg Glu Tyr Leu Leu Thr Val Leu Gly
305310315320
Pro Ile Thr Val Asn Val Thr Glu Thr Val Asn
325330
<210> 16
<211> 367
<212> PRT
<213> Polistes annularis
<220>
<223> paper wasp hyaluronidase
<400> 16
Tyr Val Ser Leu Ser Pro Asp Ser Val Phe Asn Ile Ile Thr Asp Asp
1 51015
Ile Ser His Gln Ile Leu Ser Arg Ser Asn Cys Glu Arg Ser Lys Arg
202530
Pro Lys Arg Val Phe Ser Ile Tyr Trp Asn Val Pro Thr Phe Met Cys
354045
His Gln Tyr Gly Met Asn Phe Asp Glu Val Thr Asp Phe Asn Ile Lys
505560
His Asn Ser Lys Asp Asn Phe Arg Gly Glu Thr Ile Ser Ile Tyr Tyr
65707580
Asp Pro Gly Lys Phe Pro Ala Leu Met Pro Leu Lys Asn Gly Asn Tyr
859095
Glu Glu Arg Asn Gly Gly Val Pro Gln Arg Gly Asn Ile Thr Ile His
100105110
Leu Gln Gln Phe Asn Glu Asp Leu Asp Lys Met Thr Pro Asp Lys Asn
115120125
Phe Gly Gly Ile Gly Val Ile Asp Phe Glu Arg Trp Lys Pro Ile Phe
130135140
Arg Gln Asn Trp Gly Asn Thr Glu Ile His Lys Lys Tyr Ser Ile Glu
145150155160
Leu Val Arg Lys Glu His Pro Lys Trp Ser Glu Ser Met Ile Glu Ala
165170175
Glu Ala Thr Lys Lys Phe Glu Lys Tyr Ala Arg Tyr Phe Met Glu Glu
180185190
Thr Leu Lys Leu Ala Lys Lys Thr Arg Lys Arg Ala Lys Trp Gly Tyr
195200205
Tyr Gly Phe Pro Tyr Cys Tyr Asn Val Thr Pro Asn Asn Pro Gly Pro
210215220
Asp Cys Asp Ala Lys Ala Thr Ile Glu Asn Asp Arg Leu Ser Trp Met
225230235240
Tyr Asn Asn Gln Glu Ile Leu Phe Pro Ser Val Tyr Val Arg His Glu
245250255
Gln Lys Pro Glu Glu Arg Val Tyr Leu Val Gln Gly Arg Ile Lys Glu
260265270
Ala Val Arg Ile Ser Asn Asn Leu Glu His Ser Pro Ser Val Leu Ala
275280285
Tyr Trp Trp Tyr Val Tyr Gln Asp Lys Met Asp Ile Tyr Leu Ser Glu
290295300
Thr Asp Val Glu Lys Thr Phe Gln Glu Ile Val Thr Asn Gly Gly Asp
305310315320
Gly Ile Ile Ile Trp Gly Ser Ser Ser Asp Val Asn Ser Leu Ser Lys
325330335
Cys Lys Arg Leu Arg Glu Tyr Leu Leu Asn Thr Leu Gly Pro Phe Ala
340345350
Val Asn Val Thr Glu Thr Val Asn Gly Arg Ser Ser Leu Asn Phe
355360365
<210> 17
<211> 462
<212> PRT
<213> Mus musculus
<220>
<223> mouse hyaluronidase-1
<400> 17
Met Leu Gly Leu Thr Gln His Ala Gln Lys Val Trp Arg Met Lys Pro
151015
Phe Ser Pro Glu Val Ser Pro Gly Ser Ser Pro Ala Thr Ala Gly His
202530
Leu Leu Arg Ile Ser Thr Leu Phe Leu Thr Leu Leu Glu Leu Ala Gln
35 4045
Val Cys Arg Gly Ser Val Val Ser Asn Arg Pro Phe Ile Thr Val Trp
505560
Asn Gly Asp Thr His Trp Cys Leu Thr Glu Tyr Gly Val Asp Val Asp
65707580
Val Ser Val Phe Asp Val Val Ala Asn Lys Glu Gln Ser Phe Gln Gly
859095
Ser Asn Met Thr Ile Phe Tyr Arg Glu Glu Leu Gly Thr Tyr Pro Tyr
100105110
Tyr Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro Gln Asn Ala
115120125
Ser Leu Val Thr His Leu Ala His Thr Phe Gln Asp Ile Lys Ala Ala
130135140
Met Pro Glu Pro Asp Phe Ser Gly Leu Ala Val Ile Asp Trp Glu Ala
145150155160
Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Ser Lys Asp Ile Tyr Arg
165170175
Gln Arg Ser Met Glu Leu Val Gln Ala Glu His Pro Asp Trp Pro Glu
180185190
Thr Leu Val Glu Ala Ala Ala Lys Asn Gln Phe Gln Glu Ala Ala Glu
195200205
Ala Trp Met Ala Gly Thr Leu Gln Leu Gly Gln Val Leu Arg Pro Arg
210215220
Gly Leu Trp Gly Tyr Tyr Gly Phe Pro Asp Cys Tyr Asn Asn Asp Phe
225230235240
Leu Ser Leu Asn Tyr Thr Gly Gln Cys Pro Val Phe Val Arg Asp Gln
245250255
Asn Asp Gln Leu Gly Trp Leu Trp Asn Gln Ser Tyr Ala Leu Tyr Pro
260265270
Ser Ile Tyr Leu Pro Ala Ala Leu Met Gly Thr Gly Lys Ser Gln Met
275280285
Tyr Val Arg His Arg Val Gln Glu Ala Leu Arg Val Ala Ile Val Ser
290295300
Arg Asp Pro His Val Pro Val Met Pro Tyr Val Gln Ile Phe Tyr Glu
305310315320
Met Thr Asp Tyr Leu Leu Pro Leu Glu Glu Leu Glu His Ser Leu Gly
325330335
Glu Ser Ala Ala Gln Gly Val Ala Gly Ala Val Leu Trp Leu Ser Ser
340345350
Asp Lys Thr Ser Thr Lys Glu Ser Cys Gln Ala Ile Lys Ala Tyr Met
355360365
Asp Ser Thr Leu Gly Pro Phe Ile Val Asn Val Thr Ser Ala Ala Leu
370375380
Leu Cys Ser Glu Ala Leu Cys Ser Gly His Gly Arg Cys Val Arg His
385390395400
Pro Ser Tyr Pro Glu Ala Leu Leu Thr Leu Asn Pro Ala Ser Phe Ser
405410415
Ile Glu Leu Thr His Asp Gly Arg Pro Pro Ser Leu Lys Gly Thr Leu
420425430
Ser Leu Lys Asp Arg Ala Gln Met Ala Met Lys Phe Arg Cys Arg Cys
435440445
Tyr Arg Gly Trp Arg Gly Lys Trp Cys Asp Lys Arg Gly Met
450455460
<210> 18
<211> 473
<212> PRT
<213> Mus musculus
<220>
<223> mouse hyaluronidase-2 precursor
<400> 18
Met Arg Ala Gly Leu Gly Pro Ile Ile Thr Leu Ala Leu Val Leu Glu
151015
Val Ala Trp Ala Gly Glu Leu Lys Pro Thr Ala Pro Pro Ile Phe Thr
202530
Gly Arg Pro Phe Val Val Ala Trp Asn Val Pro Thr Gln Glu Cys Ala
354045
Pro Arg His Lys Val Pro Leu Asp Leu Arg Ala Phe Asp Val Lys Ala
505560
Thr Pro Asn Glu Gly Phe Phe Asn Gln Asn Ile Thr Thr Phe Tyr Tyr
65707580
Asp Arg Leu Gly Leu Tyr Pro Arg Phe Asp Ala Ala Gly Thr Ser Val
859095
His Gly Gly Val Pro Gln Asn Gly Ser Leu Cys Ala His Leu Pro Met
100105110
Leu Lys Glu Ser Val Glu Arg Tyr Ile Gln Thr Gln Glu Pro Gly Gly
115120125
Leu Ala Val Ile Asp Trp Glu Glu Trp Arg Pro Val Trp Val Arg Asn
130135140
Trp Gln Glu Lys Asp Val Tyr Arg Gln Ser Ser Arg Gln Leu Val Ala
145150155160
Ser Arg His Pro Asp Trp Pro Ser Asp Arg Val Met Lys Gln Ala Gln
165170175
Tyr Glu Phe Glu Phe Ala Ala Arg Gln Phe Met Leu Asn Thr Leu Arg
180185190
Tyr Val Lys Ala Val Arg Pro Gln His Leu Trp Gly Phe Tyr Leu Phe
195200205
Pro Asp Cys Tyr Asn His Asp Tyr Val Gln Asn Trp Glu Ser Tyr Thr
210215220
Gly Arg Cys Pro Asp Val Glu Val Ala Arg Asn Asp Gln Leu Ala Trp
225230235240
Leu Trp Ala Glu Ser Thr Ala Leu Phe Pro Ser Val Tyr Leu Asp Glu
245250255
Thr Leu Ala Ser Ser Val His Ser Arg Asn Phe Val Ser Phe Arg Val
260265270
Arg Glu Ala Leu Arg Val Ala His Thr His His Ala Asn His Ala Leu
275280285
Pro Val Tyr Val Phe Thr Arg Pro Thr Tyr Thr Arg Gly Leu Thr Gly
290295300
Leu Ser Gln Val Asp Leu Ile Ser Thr Ile Gly Glu Ser Ala Ala Leu
305310315320
Gly Ser Ala Gly Val Ile Phe Trp Gly Asp Ser Glu Asp Ala Ser Ser
325330335
Met Glu Thr Cys Gln Tyr Leu Lys Asn Tyr Leu Thr Gln Leu Leu Val
340345350
Pro Tyr Ile Val Asn Val Ser Trp Ala Thr Gln Tyr Cys Ser Trp Thr
355360365
Gln Cys His Gly His Gly Arg Cys Val Arg Arg Asn Pro Ser Ala Asn
370375380
Thr Phe Leu His Leu Asn Ala Ser Ser Phe Arg Leu Val Pro Gly His
385390395400
Thr Pro Ser Glu Pro Gln Leu Arg Pro Glu Gly Gln Leu Ser Glu Ala
405410415
Asp Leu Asn Tyr Leu Gln Lys His Phe Arg Cys Gln Cys Tyr Leu Gly
420425430
Trp Gly Gly Glu Gln Cys Gln Arg Asn Tyr Lys Gly Ala Ala Gly Asn
435440445
Ala Ser Arg Ala Trp Ala Gly Ser His Leu Thr Ser Leu Leu Gly Leu
450455460
Val Ala Val Ala Leu Thr Trp Thr Leu
465470
<210> 19
<211> 412
<212> PRT
<213> Mus musculus
<220>
<223> mouse hyaluronidase-3 precursor
<400> 19
Met Ile Met His Leu Gly Leu Met Met Val Val Gly Leu Thr Leu Cys
151015
Leu Met His Gly Gln Ala Leu Leu Gln Val Pro Glu His Pro Phe Ser
202530
Val Val Trp Asn Val Pro Ser Ala Arg Cys Lys Ala His Phe Gly Val
354045
His Leu Pro Leu Asp Ala Leu Gly Ile Val Ala Asn His Gly Gln His
505560
Phe His Gly Gln Asn Ile Ser Ile Phe Tyr Lys Asn Gln Phe Gly Leu
65707580
Tyr Pro Tyr Phe Gly Pro Arg Gly Thr Ala His Asn Gly Gly Ile Pro
859095
Gln Ala Val Ser Leu Asp His His Leu Ala Arg Ala Ala His Gln Ile
100105110
Leu His Ser Leu Gly Ser Ser Phe Ala Gly Leu Ala Val Leu Asp Trp
115120125
Glu Glu Trp Tyr Pro Leu Trp Ala Gly Asn Trp Gly Pro His Arg Gln
130135140
Val Tyr Leu Ala Ala Ser Trp Val Trp Thr Gln Gln Met Phe Pro Gly
145150155160
Leu Asp Pro Gln Glu Gln Leu His Lys Ala His Thr Ser Phe Glu Gln
165170175
Ala Ala Arg Ala Leu Met Glu Tyr Thr Leu Gln Leu Gly Arg Thr Leu
180185190
Arg Pro Ser Gly Leu Trp Gly Phe Tyr Arg Tyr Pro Ala Cys Gly Asn
195200205
Gly Trp His Lys Met Ala Ser Asn Tyr Thr Gly His Cys His Ala Ala
210215220
Ile Thr Thr Gln Asn Thr Gln Leu Arg Trp Leu Trp Ala Ala Ser Ser
225230235240
Ala Leu Phe Pro Ser Ile Tyr Leu Pro Pro Arg Leu Pro Leu Ala Tyr
245250255
Arg Gln Ala Phe Val Arg His Arg Leu Glu Glu Ala Phe Arg Val Ala
260265270
Leu Leu Glu His Ser His Pro Leu Pro Val Leu Ala Tyr Ser Arg Leu
275280 285
Thr His Arg Ser Ser Gly Arg Phe Leu Ser Leu Asp Asp Leu Met Gln
290295300
Thr Ile Gly Val Ser Ala Ala Leu Gly Thr Ala Gly Val Val Leu Trp
305310315320
Gly Asp Leu Ser Phe Ser Ser Ser Glu Glu Lys Cys Trp Arg Leu His
325330335
Asp Tyr Leu Val Gly Thr Leu Gly Pro Tyr Val Ile Asn Val Thr Lys
340345350
Ala Asp Met Ala Cys Ser His Gln Arg Cys His Gly His Gly Arg Cys
355360365
Ala Arg Lys Asp Pro Gly Gln Met Glu Ala Phe Leu His Leu Gln Pro
370375380
Asp Asp Ser Leu Gly Ala Trp Asn Ser Phe Arg Cys His Cys Tyr Ser
385390395400
Gly Trp Ala Gly Pro Thr Cys Leu Glu Pro Lys Pro
405410
<210> 20
<211> 435
<212> PRT
<213> Sus scrofa
<220>
<223> pig hyaluronidase-1 precursor
<400> 20
Met Ala Ala His Leu Leu Pro Ile Cys Thr Leu Phe Leu Asn Leu Leu
151015
Ser Val Ala Gln Gly Ser Arg Asp Pro Val Val Leu Asn Arg Pro Phe
202530
Thr Thr Ile Trp Asn Ala Asn Thr Gln Trp Cys Leu Lys Arg His Gly
354045
Val Asp Val Asp Val Ser Val Phe Glu Val Val Val Asn Pro Gly Gln
505560
Thr Phe Arg Gly Pro Asn Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly
65707580
Thr Tyr Pro Tyr Tyr Thr Ser Ala Gly Glu Pro Val Phe Gly Gly Leu
859095
Pro Gln Asn Ala Ser Leu Asp Val His Leu Asn Arg Thr Phe Lys Asp
100105110
Ile Leu Ala Ala Met Pro Glu Ser Asn Phe Ser Gly Leu Ala Val Ile
115120125
Asp Trp Glu Ala Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Ala Lys
130135140
Asp Ile Tyr Arg Gln Arg Ser Arg Ala Leu Val Gln Lys Gln His Pro
145150155160
Asp Trp Pro Ala Pro Trp Val Glu Ala Ala Ala Gln Asp Gln Phe Gln
165170175
Glu Ala Ala Gln Thr Trp Met Ala Gly Thr Leu Lys Leu Gly Gln Thr
180185190
Leu Arg Pro His Gly Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr
195200205
Asn Tyr Asp Phe Gln Ser Ser Asn Tyr Thr Gly Gln Cys Pro Pro Gly
210215220
Val Ser Ala Gln Asn Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg
225230235240
Ala Leu Tyr Pro Ser Ile Tyr Leu Pro Ser Ala Leu Glu Gly Thr Asn
245250255
Lys Thr Gln Leu Tyr Val Gln His Arg Val Asn Glu Ala Phe Arg Val
260265270
Ala Ala Ala Ala Gly Asp Pro Asn Leu Pro Val Leu Pro Tyr Ala Gln
275280285
Ile Phe His Asp Met Thr Asn Arg Leu Leu Ser Arg Glu Glu Leu Glu
290295300
His Ser Leu Gly Glu Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu
305310315320
Trp Val Ser Trp Glu Asn Thr Arg Thr Lys Glu Ser Cys Gln Ser Ile
325330335
Lys Glu Tyr Val Asp Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr
340345350
Ser Gly Ala Leu Leu Cys Ser Gln Ala Val Cys Ser Gly His Gly Arg
355360365
Cys Val Arg Arg Pro Ser His Thr Glu Ala Leu Pro Ile Leu Asn Pro
370375380
Ser Ser Phe Ser Ile Lys Pro Thr Pro Gly Gly Gly Pro Leu Thr Leu
385390395400
Gln Gly Ala Leu Ser Leu Lys Asp Arg Val Gln Met Ala Glu Glu Phe
405410415
Gln Cys Arg Cys Tyr Pro Gly Trp Arg Gly Thr Trp Cys Glu Gln Gln
420425430
Gly Thr Arg
435
<210> 21
<211> 419
<212> PRT
<213> Sus scrofa
<220>
<223> pig hyaluronidase-3 precursor
<400> 21
Met Thr Met Gln Leu Gly Leu Ala Leu Val Leu Gly Val Ala Met Cys
151015
Leu Gly Cys Gly Gln Pro Leu Leu Arg Ala Pro Glu Arg Pro Phe Cys
202530
Val Leu Trp Asn Val Pro Ser Ala Arg Cys Lys Ala Arg Phe Gly Val
354045
His Leu Pro Leu Glu Ala Leu Gly Ile Thr Ala Asn His Gly Gln Arg
505560
Phe His Gly Gln Asn Ile Thr Ile Phe Tyr Lys Ser Gln Leu Gly Leu
65707580
Tyr Pro Tyr Phe Gly Pro Arg Gly Thr Ala His Asn Gly Gly Ile Pro
859095
Gln Ala Val Ser Leu Asp His His Leu Ala Arg Ala Ala Tyr Gln Ile
100105110
His Arg Ser Leu Arg Pro Gly Phe Thr Gly Leu Ala Val Leu Asp Trp
115120125
Glu Glu Trp Cys Pro Leu Trp Ala Gly Asn Trp Gly Arg Arg Gln Ala
130135140
Tyr Gln Ala Ala Ser Cys Ala Trp Ala Gln Arg Val Tyr Pro Asn Leu
145150155160
Asp Pro Gln Glu Gln Leu Cys Lys Ala Arg Ala Gly Phe Glu Glu Ala
165170175
Ala Arg Ala Leu Met Glu Asp Thr Leu Arg Leu Gly Arg Met Leu Arg
180185190
Pro His Gly Leu Trp Gly Phe Tyr His Tyr Pro Ala Cys Gly Asn Gly
195200205
Trp His Gly Thr Ala Ser Asn Tyr Thr Gly His Cys His Ala Ala Ala
210215220
Leu Ala Arg Asn Thr Gln Leu Tyr Trp Leu Trp Ala Ala Ser Ser Ala
225230235240
Leu Phe Pro Ser Ile Tyr Leu Pro Pro Gly Leu Pro Pro Ala Tyr His
245250255
Gln Ala Phe Val Arg Tyr Arg Leu Glu Glu Ala Phe Arg Val Ala Leu
260265270
Val Gly His Pro His Pro Leu Pro Val Leu Ala Tyr Ala Arg Leu Thr
275280285
His Arg Asn Ser Gly Arg Phe Leu Ser Gln Asp Glu Leu Val Gln Thr
290295300
Ile Gly Val Ser Ala Ala Leu Gly Ala Ser Gly Val Val Leu Trp Gly
305310315320
Asp Leu Ser Phe Ser Ser Ser Glu Glu Glu Cys Trp His Leu Arg Gly
325330335
Tyr Leu Val Gly Thr Leu Gly Pro Tyr Val Ile Asn Val Thr Arg Ala
340345350
Ala Met Ala Cys Ser His Gln Arg Cys His Gly His Gly Arg Cys Ala
355360365
Trp Gln Asp Pro Gly Gln Leu Lys Val Phe Leu His Leu His Pro Gly
370375380
Gly Ser Pro Gly Ala Trp Glu Ser Phe Ser Cys Arg Cys Tyr Trp Gly
385390395400
Trp Ala Gly Pro Thr Cys Gln Glu Pro Arg Pro Glu Leu Gly Pro Glu
405410415
Glu Ala Thr
<210> 22
<211> 449
<212> PRT
<213> Rattus norvegicus
<220>
<223> rat hyaluronidase-1 precursor
<400> 22
Met Lys Pro Phe Ser Pro Glu Val Ser Pro Asp Pro Cys Pro Ala Thr
151015
Ala Ala His Leu Leu Arg Thr Tyr Thr Leu Phe Leu Thr Leu Leu Glu
202530
Leu Ala Gln Gly Cys Arg Gly Ser Met Val Ser Asn Arg Pro Phe Ile
354045
Thr Val Trp Asn Ala Asp Thr His Trp Cys Leu Lys Asp His Gly Val
505560
Asp Val Asp Val Ser Val Phe Asp Val Val Ala Asn Lys Glu Gln Asn
65707580
Phe Gln Gly Pro Asn Met Thr Ile Phe Tyr Arg Glu Glu Leu Gly Thr
859095
Tyr Pro Tyr Tyr Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu Pro
100105110
Gln Asn Ala Ser Leu Val Thr His Leu Ala His Ala Phe Gln Asp Ile
115120125
Lys Ala Ala Met Pro Glu Pro Asp Phe Ser Gly Leu Ala Val Ile Asp
130135140
Trp Glu Ala Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Ser Lys Asp
145150155160
Ile Tyr Gln Gln Arg Ser Met Glu Leu Val Arg Ala Glu His Pro Asp
165170175
Trp Pro Glu Thr Leu Val Glu Ala Glu Ala Gln Gly Gln Phe Gln Glu
180185190
Ala Ala Glu Ala Trp Met Ala Gly Thr Leu Gln Leu Gly Gln Val Leu
195200205
Arg Pro Arg Gly Leu Trp Gly Tyr Tyr Gly Phe Pro Asp Cys Tyr Asn
210215220
Tyr Asp Phe Leu Ser Pro Asn Tyr Thr Gly Gln Cys Ser Leu Ser Ile
225230235240
His Asp Gln Asn Asp Gln Leu Gly Trp Leu Trp Asn Gln Ser Tyr Ala
245250255
Leu Tyr Pro Ser Ile Tyr Leu Pro Ala Ala Leu Met Gly Thr Gly Lys
260265270
Ser Gln Met Tyr Val Arg Tyr Arg Val Gln Glu Ala Phe Arg Leu Ala
275280285
Leu Val Ser Arg Asp Pro His Val Pro Ile Met Pro Tyr Val Gln Ile
290295300
Phe Tyr Glu Lys Thr Asp Tyr Leu Leu Pro Leu Glu Glu Leu Glu His
305310315320
Ser Leu Gly Glu Ser Ala Ala Gln Gly Ala Ala Gly Ala Val Leu Trp
325330335
Ile Ser Ser Glu Lys Thr Ser Thr Lys Glu Ser Cys Gln Ala Ile Lys
340345350
Ala Tyr Met Asp Ser Thr Leu Gly Pro Phe Ile Leu Asn Val Thr Ser
355360365
Ala Ala Leu Leu Cys Ser Glu Ala Leu Cys Ser Gly Arg Gly Arg Cys
370375380
Val Arg His Pro Ser Tyr Pro Glu Ala Leu Leu Thr Leu Ser Pro Ala
385390395400
Ser Phe Ser Ile Glu Pro Thr His Asp Gly Arg Pro Leu Ser Leu Lys
405410415
Gly Thr Leu Ser Leu Lys Asp Arg Ala Gln Met Ala Met Lys Phe Lys
420425430
Cys Arg Cys Tyr Arg Gly Trp Ser Gly Glu Trp Cys Lys Lys Gln Asp
435440445
Met
<210> 23
<211> 473
<212> PRT
<213> Rattus norvegicus
<220>
<223> rat hyaluronidase-2 precursor
<400> 23
Met Arg Ala Gly Leu Gly Pro Ile Ile Thr Leu Ala Leu Val Leu Glu
151015
Val Ala Trp Ala Ser Glu Leu Lys Pro Thr Ala Pro Pro Ile Phe Thr
202530
Gly Arg Pro Phe Val Val Ala Trp Asn Val Pro Thr Gln Glu Cys Ala
354045
Pro Arg His Lys Val Pro Leu Asp Leu Arg Ala Phe Asp Val Glu Ala
505560
Thr Pro Asn Glu Gly Phe Phe Asn Gln Asn Ile Thr Thr Phe Tyr Tyr
65707580
Asp Arg Leu Gly Leu Tyr Pro Arg Phe Asp Ala Ala Gly Met Ser Val
859095
His Gly Gly Val Pro Gln Asn Gly Ser Leu Cys Ala His Leu Pro Met
100105110
Leu Lys Glu Ala Val Glu Arg Tyr Ile Gln Thr Gln Glu Pro Ala Gly
115120125
Leu Ala Val Ile Asp Trp Glu Glu Trp Arg Pro Val Trp Val Arg Asn
130135140
Trp Gln Glu Lys Asp Val Tyr Arg Gln Ser Ser Arg Gln Leu Val Ala
145150155160
Ser Arg His Pro Asp Trp Pro Ser Asp Arg Ile Val Lys Gln Ala Gln
165170175
Tyr Glu Phe Glu Phe Ala Ala Arg Gln Phe Met Leu Asn Thr Leu Arg
180185190
Tyr Val Lys Ala Val Arg Pro Gln His Leu Trp Gly Phe Tyr Leu Phe
195200205
Pro Asp Cys Tyr Asn His Asp Tyr Val Gln Asn Trp Asp Ser Tyr Thr
210215220
Gly Arg Cys Pro Asp Val Glu Val Ala Gln Asn Asp Gln Leu Ala Trp
225230235240
Leu Trp Ala Glu Asn Thr Ala Leu Phe Pro Ser Val Tyr Leu Asp Lys
245250255
Thr Leu Ala Ser Ser Lys His Ser Arg Asn Phe Val Ser Phe Arg Val
260265270
Gln Glu Ala Leu Arg Val Ala His Thr His His Ala Asn His Ala Leu
275280285
Pro Val Tyr Val Phe Thr Arg Pro Thr Tyr Thr Arg Arg Leu Thr Glu
290295300
Leu Asn Gln Met Asp Leu Ile Ser Thr Ile Gly Glu Ser Ala Ala Leu
305310315320
Gly Ser Ala Gly Val Ile Phe Trp Gly Asp Ser Val Tyr Ala Ser Ser
325330335
Met Glu Asn Cys Gln Asn Leu Lys Lys Tyr Leu Thr Gln Thr Leu Val
340345350
Pro Tyr Ile Val Asn Val Ser Trp Ala Thr Gln Tyr Cys Ser Trp Thr
355360365
Gln Cys His Gly His Gly Arg Cys Val Arg Arg Asn Pro Ser Ala Ser
370375380
Thr Phe Leu His Leu Ser Pro Ser Ser Phe Arg Leu Val Pro Gly Arg
385390395400
Thr Pro Ser Glu Pro Gln Leu Arg Pro Glu Gly Glu Leu Ser Glu Asp
405410415
Asp Leu Ser Tyr Leu Gln Met His Phe Arg Cys His Cys Tyr Leu Gly
420425430
Trp Gly Gly Glu Gln Cys Gln Trp Asn His Lys Arg Ala Ala Gly Asp
435440445
Ala Ser Arg Ala Trp Ala Gly Ala His Leu Ala Ser Leu Leu Gly Leu
450455460
Val Ala Met Thr Leu Thr Trp Thr Leu
465470
<210> 24
<211> 412
<212> PRT
<213> Rattus norvegicus
<220>
<223> rat hyaluronidase-3 precursor
<400> 24
Met Ile Thr Gln Leu Gly Leu Thr Leu Val Val Gly Leu Thr Leu Cys
151015
Leu Val His Val Gln Ala Leu Leu Gln Val Pro Glu Phe Pro Phe Ser
202530
Val Leu Trp Asn Val Pro Ser Ala Arg Cys Lys Thr Arg Phe Gly Val
354045
His Leu Pro Leu Asp Ala Leu Gly Ile Ile Ala Asn His Gly Gln Arg
505560
Phe His Gly Gln Asn Ile Thr Ile Phe Tyr Lys Asn Gln Phe Gly Leu
65707580
Tyr Pro Tyr Phe Gly Pro Arg Gly Thr Ala His Asn Gly Gly Ile Pro
859095
Gln Ala Val Ser Leu Asp His His Leu Ala Gln Ala Ala His Gln Ile
100105110
Leu His Asn Leu Gly Ser Ser Phe Ala Gly Leu Ala Val Leu Asp Trp
115120125
Glu Glu Trp Tyr Pro Leu Trp Ala Gly Asn Trp Gly Thr His Arg Gln
130135140
Val Tyr Gln Ala Ala Ser Trp Ala Trp Ala Gln Gln Met Phe Pro Asp
145150155160
Leu Asn Pro Gln Glu Gln Leu His Lys Ala Gln Thr Gly Phe Glu Gln
165170175
Ala Ala Arg Ala Leu Met Glu His Thr Leu Arg Leu Gly Gln Met Leu
180185190
Arg Pro His Gly Leu Trp Gly Phe Tyr Arg Tyr Pro Val Cys Gly Asn
195200205
Gly Trp His Asn Met Ala Ser Asn Tyr Thr Gly His Cys His Pro Ala
210215220
Ile Ile Thr Arg Asn Thr Gln Leu Arg Trp Leu Trp Ala Ala Ser Ser
225230235240
Ala Leu Phe Pro Ser Ile Tyr Leu Pro Pro Arg Leu Pro Pro Ala Tyr
245250255
His Gln Thr Phe Val Arg His Arg Leu Glu Glu Ala Phe Arg Val Ala
260265270
Leu Thr Gly His Ala His Pro Leu Pro Val Leu Ala Tyr Val Arg Leu
275280285
Thr His Arg Ser Ser Gly Arg Phe Leu Ser Leu Asp Asp Leu Met Gln
290295300
Thr Ile Gly Val Ser Ala Ala Leu Gly Ala Ala Gly Val Val Leu Trp
305310315320
Gly Asp Leu Ser Val Ser Ser Ser Glu Glu Glu Cys Trp Arg Leu His
325330335
Asp Tyr Leu Val Gly Thr Leu Gly Pro Tyr Val Ile Asn Val Thr Lys
340345350
Ala Ala Thr Ala Cys Ser His Gln Arg Cys His Gly His Gly Arg Cys
355360365
Ser Trp Lys Asp Pro Gly Gln Met Glu Ala Phe Leu His Leu Gln Pro
370375380
Asp Asp Asn Leu Gly Ala Trp Lys Ser Phe Arg Cys Arg Cys Tyr Leu
385390395400
Gly Trp Ser Gly Pro Thr Cys Leu Glu Pro Lys Pro
405410
<210> 25
<211> 545
<212> PRT
<213> Oryctolagus cuniculus
<220>
<223> rabbit hyaluronidase PH20 precursor
<400> 25
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Gly Ser Ala Val Glu
151015
Leu Ser Gly Val Phe Gln Ile Val Phe Ile Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Ala Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Thr Glu Phe Cys Leu Gly Lys Ser
505560
Gly Glu Pro Leu Asp Met Ser Leu Phe Ser Leu Phe Gly Ser Pro Arg
65707580
Lys Asn Lys Thr Gly Gln Gly Ile Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Pro His Thr Gly Ala Ile Val His Gly
100105110
Arg Ile Pro Gln Leu Gly Pro Leu Gln Gln His Leu Thr Lys Leu Arg
115120125
Gln Glu Ile Leu Tyr Tyr Met Pro Lys Asp Asn Val Gly Leu Ala Val
130135140
Ile Asp Trp Glu Glu Trp Leu Pro Thr Trp Leu Arg Asn Trp Lys Pro
145150155160
Lys Asp Ile Tyr Arg Ile Lys Ser Ile Glu Leu Val Lys Ser Gln His
165170175
Pro Gln Tyr Asn His Ser Tyr Ala Thr Glu Lys Ala Lys Arg Asp Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Met Glu Glu Thr Leu Lys Leu Gly Arg
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Asp Lys Pro Asn Leu Tyr Lys Gly Ser Cys Phe
225230235240
Asp Ile Glu Lys Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Lys Glu
245250255
Ser Thr Ala Leu Phe Pro Ser Val Tyr Leu Thr Ser Arg Ala Arg Ser
260265270
Ala Thr Ala Leu Ser Lys Leu Tyr Val Val Arg Asn Arg Val His Glu
275280285
Ala Ile Arg Val Ser Lys Ile Pro Asp Asp Lys Ser Pro Leu Pro Asn
290295300
Phe Val Tyr Thr Arg Leu Val Phe Thr Asp Gln Ile Phe Gln Phe Leu
305310315320
Ser His His Asp Leu Val Tyr Thr Ile Gly Glu Ile Val Ala Leu Gly
325330335
Ala Ser Gly Ile Val Val Trp Gly Ser Gln Ser Leu Ala Arg Ser Met
340345350
Lys Ser Cys Leu His Leu Asp Asn Tyr Met Lys Thr Ile Leu Asn Pro
355360365
Tyr Leu Ile Asn Val Thr Leu Ala Ala Lys Met Cys Asn Gln Val Leu
370375380
Cys Gln Glu Gln Gly Val Cys Thr Arg Lys Asn Trp Asn Pro Asn Asp
385390395400
Tyr Leu His Leu Asn Pro Gly Asn Phe Ala Ile Gln Leu Gly Ser Asn
405410415
Gly Thr Tyr Lys Val Asp Gly Lys Pro Thr Leu Thr Asp Leu Glu Gln
420425430
Phe Ser Lys Asn Phe Gln Cys Ser Cys Tyr Thr Asn Leu Asn Cys Lys
435440445
Glu Arg Thr Asp Met Asn Asn Val Arg Thr Val Asn Val Cys Ala Val
450455460
Glu Asn Val Cys Ile Asp Thr Asn Val Gly Pro Gln Ala Val Thr Tyr
465470475480
Ala Pro Lys Glu Lys Lys Asp Val Ala His Ile Leu Ser Asn Thr Thr
485490495
Ser Ile Asn Ser Ser Thr Thr Met Ser Leu Pro Phe Pro Arg Lys His
500505510
Val Ser Gly Cys Leu Leu Val Leu Cys Met Tyr Ser Gln Tyr Leu Asn
515520525
Ile Cys Tyr Arg Leu Val Ala Ile Gly Ile Gln His Gly Tyr Tyr Leu
530535540
Lys
545
<210> 26
<211> 476
<212> PRT
<213> Ovis aries
<220>
<223> sheep hyaluronidase-2 precursor
<400> 26
Met Trp Thr Gly Leu Gly Pro Ala Val Thr Leu Ala Leu Val Leu Val
151015
Val Ala Trp Ala Thr Glu Leu Lys Pro Thr Ala Pro Pro Ile Phe Thr
202530
Gly Arg Pro Phe Val Val Ala Trp Asp Val Pro Thr Gln Asp Cys Gly
354045
Pro Arg His Lys Met Pro Leu Asp Pro Lys Asp Met Lys Ala Phe Asp
505560
Val Gln Ala Ser Pro Asn Glu Gly Phe Val Asn Gln Asn Ile Thr Ile
65707580
Phe Tyr Arg Asp Arg Leu Gly Met Tyr Pro His Phe Asn Ser Val Gly
859095
Arg Ser Val His Gly Gly Val Pro Gln Asn Gly Ser Leu Trp Val His
100105110
Leu Glu Met Leu Lys Gly His Val Glu His Tyr Ile Arg Thr Gln Glu
115120125
Pro Ala Gly Leu Ala Val Ile Asp Trp Glu Asp Trp Arg Pro Val Trp
130135140
Val Arg Asn Trp Gln Asp Lys Asp Val Tyr Arg Arg Leu Ser Arg Gln
145150155160
Leu Val Ala Ser His His Pro Asp Trp Pro Pro Glu Arg Ile Val Lys
165170175
Glu Ala Gln Tyr Glu Phe Glu Phe Ala Ala Arg Gln Phe Met Leu Glu
180185190
Thr Leu Arg Phe Val Lys Ala Phe Arg Pro Arg His Leu Trp Gly Phe
195200205
Tyr Leu Phe Pro Asp Cys Tyr Asn His Asp Tyr Val Gln Asn Trp Glu
210215220
Thr Tyr Thr Gly Arg Cys Pro Asp Val Glu Val Ser Arg Asn Asp Gln
225230235240
Leu Ser Trp Leu Trp Ala Glu Ser Thr Ala Leu Phe Pro Ser Val Tyr
245250255
Leu Glu Glu Thr Leu Ala Ser Ser Thr His Gly Arg Asn Phe Val Ser
260265270
Phe Arg Val Gln Glu Ala Leu Arg Val Ala Asp Val His His Ala Asn
275280285
His Ala Leu Pro Val Tyr Val Phe Thr Arg Pro Thr Tyr Ser Arg Gly
290295300
Leu Thr Gly Leu Ser Glu Met Asp Leu Ile Ser Thr Ile Gly Glu Ser
305310315320
Ala Ala Leu Gly Ala Ala Gly Val Ile Leu Trp Gly Asp Ala Gly Phe
325330335
Thr Thr Ser Asn Glu Thr Cys Arg Arg Leu Lys Asp Tyr Leu Thr Arg
340345350
Ser Leu Val Pro Tyr Val Val Asn Val Ser Trp Ala Ala Gln Tyr Cys
355360365
Ser Trp Ala Gln Cys His Gly His Gly Arg Cys Val Arg Arg Asp Pro
370375380
Asn Ala His Thr Phe Leu His Leu Ser Ala Ser Ser Phe Arg Leu Val
385390395400
Pro Ser His Ala Pro Asp Glu Pro Arg Leu Arg Pro Glu Gly Glu Leu
405410415
Ser Trp Ala Asp Arg Asn His Leu Gln Thr His Phe Arg Cys Gln Cys
420425430
Tyr Leu Gly Trp Gly Gly Glu Gln Cys Gln Trp Asp Arg Arg Arg Ala
435440445
Ala Gly Gly Ala Ser Gly Ala Trp Ala Gly Ser His Leu Thr Gly Leu
450455460
Leu Ala Val Ala Val Leu Ala Phe Thr Trp Thr Ser
465470475
<210> 27
<211> 114
<212> PRT
<213> Ovis aries
<220>
<223> sheep sperm membrane protein PH20 (partial
sequence)
<400> 27
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Leu Ser Lys Ile
151015
Ala Ser Val Glu Ser Pro Leu Pro Val Phe Val Tyr His Arg Pro Val
202530
Phe Thr Asp Gly Ser Ser Thr Tyr Leu Ser Gln Gly Asp Leu Val Asn
354045
Ser Val Gly Glu Ile Val Ala Leu Gly Ala Ser Gly Ile Ile Met Trp
505560
Gly Ser Leu Asn Leu Ser Leu Thr Met Gln Ser Cys Met Asn Leu Gly
65707580
Asn Tyr Leu Asn Thr Thr Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
859095
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
100105110
Ile Arg
<210> 28
<211> 414
<212> PRT
<213> Pongo pygmaeus
<220>
<223> orangutan hyaluronidase-3 precursor
<400> 28
Met Thr Thr Arg Leu Gly Pro Ala Leu Val Leu Gly Val Ala Leu Cys
151015
Leu Gly Cys Gly Gln Pro Leu Pro Gln Val Pro Glu Arg Pro Phe Ser
202530
Val Leu Trp Asn Val Pro Ser Ala His Cys Lys Ser Arg Phe Gly Val
354045
His Leu Pro Leu Asn Ala Leu Gly Ile Ile Ala Asn Arg Gly Gln His
505560
Phe His Gly Gln Asn Met Thr Ile Phe Tyr Lys Asn Gln Leu Gly Leu
65707580
Tyr Pro Tyr Phe Gly Pro Lys Gly Thr Ala His Asn Gly Gly Ile Pro
859095
Gln Ala Leu Pro Leu Asp Arg His Leu Ala Leu Ala Ala Tyr Gln Ile
100105110
His His Ser Leu Arg Pro Gly Phe Ala Gly Pro Ala Val Leu Asp Trp
115120125
Glu Glu Trp Cys Pro Leu Trp Ala Gly Asn Trp Gly Arg Arg Arg Ala
130135140
Tyr Gln Ala Ala Ser Trp Ala Trp Ala Gln Gln Val Phe Pro Asp Leu
145150155160
Asp Pro Gln Glu Gln Leu Tyr Lys Ala Tyr Thr Gly Phe Glu Gln Ala
165170175
Ala Arg Ala Leu Met Glu Asp Thr Leu Arg Val Ala Gln Ala Leu Arg
180185190
Pro His Gly Leu Trp Gly Phe Tyr His Tyr Pro Ala Cys Gly Asn Gly
195200205
Trp His Ser Met Ala Ser Asn Tyr Thr Gly Arg Cys His Ala Ala Thr
210215220
Leu Ala Arg Asn Thr Gln Leu His Trp Leu Trp Ala Ala Ser Ser Ala
225230235240
Leu Phe Pro Ser Ile Tyr Leu Pro Pro Arg Leu Pro Pro Ala His His
245250255
Gln Ala Phe Val Arg His Arg Leu Glu Glu Ala Phe Arg Val Ala Leu
260265270
Val Gly His Leu Pro Val Leu Ala Tyr Val Arg Leu Thr His Arg Arg
275280285
Ser Gly Arg Phe Leu Ser Gln Asp Asp Leu Val Gln Thr Ile Gly Val
290295300
Ser Ala Ala Leu Gly Ala Ala Gly Val Val Leu Trp Gly Asp Leu Ser
305310315320
Leu Ser Ser Ser Glu Glu Glu Cys Trp His Leu His Asp Tyr Leu Val
325330335
Asp Thr Leu Gly Pro Tyr Gly Ile Asn Val Thr Arg Ala Ala Met Ala
340345350
Cys Ser His Gln Arg Cys His Gly His Gly Arg Cys Ala Arg Arg Asp
355360365
Pro Gly Gln Met Glu Ala Phe Leu His Leu Trp Pro Asp Gly Ser Leu
370375380
Gly Asp Trp Lys Ser Phe Ser Cys His Cys Tyr Trp Gly Trp Ala Gly
385390395400
Pro Thr Cys Gln Glu Pro Arg Leu Gly Pro Lys Glu Ala Val
405410
<210> 29
<211> 510
<212> PRT
<213> Macaca fascicularis
<220>
<223> cynomolgus monkey hyaluronidase PH20 precursor
<400> 29
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Ile Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asn Glu Pro Leu Asp Met Ser Leu Phe Thr Leu Met Gly Ser Pro Arg
65707580
Ile Asn Val Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Leu Thr Thr Gly Val Thr Val His Gly
100105110
Gly Ile Pro Gln Lys Val Ser Leu Gln Asp His Leu Asp Lys Ser Lys
115120125
Gln Asp Ile Leu Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Pro Gln Ala Thr Asp Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Met Leu Glu Thr Ile Lys Leu Gly Arg
195200205
Ser Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Arg Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asp
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Val Val
260265270
Val Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Asn Pro Leu Pro Val Phe Val Tyr Ala
290295300
Arg Leu Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Arg Glu Glu
305310315320
Leu Val Ser Thr Leu Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Ser Leu Ser Ile Thr Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Thr Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asp Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Asp Ile Arg Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val His Gly Lys Pro Thr Val Glu Asp Leu Glu Glu Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Thr Asn Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Ser Leu Lys Pro Pro Val Glu Thr Glu Gly Ser Pro Pro
465470475480
Ile Phe Tyr Asn Thr Ser Ser Ser Thr Val Ser Thr Thr Met Phe Ile
485490495
Val Asn Ile Leu Phe Leu Ile Ile Ser Ser Val Ala Ser Leu
500505510
<210> 30
<211> 529
<212> PRT
<213> Cavia porcellus
<220>
<223> guinea pig hyaluronidase PH20 precursor
<400> 30
Met Gly Ala Phe Thr Phe Lys His Ser Phe Phe Gly Ser Phe Val Glu
151015
Cys Ser Gly Val Leu Gln Thr Val Phe Ile Phe Leu Leu Ile Pro Cys
202530
Cys Leu Ala Asp Lys Arg Ala Pro Pro Leu Ile Pro Asn Val Pro Leu
354045
Leu Trp Val Trp Asn Ala Pro Thr Glu Phe Cys Ile Gly Gly Thr Asn
505560
Gln Pro Leu Asp Met Ser Phe Phe Ser Ile Val Gly Thr Pro Arg Lys
65707580
Asn Ile Thr Gly Gln Ser Ile Thr Leu Tyr Tyr Val Asp Arg Leu Gly
859095
Tyr Tyr Pro Tyr Ile Asp Pro His Thr Gly Ala Ile Val His Gly Gly
100105110
Leu Pro Gln Leu Met Asn Leu Gln Gln His Leu Arg Lys Ser Arg Gln
115120125
Asp Ile Leu Phe Tyr Met Pro Thr Asp Ser Val Gly Leu Ala Val Ile
130135140
Asp Trp Glu Glu Trp Arg Pro Thr Trp Thr Arg Asn Trp Arg Pro Lys
145150155160
Asp Ile Tyr Arg Asn Lys Ser Ile Glu Leu Val Lys Ser Gln His Pro
165170175
Gln Tyr Asn His Ser Tyr Ala Val Ala Val Ala Lys Arg Asp Phe Glu
180185190
Arg Thr Gly Lys Ala Phe Met Leu Glu Thr Leu Lys Leu Gly Lys Ser
195200205
Leu Arg Pro Ser Ser Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr
210215220
Asn Thr His Phe Thr Lys Pro Asn Tyr Asp Gly His Cys Pro Pro Ile
225230235240
Glu Leu Gln Arg Asn Asn Asp Leu Gln Trp Leu Trp Asn Asp Ser Thr
245250255
Ala Leu Tyr Pro Ser Val Tyr Leu Thr Ser Arg Val Arg Ser Ser Gln
260265270
Asn Gly Ala Leu Tyr Val Arg Asn Arg Val His Glu Ser Ile Arg Val
275280285
Ser Lys Leu Met Asp Asp Lys Asn Pro Leu Pro Ile Tyr Val Tyr Ile
290295300
Arg Leu Val Phe Thr Asp Gln Thr Thr Thr Phe Leu Glu Leu Asp Asp
305310315320
Leu Val His Ser Val Gly Glu Ile Val Pro Leu Gly Val Ser Gly Ile
325330335
Ile Ile Trp Gly Ser Leu Ser Leu Thr Arg Ser Leu Val Ser Cys Ile
340345350
Gly Leu Glu Asn Tyr Met Lys Gly Thr Leu Leu Pro Tyr Leu Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Gly Gln Val Leu Cys Lys Asn Gln
370375380
Gly Ile Cys Thr Arg Lys Asp Trp Asn Thr Asn Thr Tyr Leu His Leu
385390395400
Asn Ala Thr Asn Phe Asp Ile Glu Leu Gln Gln Asn Gly Lys Phe Val
405410415
Val His Gly Lys Pro Ser Leu Glu Asp Leu Gln Glu Phe Ser Lys Asn
420425430
Phe His Cys Ser Cys Tyr Thr Asn Val Ala Cys Lys Asp Arg Leu Asp
435440445
Val His Asn Val Arg Ser Val Asn Val Cys Thr Ala Asn Asn Ile Cys
450455460
Ile Asp Ala Val Leu Asn Phe Pro Ser Leu Asp Asp Asp Asp Glu Pro
465470475480
Pro Ile Thr Asp Asp Thr Ser Gln Asn Gln Asp Ser Ile Ser Asp Ile
485490495
Thr Ser Ser Ala Pro Pro Ser Ser His Ile Leu Pro Lys Asp Leu Ser
500505510
Trp Cys Leu Phe Leu Leu Ser Ile Phe Ser Gln His Trp Lys Tyr Leu
515520525
Leu
<210> 31
<211> 512
<212> PRT
<213> Rattus norvegicus
<220>
<223> rat hyaluronidase PH20 precursor
<400> 31
Met Gly Glu Leu Gln Phe Lys Trp Leu Phe Trp Arg Ser Phe Ala Glu
151015
Ser Gly Gly Thr Phe Gln Thr Val Leu Ile Phe Leu Phe Ile Pro Tyr
202530
Ser Leu Thr Val Asp Tyr Arg Ala Thr Pro Val Leu Ser Asp Thr Thr
354045
Phe Val Trp Val Trp Asn Val Pro Thr Glu Ala Cys Val Glu Asn Val
505560
Thr Glu Pro Ile Asp Leu Ser Phe Phe Ser Leu Ile Gly Ser Pro Arg
65707580
Lys Thr Ala Ile Gly Gln Pro Val Thr Leu Phe Tyr Val Asp Arg Leu
859095
Gly Asn Tyr Pro His Ile Asp Ala Gln Gln Thr Glu His His Gly Gly
100105110
Ile Pro Gln Lys Gly Asp Leu Thr Thr His Leu Val Lys Ala Lys Glu
115 120125
Asp Val Glu Arg Tyr Ile Pro Thr Asp Lys Leu Gly Leu Ala Ile Ile
130135140
Asp Trp Glu Glu Trp Arg Pro Thr Trp Met Arg Asn Trp Thr Pro Lys
145150155160
Asp Ile Tyr Arg Asn Lys Ser Ile Glu Leu Val Gln Ala Ala Asp Pro
165170175
Ala Ile Asn Ile Thr Glu Ala Thr Val Arg Ala Lys Ala Gln Phe Glu
180185190
Gly Ala Ala Lys Glu Phe Met Glu Gly Thr Leu Lys Leu Gly Lys His
195200205
Ile Arg Pro Lys His Leu Trp Gly Phe Tyr Leu Phe Pro Asp Cys Tyr
210215220
Asn Asn Lys Phe Gln Val Asp Asn Tyr Asp Gly Gln Cys Pro Asp Val
225230235240
Glu Lys Lys Arg Asn Asp Asp Leu Asp Trp Leu Trp Lys Glu Ser Thr
245250255
Gly Leu Tyr Pro Ser Val Tyr Leu Lys Lys Asp Leu Lys Ser Ser Arg
260265270
Lys Ala Thr Leu Tyr Val Arg Tyr Arg Val Leu Glu Ser Ile Arg Val
275280285
Ser Lys Val Ser Asp Glu Ser Asn Pro Val Pro Ile Phe Val Tyr Ile
290295300
Arg Leu Val Phe Thr Asp His Val Ser Glu Tyr Leu Leu Glu Asp Asp
305310315320
Leu Val Asn Thr Ile Gly Glu Ile Val Ala Gln Gly Thr Ser Gly Ile
325330335
Ile Ile Trp Asp Ala Met Ser Leu Ala Gln Arg Ser Ala Gly Cys Pro
340345350
Ile Leu Arg Gln Tyr Met Lys Thr Thr Leu Asn Pro Tyr Ile Val Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Thr Leu Cys Lys Glu Lys
370375380
Gly Met Cys Ser Arg Lys Thr Glu Ser Ser Asp Ala Tyr Leu His Leu
385390395400
Asp Pro Ser Ser Phe Ser Ile Asn Val Thr Glu Ala Gly Lys Tyr Glu
405410415
Val Leu Gly Lys Pro Glu Val Lys Asp Leu Glu Tyr Phe Ser Glu His
420425430
Phe Lys Cys Ser Cys Phe Ser Lys Met Thr Cys Glu Glu Thr Ser Asp
435440445
Met Arg Ser Ile Gln Asp Val Asn Val Cys Met Gly Asp Asn Val Cys
450455460
Ile Lys Ala Thr Leu Gly Pro Asn Ser Ala Phe His Leu Leu Pro Gly
465470475480
Lys Gly Leu Leu Leu Met Thr Thr Leu Ala His Ile Leu His His Leu
485490495
Pro His Asp Ile Phe Val Phe Pro Trp Lys Met Leu Val Ser Thr Pro
500505510
<210> 32
<211> 512
<212> PRT
<213> Mus musculus
<220>
<223> mouse hyaluronidase PH20 precursor
<400> 32
Met Gly Glu Leu Arg Phe Lys His Leu Phe Trp Gly Ser Phe Val Glu
151015
Ser Gly Gly Thr Phe Gln Thr Val Leu Ile Phe Leu Leu Ile Pro Cys
202530
Ser Leu Thr Val Asp Tyr Arg Ala Ala Pro Ile Leu Ser Asn Thr Thr
354045
Phe Leu Trp Ile Trp Asn Val Pro Thr Glu Arg Cys Val Gly Asn Val
505560
Asn Asp Pro Ile Asp Leu Ser Phe Phe Ser Leu Ile Gly Ser Pro Arg
65707580
Lys Thr Ala Thr Gly Gln Pro Val Thr Leu Phe Tyr Val Asp Arg Leu
859095
Gly Leu Tyr Pro His Ile Asp Ala Asn Gln Ala Glu His Tyr Gly Gly
100105110
Ile Pro Gln Arg Gly Asp Tyr Gln Ala His Leu Arg Lys Ala Lys Thr
115120125
Asp Ile Glu His Tyr Ile Pro Asp Asp Lys Leu Gly Leu Ala Ile Ile
130135140
Asp Trp Glu Glu Trp Arg Pro Thr Trp Leu Arg Asn Trp Lys Pro Lys
145150155160
Asp Asn Tyr Arg Asn Lys Ser Ile Glu Leu Val Gln Ser Thr Asn Pro
165170175
Gly Leu Ser Ile Thr Glu Ala Thr Gln Lys Ala Ile Gln Gln Phe Glu
180185190
Glu Ala Gly Arg Lys Phe Met Glu Gly Thr Leu His Leu Gly Lys Phe
195200205
Leu Arg Pro Asn Gln Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr
210215220
Asn Asn Lys Phe Gln Asp Pro Lys Tyr Asp Gly Gln Cys Pro Ala Val
225230235240
Glu Lys Lys Arg Asn Asp Asn Leu Lys Trp Leu Trp Lys Ala Ser Thr
245250255
Gly Leu Tyr Pro Ser Val Tyr Leu Lys Lys Asp Leu Lys Ser Asn Arg
260265270
Gln Ala Thr Leu Tyr Val Arg Tyr Arg Val Val Glu Ala Ile Arg Val
275280285
Ser Lys Val Gly Asn Ala Ser Asp Pro Val Pro Ile Phe Val Tyr Ile
290295300
Arg Leu Val Phe Thr Asp Arg Thr Ser Glu Tyr Leu Leu Glu Asp Asp
305310315320
Leu Val Asn Thr Ile Gly Glu Ile Val Ala Leu Gly Thr Ser Gly Ile
325330335
Ile Ile Trp Asp Ala Met Ser Leu Ala Gln Arg Ala Ala Gly Cys Pro
340345350
Ile Leu His Lys Tyr Met Gln Thr Thr Leu Asn Pro Tyr Ile Val Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Thr Leu Cys Asn Glu Lys
370375380
Gly Met Cys Ser Arg Arg Lys Glu Ser Ser Asp Val Tyr Leu His Leu
385390395400
Asn Pro Ser His Phe Asp Ile Met Leu Thr Glu Thr Gly Lys Tyr Glu
405410415
Val Leu Gly Asn Pro Arg Val Gly Asp Leu Glu Tyr Phe Ser Glu His
420425430
Phe Lys Cys Ser Cys Phe Ser Arg Met Thr Cys Lys Glu Thr Ser Asp
435440445
Val Lys Asn Val Gln Asp Val Asn Val Cys Val Gly Asp Asn Val Cys
450455460
Ile Lys Ala Lys Val Glu Pro Asn Pro Ala Phe Tyr Leu Leu Pro Gly
465470475480
Lys Ser Leu Leu Phe Met Thr Thr Leu Gly His Val Leu Tyr His Leu
485490495
Pro Gln Asp Ile Phe Val Phe Pro Arg Lys Thr Leu Val Ser Thr Pro
500505510
<210> 33
<211> 807
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus subsp. aureus COL
hyaluronate lyase
<400> 33
Met Thr Tyr Arg Ile Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Val Ile Thr Leu Asn Gly Gly Glu Phe Arg Ser Val
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp
354045
Tyr Glu Lys Leu Arg Asn Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Lys Tyr Asp Glu Asn Asn Pro Asp Met Lys Lys Lys Phe Asp Ala Thr
65707580
Glu Lys Glu Ala Thr Asn Leu Leu Lys Glu Met Lys Thr Glu Ser Gly
859095
Arg Lys Tyr Leu Trp Ser Gly Ala Glu Thr Leu Glu Thr Asn Ser Ser
100105110
His Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ala Met
115120125
Arg Asn Pro Lys Thr Thr Leu Asn Thr Asp Glu Asn Lys Lys Lys Val
130135140
Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro
145150155160
Asp Lys Lys Val Lys Glu Leu Ser Glu Asn Phe Thr Lys Thr Thr Gly
165170175
Lys Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Lys
180185190
Ser Leu Thr Asn Thr Leu Ile Leu Leu Asn Asp Gln Phe Ser Asn Glu
195200205
Glu Lys Lys Lys Phe Thr Ala Pro Ile Lys Thr Phe Ala Pro Asp Ser
210215220
Asp Lys Ile Leu Ser Ser Val Gly Lys Ala Glu Leu Ala Lys Gly Gly
225230235240
Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Cys Ile Ile Glu
245250255
Glu Asp Lys Asp Met Met Lys Lys Ser Ile Asp Ser Phe Asn Lys Val
260265270
Phe Thr Tyr Val Gln Asp Ser Ala Thr Gly Lys Glu Arg Asn Gly Phe
275280285
Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr Gly
290295300
Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro Met
305310315320
Ile Lys Glu Thr Pro Phe Asn Asp Lys Thr Gln Asn Asp Thr Thr Leu
325330335
Lys Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu
340345350
Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr
355360365
Ser His Ser Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Ser
370375380
Asp Ala Met Asp Asp Ser Thr Lys Ala Lys Tyr Lys Lys Ile Val Lys
385390395400
Ser Ser Val Glu Ser Asp Ser Ser Tyr Lys Gln Asn Asp Tyr Leu Asn
405410415
Ser Tyr Ser Asp Ile Asp Lys Met Lys Ser Leu Met Thr Asp Asn Ser
420425430
Ile Ser Lys Asn Gly Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met
435440445
Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly Leu
450455460
Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Ser Ile Asn Gly Glu
465470475480
Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn
485490495
Ser Asp Val Lys His Tyr His Asp Asn Phe Trp Val Thr Ala Asp Met
500505510
Lys Arg Leu Ser Gly Thr Thr Thr Leu Asp Asn Glu Ile Leu Lys Asp
515520525
Thr Asp Asp Lys Lys Ser Ser Lys Thr Phe Val Gly Gly Thr Lys Val
530535540
Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys
545550555560
Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val
565570575
Phe Leu Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val
580585590
Thr Thr Ile Glu Asn Arg Lys Ala Asn Gly Tyr Thr Leu Tyr Thr Asp
595600605
Asp Lys Gln Thr Thr Asn Ser Asp Asn Gln Glu Asn Asn Ser Val Phe
610615620
Leu Glu Ser Thr Asp Thr Lys Lys Asn Ile Gly Tyr His Phe Leu Asn
625630635640
Lys Pro Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp Lys
645650655
Glu Ile Asn Lys Ser Gln Lys Asp Thr Gln Lys Thr Asp Glu Tyr Tyr
660665670
Glu Val Thr Gln Lys His Ser Asn Ser Asp Asn Lys Tyr Gly Tyr Val
675680685
Leu Tyr Pro Gly Leu Ser Lys Asp Val Phe Lys Thr Lys Lys Asp Glu
690695700
Val Thr Val Val Lys Gln Glu Asp Asp Phe His Val Val Lys Asp Asn
705710715720
Glu Ser Val Trp Ala Gly Val Asn Tyr Ser Asn Ser Thr Gln Thr Phe
725730735
Asp Ile Asn Asn Thr Lys Val Glu Val Lys Ala Lys Gly Met Phe Ile
740745750
Leu Lys Lys Lys Asp Asp Asn Thr Tyr Glu Cys Ser Phe Tyr Asn Pro
755760765
Glu Ser Thr Asn Ser Ala Ser Asp Ile Glu Ser Lys Ile Ser Met Thr
770775780
Gly Tyr Ser Ile Thr Asn Lys Asn Thr Ser Thr Ser Asn Glu Ser Gly
785790795800
Val His Phe Glu Leu Thr Lys
805
<210> 34
<211> 371
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes bacteriophage H4489A
hyaluronidase
<400> 34
Met Thr Glu Asn Ile Pro Leu Arg Val Gln Phe Lys Arg Met Ser Ala
151015
Asp Glu Trp Ala Arg Ser Asp Val Ile Leu Leu Glu Gly Glu Ile Gly
202530
Phe Glu Thr Asp Thr Gly Phe Ala Lys Phe Gly Asp Gly Gln Asn Thr
354045
Phe Ser Lys Leu Lys Tyr Leu Thr Gly Pro Lys Gly Pro Lys Gly Asp
505560
Thr Gly Leu Gln Gly Lys Thr Gly Gly Thr Gly Pro Arg Gly Pro Ala
65707580
Gly Lys Pro Gly Thr Thr Asp Tyr Asp Gln Leu Gln Asn Lys Pro Asp
859095
Leu Gly Ala Phe Ala Gln Lys Glu Glu Thr Asn Ser Lys Ile Thr Lys
100105110
Leu Glu Ser Ser Lys Ala Asp Lys Ser Ala Val Tyr Ser Lys Ala Glu
115120125
Ser Lys Ile Glu Leu Asp Lys Lys Leu Ser Leu Thr Gly Gly Ile Val
130135140
Thr Gly Gln Leu Gln Phe Lys Pro Asn Lys Ser Gly Ile Lys Pro Ser
145150155160
Ser Ser Val Gly Gly Ala Ile Asn Ile Asp Met Ser Lys Ser Glu Gly
165170175
Ala Ala Met Val Met Tyr Thr Asn Lys Asp Thr Thr Asp Gly Pro Leu
180185190
Met Ile Leu Arg Ser Asp Lys Asp Thr Phe Asp Gln Ser Ala Gln Phe
195200205
Val Asp Tyr Ser Gly Lys Thr Asn Ala Val Asn Ile Val Met Arg Gln
210215220
Pro Ser Ala Pro Asn Phe Ser Ser Ala Leu Asn Ile Thr Ser Ala Asn
225230235240
Glu Gly Gly Ser Ala Met Gln Ile Arg Gly Val Glu Lys Ala Leu Gly
245250255
Thr Leu Lys Ile Thr His Glu Asn Pro Asn Val Glu Ala Lys Tyr Asp
260265270
Glu Asn Ala Ala Ala Leu Ser Ile Asp Ile Val Lys Lys Gln Lys Gly
275280285
Gly Lys Gly Thr Ala Ala Gln Gly Ile Tyr Ile Asn Ser Thr Ser Gly
290295300
Thr Ala Gly Lys Met Leu Arg Ile Arg Asn Lys Asn Glu Asp Lys Phe
305310315320
Tyr Val Gly Pro Asp Gly Gly Phe His Ser Gly Ala Asn Ser Thr Val
325330335
Ala Gly Asn Leu Thr Val Lys Asp Pro Thr Ser Gly Lys His Ala Ala
340345350
Thr Lys Asp Tyr Val Asp Glu Lys Ile Ala Glu Leu Lys Lys Leu Ile
355360365
Leu Lys Lys
370
<210> 35
<211> 1628
<212> PRT
<213> Clostridium perfringens
<220>
<223> Clostridium perfringens str. 13 hyaluronidase
<400> 35
Met Asn Lys Asn Ile Arg Lys Ile Ile Thr Ser Thr Val Leu Ala Ala
151015
Met Thr Ile Ser Val Leu Pro Ser Asn Leu Val Val Phe Ala Thr Asp
202530
Gly Ile Thr Glu Asn Phe Tyr Glu Ile Tyr Pro Lys Pro Gln Glu Ile
354045
Ser Tyr Ser Gly Gly Glu Phe Gln Ile Ser Asp Glu Ile Asn Ile Val
505560
Tyr Asp Asp Gly Ile Asp Thr Tyr Thr Lys Lys Arg Val Asp Glu Val
65707580
Leu Glu Ala Ser Asn Leu Glu Ala Thr Val Ser Asn Glu Ile Val Pro
859095
Gly Lys Thr Asn Phe Leu Val Gly Ile Asn Glu Ser Gly Gly Val Val
100105110
Asp Asn Tyr Phe Asn Lys Asn Ile Pro His Asp Glu Ser Phe Phe Asp
115120125
Glu Lys Met Asp Ala Asn Ile Val Ser Val Lys Asp Gly Val Ile Gly
130135140
Val Ile Gly Glu Asp Thr Asp Ser Ala Phe Tyr Gly Val Thr Thr Leu
145150155160
Lys His Val Phe Asn Gln Leu Glu Glu Gly Asn Lys Ile Gln Ser Phe
165170175
Arg Ala Asp Asp Tyr Ala Glu Val Ala His Arg Gly Phe Ile Glu Gly
180185190
Tyr Tyr Gly Asn Pro Trp Ser Asn Glu Asp Arg Ala Glu Leu Met Lys
195200205
Phe Gly Gly Asp Tyr Lys Leu Asn Gln Tyr Val Phe Ala Pro Lys Asp
210215220
Asp Pro Tyr His Asn Ser Lys Trp Arg Asp Leu Tyr Pro Glu Glu Lys
225230235240
Leu Ser Glu Ile Lys Lys Leu Ala Gln Val Gly Asn Glu Thr Lys Asn
245250255
Arg Tyr Val Tyr Ala Leu His Pro Phe Met Asn Asn Pro Val Arg Phe
260265270
Asp Thr Glu Glu Asn Tyr Gln Asn Asp Leu Gly Val Ile Lys Ala Lys
275280285
Phe Thr Gln Leu Leu Glu Asn Asp Val Arg Gln Phe Ala Ile Leu Ala
290295300
Asp Asp Ala Ser Ala Pro Ala Gln Gly Ala Ser Met Tyr Val Lys Leu
305310315320
Leu Thr Asp Leu Thr Arg Trp Leu Glu Glu Gln Gln Ser Thr Tyr Pro
325330335
Asp Leu Lys Thr Asp Leu Met Phe Cys Pro Ser Asp Tyr Tyr Gly Asn
340345350
Gly Ser Ser Ala Gln Leu Lys Glu Leu Asn Lys Ala Glu Asp Asn Val
355360365
Ser Ile Val Met Thr Gly Gly Arg Ile Trp Gly Glu Val Asp Glu Asn
370375380
Phe Ala Asn Asn Phe Met Asn Asn Ile Ser Thr Glu Gly His Pro Gly
385390395400
Arg Ala Pro Phe Phe Trp Ile Asn Trp Pro Cys Ser Asp Asn Ser Lys
405410415
Gln His Leu Ile Met Gly Gly Asn Asp Thr Phe Leu His Pro Gly Val
420425430
Asp Pro Ser Lys Ile Asp Gly Ile Val Leu Asn Pro Met Gln Gln Ala
435440445
Glu Ala Asn Lys Ser Ala Leu Phe Ala Ile Ala Asp Tyr Ala Trp Asn
450455460
Ile Trp Asp Asn Lys Glu Glu Ala Asp Glu Asn Trp Asn Asp Ser Phe
465470475480
Lys Tyr Met Asp His Gly Thr Ala Glu Glu Thr Asn Ser Ser Leu Ala
485490495
Leu Arg Glu Ile Ser Lys His Met Ile Asn Gln Asn Met Asp Gly Arg
500505510
Val Arg Pro Leu Gln Glu Ser Val Glu Leu Ala Pro Lys Leu Glu Ala
515520525
Phe Lys Gln Lys Tyr Asp Ser Gly Ala Ser Ile Lys Glu Asp Ala Leu
530535540
Glu Leu Ile Ala Glu Phe Thr Asn Leu Gln Lys Ala Ala Asp Tyr Tyr
545550555560
Lys Asn Asn Pro Gly Asn Glu Arg Thr Arg Asp Gln Ile Ile Tyr Trp
565570575
Leu Asn Cys Trp Glu Asp Thr Met Asp Ala Ala Ile Gly Tyr Leu Lys
580585590
Ser Ala Ile Ala Ile Glu Glu Gly Asp Asp Glu Ala Ala Trp Ala Asn
595600605
Tyr Ser Glu Ala Gln Gly Ala Phe Glu Lys Ser Lys Thr Tyr Gly Phe
610615620
His Tyr Val Asp His Thr Glu Tyr Ala Glu Val Gly Val Gln His Ile
625630635640
Val Pro Phe Ile Lys Ser Met Gly Gln Asn Leu Ser Val Val Ile Gly
645650655
Ser Ile Val Asp Pro Asn Arg Ile Ile Ala Thr Tyr Ile Ser Asn Arg
660665670
Gln Asp Ala Pro Thr Gly Asn Pro Asp Asn Ile Phe Asp Asn Asn Ala
675680685
Ser Thr Glu Leu Val Tyr Lys Asn Pro Asn Arg Ile Asp Val Gly Thr
690695700
Tyr Val Gly Val Lys Tyr Ser Asn Pro Ile Thr Leu Asn Asn Val Glu
705710715720
Phe Leu Met Gly Ala Asn Ser Asn Pro Asn Asp Thr Met Gln Lys Ala
725730735
Lys Ile Gln Tyr Thr Val Asp Gly Arg Glu Trp Ile Asp Leu Glu Glu
740745750
Gly Val Glu Tyr Thr Met Pro Gly Ala Ile Lys Val Glu Asn Leu Asp
755760765
Leu Lys Val Arg Gly Val Arg Leu Ile Ala Thr Glu Ala Arg Glu Asn
770775780
Thr Trp Leu Gly Val Arg Asp Ile Asn Val Asn Lys Lys Glu Asp Ser
785790795800
Asn Ser Gly Val Glu Phe Asn Pro Ser Leu Ile Arg Ser Glu Ser Trp
805810815
Gln Val Tyr Glu Gly Asn Glu Ala Asn Leu Leu Asp Gly Asp Asp Asn
820825830
Thr Gly Val Trp Tyr Lys Thr Leu Asn Gly Asp Thr Ser Leu Ala Gly
835840845
Glu Phe Ile Gly Leu Asp Leu Gly Lys Glu Ile Lys Leu Asp Gly Ile
850855860
Arg Phe Val Ile Gly Lys Asn Gly Gly Gly Ser Ser Asp Lys Trp Asn
865870875880
Lys Phe Lys Leu Glu Tyr Ser Leu Asp Asn Glu Ser Trp Thr Thr Ile
885890895
Lys Glu Tyr Asp Lys Thr Gly Ala Pro Ala Gly Lys Asp Val Ile Glu
900905910
Glu Ser Phe Glu Thr Pro Ile Ser Ala Lys Tyr Ile Arg Leu Thr Asn
915920925
Met Glu Asn Ile Asn Lys Trp Leu Thr Phe Ser Glu Phe Ala Ile Ile
930935940
Ser Asp Glu Leu Glu Asn Ala Gly Asn Lys Glu Asn Val Tyr Thr Asn
945950955960
Thr Glu Leu Asp Leu Leu Ser Leu Ala Lys Glu Asp Val Thr Lys Leu
965970975
Ile Pro Thr Asp Asp Ile Ser Leu Asn His Gly Glu Tyr Ile Gly Val
980985990
Lys Leu Asn Arg Ile Lys Asp Leu Ser Asn Ile Asn Leu Glu Ile Ser
99510001005
Asn Asp Thr Gly Leu Lys Leu Gln Ser Ser Met Asn Gly Val Glu Trp
101010151020
Thr Glu Ile Thr Asp Lys Asn Thr Leu Glu Asp Gly Arg Tyr Val Arg
1025103010351040
Leu Ile Asn Thr Ser Asn Glu Ala Val Asn Phe Asn Leu Thr Lys Phe
104510501055
Glu Val Asn Ser Asn Glu Val Tyr Glu Pro Ser Leu Val Asp Ala Tyr
106010651070
Val Gly Asp Asp Gly Ala Lys Lys Ala Val Asp Gly Asp Leu Lys Thr
107510801085
Arg Val Lys Phe Leu Gly Ala Pro Ser Thr Gly Asp Thr Ile Val Tyr
109010951100
Asp Leu Gly Gln Glu Ile Leu Val Asp Asn Leu Lys Tyr Val Val Leu
1105111011151120
Asp Thr Glu Val Asp His Val Arg Asp Gly Lys Ile Gln Leu Ser Leu
112511301135
Asp Gly Glu Thr Trp Thr Asp Ala Ile Thr Ile Gly Asp Gly Val Glu
114011451150
Asn Gly Val Asp Asp Met Phe Ser Thr Pro Leu Lys Asn Gly Tyr Lys
115511601165
His Gly Asn Gln Ser Gly Gly Ile Val Pro Ile Asp Ser Ala Tyr Val
117011751180
Glu Gly Asp Asn Leu Asn Gln Lys Ala Arg Tyr Val Arg Ile Leu Phe
1185119011951200
Thr Ala Pro Tyr Arg His Arg Trp Thr Val Ile Asn Glu Leu Met Ile
120512101215
Asn Asn Gly Glu Tyr Ile Ser Thr Val Asn Asp Pro Thr Tyr Ile Ser
122012251230
Asn Pro Ile Glu Glu Arg Gly Phe Ala Pro Ser Asn Leu Arg Asp Gly
123512401245
Asn Leu Thr Thr Ser Tyr Lys Pro Asn Thr Asn Asn Gly Glu Ile Ser
125012551260
Glu Gly Ser Ile Thr Tyr Arg Leu Ser Glu Lys Thr Asp Val Arg Lys
1265127012751280
Val Thr Ile Val Gln Ser Gly Ser Ser Ile Ser Asn Ala Lys Val Met
128512901295
Ala Arg Val Gly Asp Gly Ser Glu Asn Val Thr Asp Gln Trp Val Gln
130013051310
Leu Gly Thr Leu Ser Asn Ser Leu Asn Glu Phe Ile Asn Arg Asp Tyr
131513201325
Asn Asn Ile Tyr Glu Ile Lys Ile Glu Trp Thr Asp Val Ala Pro Asn
133013351340
Ile Tyr Glu Ile Ile Thr Leu Asn Gln Glu Phe Glu Phe Pro Val Asn
1345135013551360
Asp Ser Leu Lys Ala Lys Tyr Asp Glu Leu Ile Asn Leu Ser Gly Asp
136513701375
Glu Tyr Thr Leu Ser Ser Phe Glu Thr Leu Lys Glu Ala Leu Asn Glu
138013851390
Ala Lys Ser Ile Leu Asp Asp Ser Asn Ser Ser Gln Lys Lys Ile Asp
139514001405
Lys Ala Leu Glu Lys Leu Asn Lys Ala Glu Glu Arg Leu Asp Leu Arg
141014151420
Ala Thr Asp Phe Glu Asp Phe Asn Lys Val Leu Thr Leu Gly Asn Ser
1425143014351440
Leu Val Glu Glu Glu Tyr Thr Ala Glu Ser Trp Ala Leu Phe Ser Glu
144514501455
Val Leu Glu Ala Ala Asn Glu Ala Asn Lys Asn Lys Ala Asp Tyr Thr
146014651470
Gln Asp Gln Ile Asn Gln Ile Val Ile Asp Leu Asp Ala Ser Ile Lys
147514801485
Ala Leu Val Lys Glu Thr Pro Glu Val Asp Lys Thr Asn Leu Gly Glu
149014951500
Leu Ile Asn Gln Gly Lys Ser Leu Leu Asp Glu Ser Val Glu Gly Phe
1505151015151520
Asn Val Gly Glu Tyr His Lys Gly Ala Lys Asp Gly Leu Thr Val Glu
152515301535
Ile Asn Lys Ala Glu Glu Val Phe Asn Lys Glu Asp Ala Thr Glu Glu
154015451550
Glu Ile Asn Leu Ala Lys Glu Ser Leu Glu Gly Ala Ile Ala Arg Phe
155515601565
Asn Ser Leu Leu Ile Glu Glu Ser Thr Gly Asp Phe Asn Gly Asn Gly
157015751580
Lys Ile Asp Ile Gly Asp Leu Ala Met Val Ser Lys Asn Ile Gly Ser
1585159015951600
Thr Thr Asn Thr Ser Leu Asp Leu Asn Lys Asp Gly Ser Ile Asp Glu
160516101615
Tyr Glu Ile Ser Phe Ile Asn His Arg Ile Leu Asn
16201625
<210> 36
<211> 435
<212> PRT
<213> Homo sapiens
<220>
<223> human hyaluronidase-1 precursor
<220>
<221> SIGNAL
<222> (1)...(21)
<223> signal sequence
<400> 36
Met Ala Ala His Leu Leu Pro Ile Cys Ala Leu Phe Leu Thr Leu Leu
151015
Asp Met Ala Gln Gly Phe Arg Gly Pro Leu Leu Pro Asn Arg Pro Phe
202530
Thr Thr Val Trp Asn Ala Asn Thr Gln Trp Cys Leu Glu Arg His Gly
354045
Val Asp Val Asp Val Ser Val Phe Asp Val Val Ala Asn Pro Gly Gln
505560
Thr Phe Arg Gly Pro Asp Met Thr Ile Phe Tyr Ser Ser Gln Leu Gly
65707580
Thr Tyr Pro Tyr Tyr Thr Pro Thr Gly Glu Pro Val Phe Gly Gly Leu
859095
Pro Gln Asn Ala Ser Leu Ile Ala His Leu Ala Arg Thr Phe Gln Asp
100105110
Ile Leu Ala Ala Ile Pro Ala Pro Asp Phe Ser Gly Leu Ala Val Ile
115120125
Asp Trp Glu Ala Trp Arg Pro Arg Trp Ala Phe Asn Trp Asp Thr Lys
130135140
Asp Ile Tyr Arg Gln Arg Ser Arg Ala Leu Val Gln Ala Gln His Pro
145150155160
Asp Trp Pro Ala Pro Gln Val Glu Ala Val Ala Gln Asp Gln Phe Gln
165170175
Gly Ala Ala Arg Ala Trp Met Ala Gly Thr Leu Gln Leu Gly Arg Ala
180185190
Leu Arg Pro Arg Gly Leu Trp Gly Phe Tyr Gly Phe Pro Asp Cys Tyr
195200205
Asn Tyr Asp Phe Leu Ser Pro Asn Tyr Thr Gly Gln Cys Pro Ser Gly
210215220
Ile Arg Ala Gln Asn Asp Gln Leu Gly Trp Leu Trp Gly Gln Ser Arg
225230235240
Ala Leu Tyr Pro Ser Ile Tyr Met Pro Ala Val Leu Glu Gly Thr Gly
245250255
Lys Ser Gln Met Tyr Val Gln His Arg Val Ala Glu Ala Phe Arg Val
260265270
Ala Val Ala Ala Gly Asp Pro Asn Leu Pro Val Leu Pro Tyr Val Gln
275280285
Ile Phe Tyr Asp Thr Thr Asn His Phe Leu Pro Leu Asp Glu Leu Glu
290295300
His Ser Leu Gly Glu Ser Ala Ala Gln Gly Ala Ala Gly Val Val Leu
305310315320
Trp Val Ser Trp Glu Asn Thr Arg Thr Lys Glu Ser Cys Gln Ala Ile
325330335
Lys Glu Tyr Met Asp Thr Thr Leu Gly Pro Phe Ile Leu Asn Val Thr
340345350
Ser Gly Ala Leu Leu Cys Ser Gln Ala Leu Cys Ser Gly His Gly Arg
355360365
Cys Val Arg Arg Thr Ser His Pro Lys Ala Leu Leu Leu Leu Asn Pro
370375380
Ala Ser Phe Ser Ile Gln Leu Thr Pro Gly Gly Gly Pro Leu Ser Leu
385390395400
Arg Gly Ala Leu Ser Leu Glu Asp Gln Ala Gln Met Ala Val Glu Phe
405410415
Lys Cys Arg Cys Tyr Pro Gly Trp Gln Ala Pro Trp Cys Glu Arg Lys
420425430
Ser Met Trp
435
<210> 37
<211> 473
<212> PRT
<213> Homo sapiens
<220>
<223> human hyaluronidase-2 precursor
<220>
<221> SIGNAL
<222> (1)...(20)
<223> signal sequence
<400> 37
Met Arg Ala Gly Pro Gly Pro Thr Val Thr Leu Ala Leu Val Leu Ala
151015
Val Ala Trp Ala Met Glu Leu Lys Pro Thr Ala Pro Pro Ile Phe Thr
20 2530
Gly Arg Pro Phe Val Val Ala Trp Asp Val Pro Thr Gln Asp Cys Gly
354045
Pro Arg Leu Lys Val Pro Leu Asp Leu Asn Ala Phe Asp Val Gln Ala
505560
Ser Pro Asn Glu Gly Phe Val Asn Gln Asn Ile Thr Ile Phe Tyr Arg
65707580
Asp Arg Leu Gly Leu Tyr Pro Arg Phe Asp Ser Ala Gly Arg Ser Val
859095
His Gly Gly Val Pro Gln Asn Val Ser Leu Trp Ala His Arg Lys Met
100105110
Leu Gln Lys Arg Val Glu His Tyr Ile Arg Thr Gln Glu Ser Ala Gly
115120125
Leu Ala Val Ile Asp Trp Glu Asp Trp Arg Pro Val Trp Val Arg Asn
130135140
Trp Gln Asp Lys Asp Val Tyr Arg Arg Leu Ser Arg Gln Leu Val Ala
145150155160
Ser Arg His Pro Asp Trp Pro Pro Asp Arg Ile Val Lys Gln Ala Gln
165170175
Tyr Glu Phe Glu Phe Ala Ala Gln Gln Phe Met Leu Glu Thr Leu Arg
180185190
Tyr Val Lys Ala Val Arg Pro Arg His Leu Trp Gly Phe Tyr Leu Phe
195200205
Pro Asp Cys Tyr Asn His Asp Tyr Val Gln Asn Trp Glu Ser Tyr Thr
210215220
Gly Arg Cys Pro Asp Val Glu Val Ala Arg Asn Asp Gln Leu Ala Trp
225230235240
Leu Trp Ala Glu Ser Thr Ala Leu Phe Pro Ser Val Tyr Leu Asp Glu
245250255
Thr Leu Ala Ser Ser Arg His Gly Arg Asn Phe Val Ser Phe Arg Val
260265270
Gln Glu Ala Leu Arg Val Ala Arg Thr His His Ala Asn His Ala Leu
275280285
Pro Val Tyr Val Phe Thr Arg Pro Thr Tyr Ser Arg Arg Leu Thr Gly
290295300
Leu Ser Glu Met Asp Leu Ile Ser Thr Ile Gly Glu Ser Ala Ala Leu
305310315320
Gly Ala Ala Gly Val Ile Leu Trp Gly Asp Ala Gly Tyr Thr Thr Ser
325330335
Thr Glu Thr Cys Gln Tyr Leu Lys Asp Tyr Leu Thr Arg Leu Leu Val
340345350
Pro Tyr Val Val Asn Val Ser Trp Ala Thr Gln Tyr Cys Ser Arg Ala
355360365
Gln Cys His Gly His Gly Arg Cys Val Arg Arg Asn Pro Ser Ala Ser
370375380
Thr Phe Leu His Leu Ser Thr Asn Ser Phe Arg Leu Val Pro Gly His
385390395400
Ala Pro Gly Glu Pro Gln Leu Arg Pro Val Gly Glu Leu Ser Trp Ala
405410415
Asp Ile Asp His Leu Gln Thr His Phe Arg Cys Gln Cys Tyr Leu Gly
420425430
Trp Ser Gly Glu Gln Cys Gln Trp Asp His Arg Gln Ala Ala Gly Gly
435440445
Ala Ser Glu Ala Trp Ala Gly Ser His Leu Thr Ser Leu Leu Ala Leu
450455460
Ala Ala Leu Ala Phe Thr Trp Thr Leu
465470
<210> 38
<211> 417
<212> PRT
<213> Homo sapiens
<220>
<223> human hyaluronidase-3 precursor
<220>
<221> SIGNAL
<222> (1)...(20)
<223> signal sequence
<400> 38
Met Thr Thr Gln Leu Gly Pro Ala Leu Val Leu Gly Val Ala Leu Cys
151015
Leu Gly Cys Gly Gln Pro Leu Pro Gln Val Pro Glu Arg Pro Phe Ser
202530
Val Leu Trp Asn Val Pro Ser Ala His Cys Glu Ala Arg Phe Gly Val
354045
His Leu Pro Leu Asn Ala Leu Gly Ile Ile Ala Asn Arg Gly Gln His
505560
Phe His Gly Gln Asn Met Thr Ile Phe Tyr Lys Asn Gln Leu Gly Leu
65707580
Tyr Pro Tyr Phe Gly Pro Arg Gly Thr Ala His Asn Gly Gly Ile Pro
859095
Gln Ala Leu Pro Leu Asp Arg His Leu Ala Leu Ala Ala Tyr Gln Ile
100105110
His His Ser Leu Arg Pro Gly Phe Ala Gly Pro Ala Val Leu Asp Trp
115120125
Glu Glu Trp Cys Pro Leu Trp Ala Gly Asn Trp Gly Arg Arg Arg Ala
130135140
Tyr Gln Ala Ala Ser Trp Ala Trp Ala Gln Gln Val Phe Pro Asp Leu
145150155160
Asp Pro Gln Glu Gln Leu Tyr Lys Ala Tyr Thr Gly Phe Glu Gln Ala
165170175
Ala Arg Ala Leu Met Glu Asp Thr Leu Arg Val Ala Gln Ala Leu Arg
180185190
Pro His Gly Leu Trp Gly Phe Tyr His Tyr Pro Ala Cys Gly Asn Gly
195200205
Trp His Ser Met Ala Ser Asn Tyr Thr Gly Arg Cys His Ala Ala Thr
210215220
Leu Ala Arg Asn Thr Gln Leu His Trp Leu Trp Ala Ala Ser Ser Ala
225230235240
Leu Phe Pro Ser Ile Tyr Leu Pro Pro Arg Leu Pro Pro Ala His His
245250255
Gln Ala Phe Val Arg His Arg Leu Glu Glu Ala Phe Arg Val Ala Leu
260265270
Val Gly His Arg His Pro Leu Pro Val Leu Ala Tyr Val Arg Leu Thr
275280285
His Arg Arg Ser Gly Arg Phe Leu Ser Gln Asp Asp Leu Val Gln Ser
290295300
Ile Gly Val Ser Ala Ala Leu Gly Ala Ala Gly Val Val Leu Trp Gly
305310315320
Asp Leu Ser Leu Ser Ser Ser Glu Glu Glu Cys Trp His Leu His Asp
325330335
Tyr Leu Val Asp Thr Leu Gly Pro Tyr Val Ile Asn Val Thr Arg Ala
340345350
Ala Met Ala Cys Ser His Gln Arg Cys His Gly His Gly Arg Cys Ala
355360365
Arg Arg Asp Pro Gly Gln Met Glu Ala Phe Leu His Leu Trp Pro Asp
370375380
Gly Ser Leu Gly Asp Trp Lys Ser Phe Ser Cys His Cys Tyr Trp Gly
385390395400
Trp Ala Gly Pro Thr Cys Gln Glu Pro Arg Pro Gly Pro Lys Glu Ala
405410415
Val
<210> 39
<211> 481
<212> PRT
<213> Homo sapiens
<220>
<223> human hyaluronidase-4
<400> 39
Met Lys Val Leu Ser Glu Gly Gln Leu Lys Leu Cys Val Val Gln Pro
151015
Val His Leu Thr Ser Trp Leu Leu Ile Phe Phe Ile Leu Lys Ser Ile
202530
Ser Cys Leu Lys Pro Ala Arg Leu Pro Ile Tyr Gln Arg Lys Pro Phe
354045
Ile Ala Ala Trp Asn Ala Pro Thr Asp Gln Cys Leu Ile Lys Tyr Asn
505560
Leu Arg Leu Asn Leu Lys Met Phe Pro Val Ile Gly Ser Pro Leu Ala
65707580
Lys Ala Arg Gly Gln Asn Val Thr Ile Phe Tyr Val Asn Arg Leu Gly
859095
Tyr Tyr Pro Trp Tyr Thr Ser Gln Gly Val Pro Ile Asn Gly Gly Leu
100105110
Pro Gln Asn Ile Ser Leu Gln Val His Leu Glu Lys Ala Asp Gln Asp
115120125
Ile Asn Tyr Tyr Ile Pro Ala Glu Asp Phe Ser Gly Leu Ala Val Ile
130135140
Asp Trp Glu Tyr Trp Arg Pro Gln Trp Ala Arg Asn Trp Asn Ser Lys
145150155160
Asp Val Tyr Arg Gln Lys Ser Arg Lys Leu Ile Ser Asp Met Gly Lys
165170175
Asn Val Ser Ala Thr Asp Ile Glu Tyr Leu Ala Lys Val Thr Phe Glu
180185190
Glu Ser Ala Lys Ala Phe Met Lys Glu Thr Ile Lys Leu Gly Ile Lys
195200205
Ser Arg Pro Lys Gly Leu Trp Gly Tyr Tyr Leu Tyr Pro Asp Cys His
210215220
Asn Tyr Asn Val Tyr Ala Pro Asn Tyr Ser Gly Ser Cys Pro Glu Asp
225230235240
Glu Val Leu Arg Asn Asn Glu Leu Ser Trp Leu Trp Asn Ser Ser Ala
245250255
Ala Leu Tyr Pro Ser Ile Gly Val Trp Lys Ser Leu Gly Asp Ser Glu
260265270
Asn Ile Leu Arg Phe Ser Lys Phe Arg Val His Glu Ser Met Arg Ile
275280285
Ser Thr Met Thr Ser His Asp Tyr Ala Leu Pro Val Phe Val Tyr Thr
290295300
Arg Leu Gly Tyr Arg Asp Glu Pro Leu Phe Phe Leu Ser Lys Gln Asp
305310315320
Leu Val Ser Thr Ile Gly Glu Ser Ala Ala Leu Gly Ala Ala Gly Ile
325330335
Val Ile Trp Gly Asp Met Asn Leu Thr Ala Ser Lys Ala Asn Cys Thr
340345350
Lys Val Lys Gln Phe Val Ser Ser Asp Leu Gly Ser Tyr Ile Ala Asn
355360365
Val Thr Arg Ala Ala Glu Val Cys Ser Leu His Leu Cys Arg Asn Asn
370375380
Gly Arg Cys Ile Arg Lys Met Trp Asn Ala Pro Ser Tyr Leu His Leu
385390395400
Asn Pro Ala Ser Tyr His Ile Glu Ala Ser Glu Asp Gly Glu Phe Thr
405410415
Val Lys Gly Lys Ala Ser Asp Thr Asp Leu Ala Val Met Ala Asp Thr
420425430
Phe Ser Cys His Cys Tyr Gln Gly Tyr Glu Gly Ala Asp Cys Arg Glu
435440445
Ile Lys Thr Ala Asp Gly Cys Ser Gly Val Ser Pro Ser Pro Gly Ser
450455460
Leu Met Thr Leu Cys Leu Leu Leu Leu Ala Ser Tyr Arg Ser Ile Gln
465470475480
Leu
<210> 40
<211> 467
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-467
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 40
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala
465
<210> 41
<211> 477
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-477
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 41
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu
465470475
<210> 42
<211> 478
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-478
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 42
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro
465470475
<210> 43
<211> 479
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-479
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 43
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355 360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln
465470475
<210> 44
<211> 480
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-480
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 44
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
<210> 45
<211> 481
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-481
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 45
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe
<210> 46
<211> 483
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-483
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 46
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395 400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn
<210> 47
<211> 432
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-467
<400> 47
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
<210> 48
<211> 448
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-483
<400> 48
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
<210> 49
<211> 1446
<212> DNA
<213> Homo sapiens
<220>
<223> DNA encoding soluble human PH20 precursor
<400> 49
atgggagtgc taaaattcaa gcacatcttt ttcagaagct ttgttaaatc aagtggagta 60
tcccagatag ttttcacctt ccttctgatt ccatgttgct tgactctgaa tttcagagca 120
cctcctgtta ttccaaatgt gcctttcctc tgggcctgga atgccccaag tgaattttgt 180
cttggaaaat ttgatgagcc actagatatg agcctcttct ctttcatagg aagcccccga 240
ataaacgcca ccgggcaagg tgttacaata ttttatgttg atagacttgg ctactatcct 300
tacatagatt caatcacagg agtaactgtg aatggaggaa tcccccagaa gatttcctta 360
caagaccatc tggacaaagc taagaaagac attacatttt atatgccagt agacaatttg 420
ggaatggctg ttattgactg ggaagaatgg agacccactt gggcaagaaa ctggaaacct 480
aaagatgttt acaagaatag gtctattgaa ttggttcagc aacaaaatgt acaacttagt 540
ctcacagagg ccactgagaa agcaaaacaa gaatttgaaa aggcagggaa ggatttcctg 600
gtagagacta taaaattggg aaaattactt cggccaaatc acttgtgggg ttattatctt 660
tttccggatt gttacaacca tcactataag aaacccggtt acaatggaag ttgcttcaat 720
gtagaaataa aaagaaatga tgatctcagc tggttgtgga atgaaagcac tgctctttac 780
ccatccattt atttgaacac tcagcagtct cctgtagctg ctacactcta tgtgcgcaat 840
cgagttcggg aagccatcag agtttccaaa atacctgatg caaaaagtcc acttccggtt 900
tttgcatata cccgcatagt ttttactgat caagttttga aattcctttc tcaagatgaa 960
cttgtgtata catttggcga aactgttgct ctgggtgctt ctggaattgt aatatgggga1020
accctcagta taatgcgaag tatgaaatct tgcttgctcc tagacaatta catggagact1080
atactgaatc cttacataat caacgtcaca ctagcagcca aaatgtgtag ccaagtgctt1140
tgccaggagc aaggagtgtg tataaggaaa aactggaatt caagtgacta tcttcacctc1200
aacccagata attttgctat tcaacttgag aaaggtggaa agttcacagt acgtggaaaa1260
ccgacacttg aagacctgga gcaattttct gaaaaatttt attgcagctg ttatagcacc1320
ttgagttgta aggagaaagc tgatgtaaaa gacactgatg ctgttgatgt gtgtattgct1380
gatggtgtct gtatagatgc ttttctaaaa cctcccatgg agacagaaga acctcaaatt1440
ttctac1446
<210> 50
<211> 509
<212> PRT
<213> Homo sapiens
<220>
<223> precursor human PH20 variant P48A
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 50
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Ala
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu Ile Ile Ser Ser Val Ala Ser Leu
500505
<210> 51
<211> 509
<212> PRT
<213> Homo sapiens
<220>
<223> precursor human PH20 variant L499W
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 51
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Trp Phe Leu Ile Ile Ser Ser Val Ala Ser Leu
500505
<210> 52
<211> 6630
<212> DNA
<213> Artificial Sequence
<220>
<223> HZ24 vector
<400> 52
tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc 120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg 180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc 240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat 300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc 360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga 420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg 480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac 540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt 600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc 660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagc 720
tcgtttagtg aaccgtcaga tcactagaag ctttattgcg gtagtttatc acagttaaat 780
tgctaacgca gtcagtgctt ctgacacaac agtctcgaac ttaagctgca gaagttggtc 840
gtgaggcact gggcaggtaa gtatcaaggt tacaagacag gtttaaggag accaatagaa 900
actgggcttg tcgagacaga gaagactctt gcgtttctga taggcaccta ttggtcttac 960
tgacatccac tttgcctttc tctccacagg tgtccactcc cagttcaatt acagctctta1020
aggctagagt acttaatacg actcactata ggctagcatg ggagtgctaa aattcaagca1080
catctttttc agaagctttg ttaaatcaag tggagtatcc cagatagttt tcaccttcct1140
tctgattcca tgttgcttga ctctgaattt cagagcacct cctgttattc caaatgtgcc1200
tttcctctgg gcctggaatg ccccaagtga attttgtctt ggaaaatttg atgagccact1260
agatatgagc ctcttctctt tcataggaag cccccgaata aacgccaccg ggcaaggtgt1320
tacaatattt tatgttgata gacttggcta ctatccttac atagattcaa tcacaggagt1380
aactgtgaat ggaggaatcc cccagaagat ttccttacaa gaccatctgg acaaagctaa1440
gaaagacatt acattttata tgccagtaga caatttggga atggctgtta ttgactggga1500
agaatggaga cccacttggg caagaaactg gaaacctaaa gatgtttaca agaataggtc1560
tattgaattg gttcagcaac aaaatgtaca acttagtctc acagaggcca ctgagaaagc1620
aaaacaagaa tttgaaaagg cagggaagga tttcctggta gagactataa aattgggaaa1680
attacttcgg ccaaatcact tgtggggtta ttatcttttt ccggattgtt acaaccatca1740
ctataagaaa cccggttaca atggaagttg cttcaatgta gaaataaaaa gaaatgatga1800
tctcagctgg ttgtggaatg aaagcactgc tctttaccca tccatttatt tgaacactca1860
gcagtctcct gtagctgcta cactctatgt gcgcaatcga gttcgggaag ccatcagagt1920
ttccaaaata cctgatgcaa aaagtccact tccggttttt gcatataccc gcatagtttt1980
tactgatcaa gttttgaaat tcctttctca agatgaactt gtgtatacat ttggcgaaac2040
tgttgctctg ggtgcttctg gaattgtaat atggggaacc ctcagtataa tgcgaagtat2100
gaaatcttgc ttgctcctag acaattacat ggagactata ctgaatcctt acataatcaa2160
cgtcacacta gcagccaaaa tgtgtagcca agtgctttgc caggagcaag gagtgtgtat2220
aaggaaaaac tggaattcaa gtgactatct tcacctcaac ccagataatt ttgctattca2280
acttgagaaa ggtggaaagt tcacagtacg tggaaaaccg acacttgaag acctggagca2340
attttctgaa aaattttatt gcagctgtta tagcaccttg agttgtaagg agaaagctga2400
tgtaaaagac actgatgctg ttgatgtgtg tattgctgat ggtgtctgta tagatgcttt2460
tctaaaacct cccatggaga cagaagaacc tcaaattttc tactgaggat ccatagctaa2520
cgcccctctc cctccccccc ccctaacgtt actggccgaa gccgcttgga ataaggccgg2580
tgtgcgtttg tctatatgtt attttccacc atattgccgt cttttggcaa tgtgagggcc2640
cggaaacctg gccctgtctt cttgacgagc attcctaggg gtctttcccc tctcgccaaa2700
ggaatgcaag gtctgttgaa tgtcgtgaag gaagcagttc ctctggaagc ttcttgaaga2760
caaacaacgt ctgtagcgac cctttgcagg cagcggaacc ccccacctgg cgacaggtgc2820
ctctgcggcc aaaagccacg tgtataagat acacctgcaa aggcggcaca accccagtgc2880
cacgttgtga gttggatagt tgtggaaaga gtcaaatggc tctcctcaag cgtattcaac2940
aaggggctga aggatgccca gaaggtaccc cattgtatgg gatctgatct ggggcctcgg3000
tgcacatgct ttacatgtgt ttagtcgagg ttaaaaaaac gtctaggccc cccgaaccac3060
ggggacgtgg ttttcctttg aaaaacacga tgataagctt gccacaaccc acagcggccg3120
ctgccatcat ggttcgacca ttgaactgca tcgtcgccgt gtcccaaaat atggggattg3180
gcaagaacgg agacctaccc tggcctccgc tcaggaacga gttcaagtac ttccaaagaa3240
tgaccacaac ctcttcagtg gaaggtaaac agaatctggt gattatgggt aggaaaacct3300
ggttctccat tcctgagaag aatcgacctt taaaggacag aattaatata gttctcagta3360
gagaactcaa agaaccacca cgaggagctc attttcttgc caaaagtttg gatgatgcct3420
taagacttat tgaacaaccg gaattggcaa gtaaagtaga catggtttgg atagtcggag3480
gcagttctgt ttaccaggaa gccatgaatc aaccaggcca cctcagactc tttgtgacaa3540
ggatcatgca ggaatttgaa agtgacacgt ttttcccaga aattgatttg gggaaatata3600
aacttctccc agaataccca ggcgtcctct ctgaggtcca ggaggaaaaa ggcatcaagt3660
ataagtttga agtctacgag aagaaagact aaacgcgtgg tacctctaga gtcgacccgg3720
gcggccgctt cgagcagaca tgataagata cattgatgag tttggacaaa ccacaactag3780
aatgcagtga aaaaaatgct ttatttgtga aatttgtgat gctattgctt tatttgtaac3840
cattataagc tgcaataaac aagttaacaa caacaattgc attcatttta tgtttcaggt3900
tcagggggag atgtgggagg ttttttaaag caagtaaaac ctctacaaat gtggtaaaat3960
cgataaggat ccgggctggc gtaatagcga agaggcccgc accgatcgcc cttcccaaca4020
gttgcgcagc ctgaatggcg aatggacgcg ccctgtagcg gcgcattaag cgcggcgggt4080
gtggtggtta cgcgcagcgt gaccgctaca cttgccagcg ccctagcgcc cgctcctttc4140
gctttcttcc cttcctttct cgccacgttc gccggctttc cccgtcaagc tctaaatcgg4200
gggctccctt tagggttccg atttagtgct ttacggcacc tcgaccccaa aaaacttgat4260
tagggtgatg gttcacgtag tgggccatcg ccctgataga cggtttttcg ccctttgacg4320
ttggagtcca cgttctttaa tagtggactc ttgttccaaa ctggaacaac actcaaccct4380
atctcggtct attcttttga tttataaggg attttgccga tttcggccta ttggttaaaa4440
aatgagctga tttaacaaaa atttaacgcg aattttaaca aaatattaac gcttacaatt4500
tcctgatgcg gtattttctc cttacgcatc tgtgcggtat ttcacaccgc atatggtgca4560
ctctcagtac aatctgctct gatgccgcat agttaagcca gccccgacac ccgccaacac4620
ccgctgacgc gccctgacgg gcttgtctgc tcccggcatc cgcttacaga caagctgtga4680
ccgtctccgg gagctgcatg tgtcagaggt tttcaccgtc atcaccgaaa cgcgcgagac4740
gaaagggcct cgtgatacgc ctatttttat aggttaatgt catgataata atggtttctt4800
agacgtcagg tggcactttt cggggaaatg tgcgcggaac ccctatttgt ttatttttct4860
aaatacattc aaatatgtat ccgctcatga gacaataacc ctgataaatg cttcaataat4920
attgaaaaag gaagagtatg agtattcaac atttccgtgt cgcccttatt cccttttttg4980
cggcattttg ccttcctgtt tttgctcacc cagaaacgct ggtgaaagta aaagatgctg5040
aagatcagtt gggtgcacga gtgggttaca tcgaactgga tctcaacagc ggtaagatcc5100
ttgagagttt tcgccccgaa gaacgttttc caatgatgag cacttttaaa gttctgctat5160
gtggcgcggt attatcccgt attgacgccg ggcaagagca actcggtcgc cgcatacact5220
attctcagaa tgacttggtt gagtactcac cagtcacaga aaagcatctt acggatggca5280
tgacagtaag agaattatgc agtgctgcca taaccatgag tgataacact gcggccaact5340
tacttctgac aacgatcgga ggaccgaagg agctaaccgc ttttttgcac aacatggggg5400
atcatgtaac tcgccttgat cgttgggaac cggagctgaa tgaagccata ccaaacgacg5460
agcgtgacac cacgatgcct gtagcaatgg caacaacgtt gcgcaaacta ttaactggcg5520
aactacttac tctagcttcc cggcaacaat taatagactg gatggaggcg gataaagttg5580
caggaccact tctgcgctcg gcccttccgg ctggctggtt tattgctgat aaatctggag5640
ccggtgagcg tgggtctcgc ggtatcattg cagcactggg gccagatggt aagccctccc5700
gtatcgtagt tatctacacg acggggagtc aggcaactat ggatgaacga aatagacaga5760
tcgctgagat aggtgcctca ctgattaagc attggtaact gtcagaccaa gtttactcat5820
atatacttta gattgattta aaacttcatt tttaatttaa aaggatctag gtgaagatcc5880
tttttgataa tctcatgacc aaaatccctt aacgtgagtt ttcgttccac tgagcgtcag5940
accccgtaga aaagatcaaa ggatcttctt gagatccttt ttttctgcgc gtaatctgct6000
gcttgcaaac aaaaaaacca ccgctaccag cggtggtttg tttgccggat caagagctac6060
caactctttt tccgaaggta actggcttca gcagagcgca gataccaaat actgttcttc6120
tagtgtagcc gtagttaggc caccacttca agaactctgt agcaccgcct acatacctcg6180
ctctgctaat cctgttacca gtggctgctg ccagtggcga taagtcgtgt cttaccgggt6240
tggactcaag acgatagtta ccggataagg cgcagcggtc gggctgaacg gggggttcgt6300
gcacacagcc cagcttggag cgaacgacct acaccgaact gagataccta cagcgtgagc6360
tatgagaaag cgccacgctt cccgaaggga gaaaggcgga caggtatccg gtaagcggca6420
gggtcggaac aggagagcgc acgagggagc ttccaggggg aaacgcctgg tatctttata6480
gtcctgtcgg gtttcgccac ctctgacttg agcgtcgatt tttgtgatgc tcgtcagggg6540
ggcggagcct atggaaaaac gccagcaacg cggccttttt acggttcctg gccttttgct6600
ggccttttgc tcacatggct cgacagatct6630
<210> 53
<211> 186
<212> PRT
<213> Mus musculus
<220>
<223> mouse dihydrofolate reductase protein
<400> 53
Val Arg Pro Leu Asn Cys Ile Val Ala Val Ser Gln Asn Met Gly Ile
151015
Gly Lys Asn Gly Asp Leu Pro Trp Pro Pro Leu Arg Asn Glu Phe Lys
202530
Tyr Phe Gln Arg Met Thr Thr Thr Ser Ser Val Glu Gly Lys Gln Asn
354045
Leu Val Ile Met Gly Arg Lys Thr Trp Phe Ser Ile Pro Glu Lys Asn
505560
Arg Pro Leu Lys Asp Arg Ile Asn Ile Val Leu Ser Arg Glu Leu Lys
65707580
Glu Pro Pro Arg Gly Ala His Phe Leu Ala Lys Ser Leu Asp Asp Ala
859095
Leu Arg Leu Ile Glu Gln Pro Glu Leu Ala Ser Lys Val Asp Met Val
100105110
Trp Ile Val Gly Gly Ser Ser Val Tyr Gln Glu Ala Met Asn Gln Pro
115120125
Gly His Leu Arg Leu Phe Val Thr Arg Ile Met Gln Glu Phe Glu Ser
130135140
Asp Thr Phe Phe Pro Glu Ile Asp Leu Gly Lys Tyr Lys Leu Leu Pro
145150155160
Glu Tyr Pro Gly Val Leu Ser Glu Val Gln Glu Glu Lys Gly Ile Lys
165170175
Tyr Lys Phe Glu Val Tyr Glu Lys Lys Asp
180185
<210> 54
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> His tag
<400> 54
His His His His His His
15
<210> 55
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> Flag tag
<400> 55
Asp Tyr Lys Asp Asp Asp Asp Lys
15
<210> 56
<211> 1449
<212> DNA
<213> Homo sapiens
<220>
<223> PH20 mRNA sequence from 3D35M cells (contains c to
a at base 1131)
<400> 56
atgggagtgc taaaattcaa gcacatcttt ttcagaagct ttgttaaatc aagtggagta 60
tcccagatag ttttcacctt ccttctgatt ccatgttgct tgactctgaa tttcagagca 120
cctcctgtta ttccaaatgt gcctttcctc tgggcctgga atgccccaag tgaattttgt 180
cttggaaaat ttgatgagcc actagatatg agcctcttct ctttcatagg aagcccccga 240
ataaacgcca ccgggcaagg tgttacaata ttttatgttg atagacttgg ctactatcct 300
tacatagatt caatcacagg agtaactgtg aatggaggaa tcccccagaa gatttcctta 360
caagaccatc tggacaaagc taagaaagac attacatttt atatgccagt agacaatttg 420
ggaatggctg ttattgactg ggaagaatgg agacccactt gggcaagaaa ctggaaacct 480
aaagatgttt acaagaatag gtctattgaa ttggttcagc aacaaaatgt acaacttagt 540
ctcacagagg ccactgagaa agcaaaacaa gaatttgaaa aggcagggaa ggatttcctg 600
gtagagacta taaaattggg aaaattactt cggccaaatc acttgtgggg ttattatctt 660
tttccggatt gttacaacca tcactataag aaacccggtt acaatggaag ttgcttcaat 720
gtagaaataa aaagaaatga tgatctcagc tggttgtgga atgaaagcac tgctctttac 780
ccatccattt atttgaacac tcagcagtct cctgtagctg ctacactcta tgtgcgcaat 840
cgagttcggg aagccatcag agtttccaaa atacctgatg caaaaagtcc acttccggtt 900
tttgcatata cccgcatagt ttttactgat caagttttga aattcctttc tcaagatgaa 960
cttgtgtata catttggcga aactgttgct ctgggtgctt ctggaattgt aatatgggga1020
accctcagta taatgcgaag tatgaaatct tgcttgctcc tagacaatta catggagact1080
atactgaatc cttacataat caacgtcaca ctagcagcca aaatgtgtag tcaagtgctt1140
tgccaggagc aaggagtgtg tataaggaaa aactggaatt caagtgacta tcttcacctc1200
aacccagata attttgctat tcaacttgag aaaggtggaa agttcacagt acgtggaaaa1260
ccgacacttg aagacctgga gcaattttct gaaaaatttt attgcagctg ttatagcacc1320
ttgagttgta aggagaaagc tgatgtaaaa gacactgatg ctgttgatgt gtgtattgct1380
gatggtgtct gtatagatgc ttttctaaaa cctcccatgg agacagaaga acctcaaatt1440
ttctactga1449
<210> 57
<211> 17
<212> PRT
<213> Homo sapiens
<220>
<223> C-terminal peptide cleaved from soluble human
PH20, amino acid residues 431-447
<400> 57
Asp Ala Phe Lys Leu Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe
151015
Tyr
<210> 58
<211> 16
<212> PRT
<213> Homo sapiens
<220>
<223> C-terminal peptide cleaved from soluble human
PH20, amino acid residues 431-446
<400> 58
Asp Ala Phe Lys Leu Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe
151015
<210> 59
<211> 15
<212> PRT
<213> Homo sapiens
<220>
<223> C-terminal peptide cleaved from soluble human
PH20, amino acid residues 431-445
<400> 59
Asp Ala Phe Lys Leu Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
151015
<210> 60
<211> 14
<212> PRT
<213> Homo sapiens
<220>
<223> C-terminal peptide cleaved from soluble human
PH20, amino acid residues 431-444
<400> 60
Asp Ala Phe Lys Leu Pro Pro Met Glu Thr Glu Glu Pro Gln
1510
<210> 61
<211> 13
<212> PRT
<213> Homo sapiens
<220>
<223> C-terminal peptide cleaved from soluble human
PH20, amino acid residues 431-443
<400> 61
Asp Ala Phe Lys Leu Pro Pro Met Glu Thr Glu Glu Pro
1510
<210> 62
<211> 12
<212> PRT
<213> Homo sapiens
<220>
<223> C-terminal peptide cleaved from soluble human
PH20, amino acid residues 431-442
<400> 62
Asp Ala Phe Lys Leu Pro Pro Met Glu Thr Glu Glu
1510
<210> 63
<211> 520
<212> PRT
<213> Ovis aries
<220>
<223> sheep PH20
<400> 63
Leu Asp Phe Pro Ala Pro Pro Leu Ile Ser Asn Thr Ser Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ala Glu Arg Cys Val Lys Ile Phe Lys Leu Pro
202530
Pro Asp Leu Arg Leu Phe Ser Val Lys Gly Ser Pro Gln Lys Ser Ala
354045
Thr Gly Gln Phe Ile Thr Leu Phe Tyr Ala Asp Arg Leu Gly Tyr Tyr
505560
Pro His Ile Asp Glu Lys Thr Gly Asn Thr Val Tyr Gly Gly Ile Pro
65707580
Gln Leu Gly Asn Leu Lys Asn His Leu Glu Lys Ala Lys Lys Asp Ile
859095
Ala Tyr Tyr Ile Pro Asn Asp Ser Val Gly Leu Ala Val Ile Asp Trp
100105110
Glu Asn Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Arg Asp Glu Ser Val Glu Leu Val Leu Gln Lys Asn Pro Gln Leu
130135140
Ser Phe Pro Glu Ala Ser Lys Ile Ala Lys Val Asp Phe Glu Thr Ala
145150155160
Gly Lys Ser Phe Met Gln Glu Thr Leu Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
Asn Tyr Asn Gln Pro Thr Tyr Asn Gly Asn Cys Ser Asp Leu Glu Lys
195200205
Arg Arg Asn Asp Asp Leu Asp Trp Leu Trp Lys Glu Ser Thr Ala Leu
210215220
Phe Pro Ser Val Tyr Leu Asn Ile Lys Leu Lys Ser Thr Pro Lys Ala
225230235240
Ala Phe Tyr Val Arg Asn Arg Val Gln Glu Ala Ile Arg Leu Ser Lys
245250255
Ile Ala Ser Val Glu Ser Pro Leu Pro Val Phe Val Tyr His Arg Pro
260265270
Val Phe Thr Asp Gly Ser Ser Thr Tyr Leu Ser Gln Gly Asp Leu Val
275280285
Asn Ser Val Gly Glu Ile Val Ala Leu Gly Ala Ser Gly Ile Ile Met
290295300
Trp Gly Ser Leu Asn Leu Ser Leu Thr Met Gln Ser Cys Met Asn Leu
305310315320
Gly Asn Tyr Asn Thr Thr Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys His Asp Glu Gly Val Cys
340345350
Thr Arg Lys Gln Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Ile
355360365
Met Asn Phe Ala Ile Gln Thr Gly Lys Gly Gly Lys Tyr Thr Val Pro
370375380
Gly Lys Val Thr Leu Glu Asp Leu Gln Thr Phe Ser Asp Lys Phe Tyr
385390395400
Cys Ser Cys Tyr Ala Asn Ile Asn Cys Lys Lys Arg Val Asp Ile Lys
405410415
Asn Val His Ser Val Asn Val Cys Met Ala Glu Asp Ile Cys Ile Glu
420425430
Gly Pro Val Lys Leu Gln Pro Ser Asp His Ser Ser Ser Gln Asn Glu
435440445
Ala Ser Thr Thr Thr Val Ser Ser Ile Ser Pro Ser Thr Thr Ala Thr
450455460
Thr Val Val Ser Pro Cys Thr Pro Glu Lys Gln Ser Pro Glu Cys Leu
465470475480
Lys Val Arg Cys Leu Glu Ala Ile Ala Asn Val Thr Gln Thr Gly Cys
485490495
Gln Gly Val Lys Trp Lys Asn Thr Ser Ser Gln Ser Gln Ser Ser Ile
500505510
Gln Asn Ile Lys Asn Gln Thr Thr
515520
<210> 64
<211> 474
<212> PRT
<213> Bos taurus
<220>
<223> cow hyaluronidase PH20
<400> 64
Met Gly Met Phe Arg Arg His His Ile Ser Phe Arg Ser Phe Ala Gly
151015
Ser Ser Gly Thr Pro Gln Ala Val Phe Thr Phe Leu Leu Leu Pro Cys
202530
Cys Leu Ala Leu Asp Phe Arg Ala Pro Pro Leu Ile Ser Asn Thr Ser
354045
Phe Leu Trp Ala Trp Asn Ala Pro Val Glu Arg Cys Val Asn Arg Arg
505560
Phe Gln Leu Pro Pro Asp Leu Arg Leu Phe Ser Val Lys Gly Ser Pro
65707580
Gln Lys Ser Ala Thr Gly Gln Phe Ile Thr Leu Phe Tyr Ala Asp Arg
859095
Leu Gly Tyr Tyr Pro His Ile Asp Glu Lys Thr Gly Lys Thr Val Phe
100105110
Gly Gly Ile Pro Gln Leu Gly Asn Leu Lys Ser His Leu Glu Lys Ala
115120125
Lys Asn Asp Ile Ala Tyr Tyr Ile Pro Asn Asp Ser Val Gly Leu Ala
130135140
Val Ile Asp Trp Glu Asn Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys
145 150155160
Pro Lys Asp Val Tyr Arg Asp Glu Ser Val Glu Leu Val Leu Gln Lys
165170175
Asn Pro Gln Leu Ser Phe Pro Glu Ala Ser Lys Ile Ala Lys Val Asp
180185190
Phe Glu Thr Ala Gly Lys Ser Phe Met Gln Glu Thr Leu Lys Leu Gly
195200205
Lys Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp
210215220
Cys Tyr Asn His Asn His Asn Gln Pro Thr Tyr Asn Gly Asn Cys Pro
225230235240
Asp Val Glu Lys Arg Arg Asn Asp Asp Leu Glu Trp Leu Trp Lys Glu
245250255
Ser Thr Ala Leu Phe Pro Ser Val Tyr Leu Asn Ile Arg Leu Lys Ser
260265270
Thr Gln Asn Ala Ala Leu Tyr Val Arg Asn Arg Val Gln Glu Ala Ile
275280285
Arg Leu Ser Lys Ile Ala Ser Val Glu Ser Pro Leu Pro Val Phe Val
290295300
Tyr Ala Arg Pro Val Phe Thr Asp Gly Ser Ser Thr Tyr Leu Ser Gln
305310315320
Gly Asp Leu Val Asn Ser Val Gly Glu Ile Val Ser Leu Gly Ala Ser
325330335
Gly Ile Ile Met Trp Gly Ser Leu Asn Leu Ser Leu Ser Val Gln Ser
340345350
Cys Met Asn Leu Gly Thr Tyr Leu Asn Thr Thr Leu Asn Pro Tyr Ile
355360365
Ile Asn Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys His
370375380
Asp Gly Gly Val Cys Thr Arg Lys His Trp Asn Ser Ser Asp Tyr Leu
385390395400
His Leu Asn Pro Met Asn Phe Ala Ile Gln Thr Gly Glu Gly Gly Lys
405410415
Tyr Thr Val Pro Gly Thr Leu Thr Leu Glu Asp Leu Gln Lys Phe Ser
420425430
Asp Thr Phe Tyr Cys Ser Cys Tyr Ser Asn Leu Ser Cys Lys Lys Arg
435440445
Val Asp Ile Lys Asn Val His Ser Val Asp Val Cys Met Ala Glu Asp
450455460
Val Cys Ile Asp Ala Phe Leu Lys Pro Pro
465470
<210> 65
<211> 517
<212> PRT
<213> Ovis aries
<220>
<223> sheep PH20
<400> 65
Asp Phe Arg Ala Pro Pro Leu Ile Ser Asn Thr Ser Phe Leu Trp Ala
151015
Trp Asn Ala Pro Ala Glu Arg Cys Ile Lys Ile Phe Lys Leu Pro Pro
202530
Asp Leu Arg Leu Phe Ser Val Lys Gly Ser Pro Gln Lys Ser Ala Thr
354045
Gly Gln Phe Ile Thr Leu Phe Tyr Ala Asp Arg Leu Gly Tyr Tyr Pro
505560
His Ile Asp Glu Lys Thr Gly Asn Thr Val Tyr Gly Gly Ile Pro Gln
65707580
Leu Gly Asn Leu Lys Asn His Leu Glu Lys Ala Lys Lys Asp Ile Ala
859095
Tyr Tyr Ile Pro Asn Asp Ser Val Gly Leu Ala Val Ile Asp Trp Glu
100105110
Asn Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val Tyr
115120125
Arg Asp Glu Ser Val Glu Leu Val Leu Gln Lys Asn Pro Gln Leu Ser
130135140
Phe Pro Glu Ala Ser Lys Ile Ala Lys Val Asp Phe Glu Thr Ala Gly
145150155160
Lys Ser Phe Met Gln Glu Thr Leu Lys Leu Gly Lys Leu Leu Arg Pro
165170175
Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His Asn
180185190
Tyr Asn Gln Pro Thr Tyr Asn Gly Asn Cys Ser Asp Leu Glu Lys Arg
195200205
Arg Asn Asp Asp Leu Asp Trp Leu Trp Lys Glu Ser Thr Ala Leu Phe
210215220
Pro Ser Val Tyr Leu Asn Ile Lys Leu Lys Ser Thr Pro Lys Ala Ala
225230235240
Phe Tyr Val Arg Asn Arg Val Gln Glu Ala Ile Arg Leu Ser Lys Ile
245250255
Ala Ser Val Glu Ser Pro Leu Pro Val Phe Val Tyr His Arg Pro Val
260265270
Phe Thr Asp Gly Ser Ser Thr Tyr Leu Ser Gln Gly Asp Leu Val Asn
275280285
Ser Val Gly Glu Ile Val Ala Leu Gly Ala Ser Gly Ile Ile Met Trp
290295300
Gly Ser Leu Asn Leu Ser Leu Thr Met Gln Ser Cys Met Asn Leu Gly
305310315320
Asn Tyr Leu Asn Thr Thr Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys His Asp Glu Gly Val Cys
340345350
Thr Arg Lys Gln Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Met
355360365
Asn Phe Ala Ile Gln Thr Gly Lys Gly Gly Lys Tyr Thr Val Pro Gly
370375380
Lys Val Thr Leu Glu Asp Leu Gln Thr Phe Ser Asp Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ala Asn Ile Asn Cys Lys Lys Arg Val Asp Ile Lys Asn
405410415
Val His Ser Val Asn Val Cys Met Ala Glu Asp Ile Cys Ile Glu Gly
420425430
Pro Val Lys Leu Gln Pro Ser Asp His Ser Ser Ser Gln Asn Glu Ala
435440445
Ser Thr Thr Thr Val Ser Ser Ile Ser Pro Ser Thr Thr Ala Thr Thr
450455460
Val Ser Pro Cys Thr Pro Glu Lys Gln Ser Pro Glu Cys Leu Lys Val
465470475480
Arg Cys Leu Glu Ala Ile Ala Asn Val Thr Gln Thr Gly Cys Gln Gly
485490495
Val Lys Trp Lys Asn Thr Ser Ser Gln Ser Ser Ile Gln Asn Ile Lys
500505510
Asn Gln Thr Thr Tyr
515
<210> 66
<211> 1620
<212> DNA
<213> Ovis aries
<220>
<223> DNA encoding sheep PH20
<400> 66
ttttccgtgt tggttggctc tggacttcag agcaccccct ctcatttcaa acacttcttt 60
cctctgggcc tggaatgccc cagctgaacg ttgtattaaa atctttaaac tacctccaga 120
tctgagactc ttctctgtaa aaggaagccc ccaaaaaagt gctacgggac aatttattac 180
attattttat gctgatagac ttggctacta tcctcatata gatgaaaaaa caggcaacac 240
tgtatatgga ggaattcccc agttgggaaa cttaaaaaat catttggaaa aagccaaaaa 300
agacattgcc tattacatac caaatgacag cgtgggcttg gcggtcattg actgggaaaa 360
ctggaggcct acctgggcaa gaaactggaa acctaaagat gtttacaggg atgagtctgt 420
tgagttggtt ctgcaaaaaa atccacaact cagtttccca gaggcttcca agattgcaaa 480
agtggatttt gagacagcag gaaagagttt catgcaagag actttaaaac tgggaaaatt 540
acttcggcca aatcacttat ggggttatta tctttttcct gattgttaca atcataatta 600
taaccagcct acttacaatg gaaattgctc tgatttagaa aaaaggagaa atgatgatct 660
cgactggttg tggaaggaaa gcactgccct tttcccttct gtttatttga atatcaagtt 720
aaaatctact ccaaaagctg ccttctatgt tcgtaatcgt gtccaggaag ccattcggtt 780
gtctaaaata gcgagtgttg aaagtccact tcccgttttt gtatatcacc gtccagtttt 840
tactgatggg tcttcaacat acctttctca gggtgacctt gtgaattcgg ttggtgagat 900
cgttgctcta ggtgcctctg ggattataat gtggggcagt ctcaatctaa gcctaactat 960
gcaatcttgc atgaacctag gcaattactt gaacactaca ctgaatcctt acataatcaa1020
cgtcacccta gcagccaaaa tgtgcagcca agtgctttgc cacgatgaag gagtgtgtac1080
aaggaaacaa tggaattcaa gcgactatct tcacctgaac ccaatgaatt ttgctattca1140
aactgggaaa ggtggaaaat acacagtacc tgggaaagtc acacttgaag acctgcaaac1200
gttttctgat aaattttatt gcagttgtta tgccaacatc aactgtaaga agagagttga1260
tataaaaaat gttcatagtg ttaatgtatg tatggcagaa gacatttgta tagagggccc1320
tgtgaagtta caacccagtg atcattcctc tagccagaat gaggcatcta ctaccaccgt1380
cagcagtatc tcaccctcta ctacagccac cacagtatct ccatgtactc ctgagaaaca1440
gtcccctgag tgcctcaaag tcaggtgttt ggaagccatc gccaacgtca cccaaacggg1500
gtgtcaaggt gttaaatgga agaacacttc cagtcagtca agtattcaaa atattaaaaa1560
tcaaacaacc tattaaaata taaattcagt gcttataaaa aaaaaaaaaa aaaaaaaaaa1620
<210> 67
<211> 793
<212> PRT
<213> Arthrobacter sp.
<220>
<223> Arthrobacter sp. FB24 hyaluronate lyase
<400> 67
Met Thr Arg Glu Phe Ser Arg Arg Thr Ala Leu Lys Gly Ala Ala Leu
151015
Ser Gly Leu Leu Leu Ala Met Val His Gly Pro Ala His Ala Ala Ala
202530
Thr Ala Asn Ala Thr Leu Thr Pro Ala Asp Phe Ala Gly Leu Arg Gln
354045
Arg Trp Val Asp Gln Ile Thr Gly Arg Lys Val Leu Val Ala Gly Asp
505560
Asn Asp Phe Val Thr Ala Leu Ala Ala Leu Asp Lys Lys Ala Arg Thr
65707580
Ala Ile Asp Leu Leu Glu Arg Ser Ala Gly Arg Leu Thr Val Phe Ser
859095
Asp Leu Ser Leu Ala Lys Asp Thr Asp Leu Val Thr Thr His Thr Arg
100105110
Leu Ala Thr Met Ala Thr Ala Trp Ala Thr Pro Gly Ser Glu His Phe
115120125
Ala Asp Ala Gly Leu Leu Ala Ala Ile Arg Ala Gly Leu Ala Asp Ala
130135140
Asn Ser Leu Cys Tyr Asn Ala Ser Lys Glu Glu Gln Gly Asn Trp Trp
145150155160
Ser Trp Glu Ile Gly Thr Pro Lys Ala Leu Ala Asp Thr Met Val Leu
165170175
Leu His Ala Glu Leu Thr Ala Ala Glu Arg Ala Ala Tyr Cys Ala Ala
180185190
Ile Asp His Phe Val Pro Asp Pro Trp Gln Gln Phe Pro Pro Lys Arg
195200205
Gly Lys Ile Thr Ser Val Gly Ala Asn Arg Val Asp Leu Cys Gln Ala
210215220
Val Thr Ile Arg Ser Leu Val Asp Glu Asp Ala Glu Lys Leu Thr His
225230235240
Ala Val Ala Gly Leu Ser Glu Val Trp Gln Tyr Val Ser Ala Gly Asn
245250255
Gly Phe Phe Thr Asp Gly Ser Phe Ile Gln His Ser Thr Thr Pro Tyr
260265270
Thr Gly Ser Tyr Gly Val Val Leu Leu Thr Gly Leu Ser Lys Leu Phe
275280285
Ala Leu Leu Gly Gly Thr Gly Ala Glu Val Ser Asp Pro Ser Arg Asp
290295300
Ile Leu Phe Lys Thr Val Glu Gly Ser Phe Ala Pro Phe Met Val Ala
305310 315320
Gly Ala Met Ala Asp Ser Val Arg Gly Arg Ser Ile Ser Arg Glu Ser
325330335
Asn Thr Gly Phe Asp Leu Gly Ala Ser Thr Ile Glu Ser Ile Leu Leu
340345350
Leu Ala Arg Ala Val Asp Pro Val Thr Ala Arg Arg Trp Arg Ser Leu
355360365
Cys Leu Ala Trp Ile Asn Gln Asn Arg Lys Ala Pro Ile Leu Ala Asp
370375380
Ala Gly Val Gly Arg Thr Ala Leu Val Lys Glu Leu Leu Ala Met Gly
385390395400
Leu Thr Glu Thr Asp Leu Pro Gly Gly His Tyr Leu Phe Pro Ala Met
405410415
Asp Arg Thr Met His His Ser Gln Gly Trp Thr Leu Ser Thr Ala Met
420425430
Ala Ser Ser Arg Ile Ala Trp Tyr Glu Cys Gly Asn Gly Glu Asn Asn
435440445
Arg Gly Tyr His Thr Gly Ser Gly Met Thr Tyr Val Tyr Asp Gly Asp
450455460
Leu Gly Gln Tyr Asp Asp Ala Phe Trp Ala Thr Ala Asn His Cys Arg
465470475480
Leu Pro Gly Ile Thr Val Asp Thr Ser Ser Leu Pro Asp Lys Val Glu
485490495
Gly Glu Trp Gly Ala Ala Thr Pro Ala Asn Glu Trp Thr Gly Ser Thr
500505510
Ala Tyr Gly Asp Val Ala Ala Val Gly Gln His Leu Ile Gly Pro Gly
515520525
Gly Thr Gly Leu Thr Ala Arg Lys Ser Trp Phe Val Ser Lys Asp Val
530535540
Ile Val Cys Leu Gly Ala Asp Ile Arg Thr Gly Ser Gly Ser Arg Ile
545550555560
Glu Thr Val Val Asp His Arg Asn Leu His Ala Gly Phe Asn Ala Met
565570575
Gly Thr Ala Ala Gly Thr Val Ala Ala Thr Pro Gly His Pro Glu Val
580585590
Leu Thr Val Asp Arg Trp Val His Leu Glu Gly Phe Gly Gly Tyr Val
595600605
Val Leu Asp Ala Ala Pro Leu Gln Val Leu Arg Glu Gln Arg Glu Gly
610615620
Ser Trp Ser Glu Val Asn Val Lys Gly Ser Ala Ala Arg Gln Thr Arg
625 630635640
Asn Tyr Ala Thr Leu Tyr Phe Asp His Gly His Glu Pro Glu Ala Ala
645650655
Ser Tyr Ala Tyr Leu Val Ala Pro Gly Ala Ser Ala Ser Met Thr Ser
660665670
Ser Leu Ser Gly Gln Ser Phe His Thr Val Leu Arg Asn Asp Glu Val
675680685
Ala Gln Ala Val Lys Phe Lys Lys Glu Lys Thr Thr Ala Ala Thr Phe
690695700
Trp Arg Pro Gly Thr Val Gly Asp Leu Ala Leu Ser Gly Pro Ala Cys
705710715720
Val Val Val Lys Glu Val Gly Asp Arg Leu Ser Ile Ala Val Ser Asp
725730735
Pro Thr Gln Asn Ala Ser Thr Leu Thr Leu Arg Leu Lys Thr Lys Arg
740745750
Phe Phe Arg Ile Ile Glu Gly Gln Gly Ala Ser Leu Ser His Gly Ala
755760765
Asp Gly Phe Thr Val Leu Glu Val Asp Ile Ala Asn His Ala Gly Arg
770775780
Thr Lys Gln Ile Glu Leu Ser Ala Glu
785790
<210> 68
<211> 557
<212> PRT
<213> Bdellovibrio bacteriovorus
<220>
<223> Bdellovibrio bacteriovorus HD100 hypothetical
hyaluronan lyase
<400> 68
Met Thr Lys Phe Phe Phe Leu Leu Thr Leu Ile Ser Ala Thr Ala Phe
151015
Ala Gln Ser Glu Pro Asp Trp Thr Ala Gly Val Pro Val Pro Pro Gly
202530
Gly Arg Ser Asn Ile Tyr Ser Trp Asn Asp Phe Asp Phe Gln Ala Thr
35 4045
Leu Asn Lys Gly Lys Ile His Ala Gln Val Tyr Pro Val Thr Val Thr
505560
Gly Met Leu Pro Pro Tyr Glu Pro Val Arg Arg Leu Ile Glu Glu Lys
65707580
Asn Ser Asn Pro Leu Arg Lys Trp Ile Gln Ser Leu Met Lys Gly Leu
859095
Ser Gly Phe Arg Ser Phe Glu Asp Val Leu Lys Asn Leu Gly Leu His
100105110
Lys Tyr Pro Leu Glu Asn Glu Arg Gly Val Tyr Ala Val Pro Tyr Pro
115120125
Asn Glu Ile Arg Pro Asp Thr Leu Met Gly Phe Gly Leu Ile Glu Arg
130135140
Asn Gly Ala Glu Gly Phe Thr Phe Ser Cys Ala Ala Cys His Ser Ser
145150155160
Asn Leu Phe Gly Lys Thr Val Leu Gly Met Thr Asn Arg Phe Pro Arg
165170175
Ala Asn Glu Phe Phe Ile Lys Ala Lys Lys Val Met Pro Leu Met Asp
180185190
Pro His Ile Phe Gln Ala Tyr Thr Arg Ala Thr Asp Ala Glu Thr Ala
195200205
Leu Leu Val Glu Ser Lys Glu Arg Leu Lys Ser Val Ala Leu Lys Gln
210215220
Pro Ile Ala Leu Gly Leu Asp Thr Ser Leu Ala Gln Val Ser Leu Ser
225230235240
Leu Asn Arg Arg Ala Lys Asp Gly Tyr Ala Asn Tyr Ser Asp Lys Ala
245250255
Ala Arg Ser Pro Arg Ala Asp Ala Tyr Leu Asp Asn Lys Pro Ala Asp
260265270
Ser Lys Pro Ala Val Trp Trp Asn Val Lys Tyr Lys Asn Arg Trp Leu
275280285
Ser Asp Gly Ser Val Leu Ser Gly Asn Pro Ile Phe Thr Asn Leu Ile
290295300
Trp Asn Glu Ile Gly Arg Gly Ala Asp Leu His Glu Leu Glu Gln Trp
305310315320
Leu Ala Asp Asn Asp His Ile Ile Lys Glu Leu Thr Thr Ala Val Phe
325330335
Ala Ser Glu Ala Pro His Ile Thr Asp Phe Tyr Pro Ala Glu Lys Ile
340345350
Asp Leu Gly Arg Ala Lys Ala Gly Glu Gln Ile Phe Lys Asn Thr Cys
355360365
Ala Lys Cys His Gly His Tyr Glu Lys Ala Trp Asn Leu Pro Gln Ala
370375380
Leu Val Leu Ser Ala Ala Glu Arg Leu Lys Thr Val Glu Val Arg Tyr
385390395400
Lys Glu Lys Thr Pro Val Val Asn Val Gly Thr Asp Pro Phe Arg Arg
405410415
Gln Gly Met Lys Ser Leu Glu Gln Leu Asn Asp Leu Glu Ile Ser Lys
420425430
Lys Asn Gly Ile Val Ile Lys Ala Gln Glu Gly Tyr Val Pro Pro Pro
435440445
Leu Val Gly Ile Trp Ala Arg Trp Pro Tyr Met His Asn Asn Ser Ile
450455460
Pro Asn Leu Cys Val Leu Leu Thr Pro Ala Lys Lys Arg Pro Ser Ile
465470475480
Tyr Tyr Ser Gly Glu Ala Leu Asn Lys Asp Thr Asp Tyr Asp Phe Ser
485490495
Cys Gly Gly Tyr Pro Ile Gly Asp Lys Thr Pro Lys Ala Trp Lys Thr
500505510
Arg Glu His Leu Tyr Asp Thr Arg Asn Pro Gly Met Gly Asn Met Gly
515520525
His Asp Glu Gly Ile Phe Ile Lys Asp Gly Lys Glu Ile Leu Ser Ala
530535540
Glu Asp Lys Tyr Asn Leu Ile Gln Phe Leu Gln Thr Leu
545550555
<210> 69
<211> 813
<212> PRT
<213> Propionibacterium acnes
<220>
<223> Propionibacterium acnes KPA171202 hyaluronate
lyase
<400> 69
Met Phe Gly Thr Pro Ser Arg Arg Thr Phe Leu Thr Ala Ser Ala Leu
151015
Ser Ala Met Ala Leu Ala Ala Ser Pro Thr Val Thr Asp Ala Ile Ala
202530
Ala Pro Gly Pro Asp Ser Trp Ser Ala Leu Cys Glu Arg Trp Ile Asp
354045
Ile Ile Thr Gly Arg Arg Ala Ala Arg Thr Ser Asp Pro Arg Ala Arg
505560
Ala Ile Ile Ala Lys Thr Asp Arg Lys Val Ala Glu Ile Leu Thr Asp
65707580
Leu Val Ser Gly Ser Ser Arg Gln Thr Val Leu Ile Ser Ala Asp Leu
859095
Arg Lys Glu Gln Ser Pro Phe Ile Thr Lys Thr Ala Arg Ala Ile Glu
100105110
Ser Met Ala Cys Ala Trp Ala Thr Pro Gly Ser Ser Tyr His Lys Asp
115120125
Pro Glu Ile Leu Ser Ala Cys Ile Glu Gly Leu Arg Asp Phe Cys Arg
130135140
Leu Arg Tyr Asn Pro Ser Gln Asp Glu Tyr Gly Asn Trp Trp Asp Trp
145150155160
Glu Asp Gly Ala Ser Arg Ala Val Ala Asp Val Met Cys Ile Leu His
165170175
Asp Val Leu Pro Pro Glu Val Met Ser Ala Ala Ala Ala Gly Ile Asp
180185190
His Phe Ile Pro Asp Pro Trp Phe Gln Gln Pro Ala Ser Val Lys Pro
195200205
Thr Ala Asn Pro Val Gln Pro Val Val Ser Thr Gly Ala Asn Arg Met
210215220
Asp Leu Thr Arg Ala Val Met Cys Arg Ser Ile Ala Thr Gly Asp Glu
225230235240
Lys Arg Leu Arg His Ala Val Asp Gly Leu Pro Asp Ala Trp Arg Val
245250255
Thr Thr Glu Gly Asp Gly Phe Arg Ala Asp Gly Gly Phe Ile Gln His
260265270
Ser His Ile Pro Tyr Thr Gly Gly Tyr Gly Asp Val Leu Phe Ser Gly
275280285
Leu Ala Met Leu Phe Pro Leu Val Ser Gly Met Arg Phe Asp Ile Val
290295300
Glu Ser Ala Arg Lys Ala Phe His Asp Gln Val Glu Arg Gly Phe Ile
305310315320
Pro Val Met Tyr Asn Gly Gln Ile Leu Asp Asp Val Arg Gly Arg Ser
325330335
Ile Ser Arg Ile Asn Glu Ser Ala Ala Met His Gly Ile Ser Ile Ala
340345350
Arg Ala Met Leu Met Met Ala Asp Ala Leu Pro Thr His Arg Ala Glu
355360365
Gln Trp Arg Gly Ile Val His Gly Trp Met Ala Arg Asn Thr Phe Asp
370375380
His Leu Ser Glu Pro Ser Thr Leu Val Asp Ile Ser Leu Phe Asp Ala
385390395400
Ala Ala Lys Ala Arg Pro Val Pro Glu Ser Ser Thr Pro Ser Tyr Phe
405410415
Ala Ser Met Asp Arg Leu Val His Arg Thr Ala Asp Trp Leu Ile Thr
420425430
Val Ser Asn Cys Ser Asp Arg Ile Ala Trp Tyr Glu Tyr Gly Asn Gly
435440445
Glu Asn Glu Trp Ala Ser Arg Thr Ser Gln Gly Met Arg Tyr Leu Leu
450455460
Leu Pro Gly Asp Met Gly Gln Tyr Glu Asp Gly Tyr Trp Ala Thr Val
465470475480
Asp Tyr Ser Ala Pro Thr Gly Thr Thr Val Asp Ser Thr Pro Leu Lys
485490495
Arg Ala Val Gly Ala Ser Trp Ala Ala Lys Thr Pro Thr Asn Glu Trp
500505510
Ser Gly Gly Leu Ala Ser Gly Ser Trp Ser Ala Ala Ala Ser His Ile
515520525
Thr Ser Gln Asp Ser Ala Leu Lys Ala Arg Arg Leu Trp Val Gly Leu
530535540
Lys Asp Ala Met Val Glu Leu Thr Thr Asp Val Thr Thr Asp Ala Ser
545550555560
Arg Ala Ile Thr Val Val Glu His Arg Lys Val Ala Ser Ser Ser Thr
565570575
Lys Leu Leu Val Asp Gly Asn Arg Val Ser Ser Ala Thr Ser Phe Gln
580585590
Asn Pro Arg Trp Ala His Leu Asp Gly Val Gly Gly Tyr Val Phe Ala
595600605
Thr Asp Thr Asp Leu Ser Ala Asp Val Ala Thr Arg Lys Gly Thr Trp
610615620
Ile Asp Val Asn Pro Ser Arg Lys Val Lys Gly Ala Asp Glu Val Ile
625630635640
Glu Arg Ala Tyr Ala Ser Leu His Val Thr His His Asp Arg Pro Val
645650655
Ala Trp Ala Leu Leu Pro Thr Ala Ser Arg Ser His Thr Met Ala Leu
660665670
Ala Thr Arg Pro Gly Val Glu Pro Phe Thr Val Leu Arg Asn Asp Ala
675680685
Thr Val Gln Ala Val Arg Ser Ala Gly Ala Leu Leu Thr Lys Asp Pro
690695700
Thr Val Val Thr Thr Leu Ala Phe Trp Lys Pro Ala Thr Cys Gly Gly
705710715720
Val Ala Val Asn Arg Pro Ala Leu Val Gln Thr Arg Glu Ser Ala Asn
725730735
Gln Met Glu Val Val Ile Val Glu Pro Thr Gln Lys Arg Gly Ser Leu
740745750
Thr Val Thr Ile Glu Gly Ser Trp Lys Val Lys Thr Ala Asp Ser His
755760765
Val Asp Val Ser Cys Glu Asn Ala Ala Gly Thr Leu His Val Asp Thr
770775780
Ala Gly Leu Gly Gly Gln Ser Val Arg Val Thr Leu Ala Arg Gln Val
785790795800
Thr Gln Thr Pro Ser Gly Gly Gly Arg His Asp Arg Ala
805810
<210> 70
<211> 1072
<212> PRT
<213> Streptococcus agalactiae
<220>
<223> Streptococcus agalactiae hyaluronate lyase
<400> 70
Met Glu Ile Lys Lys Lys Tyr Arg Ile Met Leu Tyr Ser Ala Leu Ile
151015
Leu Gly Thr Ile Leu Val Asn Asn Ser Tyr Gln Ala Lys Ala Glu Glu
202530
Leu Thr Lys Thr Thr Ser Thr Ser Gln Ile Arg Asp Thr Gln Thr Asn
354045
Asn Ile Glu Val Leu Gln Thr Glu Ser Thr Thr Val Lys Glu Thr Ser
505560
Thr Thr Thr Thr Gln Gln Asp Leu Ser Asn Pro Thr Ala Ser Thr Ala
65707580
Thr Ala Thr Ala Thr His Ser Thr Met Lys Gln Val Val Asp Asn Gln
859095
Thr Gln Asn Lys Glu Leu Val Lys Asn Gly Asp Phe Asn Gln Thr Asn
100105110
Pro Val Ser Gly Ser Trp Ser His Thr Ser Ala Arg Glu Trp Ser Ala
115120125
Trp Ile Asp Lys Glu Asn Thr Ala Asp Lys Ser Pro Ile Ile Gln Arg
130135140
Thr Glu Gln Gly Gln Val Ser Leu Ser Ser Asp Lys Gly Phe Arg Gly
145150155160
Ala Val Thr Gln Lys Val Asn Ile Asp Pro Thr Lys Lys Tyr Glu Val
165170175
Lys Phe Asp Ile Glu Thr Ser Asn Lys Ala Gly Gln Ala Phe Leu Arg
180185190
Ile Met Glu Lys Lys Asp Asn Asn Thr Arg Leu Trp Leu Ser Glu Met
195200205
Thr Ser Gly Thr Thr Asn Lys His Thr Leu Thr Lys Ile Tyr Asn Pro
210215220
Lys Leu Asn Val Ser Glu Val Thr Leu Glu Leu Tyr Tyr Glu Lys Gly
225230235240
Thr Gly Ser Ala Thr Phe Asp Asn Ile Ser Met Lys Ala Lys Gly Pro
245250255
Lys Asp Ser Glu His Pro Gln Pro Val Thr Thr Gln Ile Glu Glu Ser
260265270
Val Asn Thr Ala Leu Asn Lys Asn Tyr Val Phe Asn Lys Ala Asp Tyr
275280285
Gln Tyr Thr Leu Thr Asn Pro Ser Leu Gly Lys Ile Val Gly Gly Ile
290295300
Leu Tyr Pro Asn Ala Thr Gly Ser Thr Thr Val Lys Ile Ser Asp Lys
305310315320
Ser Gly Lys Ile Ile Lys Glu Val Pro Leu Ser Val Thr Ala Ser Thr
325330335
Glu Asp Lys Phe Thr Lys Leu Leu Asp Lys Trp Asn Asp Val Thr Ile
340345350
Gly Asn His Val Tyr Asp Thr Asn Asp Ser Asn Met Gln Lys Ile Asn
355360365
Gln Lys Leu Asp Glu Thr Asn Ala Lys Asn Ile Lys Thr Ile Lys Leu
370375380
Asp Ser Asn His Thr Phe Leu Trp Lys Asp Leu Asp Asn Leu Asn Asn
385390395400
Ser Ala Gln Leu Thr Ala Thr Tyr Arg Arg Leu Glu Asp Leu Ala Lys
405410415
Gln Ile Thr Asn Pro His Ser Thr Ile Tyr Lys Asn Glu Lys Ala Ile
420425430
Arg Thr Val Lys Glu Ser Leu Ala Trp Leu His Gln Asn Phe Tyr Asn
435440445
Val Asn Lys Asp Ile Glu Gly Ser Ala Asn Trp Trp Asp Phe Glu Ile
450455460
Gly Val Pro Arg Ser Ile Thr Ala Thr Leu Ala Leu Met Asn Asn Tyr
465470475480
Phe Thr Asp Ala Glu Ile Lys Thr Tyr Thr Asp Pro Ile Glu His Phe
485490495
Val Pro Asp Ala Gly Tyr Phe Arg Lys Thr Leu Asp Asn Pro Phe Lys
500505510
Ala Leu Gly Gly Asn Leu Val Asp Met Gly Arg Val Lys Ile Ile Glu
515520525
Gly Leu Leu Arg Lys Asp Asn Thr Ile Ile Glu Lys Thr Ser His Ser
530535540
Leu Lys Asn Leu Phe Thr Thr Ala Thr Lys Ala Glu Gly Phe Tyr Ala
545550555560
Asp Gly Ser Tyr Ile Asp His Thr Asn Val Ala Tyr Thr Gly Ala Tyr
565570575
Gly Asn Val Leu Ile Asp Gly Leu Thr Gln Leu Leu Pro Ile Ile Gln
580585590
Glu Thr Asp Tyr Lys Ile Ser Asn Gln Glu Leu Asp Met Val Tyr Lys
595600605
Trp Ile Asn Gln Ser Phe Leu Pro Leu Ile Val Lys Gly Glu Leu Met
610615620
Asp Met Ser Arg Gly Arg Ser Ile Ser Arg Glu Ala Ala Ser Ser His
625630635640
Ala Ala Ala Val Glu Val Leu Arg Gly Phe Leu Arg Leu Ala Asn Met
645650655
Ser Asn Glu Glu Arg Asn Leu Asp Leu Lys Ser Thr Ile Lys Thr Ile
660665670
Ile Thr Ser Asn Lys Phe Tyr Asn Val Phe Asn Asn Leu Lys Ser Tyr
675680685
Ser Asp Ile Ala Asn Met Asn Lys Met Leu Asn Asp Ser Thr Val Ala
690695700
Thr Lys Pro Leu Lys Ser Asn Leu Ser Thr Phe Asn Ser Met Asp Arg
705710715720
Leu Ala Tyr Tyr Asn Ala Glu Lys Asp Phe Gly Phe Ala Leu Ser Leu
725730735
His Ser Lys Arg Thr Leu Asn Tyr Glu Gly Met Asn Asp Glu Asn Thr
740745750
Arg Gly Trp Tyr Thr Gly Asp Gly Met Phe Tyr Leu Tyr Asn Ser Asp
755760765
Gln Ser His Tyr Ser Asn His Phe Trp Pro Thr Val Asn Pro Tyr Lys
770775780
Met Ala Gly Thr Thr Glu Lys Asp Ala Lys Arg Glu Asp Thr Thr Lys
785790795800
Glu Phe Met Ser Lys His Ser Lys Asp Ala Lys Glu Lys Thr Gly Gln
805810815
Val Thr Gly Thr Ser Asp Phe Val Gly Ser Val Lys Leu Asn Asp His
820825830
Phe Ala Leu Ala Ala Met Asp Phe Thr Asn Trp Asp Arg Thr Leu Thr
835840845
Ala Gln Lys Gly Trp Val Ile Leu Asn Asp Lys Ile Val Phe Leu Gly
850855860
Ser Asn Ile Lys Asn Thr Asn Gly Ile Gly Asn Val Ser Thr Thr Ile
865870875880
Asp Gln Arg Lys Asp Asp Ser Lys Thr Pro Tyr Thr Thr Tyr Val Asn
885890895
Gly Lys Thr Ile Asp Leu Lys Gln Ala Ser Ser Gln Gln Phe Thr Asp
900905910
Thr Lys Ser Val Phe Leu Glu Ser Lys Glu Pro Gly Arg Asn Ile Gly
915920925
Tyr Ile Phe Phe Lys Asn Ser Thr Ile Asp Ile Glu Arg Lys Glu Gln
930935940
Thr Gly Thr Trp Asn Ser Ile Asn Arg Thr Ser Lys Asn Thr Ser Ile
945950955960
Val Ser Asn Pro Phe Ile Thr Ile Ser Gln Lys His Asp Asn Lys Gly
965970975
Asp Ser Tyr Gly Tyr Met Met Val Pro Asn Ile Asp Arg Thr Ser Phe
980985990
Asp Lys Leu Ala Asn Ser Lys Glu Val Glu Leu Leu Glu Asn Ser Ser
99510001005
Lys Gln Gln Val Ile Tyr Asp Lys Asn Ser Gln Thr Trp Ala Val Ile
1010 10151020
Lys His Asp Asn Gln Glu Ser Leu Ile Asn Asn Gln Phe Lys Met Asn
1025103010351040
Lys Ala Gly Leu Tyr Leu Val Gln Lys Val Gly Asn Asp Tyr Gln Asn
104510501055
Val Tyr Tyr Gln Pro Gln Thr Met Thr Lys Thr Asp Gln Leu Ala Ile
106010651070
<210> 71
<211> 1072
<212> PRT
<213> Streptococcus agalactiae
<220>
<223> Streptococcus agalactiae 18RS21 hyaluronate lyase
<400> 71
Met Glu Ile Lys Lys Lys His Arg Ile Met Leu Tyr Ser Ala Leu Ile
151015
Leu Gly Thr Ile Leu Val Asn Asn Ser Tyr Gln Ala Lys Ala Glu Glu
202530
Leu Thr Lys Thr Thr Ser Thr Ser Gln Ile Arg Asp Thr Gln Thr Asn
354045
Asn Ile Glu Val Leu Gln Thr Glu Ser Thr Thr Val Lys Glu Thr Ser
505560
Thr Thr Thr Thr Gln Gln Asp Leu Ser Asn Pro Thr Ala Ser Thr Ala
65707580
Thr Ala Thr Ala Thr His Ser Thr Met Lys Gln Val Val Asp Asn Gln
859095
Thr Gln Asn Lys Glu Leu Val Lys Asn Gly Asp Phe Asn Gln Thr Asn
100105110
Pro Val Ser Gly Ser Trp Ser His Thr Ser Ala Arg Glu Trp Ser Ala
115120125
Trp Ile Asp Lys Glu Asn Thr Ala Asp Lys Ser Pro Ile Ile Gln Arg
130135140
Thr Glu Gln Gly Gln Val Ser Leu Ser Ser Asp Lys Gly Phe Arg Gly
145150155160
Ala Val Thr Gln Lys Val Asn Ile Asp Pro Thr Lys Lys Tyr Glu Val
165170175
Lys Phe Asp Ile Glu Thr Ser Asn Lys Ala Gly Gln Ala Phe Leu Arg
180185190
Ile Met Glu Lys Lys Asp Asn Asn Thr Arg Leu Trp Leu Ser Glu Met
195200205
Thr Ser Gly Thr Thr Asn Lys His Thr Leu Thr Lys Ile Tyr Asn Pro
210215220
Lys Leu Asn Val Ser Glu Val Thr Leu Glu Leu Tyr Tyr Glu Lys Gly
225230235240
Thr Gly Ser Ala Thr Phe Asp Asn Ile Ser Met Lys Ala Lys Gly Pro
245250255
Lys Asp Ser Glu His Pro Gln Pro Val Thr Thr Gln Ile Glu Glu Ser
260265270
Val Asn Thr Ala Leu Asn Lys Asn Tyr Val Phe Asn Lys Ala Asp Tyr
275280285
Gln Tyr Thr Leu Thr Asn Pro Ser Leu Gly Lys Ile Val Gly Gly Ile
290295300
Leu Tyr Pro Asn Ala Thr Gly Ser Thr Thr Val Lys Ile Ser Asp Lys
305310315320
Ser Gly Lys Ile Ile Lys Glu Val Pro Leu Ser Val Thr Ala Ser Thr
325330335
Glu Asp Lys Phe Thr Lys Leu Leu Asp Lys Trp Asn Asp Val Thr Ile
340345350
Gly Asn His Val Tyr Asp Thr Asn Asp Ser Asn Met Gln Lys Ile Asn
355360365
Gln Lys Leu Asp Glu Thr Asn Ala Lys Asn Ile Lys Thr Ile Lys Leu
370375380
Asp Ser Asn His Thr Phe Leu Trp Lys Asp Leu Asp Asn Leu Asn Asn
385390395400
Ser Ala Gln Leu Thr Ala Thr Tyr Arg Arg Leu Glu Asp Leu Ala Lys
405410415
Gln Ile Thr Asn Pro His Ser Thr Ile Tyr Lys Asn Glu Lys Ala Ile
420425430
Arg Thr Val Lys Glu Ser Leu Ala Trp Leu His Gln Asn Phe Tyr Asn
435440445
Val Asn Lys Asp Ile Glu Gly Ser Ala Asn Trp Trp Asp Phe Glu Ile
450455460
Gly Val Pro Arg Ser Ile Thr Ala Thr Leu Ala Leu Met Asn Asn Tyr
465470475480
Phe Thr Asp Ala Glu Ile Lys Thr Tyr Thr Asp Pro Ile Glu His Phe
485490495
Val Pro Asp Ala Gly Tyr Phe Arg Lys Thr Leu Asp Asn Pro Phe Lys
500505510
Ala Leu Gly Gly Asn Leu Val Asp Met Gly Arg Val Lys Ile Ile Glu
515520525
Gly Leu Leu Arg Lys Asp Asn Thr Ile Ile Glu Lys Thr Ser His Ser
530535540
Leu Lys Asn Leu Phe Thr Thr Ala Thr Lys Ala Glu Gly Phe Tyr Ala
545550555560
Asp Gly Ser Tyr Ile Asp His Thr Asn Val Ala Tyr Thr Gly Ala Tyr
565570575
Gly Asn Val Leu Ile Asp Gly Leu Thr Gln Leu Leu Pro Ile Ile Gln
580585590
Glu Thr Asp Tyr Lys Ile Ser Asn Gln Glu Leu Asp Met Val Tyr Lys
595600605
Trp Ile Asn Gln Ser Phe Leu Pro Leu Ile Val Lys Gly Glu Leu Met
610615620
Asp Met Ser Arg Gly Arg Ser Ile Ser Arg Glu Ala Ala Ser Ser His
625630635640
Ala Ala Ala Val Glu Val Leu Arg Gly Phe Leu Arg Leu Ala Asn Met
645650655
Ser Asn Glu Glu Arg Asn Leu Asp Leu Ile Ser Thr Ile Lys Thr Ile
660665670
Ile Thr Ser Asn Lys Phe Tyr Asn Val Phe Asn Asn Leu Lys Ser Tyr
675680685
Ser Asp Ile Ala Asn Met Asn Lys Met Leu Asn Asp Ser Thr Val Ala
690695700
Thr Lys Pro Leu Lys Ser Asn Leu Ser Thr Phe Asn Ser Met Asp Arg
705710715720
Leu Ala Tyr Tyr Asn Ala Glu Lys Asp Phe Gly Phe Ala Leu Ser Leu
725730735
His Ser Lys Arg Thr Leu Asn Tyr Glu Gly Met Asn Asp Glu Asn Thr
740745750
Arg Gly Trp Tyr Thr Gly Asp Gly Met Phe Tyr Leu Tyr Asn Ser Asp
755760765
Gln Ser His Tyr Ser Asn His Phe Trp Pro Thr Val Asn Pro Tyr Lys
770775780
Met Ala Gly Thr Thr Glu Lys Asp Ala Lys Arg Glu Asp Thr Thr Lys
785790795800
Glu Phe Met Ser Lys His Ser Lys Asp Ala Lys Glu Lys Thr Gly Gln
805810815
Val Thr Gly Thr Ser Asp Phe Val Gly Ser Val Lys Leu Asn Asp His
820825830
Phe Ala Leu Ala Ala Met Asp Phe Thr Asn Trp Asp Arg Thr Leu Thr
835840845
Ala Gln Lys Gly Trp Val Ile Leu Asn Asp Lys Ile Val Phe Leu Gly
850855860
Ser Asn Ile Lys Asn Thr Asn Gly Ile Gly Asn Val Ser Thr Thr Ile
865870875880
Asp Gln Arg Lys Asp Asp Ser Lys Thr Pro Tyr Thr Thr Tyr Val Asn
885890895
Gly Lys Thr Ile Asp Leu Lys Gln Ala Ser Ser Gln Gln Phe Thr Asp
900905910
Thr Lys Ser Val Phe Leu Glu Ser Lys Glu Pro Gly Arg Asn Ile Gly
915920925
Tyr Ile Phe Phe Lys Asn Ser Thr Ile Asp Ile Glu Arg Lys Glu Gln
930935940
Thr Gly Thr Trp Asn Ser Ile Asn Arg Thr Ser Lys Asn Thr Ser Ile
945950955960
Val Ser Asn Pro Phe Ile Thr Ile Ser Gln Lys His Asp Asn Lys Gly
965970975
Asp Ser Tyr Gly Tyr Met Met Val Pro Asn Ile Asp Arg Thr Ser Phe
980985990
Asp Lys Leu Ala Asn Ser Lys Glu Val Glu Leu Leu Glu Asn Ser Ser
99510001005
Lys Gln Gln Val Ile Tyr Asp Lys Asn Ser Gln Thr Trp Ala Val Ile
101010151020
Lys His Asp Asn Gln Glu Ser Leu Ile Asn Asn Gln Phe Lys Met Asn
1025103010351040
Lys Ala Gly Leu Tyr Leu Val Gln Lys Val Gly Asn Asp Tyr Gln Asn
104510501055
Val Tyr Tyr Gln Pro Gln Thr Met Thr Lys Thr Asp Gln Leu Ala Ile
106010651070
<210> 72
<211> 1081
<212> PRT
<213> Streptococcus agalactiae
<220>
<223> Streptococcus agalactiae A909 hyaluronate lyase
<400> 72
Met Glu Ile Lys Lys Lys His Arg Ile Met Leu Tyr Ser Ala Leu Ile
151015
Leu Gly Thr Ile Leu Val Asn Asn Ser Tyr Gln Ala Lys Ala Glu Glu
202530
Phe Thr Lys Thr Thr Ser Thr Ser Gln Ile Arg Asp Thr Gln Thr Asn
354045
Asn Val Glu Val Pro Gln Thr Glu Ser Thr Thr Val Lys Gly Thr Ser
505560
Thr Thr Thr Thr Gln Gln Asp Leu Ser Asn Ser Thr Ala Ser Thr Ala
65707580
Thr Ala Thr Ala Thr His Ser Thr Met Lys Gln Val Val Asp Asn Gln
859095
Thr Gln Asn Lys Glu Leu Val Lys Asn Gly Asp Phe Lys Glu Lys Ile
100105110
Ile Asp Lys Lys Ile Asp Lys Lys Ser Gln Trp Thr Asn Leu Tyr Gly
115120125
Ala Lys Asp Trp Asn Thr Tyr Ile Asp Gln Thr Lys Ser Val Asn Lys
130135 140
Ser Pro Ile Ile Gln Arg Thr Glu Gln Gly Gln Val Ser Leu Ser Ser
145150155160
Asp Lys Gly Phe Arg Gly Ala Val Thr Gln Lys Val Asn Ile Asp Pro
165170175
Thr Lys Lys Tyr Glu Val Lys Phe Asp Ile Glu Thr Ser Asn Lys Val
180185190
Gly Gln Ala Phe Leu Arg Ile Met Lys Lys Lys Asp Lys Asn Thr Arg
195200205
Leu Trp Leu Ser Glu Met Thr Ser Gly Thr Thr Asn Lys His Thr Leu
210215220
Thr Lys Ile Tyr Asn Pro Lys Leu Asn Val Ser Glu Val Thr Leu Glu
225230235240
Leu Tyr Tyr Glu Lys Gly Thr Gly Ser Val Thr Phe Asp Asn Ile Ser
245250255
Met Lys Ala Lys Gly Pro Lys Asp Ser Glu His Pro Gln Pro Val Thr
260265270
Thr Gln Ile Glu Glu Ser Val Asn Thr Ala Leu Asn Lys Asn Tyr Val
275280285
Phe Asn Lys Ala Asp Tyr Gln Tyr Thr Leu Thr Asn Pro Ser Leu Gly
290295300
Lys Ile Val Gly Gly Ile Leu Tyr Pro Ser Ala Thr Gly Ser Thr Thr
305310315320
Val Lys Ile Ser Asp Lys Ser Gly Lys Ile Ile Lys Glu Val Pro Leu
325330335
Ser Val Thr Ala Ser Thr Glu Asp Asn Phe Thr Lys Leu Leu Asp Lys
340345350
Trp Asn Asp Val Thr Ile Gly Asn His Val Tyr Asp Thr Asn Asp Ser
355360365
Asn Met Gln Lys Leu Asn Gln Lys Leu Asp Glu Thr Asn Ala Lys Asn
370375380
Ile Lys Asp Ile Lys Leu Asp Ser Asn Arg Thr Phe Leu Trp Glu Asp
385390395400
Leu Lys Gly Leu Asn Asn Ser Ala Gln Leu Thr Ala Thr Tyr Arg Arg
405410415
Leu Glu Asp Leu Ala Lys Gln Ile Thr Asn Pro His Ser Thr Ile Tyr
420425430
Lys Asn Glu Lys Ala Ile Arg Thr Val Lys Glu Ser Leu Ala Trp Leu
435440445
His Gln Asn Phe Tyr Asn Val Asn Lys Asp Ile Glu Gly Ser Ala Asn
450 455460
Trp Trp Asp Phe Glu Ile Gly Val Pro Arg Ser Ile Thr Ala Thr Leu
465470475480
Ala Leu Met Asn Asn Tyr Phe Thr Asp Ala Glu Ile Lys Thr Tyr Thr
485490495
Asp Pro Ile Glu His Phe Val Pro Asp Ala Gly Tyr Phe Arg Lys Thr
500505510
Leu Val Asn Pro Phe Lys Ala Leu Gly Gly Asn Leu Val Asp Met Gly
515520525
Arg Val Lys Ile Ile Glu Gly Leu Leu Arg Lys Asp Asn Thr Ile Ile
530535540
Lys Lys Thr Ser His Ser Leu Lys Asn Leu Phe Thr Thr Ala Thr Lys
545550555560
Ala Glu Gly Phe Tyr Ala Asp Gly Ser Tyr Ile Asp His Thr Asn Val
565570575
Ala Tyr Thr Gly Ala Tyr Gly Asn Val Leu Ile Asp Gly Leu Thr Gln
580585590
Leu Leu Pro Ile Ile Gln Glu Thr Asp Tyr Lys Ile Ser Asn Gln Glu
595600605
Leu Asp Met Val Tyr Lys Trp Ile Asn Gln Ser Phe Leu Pro Leu Ile
610615620
Val Lys Gly Glu Leu Met Asp Met Ser Arg Gly Arg Ser Ile Ser Arg
625630635640
Glu Ala Ala Ser Ser His Ala Ala Ala Val Glu Val Leu Arg Gly Phe
645650655
Leu Arg Leu Ala Asn Met Ser Asn Glu Glu Arg Asn Leu Asp Leu Lys
660665670
Ser Thr Ile Lys Thr Ile Ile Thr Ser Asn Lys Phe Tyr Asn Val Phe
675680685
Asn Asn Leu Lys Ser Tyr Ser Asp Ile Ala Asn Met Asn Lys Leu Leu
690695700
Asn Asp Ser Thr Val Ala Thr Lys Pro Leu Lys Ser Asn Leu Ser Thr
705710715720
Phe Asn Ser Met Asp Arg Leu Ala Tyr Tyr Asn Ala Glu Lys Asp Phe
725730735
Gly Phe Ala Leu Ser Leu His Ser Lys Arg Thr Leu Asn Tyr Glu Gly
740745750
Met Asn Asp Glu Asn Thr Arg Gly Trp Tyr Thr Gly Asp Gly Met Phe
755760765
Tyr Leu Tyr Asn Ser Asp Gln Ser His Tyr Ser Asn His Phe Trp Pro
770775780
Thr Val Asn Pro Tyr Lys Met Ala Gly Thr Thr Glu Lys Asp Thr Gly
785790795800
Arg Glu Asp Thr Ile Lys Lys Leu Met Asn Arg Tyr Asp Lys Thr Asn
805810815
Lys Asn Ser Lys Val Met Thr Gly Gln Val Thr Gly Thr Ser Asp Phe
820825830
Val Gly Ser Val Lys Leu Asn Asp His Phe Ala Leu Ala Ala Met Asp
835840845
Phe Thr Asn Trp Asp Arg Thr Leu Thr Ala Gln Lys Gly Trp Val Ile
850855860
Leu Asn Asp Lys Ile Val Phe Leu Gly Ser Asn Ile Lys Asn Thr Asn
865870875880
Gly Val Gly Asn Val Ser Thr Thr Ile Asp Gln Arg Lys Asp Asp Ser
885890895
Lys Thr Pro Tyr Thr Thr Tyr Val Asn Gly Lys Thr Val Asp Leu Lys
900905910
Gln Ala Ser Ser Gln Gln Phe Thr Asp Thr Lys Ser Val Phe Leu Glu
915920925
Ser Lys Glu Pro Gly Arg Asn Ile Gly Tyr Ile Phe Phe Lys Asn Ser
930935940
Thr Ile Asp Ile Glu Arg Lys Glu Gln Thr Gly Thr Trp Asn Ser Ile
945950955960
Asn Arg Thr Ser Lys Asn Thr Ser Ile Val Ser Asn Pro Phe Ile Thr
965970975
Ile Ser Gln Lys His Asp Asn Lys Gly Asp Ser Tyr Gly Tyr Met Met
980985990
Val Pro Asn Ile Asp Arg Thr Ser Phe Asp Lys Leu Ala Asn Ser Lys
99510001005
Glu Val Glu Leu Leu Glu Asn Ser Ser Lys Gln Gln Val Ile Tyr Asp
101010151020
Lys Asn Ser Gln Thr Trp Ala Val Ile Lys His Asp Asn Gln Glu Ser
1025103010351040
Leu Ile Asn Asn Gln Phe Lys Met Asn Lys Ala Gly Leu Tyr Leu Val
104510501055
Gln Lys Val Gly Asn Asp Tyr Gln Asn Val Tyr Tyr Gln Pro Gln Thr
106010651070
Met Thr Lys Thr Asp Gln Leu Ala Ile
10751080
<210> 73
<211> 984
<212> PRT
<213> Streptococcus agalactiae
<220>
<223> Streptococcus agalactiae NEM316 hyaluronate lyase
<400> 73
Met Lys Gln Val Val Asp Asn Gln Thr Gln Asn Lys Glu Leu Val Lys
151015
Asn Gly Asp Phe Asn Gln Thr Asn Pro Val Ser Gly Ser Trp Ser His
202530
Thr Ser Ala Arg Glu Trp Ser Ala Trp Ile Asp Lys Glu Asn Thr Ala
354045
Asp Lys Ser Pro Ile Ile Gln Arg Thr Glu Gln Gly Gln Val Ser Leu
505560
Ser Ser Asp Lys Gly Phe Arg Gly Ala Val Thr Gln Lys Val Asn Ile
65707580
Asp Pro Thr Lys Lys Tyr Glu Val Lys Phe Asp Ile Glu Thr Ser Asn
859095
Lys Ala Gly Gln Ala Phe Leu Arg Ile Met Glu Lys Lys Asp Asn Asn
100105110
Thr Arg Leu Trp Leu Ser Glu Met Thr Ser Gly Thr Thr Asn Lys His
115120125
Thr Leu Thr Lys Ile Tyr Asn Pro Lys Leu Asn Val Ser Glu Val Thr
130135140
Leu Glu Leu Tyr Tyr Glu Lys Gly Thr Gly Ser Ala Thr Phe Asp Asn
145150155160
Ile Ser Met Lys Ala Lys Gly Pro Lys Asp Ser Glu His Pro Gln Pro
165170175
Val Thr Thr Gln Ile Glu Glu Ser Val Asn Thr Ala Leu Asn Lys Asn
180185190
Tyr Val Phe Asn Lys Ala Asp Tyr Gln Tyr Thr Leu Thr Asn Pro Ser
195200205
Leu Gly Lys Ile Val Gly Gly Ile Leu Tyr Pro Asn Ala Thr Gly Ser
210215220
Thr Thr Val Lys Ile Ser Asp Lys Ser Gly Lys Ile Ile Lys Glu Val
225230235240
Pro Leu Ser Val Thr Ala Ser Thr Glu Asp Lys Phe Thr Lys Leu Leu
245250255
Asp Lys Trp Asn Asp Val Thr Ile Gly Asn His Val Tyr Asp Thr Asn
260265270
Asp Ser Asn Met Gln Lys Ile Asn Gln Lys Leu Asp Glu Thr Asn Ala
275280285
Lys Asn Ile Lys Thr Ile Lys Leu Asp Ser Asn His Thr Phe Leu Trp
290295300
Lys Asp Leu Asp Asn Leu Asn Asn Ser Ala Gln Leu Thr Ala Thr Tyr
305310315320
Arg Arg Leu Glu Asp Leu Ala Lys Gln Ile Thr Asn Pro His Ser Thr
325330335
Ile Tyr Lys Asn Glu Lys Ala Ile Arg Thr Val Lys Glu Ser Leu Ala
340345350
Trp Leu His Gln Asn Phe Tyr Asn Val Asn Lys Asp Ile Glu Gly Ser
355360365
Ala Asn Trp Trp Asp Phe Glu Ile Gly Val Pro Arg Ser Ile Thr Ala
370375380
Thr Leu Ala Leu Met Asn Asn Tyr Phe Thr Asp Ala Glu Ile Lys Thr
385390395400
Tyr Thr Asp Pro Ile Glu His Phe Val Pro Asp Ala Gly Tyr Phe Arg
405410415
Lys Thr Leu Asp Asn Pro Phe Lys Ala Leu Gly Gly Asn Leu Val Asp
420425430
Met Gly Arg Val Lys Ile Ile Glu Gly Leu Leu Arg Lys Asp Asn Thr
435440445
Ile Ile Glu Lys Thr Ser His Ser Leu Lys Asn Leu Phe Thr Thr Ala
450455460
Thr Lys Ala Glu Gly Phe Tyr Ala Asp Gly Ser Tyr Ile Asp His Thr
465470475480
Asn Val Ala Tyr Thr Gly Ala Tyr Gly Asn Val Leu Ile Asp Gly Leu
485490495
Thr Gln Leu Leu Pro Ile Ile Gln Glu Thr Asp Tyr Lys Ile Ser Asn
500505510
Gln Glu Leu Asp Met Val Tyr Lys Trp Ile Asn Gln Ser Phe Leu Pro
515520525
Leu Ile Val Lys Gly Glu Leu Met Asp Met Ser Arg Gly Arg Ser Ile
530535540
Ser Arg Glu Ala Ala Ser Ser His Ala Ala Ala Val Glu Val Leu Arg
545550555560
Gly Phe Leu Arg Leu Ala Asn Met Ser Asn Glu Glu Arg Asn Leu Asp
565570575
Leu Lys Ser Thr Ile Lys Thr Ile Ile Thr Ser Asn Lys Phe Tyr Asn
580585590
Val Phe Asn Asn Leu Lys Ser Tyr Ser Asp Ile Ala Asn Met Asn Lys
595600605
Met Leu Asn Asp Ser Thr Val Ala Thr Lys Pro Leu Lys Ser Asn Leu
610615620
Ser Thr Phe Asn Ser Met Asp Arg Leu Ala Tyr Tyr Asn Ala Glu Lys
625630635640
Asp Phe Gly Phe Ala Leu Ser Leu His Ser Lys Arg Thr Leu Asn Tyr
645650655
Glu Gly Met Asn Asp Glu Asn Thr Arg Asp Trp Tyr Thr Gly Asp Gly
660665670
Met Phe Tyr Leu Tyr Asn Ser Asp Gln Ser His Tyr Ser Asn His Phe
675680685
Trp Pro Thr Val Asn Pro Tyr Lys Met Ala Gly Thr Thr Glu Lys Asp
690695700
Ala Lys Arg Glu Asp Thr Thr Lys Glu Phe Met Ser Lys His Ser Lys
705710715720
Asp Ala Lys Glu Lys Thr Gly Gln Val Thr Gly Thr Ser Asp Phe Val
725730735
Gly Ser Val Lys Leu Asn Asp His Phe Ala Leu Ala Ala Met Asp Phe
740745750
Thr Asn Trp Asp Arg Thr Leu Thr Ala Gln Lys Gly Trp Val Ile Leu
755760765
Asn Asp Lys Ile Val Phe Leu Gly Ser Asn Ile Lys Asn Thr Asn Gly
770775780
Ile Gly Asn Val Ser Thr Thr Ile Asp Gln Arg Lys Asp Asp Ser Lys
785790795800
Thr Pro Tyr Thr Thr Tyr Val Asn Gly Lys Thr Ile Asp Leu Lys Gln
805810815
Ala Ser Ser Gln Gln Phe Thr Asp Thr Lys Ser Val Phe Leu Glu Ser
820825830
Lys Glu Pro Gly Arg Asn Ile Gly Tyr Ile Phe Phe Lys Asn Ser Thr
835840845
Ile Asp Ile Glu Arg Lys Glu Gln Thr Gly Thr Trp Asn Ser Ile Asn
850855860
Arg Thr Ser Lys Asn Thr Ser Ile Val Ser Asn Pro Phe Ile Thr Ile
865870875880
Ser Gln Lys His Asp Asn Lys Gly Asp Ser Tyr Gly Tyr Met Met Val
885890895
Pro Asn Ile Asp Arg Thr Ser Phe Asp Lys Leu Ala Asn Ser Lys Glu
900905910
Val Glu Leu Leu Glu Asn Ser Ser Lys Gln Gln Val Ile Tyr Asp Lys
915920925
Asn Ser Gln Thr Trp Ala Val Ile Lys His Asp Asn Gln Glu Ser Leu
930935940
Ile Asn Asn Gln Phe Lys Met Asn Lys Ala Gly Leu Tyr Leu Val Gln
945950955960
Lys Val Gly Asn Asp Tyr Gln Asn Val Tyr Tyr Gln Pro Gln Thr Met
965970975
Thr Lys Thr Asp Gln Leu Ala Ile
980
<210> 74
<211> 807
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus subsp. aureus COL
hyaluronate lyase
<400> 74
Met Thr Tyr Arg Ile Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Val Ile Thr Leu Asn Gly Gly Glu Phe Arg Ser Val
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp
354045
Tyr Glu Lys Leu Arg Asn Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Lys Tyr Asp Glu Asn Asn Pro Asp Met Lys Lys Lys Phe Asp Ala Thr
65707580
Glu Lys Glu Ala Thr Asn Leu Leu Lys Glu Met Lys Thr Glu Ser Gly
859095
Arg Lys Tyr Leu Trp Ser Gly Ala Glu Thr Leu Glu Thr Asn Ser Ser
100105110
His Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ala Met
115120125
Arg Asn Pro Lys Thr Thr Leu Asn Thr Asp Glu Asn Lys Lys Lys Val
130135140
Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro
145150155160
Asp Lys Lys Val Lys Glu Leu Ser Glu Asn Phe Thr Lys Thr Thr Gly
165170175
Lys Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Lys
180185190
Ser Leu Thr Asn Thr Leu Ile Leu Leu Asn Asp Gln Phe Ser Asn Glu
195200205
Glu Lys Lys Lys Phe Thr Ala Pro Ile Lys Thr Phe Ala Pro Asp Ser
210215220
Asp Lys Ile Leu Ser Ser Val Gly Lys Ala Glu Leu Ala Lys Gly Gly
225230235240
Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Cys Ile Ile Glu
245250255
Glu Asp Lys Asp Met Met Lys Lys Ser Ile Asp Ser Phe Asn Lys Val
260265270
Phe Thr Tyr Val Gln Asp Ser Ala Thr Gly Lys Glu Arg Asn Gly Phe
275280285
Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr Gly
290295300
Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro Met
305310315320
Ile Lys Glu Thr Pro Phe Asn Asp Lys Thr Gln Asn Asp Thr Thr Leu
325330335
Lys Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu
340345350
Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr
355360365
Ser His Ser Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Ser
370375380
Asp Ala Met Asp Asp Ser Thr Lys Ala Lys Tyr Lys Lys Ile Val Lys
385390395400
Ser Ser Val Glu Ser Asp Ser Ser Tyr Lys Gln Asn Asp Tyr Leu Asn
405410415
Ser Tyr Ser Asp Ile Asp Lys Met Lys Ser Leu Met Thr Asp Asn Ser
420425430
Ile Ser Lys Asn Gly Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met
435440445
Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly Leu
450455460
Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Ser Ile Asn Gly Glu
465470475480
Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn
485490495
Ser Asp Val Lys His Tyr His Asp Asn Phe Trp Val Thr Ala Asp Met
500505510
Lys Arg Leu Ser Gly Thr Thr Thr Leu Asp Asn Glu Ile Leu Lys Asp
515520525
Thr Asp Asp Lys Lys Ser Ser Lys Thr Phe Val Gly Gly Thr Lys Val
530535540
Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys
545550555560
Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val
565570575
Phe Leu Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val
580585590
Thr Thr Ile Glu Asn Arg Lys Ala Asn Gly Tyr Thr Leu Tyr Thr Asp
595600605
Asp Lys Gln Thr Thr Asn Ser Asp Asn Gln Glu Asn Asn Ser Val Phe
610615620
Leu Glu Ser Thr Asp Thr Lys Lys Asn Ile Gly Tyr His Phe Leu Asn
625630635640
Lys Pro Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp Lys
645650655
Glu Ile Asn Lys Ser Gln Lys Asp Thr Gln Lys Thr Asp Glu Tyr Tyr
660665670
Glu Val Thr Gln Lys His Ser Asn Ser Asp Asn Lys Tyr Gly Tyr Val
675680685
Leu Tyr Pro Gly Leu Ser Lys Asp Val Phe Lys Thr Lys Lys Asp Glu
690695700
Val Thr Val Val Lys Gln Glu Asp Asp Phe His Val Val Lys Asp Asn
705710715720
Glu Ser Val Trp Ala Gly Val Asn Tyr Ser Asn Ser Thr Gln Thr Phe
725730735
Asp Ile Asn Asn Thr Lys Val Glu Val Lys Ala Lys Gly Met Phe Ile
740745750
Leu Lys Lys Lys Asp Asp Asn Thr Tyr Glu Cys Ser Phe Tyr Asn Pro
755760765
Glu Ser Thr Asn Ser Ala Ser Asp Ile Glu Ser Lys Ile Ser Met Thr
770775780
Gly Tyr Ser Ile Thr Asn Lys Asn Thr Ser Thr Ser Asn Glu Ser Gly
785790795800
Val His Phe Glu Leu Thr Lys
805
<210> 75
<211> 420
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus strain MRSA252 hyaluronate
lyase 2
<400> 75
Met Thr Tyr Arg Met Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Val Ile Thr Leu Asn Gly Gly Glu Phe Arg Ser Ile
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Thr Asp
354045
Tyr Glu Lys Leu Arg Asn Ile Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Lys Tyr Asp Glu Asn Asn Pro Asp Met Lys Lys Lys Phe Glu Ala Thr
65707580
Glu Asn Glu Ala Glu Lys Leu Leu Lys Glu Met Lys Thr Glu Ser Asp
859095
Arg Lys Tyr Leu Trp Glu Ser Ser Lys Asp Leu Asp Thr Lys Ser Ala
100105110
Asp Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ser Glu Ala Met
115120125
Lys His Lys Asn Thr Lys Leu Lys Thr Asp Glu Asn Lys Thr Lys Val
130135140
Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro
145150155160
Asp Lys Lys Val Ala Asp Leu Thr Ser Asn Phe Lys Asn Lys Thr Ser
165170175
Arg Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Arg
180185190
Ala Leu Thr Asn Thr Leu Ile Leu Leu Gln Glu Asp Phe Thr Asp Glu
195200205
Glu Lys Lys Lys Tyr Thr Ala Pro Ile Lys Thr Phe Ala Pro Asp Ser
210215220
Asp Lys Ile Leu Ser Ser Val Gly Lys Ser Glu Pro Ala Lys Gly Gly
225230235240
Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Ser Ile Ile Glu
245250255
Glu Asp Lys Asp Met Met Lys Lys Ser Ile Asp Ser Phe Asn Thr Val
260265270
Phe Thr Tyr Ala Gln Asn Ser Ala Thr Gly Lys Glu Arg Asn Gly Phe
275280285
Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr Gly
290295300
Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro Met
305310315320
Ile Lys Glu Thr Pro Phe Asn Asp Ser Asn Gln Asn Asp Thr Thr Leu
325330335
Lys Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu
340345350
Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr
355360365
Ser His Ser Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Ser
370375380
Asp Thr Met Asp Lys Ser Thr Lys Ala Lys Tyr Lys Lys Ile Val Lys
385390395400
Thr Ser Val Glu Ser Asp Ser Ser Tyr Lys Gln Thr Asp Tyr Leu Ser
405410415
Ser Tyr Ser Asp
420
<210> 76
<211> 806
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus strain MRSA252 hyaluronate
lyase 1
<400> 76
Met Thr Asn Lys Met Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Thr Gly Val Ile Ala Leu Asn Asn Gly Glu Phe Arg Asn Val
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp
354045
Tyr Glu Lys Leu Lys Lys Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Gln Tyr Asp Glu Asn Asn Gln Asp Met Lys Lys Lys Phe Asp Ala Lys
65707580
Glu Lys Glu Ala Lys Lys Leu Leu Asp Asp Met Lys Thr Asp Thr Asn
859095
Arg Thr Tyr Leu Trp Ser Gly Ala Glu Asn Leu Glu Thr Asn Ser Ser
100105110
His Met Thr Lys Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ser Met
115120125
Gln His Lys Asn Thr Val Leu Lys Thr Val Glu Asn Lys Leu Lys Ile
130135140
Lys Glu Ala Leu Asp Trp Met His Lys Asn Val Tyr Gly Lys Asn Pro
145150155160
Ser Gln Lys Val Glu Asp Leu Thr Lys Asn Arg Lys Gly Gln Thr Thr
165170175
Pro Lys Asn Asn Ser Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro
180185190
Arg Ala Leu Thr Asn Thr Leu Leu Leu Met Asp Asp Met Leu Thr Lys
195200205
Asp Glu Met Lys Asn Tyr Ser Lys Pro Ile Ser Thr Tyr Ala Pro Ser
210215220
Ser Asp Lys Ile Leu Ser Ser Val Gly Glu Ser Glu Asp Ala Lys Gly
225230235240
Gly Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Ser Val Ile
245250255
Glu Glu Asp Val Asp Met Leu Lys Lys Ser Ile Asp Ser Phe Asn Lys
260265270
Val Phe Thr Tyr Val Gln Asp Ser Ala Thr Gly Lys Gly Arg Asn Gly
275280285
Phe Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr
290295300
Gly Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro
305310315320
Met Ile Lys Glu Ser Pro Phe Lys Thr Thr Gln Asp Asn Ala Thr Leu
325330335
Ser Asn Trp Ile Asp Glu Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu
340345350
Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr
355360365
Ser His Thr Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Asn
370375380
Asp Thr Met Asp Asp Ser Thr Lys Thr Arg Tyr Lys Gln Ile Val Lys
385390395400
Thr Ser Val Asn Ser Asp Ser Ser Tyr Asn Gln Asn Asn Tyr Leu Asn
405410415
Ser Tyr Ser Asp Ile Ala Lys Met Lys Lys Leu Met Asn Asp Ser Thr
420425430
Ile Ser Lys Asn Asp Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met
435440445
Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly Leu
450455460
Ser Met Thr Ser Lys Asn Ile Ala Arg Tyr Glu Asn Ile Asn Gly Glu
465470475480
Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn
485490495
Ser Asp Val Lys His Tyr Arg Asp Asn Phe Trp Ala Thr Ala Asp Met
500505510
Thr Cys Leu Pro Gly Thr Thr Thr Leu Asn Asp Met Pro Ser Thr Asn
515520525
Thr Lys Asn Asp Lys Ser Phe Val Gly Gly Thr Lys Leu Asn Asn Lys
530535540
Tyr Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys Thr Leu Thr
545550555560
Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val Phe Leu Gly
565570575
Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val Thr Ser Val
580585590
Glu Asn Arg Lys Ala Asn Gly Tyr Lys Leu Phe Lys Asp Asp Ile Glu
595600605
Ile Thr Thr Ser Asp Val Asn Ala Gln Glu Thr His Ser Val Phe Leu
610615620
Glu Ser Asn Asp Thr Lys Lys Asn Ile Gly Tyr His Phe Leu Asp Lys
625630635640
Pro Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp Ser Glu
645650655
Ile Asn Lys Ser Gln Lys Lys Asp Asp Lys Lys Asp Glu Tyr Tyr Glu
660665670
Val Thr Gln Thr His Asn Thr Ser Asp Ser Lys Tyr Ala Tyr Val Leu
675680685
Tyr Pro Gly Leu Ser Lys Ser Asp Phe Lys Ser Lys Asn Asn Asn Val
690695700
Ser Ile Val Lys Gln Asp Glu Asp Phe His Val Ile Lys Asp Asn Asp
705710715720
Gly Val Phe Ala Gly Val Asn Tyr Ser Asp Asn Thr Lys Ser Phe Asp
725730735
Ile Asn Gly Ile Thr Val Glu Leu Lys Glu Lys Gly Met Phe Val Ile
740745750
Lys Lys Lys Asp Asp Lys Ala Tyr Lys Cys Ser Phe Tyr Asn Pro Glu
755760765
Thr Thr Asn Thr Ala Ser Asn Ile Glu Ser Lys Ile Phe Ile Lys Gly
770775780
Tyr Thr Ile Thr Asn Lys Ser Val Ile Asn Ser Asn Asp Ala Gly Val
785790795800
Asn Phe Glu Leu Thr Lys
805
<210> 77
<211> 815
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus subsp. aureus MW2
hyaluronate lyase precursor
<400> 77
Met Thr Tyr Arg Ile Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Val Ile Thr Leu Asn Gly Gly Glu Phe Arg Ser Ile
202530
Asp Lys Tyr Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp
354045
Tyr Glu Lys Leu Arg Asn Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Lys Tyr Asp Glu Lys Asn Asp Ala Met Lys Lys Lys Phe Glu Ala Thr
65707580
Glu Asn Glu Ala Lys Lys Leu Leu Ser Glu Met Lys Thr Glu Ser Asp
859095
Arg Lys Tyr Leu Trp Glu Asn Ser Lys Asp Leu Asp Thr Lys Ser Ala
100105110
Asp Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ala Met
115120125
Lys His Lys Asp Thr Lys Leu Lys Ile Asp Glu Asn Lys Lys Lys Val
130135140
Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro
145150155160
Asp Lys Lys Val Ala Asp Leu Thr Ser Asn Phe Lys Asn Lys Thr Ser
165170175
Arg Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Arg
180185190
Ala Leu Thr Asn Thr Leu Ile Leu Leu Asn Asp Gln Phe Ser Asn Asp
195200205
Glu Lys Lys Lys Tyr Thr Ala Pro Ile Lys Thr Phe Ala Pro Glu Ser
210215220
Asp Lys Ile Leu Ser Ser Val Gly Gln Pro Glu Gln Ala Lys Gly Gly
225 230235240
Asn Leu Val Asp Ile Ala Lys Val Lys Leu Leu Glu Ser Ile Ile Glu
245250255
Glu Asp Lys Asp Ile Thr Lys Asn Ser Ile Asp Ala Phe Asn Lys Val
260265270
Phe Thr Tyr Val Gln Ser Asn Ala Thr Gly Lys Glu Arg Asn Gly Phe
275280285
Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr Gly
290295300
Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro Met
305310315320
Ile Lys Glu Thr Pro Phe Asn Asp Lys Thr Gln Asn Asp Thr Thr Leu
325330335
Lys Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu
340345350
Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr
355360365
Ser His Thr Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Ser
370375380
Asp Ala Met Asp Asp Ser Thr Lys Ala Lys Tyr Lys Gln Ile Val Lys
385390395400
Thr Ser Val Lys Ser Asp Ser Ser Tyr Gly Gln Asn Asp Thr Leu Ser
405410415
Ser Tyr Ser Asp Ile Ser Lys Met Lys Ser Leu Met Glu Asp Ser Thr
420425430
Ile Ser Thr Asn Gly Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met
435440445
Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly Leu
450455460
Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Ser Ile Asn Gly Glu
465470475480
Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn
485490495
Ser Asp Val Lys His Tyr Arg Asp Asn Phe Trp Ala Thr Ala Asp Met
500505510
Lys Arg Leu Ala Gly Thr Thr Thr Leu Glu Asn Glu Glu Pro Lys Gly
515520525
Thr Asp Val Lys Lys Ser Ser Lys Thr Phe Val Gly Gly Thr Lys Phe
530535540
Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys
545550555560
Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val
565570575
Phe Leu Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val
580585590
Thr Thr Ile Glu Asn Arg Lys Ala Asn Gly Tyr Thr Leu Tyr Thr Asp
595600605
Asp Lys Gln Thr Thr Ala Ser Asp Asn Gln Gly Thr Asn Ser Val Phe
610615620
Leu Glu Ser Thr Asn Lys Pro Lys Asn Asn Ile Gly Tyr His Phe Leu
625630635640
Asn Glu Ser Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp
645650655
Ser Asp Ile Asn Lys Ser Gln Lys Gln Asp Ser Lys Thr Asn Gln Tyr
660665670
Tyr Glu Val Thr Gln Lys His Ser Asn Thr Asp Ser Lys Tyr Ala Tyr
675680685
Val Leu Tyr Pro Gly Leu Ser Lys Asp Asp Phe Asn Thr Lys Lys Asp
690695700
Lys Val Thr Val Val Lys Gln Asp Asp Asp Phe His Val Val Lys Asp
705710715720
Asn Glu Ser Val Trp Ala Gly Val Asn Tyr Ser Asp Ser Thr Gln Thr
725730735
Phe Ile Ile Asn Asn Thr Lys Val Glu Val Lys Ala Lys Gly Met Phe
740745750
Ile Leu Lys Lys Lys Asp Asp Lys Thr Tyr Glu Cys Ser Phe Tyr Asn
755760765
Pro Glu Ser Thr Asn Thr Ala Ser Asp Ile Glu Ser Lys Ile Ser Met
770775780
Thr Gly Tyr Ser Ile Thr Asn Lys Asn Thr Ser Thr Ser Asn Glu Ser
785790795800
Gly Val Arg Phe Glu Leu Gln Gln Thr Leu Asn Lys Asp Asp Asn
805810815
<210> 78
<211> 807
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus subsp. aureus COL
hyaluronate lyase
<400> 78
Met Thr Tyr Arg Ile Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Val Ile Thr Leu Asn Gly Gly Glu Phe Arg Ser Val
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp
354045
Tyr Glu Lys Leu Arg Asn Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Lys Tyr Asp Glu Asn Asn Pro Asp Met Lys Lys Lys Phe Asp Ala Thr
65707580
Glu Lys Glu Ala Thr Asn Leu Leu Lys Glu Met Lys Thr Glu Ser Gly
859095
Arg Lys Tyr Leu Trp Ser Gly Ala Glu Thr Leu Glu Thr Asn Ser Ser
100105110
His Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ala Met
115120125
Arg Asn Pro Lys Thr Thr Leu Asn Thr Asp Glu Asn Lys Lys Lys Val
130135140
Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro
145150155160
Asp Lys Lys Val Lys Glu Leu Ser Glu Asn Phe Thr Lys Thr Thr Gly
165170175
Lys Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Lys
180185190
Ser Leu Thr Asn Thr Leu Ile Leu Leu Asn Asp Gln Phe Ser Asn Glu
195200205
Glu Lys Lys Lys Phe Thr Ala Pro Ile Lys Thr Phe Ala Pro Asp Ser
210215220
Asp Lys Ile Leu Ser Ser Val Gly Lys Ala Glu Leu Ala Lys Gly Gly
225230235240
Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Cys Ile Ile Glu
245250255
Glu Asp Lys Asp Met Met Lys Lys Ser Ile Asp Ser Phe Asn Lys Val
260265270
Phe Thr Tyr Val Gln Asp Ser Ala Thr Gly Lys Glu Arg Asn Gly Phe
275280285
Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr Gly
290295300
Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro Met
305310315320
Ile Lys Glu Thr Pro Phe Asn Asp Lys Thr Gln Asn Asp Thr Thr Leu
325330335
Lys Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu
340345350
Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr
355360365
Ser His Ser Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Ser
370375380
Asp Ala Met Asp Asp Ser Thr Lys Ala Lys Tyr Lys Lys Ile Val Lys
385390395400
Ser Ser Val Glu Ser Asp Ser Ser Tyr Lys Gln Asn Asp Tyr Leu Asn
405410415
Ser Tyr Ser Asp Ile Asp Lys Met Lys Ser Leu Met Thr Asp Asn Ser
420425430
Ile Ser Lys Asn Gly Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met
435440445
Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly Leu
450455460
Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Ser Ile Asn Gly Glu
465470475480
Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn
485490495
Ser Asp Val Lys His Tyr His Asp Asn Phe Trp Val Thr Ala Asp Met
500505510
Lys Arg Leu Ser Gly Thr Thr Thr Leu Asp Asn Glu Ile Leu Lys Asp
515520525
Thr Asp Asp Lys Lys Ser Ser Lys Thr Phe Val Gly Gly Thr Lys Val
530535540
Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys
545550555560
Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val
565570575
Phe Leu Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val
580585590
Thr Thr Ile Glu Asn Arg Lys Ala Asn Gly Tyr Thr Leu Tyr Thr Asp
595600605
Asp Lys Gln Thr Thr Asn Ser Asp Asn Gln Glu Asn Asn Ser Val Phe
610615620
Leu Glu Ser Thr Asp Thr Lys Lys Asn Ile Gly Tyr His Phe Leu Asn
625630635640
Lys Pro Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp Lys
645650655
Glu Ile Asn Lys Ser Gln Lys Asp Thr Gln Lys Thr Asp Glu Tyr Tyr
660665 670
Glu Val Thr Gln Lys His Ser Asn Ser Asp Asn Lys Tyr Gly Tyr Val
675680685
Leu Tyr Pro Gly Leu Ser Lys Asp Val Phe Lys Thr Lys Lys Asp Glu
690695700
Val Thr Val Val Lys Gln Glu Asp Asp Phe His Val Val Lys Asp Asn
705710715720
Glu Ser Val Trp Ala Gly Val Asn Tyr Ser Asn Ser Thr Gln Thr Phe
725730735
Asp Ile Asn Asn Thr Lys Val Glu Val Lys Ala Lys Gly Met Phe Ile
740745750
Leu Lys Lys Lys Asp Asp Asn Thr Tyr Glu Cys Ser Phe Tyr Asn Pro
755760765
Glu Ser Thr Asn Ser Ala Ser Asp Ile Glu Ser Lys Ile Ser Met Thr
770775780
Gly Tyr Ser Ile Thr Asn Lys Asn Thr Ser Thr Ser Asn Glu Ser Gly
785790795800
Val His Phe Glu Leu Thr Lys
805
<210> 79
<211> 809
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus RF122 hyaluronate lyase
<400> 79
Met Thr Tyr Arg Met Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Gly Ile Thr Phe Asn Asp Ser Glu Phe Arg Ser Val
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asn
354045
Tyr Glu Lys Leu Lys Asn Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Lys Tyr Asp Glu Ser Asn Pro Asp Met Lys Lys Lys Phe Glu Ala Thr
65707580
Glu Lys Glu Ala Arg Lys Leu Leu Ser Glu Met Lys Thr Glu Ser Asp
859095
Arg Lys Tyr Leu Trp Glu Asn Ser Lys Asp Leu Asp Thr Lys Ser Ala
100105110
Asp Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ala Met
115120125
Lys His Pro Lys Thr Thr Leu Lys Asn Asp Glu Asn Lys Lys Lys Val
130135140
Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro
145150155160
Gly Lys Lys Val Ala Asp Leu Lys Thr Asn Phe Ser Lys Ser Ala Pro
165170175
Gln Lys Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro
180185190
Arg Ala Leu Thr Asn Thr Leu Ile Leu Leu Lys Glu Asp Phe Thr Asp
195200205
Glu Glu Lys Lys Lys Tyr Thr Ala Pro Ile Lys Thr Phe Ala Pro Lys
210215220
Ser Asp Glu Ile Leu Ser Ser Val Gly Lys Ala Glu Pro Ala Lys Gly
225230235240
Gly Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Ser Ile Ile
245250255
Glu Glu Asp Lys Asp Met Met Lys Asn Ser Ile Asp Ser Phe Asn Lys
260265270
Val Phe Thr Tyr Val Gln Asp Ser Ala Thr Asp Lys Glu Arg Asn Gly
275280285
Phe Tyr Lys Asp Gly Ser Tyr Ile Asp His Lys Asp Val Pro Tyr Thr
290295300
Gly Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro
305310315320
Met Ile Lys Glu Thr Pro Phe Asn Asp Lys Thr Gln Asn Asn Thr Thr
325330335
Leu Thr Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly
340345350
Glu Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu
355360365
Thr Ser His Ser Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu
370375380
Ser Asp Ala Met Asp Glu Ser Thr Lys Ala Lys Tyr Lys Gln Ile Val
385390395400
Lys Asn Ser Val Lys Ser Asp Ser Ser Tyr Gly Gln Asn Asp Thr Leu
405410415
Ser Ser Tyr Ser Asp Ile Asp Lys Met Lys Ser Leu Met Thr Asp Ser
420425430
Thr Ile Ser Thr Asn Gly Leu Thr Gln Gln Leu Lys Ile Tyr Asn Ala
435440445
Met Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly
450455460
Leu Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Asn Ile Asn Gly
465470475480
Glu Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr
485490495
Asn Ser Asp Val Arg His Tyr Arg Asp Asn Phe Trp Ala Thr Ala Asp
500505510
Met Lys Arg Leu Ala Asp Thr Thr Thr Leu Glu Asn Glu Glu Pro Lys
515520525
Gly Thr Asp Val Lys Lys Ser Ser Lys Thr Phe Val Gly Gly Thr Lys
530535540
Phe Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp
545550555560
Lys Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile
565570575
Val Phe Leu Gly Thr Gly Ile Lys Thr Thr Asp Ser Ser Lys Asn Pro
580585590
Val Thr Thr Ile Glu Asn Arg Lys Ala His Gly Tyr Thr Leu Tyr Thr
595600605
Asp Asp Lys Gln Thr Thr Asn Ser Asn Asn Gln Glu Thr Asn Ser Val
610615620
Phe Leu Glu Ser Thr Asn Ser Thr Gln Asn Asn Ile Gly Tyr His Phe
625630635640
Leu Asn Lys Ser Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys
645650655
Trp Ser Asp Ile Asn Lys Ser Gln Lys Asp Thr Gln Lys Thr Asp Glu
660665670
Tyr Tyr Glu Val Thr Gln Lys His Ser Asn Thr Asp Asp Lys Tyr Ala
675680685
Tyr Val Leu Tyr Pro Gly Ile Thr Lys Asp Asn Phe Lys Ser Lys Ala
690695700
Ser Gln Val Thr Val Val Lys Gln Asp Asp Asp Phe His Val Val Lys
705710715720
Asp Asn Glu Ser Val Trp Ala Gly Val Asn Tyr Ser Asp Ser Thr Gln
725730735
Thr Phe Asp Ile Asn Gly Thr Lys Val Glu Val Lys Ala Lys Gly Met
740745750
Phe Ile Leu Lys Lys Lys Asp Asp Asn Thr Tyr Glu Cys Ser Phe Tyr
755760765
Asn Pro Glu Ser Thr Asn Ser Ala Ser Asp Ile Glu Ser Lys Ile Ser
770775780
Met Thr Gly Tyr Ser Ile Thr Asn Lys Asn Thr Ser Asn Thr Asn Glu
785790795800
Ser Gly Val Arg Phe Glu Leu Thr Lys
805
<210> 80
<211> 807
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus RF122 hyaluronate lyase
precursor
<400> 80
Met Thr Tyr Lys Met Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Val Ile Thr Leu Asn Asn Gly Glu Phe Arg Asn Val
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp
354045
Tyr Glu Lys Leu Lys Lys Thr Trp Leu Asp Val Asn Tyr Gly Asn Asp
505560
Gln Tyr Asp Glu Asn Asn Gln Asp Met Lys Lys Lys Phe Asp Ala Lys
65707580
Glu Asn Glu Ala Lys Lys Leu Leu Glu Asp Met Lys Thr Asp Thr Asn
859095
Arg Thr Tyr Leu Trp Ser Gly Ala Glu Asn Leu Glu Thr Asn Ser Ser
100105110
His Met Thr Lys Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ala Met
115120125
Arg His Lys Asn Thr Ser Leu Lys Thr Asp Glu Asn Lys Leu Lys Ile
130135140
Lys Asp Ala Ile Lys Trp Leu His His Asn Val Tyr Gly Lys Asp Pro
145150155160
Asp Lys Lys Val Ala Asp Leu Thr Thr Asn Arg Lys Glu Lys Asp Ser
165170175
Ser Lys Lys Asn Asn Ser Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr
180185190
Pro Arg Ala Leu Thr Asn Thr Leu Leu Leu Met Asp Asn Met Leu Thr
195200205
Lys Asp Glu Met Lys Asn Tyr Ser Lys Pro Ile Ser Ile Tyr Ser Pro
210215220
Ser Ser Tyr Lys Ile Leu Ser Ser Val Gly Glu Ser Glu Asp Ala Lys
225230235240
Gly Gly Asn Leu Val Asp Ile Ala Lys Val Lys Phe Leu Glu Ser Val
245250255
Ile Glu Glu Asp Val Asp Met Met Lys Lys Ser Ile Asp Ser Phe Asn
260265270
Lys Val Phe Thr Tyr Val Gln Asp Ser Ala Thr Gly Lys Ala Arg Asn
275280285
Gly Phe Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr
290295300
Thr Gly Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met
305310315320
Pro Met Ile Lys Glu Ser Pro Phe Lys His Thr Gln Asp Lys Ala Thr
325330335
Leu Ser Asn Trp Ile Asp Glu Gly Phe Met Pro Leu Ile Tyr Lys Gly
340345350
Glu Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu
355360365
Thr Ser His Thr Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu
370375380
Ser Asp Thr Met Asp Glu Ser Thr Lys Thr Lys Tyr Lys Gln Ile Val
385390395400
Lys Thr Ser Val Lys Ser Asp Ser Ser Tyr Asp Ser Asn Asp Thr Leu
405410415
Asn Ser Tyr Ser Asp Ile Asp Lys Met Lys Lys Leu Met Asn Asp Ser
420425430
Thr Ile Ser Lys Asn Asp Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp
435440445
Met Asp Arg Val Thr Tyr His Asn Lys Glu Leu Asp Phe Ala Phe Gly
450455460
Leu Ser Met Thr Ser Lys Asn Ile Ala Arg Tyr Glu Asn Ile Asn Gly
465470475480
Glu Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr
485490495
Asn Ser Asp Val Lys His Tyr Arg Asp Asn Phe Trp Ala Thr Ala Asp
500505510
Met Thr Arg Leu Pro Gly Thr Thr Thr Leu Asn Asp Met Pro Ser Thr
515520525
Asn Thr Lys Asn Asp Lys Ser Phe Val Gly Gly Thr Lys Leu Asn Asn
530535540
Lys Tyr Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys Thr Leu
545550555560
Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val Phe Ile
565570575
Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val Thr Ser
580585590
Val Glu Asn Arg Lys Ala Asn Gly Tyr Lys Leu Phe Lys Gly Asp Ile
595600605
Glu Ile Thr Thr Ser Asp Val Asn Ala Gln Glu Thr His Ser Val Phe
610615620
Leu Glu Ser Asn Asp Thr Lys Lys Asn Ile Gly Tyr His Phe Leu Asp
625630635640
Lys Pro Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp Ser
645650655
Glu Ile Asn Lys Ser Gln Lys Thr Asp Asp Lys Lys Asp Glu Tyr Tyr
660665670
Glu Val Thr Gln Thr His Asn Thr Ser Asp Ser Lys Tyr Ala Tyr Val
675680685
Leu Tyr Pro Gly Leu Ser Lys Ser Asp Phe Lys Ser Lys Asn Asn Asn
690695 700
Val Ser Ile Val Lys Gln Asp Glu Asp Phe His Val Ile Lys Asp Asn
705710715720
Asp Gly Val Phe Ala Gly Val Asn Tyr Ser Asp Ser Thr Lys Ser Phe
725730735
Asp Ile Asn Gly Thr Ile Val Glu Leu Lys Glu Lys Gly Met Phe Val
740745750
Ile Lys Lys Lys Asp Asp Asn Thr Tyr Glu Cys Ser Phe Tyr Asn Pro
755760765
Thr Ser Thr Asn Ser Thr Ser Asn Lys Glu Ser Lys Ile Ser Val Thr
770775780
Gly Tyr Thr Ile Thr Asn Gln Ser Val Ser Asn Phe Lys Glu Ser Asp
785790795800
Ile His Phe Glu Leu Thr Lys
805
<210> 81
<211> 807
<212> PRT
<213> Staphylococcus aureus
<220>
<223> Staphylococcus aureus subsp. aureus USA300_TCH1516
hyaluronate lyase
<400> 81
Met Thr Tyr Arg Ile Lys Lys Trp Gln Lys Leu Ser Thr Ile Thr Leu
151015
Leu Met Ala Gly Val Ile Thr Leu Asn Gly Gly Glu Phe Arg Ser Val
202530
Asp Lys His Gln Ile Ala Val Ala Asp Thr Asn Val Gln Thr Pro Asp
354045
Tyr Glu Lys Leu Arg Asn Thr Trp Leu Asp Val Asn Tyr Gly Tyr Asp
505560
Lys Tyr Asp Glu Asn Asn Pro Asp Met Lys Lys Lys Phe Asp Ala Thr
65707580
Glu Lys Glu Ala Thr Asn Leu Leu Lys Glu Met Lys Thr Glu Ser Gly
859095
Arg Lys Tyr Leu Trp Ser Gly Ala Glu Thr Leu Glu Thr Asn Ser Ser
100105110
His Met Thr Arg Thr Tyr Arg Asn Ile Glu Lys Ile Ala Glu Ala Met
115120125
Arg Asn Pro Lys Thr Thr Leu Asn Thr Asp Glu Asn Lys Lys Lys Val
130135140
Lys Asp Ala Leu Glu Trp Leu His Lys Asn Ala Tyr Gly Lys Glu Pro
145150155160
Asp Lys Lys Val Lys Glu Leu Ser Glu Asn Phe Thr Lys Thr Thr Gly
165170175
Lys Asn Thr Asn Leu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Lys
180185190
Ser Leu Thr Asn Thr Leu Ile Leu Leu Asn Asp Gln Phe Ser Asn Glu
195200205
Glu Lys Lys Lys Phe Thr Ala Pro Ile Lys Thr Phe Ala Pro Asp Ser
210215220
Asp Lys Ile Leu Ser Ser Val Gly Lys Ala Glu Leu Ala Lys Gly Gly
225230235240
Asn Leu Val Asp Ile Ser Lys Val Lys Leu Leu Glu Cys Ile Ile Glu
245250 255
Glu Asp Lys Asp Met Met Lys Lys Ser Ile Asp Ser Phe Asn Lys Val
260265270
Phe Thr Tyr Val Gln Asp Ser Ala Thr Gly Lys Glu Arg Asn Gly Phe
275280285
Tyr Lys Asp Gly Ser Tyr Ile Asp His Gln Asp Val Pro Tyr Thr Gly
290295300
Ala Tyr Gly Val Val Leu Leu Glu Gly Ile Ser Gln Met Met Pro Met
305310315320
Ile Lys Glu Thr Pro Phe Asn Asp Lys Thr Gln Asn Asp Thr Thr Leu
325330335
Lys Ser Trp Ile Asp Asp Gly Phe Met Pro Leu Ile Tyr Lys Gly Glu
340345350
Met Met Asp Leu Ser Arg Gly Arg Ala Ile Ser Arg Glu Asn Glu Thr
355360365
Ser His Ser Ala Ser Ala Thr Val Met Lys Ser Leu Leu Arg Leu Ser
370375380
Asp Ala Met Asp Asp Ser Thr Lys Ala Lys Tyr Lys Lys Ile Val Lys
385390395400
Ser Ser Val Glu Ser Asp Ser Ser Tyr Lys Gln Asn Asp Tyr Leu Asn
405410415
Ser Tyr Ser Asp Ile Asp Lys Met Lys Ser Leu Met Thr Asp Asn Ser
420425430
Ile Ser Lys Asn Gly Leu Thr Gln Gln Leu Lys Ile Tyr Asn Asp Met
435440445
Asp Arg Val Thr Tyr His Asn Lys Asp Leu Asp Phe Ala Phe Gly Leu
450455460
Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Ser Ile Asn Gly Glu
465470475480
Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser Tyr Leu Tyr Asn
485490495
Ser Asp Val Lys His Tyr His Asp Asn Phe Trp Val Thr Ala Asp Met
500505510
Lys Arg Leu Ser Gly Thr Thr Thr Leu Asp Asn Glu Ile Leu Lys Asp
515520525
Thr Asp Asp Lys Lys Ser Ser Lys Thr Phe Val Gly Gly Thr Lys Val
530535540
Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu Asn Gln Asp Lys
545550555560
Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn Asp Lys Ile Val
565 570575
Phe Leu Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser Lys Asn Pro Val
580585590
Thr Thr Ile Glu Asn Arg Lys Ala Asn Gly Tyr Thr Leu Tyr Thr Asp
595600605
Asp Lys Gln Thr Thr Asn Ser Asp Asn Gln Glu Asn Asn Ser Val Phe
610615620
Leu Glu Ser Thr Asp Thr Lys Lys Asn Ile Gly Tyr His Phe Leu Asn
625630635640
Lys Pro Lys Ile Thr Val Lys Lys Glu Ser His Thr Gly Lys Trp Lys
645650655
Glu Ile Asn Lys Ser Gln Lys Asp Thr Gln Lys Thr Asp Glu Tyr Tyr
660665670
Glu Val Thr Gln Lys His Ser Asn Ser Asp Asn Lys Tyr Gly Tyr Val
675680685
Leu Tyr Pro Gly Leu Ser Lys Asp Val Phe Lys Thr Lys Lys Asp Glu
690695700
Val Thr Val Val Lys Gln Glu Asp Asp Phe His Val Val Lys Asp Asn
705710715720
Glu Ser Val Trp Ala Gly Val Asn Tyr Ser Asn Ser Thr Gln Thr Phe
725730735
Asp Ile Asn Asn Thr Lys Val Glu Val Lys Ala Lys Gly Met Phe Ile
740745750
Leu Lys Lys Lys Asp Asp Asn Thr Tyr Glu Cys Ser Phe Tyr Asn Pro
755760765
Glu Ser Thr Asn Ser Ala Ser Asp Ile Glu Ser Lys Ile Ser Met Thr
770775780
Gly Tyr Ser Ile Thr Asn Lys Asn Thr Ser Thr Ser Asn Glu Ser Gly
785790795800
Val His Phe Glu Leu Thr Lys
805
<210> 82
<211> 1066
<212> PRT
<213> Streptococcus pneumoniae
<220>
<223> Streptococcus pneumoniae hyaluronidase
<400> 82
Met Gln Thr Lys Thr Lys Lys Leu Ile Val Ser Leu Ser Ser Leu Val
151015
Leu Ser Gly Phe Leu Leu Asn His Tyr Met Thr Ile Gly Ala Glu Glu
202530
Thr Thr Thr Asn Thr Ile Gln Gln Ser Gln Lys Glu Val Gln Tyr Gln
354045
Gln Arg Asp Thr Lys Asn Leu Val Glu Asn Gly Asp Phe Gly Gln Thr
505560
Glu Asp Gly Ser Ser Pro Trp Thr Gly Ser Lys Ala Gln Gly Trp Ser
65707580
Ala Trp Val Asp Gln Lys Asn Ser Ala Asp Ala Ser Thr Arg Val Ile
859095
Glu Ala Lys Asp Gly Ala Ile Thr Ile Ser Ser His Glu Lys Leu Arg
100105110
Ala Ala Leu His Arg Met Val Pro Ile Glu Ala Lys Lys Lys Tyr Lys
115120125
Leu Arg Phe Lys Ile Lys Thr Asp Asn Lys Ile Gly Ile Ala Lys Val
130135140
Arg Ile Ile Glu Glu Ser Gly Lys Asp Lys Arg Leu Trp Asn Ser Ala
145150155160
Thr Thr Ser Gly Thr Lys Asp Trp Gln Thr Ile Glu Ala Asp Tyr Ser
165170175
Pro Thr Leu Asp Val Asp Lys Ile Lys Leu Glu Leu Phe Tyr Glu Thr
180185190
Gly Thr Gly Thr Val Ser Phe Lys Asp Ile Glu Leu Val Glu Val Ala
195200205
Asp Gln Leu Ser Glu Asp Ser Gln Thr Asp Lys Gln Leu Glu Glu Lys
210215220
Ile Asp Leu Pro Ile Gly Lys Lys His Val Phe Ser Leu Ala Asp Tyr
225230235240
Thr Tyr Lys Val Glu Asn Pro Asp Val Ala Ser Val Lys Asn Gly Ile
245250255
Leu Glu Pro Leu Lys Glu Gly Thr Thr Asn Val Ile Val Ser Lys Asp
260265270
Gly Lys Glu Val Lys Lys Ile Pro Leu Lys Ile Leu Ala Ser Val Lys
275280285
Asp Ala Tyr Thr Asp Arg Leu Asp Asp Trp Asn Gly Ile Ile Ala Gly
290295300
Asn Gln Tyr Tyr Asp Ser Lys Asn Glu Gln Met Ala Lys Leu Asn Gln
305310315320
Glu Leu Glu Gly Lys Val Ala Asp Ser Leu Ser Ser Ile Ser Ser Gln
325330335
Ala Asp Arg Thr Tyr Leu Trp Glu Lys Phe Ser Asn Tyr Lys Thr Ser
340345350
Ala Asn Leu Thr Ala Thr Tyr Arg Lys Leu Glu Glu Met Ala Lys Gln
355360365
Val Thr Asn Pro Ser Ser Arg Tyr Tyr Gln Asp Glu Thr Val Val Arg
370375380
Thr Val Arg Asp Ser Met Glu Trp Met His Lys His Val Tyr Asn Ser
385390395400
Glu Lys Ser Ile Val Gly Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro
405410415
Arg Ala Ile Asn Asn Thr Leu Ser Leu Met Lys Glu Tyr Phe Ser Asp
420425430
Glu Glu Ile Lys Lys Tyr Thr Asp Val Ile Glu Lys Phe Val Pro Asp
435440445
Pro Glu His Phe Arg Lys Thr Thr Asp Asn Pro Phe Lys Ala Leu Gly
450455460
Gly Asn Leu Val Asp Met Gly Arg Val Lys Val Ile Ala Gly Leu Leu
465470475480
Arg Lys Asp Asp Gln Glu Ile Ser Ser Thr Ile Arg Ser Ile Glu Gln
485490495
Val Phe Lys Leu Val Asp Gln Gly Glu Gly Phe Tyr Gln Asp Gly Ser
500505510
Tyr Ile Asp His Thr Asn Val Ala Tyr Thr Gly Ala Tyr Gly Asn Val
515520525
Leu Ile Asp Gly Leu Ser Gln Leu Leu Pro Val Ile Gln Lys Thr Lys
530535540
Asn Pro Ile Asp Lys Asp Lys Met Gln Thr Met Tyr His Trp Ile Asp
545550555560
Lys Ser Phe Ala Pro Leu Leu Val Asn Gly Glu Leu Met Asp Met Ser
565570575
Arg Gly Arg Ser Ile Ser Arg Ala Asn Ser Glu Gly His Val Ala Ala
580585590
Val Glu Val Leu Arg Gly Ile His Arg Ile Ala Asp Met Ser Glu Gly
595600605
Glu Thr Lys Gln Cys Leu Gln Ser Leu Val Lys Thr Ile Val Gln Ser
610615620
Asp Ser Tyr Tyr Asp Val Phe Lys Asn Leu Lys Thr Tyr Lys Asp Ile
625630635640
Ser Leu Met Gln Ser Leu Leu Ser Asp Ala Gly Val Ala Ser Val Pro
645650655
Arg Pro Ser Tyr Leu Ser Ala Phe Asn Lys Met Asp Lys Thr Ala Met
660665670
Tyr Asn Ala Glu Lys Gly Phe Gly Phe Gly Leu Ser Leu Phe Ser Ser
675680685
Arg Thr Leu Asn Tyr Glu His Met Asn Lys Glu Asn Lys Arg Gly Trp
690695 700
Tyr Thr Ser Asp Gly Met Phe Tyr Leu Tyr Asn Gly Asp Leu Ser His
705710715720
Tyr Ser Asp Gly Tyr Trp Pro Thr Val Asn Pro Tyr Lys Met Pro Gly
725730735
Thr Thr Glu Thr Asp Ala Lys Arg Ala Asp Ser Asp Thr Gly Lys Val
740745750
Leu Pro Ser Ala Phe Val Gly Thr Ser Lys Leu Asp Asp Ala Asn Ala
755760765
Thr Ala Thr Met Asp Phe Thr Asn Trp Asn Gln Thr Leu Thr Ala His
770775780
Lys Ser Trp Phe Met Leu Lys Asp Lys Ile Ala Phe Leu Gly Ser Asn
785790795800
Ile Gln Asn Thr Ser Thr Asp Thr Ala Ala Thr Thr Ile Asp Gln Arg
805810815
Lys Leu Glu Ser Gly Asn Pro Tyr Lys Val Tyr Val Asn Asp Lys Glu
820825830
Ala Ser Leu Thr Glu Gln Glu Lys Asp Tyr Pro Glu Thr Gln Ser Val
835840845
Phe Leu Glu Ser Phe Asp Ser Lys Lys Asn Ile Gly Tyr Phe Phe Phe
850855860
Lys Lys Ser Ser Ile Ser Met Ser Lys Ala Leu Gln Lys Gly Ala Trp
865870875880
Lys Asp Ile Asn Glu Gly Gln Ser Asp Lys Glu Val Glu Asn Glu Phe
885890895
Leu Thr Ile Ser Gln Ala His Lys Gln Asn Arg Asp Ser Tyr Gly Tyr
900905910
Met Leu Ile Pro Asn Val Asp Arg Ala Thr Phe Asn Gln Met Ile Lys
915920925
Glu Leu Glu Ser Ser Leu Ile Glu Asn Asn Glu Thr Leu Gln Ser Val
930935940
Tyr Asp Ala Lys Gln Gly Val Trp Gly Ile Val Lys Tyr Asp Asp Ser
945950955960
Val Ser Thr Ile Ser Asn Gln Phe Gln Val Leu Lys Arg Gly Val Tyr
965970975
Thr Ile Arg Lys Glu Gly Asp Glu Tyr Lys Ile Ala Tyr Tyr Asn Pro
980985990
Glu Thr Gln Glu Ser Ala Pro Asp Gln Glu Val Phe Lys Lys Leu Glu
99510001005
Gln Ala Ala Gln Pro Gln Val Gln Asn Ser Lys Glu Lys Glu Lys Ser
101010151020
Glu Glu Glu Lys Asn His Ser Asp Gln Lys Asn Leu Pro Gln Thr Gly
1025103010351040
Glu Gly Gln Ser Ile Leu Ala Ser Leu Gly Phe Leu Leu Leu Gly Ala
104510501055
Phe Tyr Leu Phe Arg Arg Gly Lys Asn Asn
10601065
<210> 83
<211> 1078
<212> PRT
<213> Streptococcus pneumoniae
<220>
<223> Streptococcus pneumoniae strain ATCC BAA-255 / R6
hyaluronate lyase
<400> 83
Met Ile Leu Gln Tyr Val Tyr Trp Ser Val Tyr Met Gln Thr Lys Thr
151015
Lys Lys Leu Ile Val Ser Leu Ser Ser Leu Val Leu Ser Gly Phe Leu
202530
Leu Asn His Tyr Met Thr Val Gly Ala Glu Glu Thr Thr Thr Asn Thr
354045
Ile Gln Gln Ser Gln Lys Glu Val Gln Tyr Gln Gln Arg Asp Thr Lys
505560
Asn Leu Val Glu Asn Gly Asp Phe Gly Gln Thr Glu Asp Gly Ser Ser
65707580
Pro Trp Thr Gly Ser Lys Ala Gln Gly Trp Ser Ala Trp Val Asp Gln
859095
Lys Asn Ser Ser Ala Asp Ala Ser Thr Arg Val Ile Glu Ala Lys Asp
100105110
Gly Ala Ile Thr Ile Ser Ser Pro Glu Lys Leu Arg Ala Ala Val His
115120125
Arg Met Val Pro Ile Glu Ala Lys Lys Lys Tyr Lys Leu Arg Phe Lys
130135140
Ile Lys Thr Asp Asn Lys Val Gly Ile Ala Lys Val Arg Ile Ile Glu
145150155160
Glu Ser Gly Lys Asp Lys Arg Leu Trp Asn Ser Ala Thr Thr Ser Gly
165170175
Thr Lys Asp Trp Gln Thr Ile Glu Ala Asp Tyr Ser Pro Thr Leu Asp
180185190
Val Asp Lys Ile Lys Leu Glu Leu Phe Tyr Glu Thr Gly Thr Gly Thr
195200205
Val Ser Phe Lys Asp Ile Glu Leu Val Glu Val Ala Asp Gln Pro Ser
210215220
Glu Asp Ser Gln Thr Asp Lys Gln Leu Glu Glu Lys Ile Asp Leu Pro
225230235240
Ile Gly Lys Lys His Val Phe Ser Leu Ala Asp Tyr Thr Tyr Lys Val
245250255
Glu Asn Pro Asp Val Ala Ser Val Lys Asn Gly Ile Leu Glu Pro Leu
260265270
Lys Glu Gly Thr Thr Asn Val Ile Val Ser Lys Asp Gly Lys Glu Val
275280285
Lys Lys Ile Pro Leu Lys Ile Leu Ala Ser Val Lys Asp Thr Tyr Thr
290295300
Asp Arg Leu Asp Asp Trp Asn Gly Ile Ile Ala Gly Asn Gln Tyr Tyr
305310315320
Asp Ser Lys Asn Glu Gln Met Ala Lys Leu Asn Gln Glu Leu Glu Gly
325330335
Lys Val Ala Asp Ser Leu Ser Ser Ile Ser Ser Gln Ala Asp Arg Ile
340345350
Tyr Leu Trp Glu Lys Phe Ser Asn Tyr Lys Thr Ser Ala Asn Leu Thr
355360365
Ala Thr Tyr Arg Lys Leu Glu Glu Met Ala Lys Gln Val Thr Asn Pro
370375380
Ser Ser Arg Tyr Tyr Gln Asp Glu Thr Val Val Arg Thr Val Arg Asp
385390395400
Ser Met Glu Trp Met His Lys His Val Tyr Asn Ser Glu Lys Ser Ile
405410415
Val Gly Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Arg Ala Ile Asn
420425430
Asn Thr Leu Ser Leu Met Lys Glu Tyr Phe Ser Asp Glu Glu Ile Lys
435440445
Lys Tyr Thr Asp Val Ile Glu Lys Phe Val Pro Asp Pro Glu His Phe
450455460
Arg Lys Thr Thr Asp Asn Pro Phe Lys Ala Leu Gly Gly Asn Leu Val
465470475480
Asp Met Gly Arg Val Lys Val Ile Ala Gly Leu Leu Arg Lys Asp Asp
485490495
Gln Glu Ile Ser Ser Thr Ile Arg Ser Ile Glu Gln Val Phe Lys Leu
500505510
Val Asp Gln Gly Glu Gly Phe Tyr Gln Asp Gly Ser Tyr Ile Asp His
515520525
Thr Asn Val Ala Tyr Thr Gly Ala Tyr Gly Asn Val Leu Ile Asp Gly
530535540
Leu Ser Gln Leu Leu Pro Val Ile Gln Lys Thr Lys Asn Pro Ile Asp
545550555560
Lys Asp Lys Met Gln Thr Met Tyr His Trp Ile Asp Lys Ser Phe Ala
565570575
Pro Leu Leu Val Asn Gly Glu Leu Met Asp Met Ser Arg Gly Arg Ser
580585590
Ile Ser Arg Ala Asn Ser Glu Gly His Val Ala Ala Val Glu Val Leu
595600605
Arg Gly Ile His Arg Ile Ala Asp Met Ser Glu Gly Glu Thr Lys Gln
610615620
Arg Leu Gln Ser Leu Val Lys Thr Ile Val Gln Ser Asp Ser Tyr Tyr
625630635640
Asp Val Phe Lys Asn Leu Lys Thr Tyr Lys Asp Ile Ser Leu Met Gln
645650655
Ser Leu Leu Ser Asp Ala Gly Val Ala Ser Val Pro Arg Thr Ser Tyr
660665670
Leu Ser Ala Phe Asn Lys Met Asp Lys Thr Ala Met Tyr Asn Ala Glu
675680685
Lys Gly Phe Gly Phe Gly Leu Ser Leu Phe Ser Ser Arg Thr Leu Asn
690695700
Tyr Glu His Met Asn Lys Glu Asn Lys Arg Gly Trp Tyr Thr Ser Asp
705710715720
Gly Met Phe Tyr Leu Tyr Asn Gly Asp Leu Ser His Tyr Ser Asp Gly
725730735
Tyr Trp Pro Thr Val Asn Pro Tyr Lys Met Pro Gly Thr Thr Glu Thr
740745750
Asp Ala Lys Arg Ala Asp Ser Asp Thr Gly Lys Val Leu Pro Ser Ala
755760765
Phe Val Gly Thr Ser Lys Leu Asp Asp Ala Asn Ala Thr Ala Thr Met
770775780
Asp Phe Thr Asn Trp Asn Gln Thr Leu Thr Ala His Lys Ser Trp Phe
785790795800
Met Leu Lys Asp Lys Ile Ala Phe Leu Gly Ser Asn Ile Gln Asn Thr
805810815
Ser Thr Asp Thr Ala Ala Thr Thr Ile Asp Gln Arg Lys Leu Glu Ser
820825830
Ser Asn Pro Tyr Lys Val Tyr Val Asn Asp Lys Glu Ala Ser Leu Thr
835840845
Glu Gln Glu Lys Asp Tyr Pro Glu Thr Gln Ser Val Phe Leu Glu Ser
850855860
Ser Asp Ser Lys Lys Asn Ile Gly Tyr Phe Phe Phe Lys Lys Ser Ser
865870875880
Ile Ser Met Ser Lys Ala Leu Gln Lys Gly Ala Trp Lys Asp Ile Asn
885890895
Glu Gly Gln Ser Asp Lys Glu Val Glu Asn Glu Phe Leu Thr Ile Ser
900905910
Gln Ala His Lys Gln Asn Gly Asp Ser Tyr Gly Tyr Met Leu Ile Pro
915920925
Asn Val Asp Arg Ala Thr Phe Asn Gln Met Ile Lys Glu Leu Glu Ser
930935940
Ser Leu Ile Glu Asn Asn Glu Thr Leu Gln Ser Val Tyr Asp Ala Lys
945950955960
Gln Gly Val Trp Gly Ile Val Lys Tyr Asp Asp Ser Val Ser Thr Ile
965970975
Ser Asn Gln Phe Gln Val Leu Lys Arg Gly Val Tyr Thr Ile Arg Lys
980985990
Glu Gly Asp Glu Tyr Lys Ile Ala Tyr Tyr Asn Pro Glu Thr Gln Glu
99510001005
Ser Ala Pro Asp Gln Glu Val Phe Lys Lys Leu Glu Gln Ala Ala Gln
101010151020
Pro Gln Val Gln Asn Ser Lys Glu Lys Glu Lys Ser Glu Glu Glu Lys
1025103010351040
Asn His Ser Asp Gln Lys Asn Leu Pro Gln Thr Gly Glu Gly Gln Ser
104510501055
Ile Leu Ala Ser Leu Gly Phe Leu Leu Leu Gly Ala Phe Tyr Leu Phe
106010651070
Arg Arg Gly Lys Asn Asn
1075
<210> 84
<211> 1067
<212> PRT
<213> Streptococcus pneumoniae
<220>
<223> Streptococcus pneumoniae serotype 2, strain D39 /
NCTC 7466 hyaluronate lyase
<400> 84
Met Gln Thr Lys Thr Lys Lys Leu Ile Val Ser Leu Ser Ser Leu Val
151015
Leu Ser Gly Phe Leu Leu Asn His Tyr Met Thr Val Gly Ala Glu Glu
202530
Thr Thr Thr Asn Thr Ile Gln Gln Ser Gln Lys Glu Val Gln Tyr Gln
354045
Gln Arg Asp Thr Lys Asn Leu Val Glu Asn Gly Asp Phe Gly Gln Thr
505560
Glu Asp Gly Ser Ser Pro Trp Thr Gly Ser Lys Ala Gln Gly Trp Ser
65707580
Ala Trp Val Asp Gln Lys Asn Ser Ser Ala Asp Ala Ser Thr Arg Val
859095
Ile Glu Ala Lys Asp Gly Ala Ile Thr Ile Ser Ser Pro Glu Lys Leu
100105110
Arg Ala Ala Val His Arg Met Val Pro Ile Glu Ala Lys Lys Lys Tyr
115120125
Lys Leu Arg Phe Lys Ile Lys Thr Asp Asn Lys Val Gly Ile Ala Lys
130135140
Val Arg Ile Ile Glu Glu Ser Gly Lys Asp Lys Arg Leu Trp Asn Ser
145150155160
Ala Thr Thr Ser Gly Thr Lys Asp Trp Gln Thr Ile Glu Ala Asp Tyr
165170175
Ser Pro Thr Leu Asp Val Asp Lys Ile Lys Leu Glu Leu Phe Tyr Glu
180185190
Thr Gly Thr Gly Thr Val Ser Phe Lys Asp Ile Glu Leu Val Glu Val
195200205
Ala Asp Gln Pro Ser Glu Asp Ser Gln Thr Asp Lys Gln Leu Glu Glu
210215220
Lys Ile Asp Leu Pro Ile Gly Lys Lys His Val Phe Ser Leu Ala Asp
225230235240
Tyr Thr Tyr Lys Val Glu Asn Pro Asp Val Ala Ser Val Lys Asn Gly
245250255
Ile Leu Glu Pro Leu Lys Glu Gly Thr Thr Asn Val Ile Val Ser Lys
260265270
Asp Gly Lys Glu Val Lys Lys Ile Pro Leu Lys Ile Leu Ala Ser Val
275280285
Lys Asp Thr Tyr Thr Asp Arg Leu Asp Asp Trp Asn Gly Ile Ile Ala
290295300
Gly Asn Gln Tyr Tyr Asp Ser Lys Asn Glu Gln Met Ala Lys Leu Asn
305310315320
Gln Glu Leu Glu Gly Lys Val Ala Asp Ser Leu Ser Ser Ile Ser Ser
325330335
Gln Ala Asp Arg Ile Tyr Leu Trp Glu Lys Phe Ser Asn Tyr Lys Thr
340345350
Ser Ala Asn Leu Thr Ala Thr Tyr Arg Lys Leu Glu Glu Met Ala Lys
355360365
Gln Val Thr Asn Pro Ser Ser Arg Tyr Tyr Gln Asp Glu Thr Val Val
370375380
Arg Thr Val Arg Asp Ser Met Glu Trp Met His Lys His Val Tyr Asn
385390395400
Ser Glu Lys Ser Ile Val Gly Asn Trp Trp Asp Tyr Glu Ile Gly Thr
405410415
Pro Arg Ala Ile Asn Asn Thr Leu Ser Leu Met Lys Glu Tyr Phe Ser
420425430
Asp Glu Glu Ile Lys Lys Tyr Thr Asp Val Ile Glu Lys Phe Val Pro
435440445
Asp Pro Glu His Phe Arg Lys Thr Thr Asp Asn Pro Phe Lys Ala Leu
450455460
Gly Gly Asn Leu Val Asp Met Gly Arg Val Lys Val Ile Ala Gly Leu
465470475480
Leu Arg Lys Asp Asp Gln Glu Ile Ser Ser Thr Ile Arg Ser Ile Glu
485490495
Gln Val Phe Lys Leu Val Asp Gln Gly Glu Gly Phe Tyr Gln Asp Gly
500505510
Ser Tyr Ile Asp His Thr Asn Val Ala Tyr Thr Gly Ala Tyr Gly Asn
515520525
Val Leu Ile Asp Gly Leu Ser Gln Leu Leu Pro Val Ile Gln Lys Thr
530535540
Lys Asn Pro Ile Asp Lys Asp Lys Met Gln Thr Met Tyr His Trp Ile
545550555560
Asp Lys Ser Phe Ala Pro Leu Leu Val Asn Gly Glu Leu Met Asp Met
565570575
Ser Arg Gly Arg Ser Ile Ser Arg Ala Asn Ser Glu Gly His Val Ala
580585590
Ala Val Glu Val Leu Arg Gly Ile His Arg Ile Ala Asp Met Ser Glu
595600605
Gly Glu Thr Lys Gln Arg Leu Gln Ser Leu Val Lys Thr Ile Val Gln
610615620
Ser Asp Ser Tyr Tyr Asp Val Phe Lys Asn Leu Lys Thr Tyr Lys Asp
625630635640
Ile Ser Leu Met Gln Ser Leu Leu Ser Asp Ala Gly Val Ala Ser Val
645650655
Pro Arg Thr Ser Tyr Leu Ser Ala Phe Asn Lys Met Asp Lys Thr Ala
660665670
Met Tyr Asn Ala Glu Lys Gly Phe Gly Phe Gly Leu Ser Leu Phe Ser
675680685
Ser Arg Thr Leu Asn Tyr Glu His Met Asn Lys Glu Asn Lys Arg Gly
690695700
Trp Tyr Thr Ser Asp Gly Met Phe Tyr Leu Tyr Asn Gly Asp Leu Ser
705710715720
His Tyr Ser Asp Gly Tyr Trp Pro Thr Val Asn Pro Tyr Lys Met Pro
725730735
Gly Thr Thr Glu Thr Asp Ala Lys Arg Ala Asp Ser Asp Thr Gly Lys
740745750
Val Leu Pro Ser Ala Phe Val Gly Thr Ser Lys Leu Asp Asp Ala Asn
755760765
Ala Thr Ala Thr Met Asp Phe Thr Asn Trp Asn Gln Thr Leu Thr Ala
770775780
His Lys Ser Trp Phe Met Leu Lys Asp Lys Ile Ala Phe Leu Gly Ser
785790795800
Asn Ile Gln Asn Thr Ser Thr Asp Thr Ala Ala Thr Thr Ile Asp Gln
805810815
Arg Lys Leu Glu Ser Ser Asn Pro Tyr Lys Val Tyr Val Asn Asp Lys
820825830
Glu Ala Ser Leu Thr Glu Gln Glu Lys Asp Tyr Pro Glu Thr Gln Ser
835840845
Val Phe Leu Glu Ser Ser Asp Ser Lys Lys Asn Ile Gly Tyr Phe Phe
850855860
Phe Lys Lys Ser Ser Ile Ser Met Ser Lys Ala Leu Gln Lys Gly Ala
865870875880
Trp Lys Asp Ile Asn Glu Gly Gln Ser Asp Lys Glu Val Glu Asn Glu
885890895
Phe Leu Thr Ile Ser Gln Ala His Lys Gln Asn Gly Asp Ser Tyr Gly
900905910
Tyr Met Leu Ile Pro Asn Val Asp Arg Ala Thr Phe Asn Gln Met Ile
915920925
Lys Glu Leu Glu Ser Ser Leu Ile Glu Asn Asn Glu Thr Leu Gln Ser
930935940
Val Tyr Asp Ala Lys Gln Gly Val Trp Gly Ile Val Lys Tyr Asp Asp
945950955960
Ser Val Ser Thr Ile Ser Asn Gln Phe Gln Val Leu Lys Arg Gly Val
965970975
Tyr Thr Ile Arg Lys Glu Gly Asp Glu Tyr Lys Ile Ala Tyr Tyr Asn
980985990
Pro Glu Thr Gln Glu Ser Ala Pro Asp Gln Glu Val Phe Lys Lys Leu
99510001005
Glu Gln Ala Ala Gln Pro Gln Val Gln Asn Ser Lys Glu Lys Glu Lys
101010151020
Ser Glu Glu Glu Lys Asn His Ser Asp Gln Lys Asn Leu Pro Gln Thr
1025103010351040
Gly Glu Gly Gln Ser Ile Leu Ala Ser Leu Gly Phe Leu Leu Leu Gly
104510501055
Ala Phe Tyr Leu Phe Arg Arg Gly Lys Asn Asn
10601065
<210> 85
<211> 805
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes serotype M1, strain GAS
extracellular hyaluronate lyase
<400> 85
Met Asn Thr Tyr Phe Cys Thr His His Lys Gln Leu Leu Leu Tyr Ser
151015
Asn Leu Phe Leu Ser Phe Ala Met Met Gly Gln Gly Thr Ala Ile Tyr
202530
Ala Asp Thr Leu Thr Ser Asn Ser Glu Pro Asn Asn Thr Tyr Phe Gln
354045
Thr Gln Thr Leu Thr Thr Thr Asp Ser Glu Lys Lys Val Val Gln Pro
505560
Gln Gln Lys Asp Tyr Tyr Thr Glu Leu Leu Asp Gln Trp Asn Ser Ile
65707580
Ile Ala Gly Asn Asp Ala Tyr Asp Lys Thr Asn Pro Asp Met Val Thr
859095
Phe His Asn Lys Ala Glu Lys Asp Ala Gln Asn Ile Ile Lys Ser Tyr
100105110
Gln Gly Pro Asp His Glu Asn Arg Thr Tyr Leu Trp Glu His Ala Lys
115120125
Asp Tyr Ser Ala Ser Ala Asn Ile Thr Lys Thr Tyr Arg Asn Ile Glu
130135140
Lys Ile Ala Lys Gln Ile Thr Asn Pro Glu Ser Cys Tyr Tyr Gln Asp
145150155160
Ser Lys Ala Ile Ala Ile Val Lys Asp Gly Met Ala Phe Met Tyr Glu
165170175
His Ala Tyr Asn Leu Asp Arg Glu Asn His Gln Thr Thr Gly Lys Glu
180 185190
Asn Lys Glu Asn Trp Trp Val Tyr Glu Ile Gly Thr Pro Arg Ala Ile
195200205
Asn Asn Thr Leu Ser Leu Met Tyr Pro Tyr Phe Thr Gln Glu Glu Ile
210215220
Leu Lys Tyr Thr Ala Pro Ile Glu Lys Phe Val Pro Asp Pro Thr Arg
225230235240
Phe Arg Val Arg Ala Ala Asn Phe Ser Pro Phe Glu Ala Asn Ser Gly
245250255
Asn Leu Ile Asp Met Gly Arg Val Lys Leu Ile Ser Gly Ile Leu Arg
260265270
Lys Asp Asp Leu Glu Ile Ser Asp Thr Ile Lys Ala Ile Glu Lys Val
275280285
Phe Thr Leu Val Asp Glu Gly Asn Gly Phe Tyr Gln Asp Gly Ser Leu
290295300
Ile Asp His Val Val Thr Asn Ala Gln Ser Pro Leu Tyr Lys Lys Gly
305310315320
Ile Ala Tyr Thr Gly Ala Tyr Gly Asn Val Leu Ile Asp Gly Leu Ser
325330335
Gln Leu Ile Pro Ile Ile Gln Lys Thr Lys Ser Pro Ile Lys Ala Asp
340345350
Lys Met Ala Thr Ile Tyr His Trp Ile Asn His Ser Phe Phe Pro Ile
355360365
Ile Val Arg Gly Glu Met Met Asp Met Thr Arg Gly Arg Ser Ile Ser
370375380
Arg Phe Asn Ala Gln Ser His Val Ala Gly Ile Glu Ala Leu Arg Ala
385390395400
Ile Leu Arg Ile Ala Asp Met Ser Glu Glu Pro His Arg Leu Ala Leu
405410415
Lys Thr Arg Ile Lys Thr Leu Val Thr Gln Gly Asn Ala Phe Tyr Asn
420425430
Val Tyr Asp Asn Leu Lys Thr Tyr His Asp Ile Lys Leu Met Lys Glu
435440445
Leu Leu Ser Asp Thr Ser Val Pro Val Gln Lys Leu Asp Ser Tyr Val
450455460
Ala Ser Phe Asn Ser Met Asp Lys Leu Ala Leu Tyr Asn Asn Lys His
465470475480
Asp Phe Ala Phe Gly Leu Ser Met Phe Ser Asn Arg Thr Gln Asn Tyr
485490495
Glu Ala Met Asn Asn Glu Asn Leu His Gly Trp Phe Thr Ser Asp Gly
500505510
Met Phe Tyr Leu Tyr Asn Asn Asp Leu Gly His Tyr Ser Glu Asn Tyr
515520525
Trp Ala Thr Val Asn Pro Tyr Arg Leu Pro Gly Thr Thr Glu Thr Glu
530535540
Gln Lys Pro Leu Glu Gly Thr Pro Glu Asn Ile Lys Thr Asn Tyr Gln
545550555560
Gln Val Gly Met Thr Gly Leu Ser Asp Asp Ala Phe Val Ala Ser Lys
565570575
Lys Leu Asn Asn Thr Ser Ala Leu Ala Ala Met Thr Phe Thr Asn Trp
580585590
Asn Lys Ser Leu Thr Leu Asn Lys Gly Trp Phe Ile Leu Gly Asn Lys
595600605
Ile Ile Phe Val Gly Ser Asn Ile Lys Asn Gln Ser Ser His Lys Ala
610615620
Tyr Thr Thr Ile Glu Gln Arg Lys Glu Asn Gln Lys Tyr Pro Tyr Cys
625630635640
Ser Tyr Val Asn Asn Gln Pro Val Asp Leu Asn Asn Gln Leu Val Asp
645650655
Phe Thr Asn Thr Lys Ser Ile Phe Leu Glu Ser Asp Asp Pro Ala Gln
660665670
Asn Ile Gly Tyr Tyr Phe Phe Lys Pro Thr Thr Leu Ser Ile Ser Lys
675680685
Ala Leu Gln Thr Gly Lys Trp Gln Asn Ile Lys Ala Asp Asp Lys Ser
690695700
Pro Glu Ala Ile Lys Glu Val Ser Asn Thr Phe Ile Thr Ile Met Gln
705710715720
Asn His Thr Gln Asp Gly Asp Arg Tyr Ala Tyr Met Met Leu Pro Asn
725730735
Met Thr Arg Gln Glu Phe Glu Thr Tyr Ile Ser Lys Leu Asp Ile Asp
740745750
Leu Leu Glu Asn Asn Asp Lys Leu Ala Ala Val Tyr Asp His Asp Ser
755760765
Gln Gln Met His Val Ile His Tyr Gly Lys Lys Ala Thr Met Phe Ser
770775780
Asn His Asn Leu Ser His Gln Gly Phe Tyr Ser Phe Pro His Pro Val
785790795800
Arg Gln Asn Gln Gln
805
<210> 86
<211> 780
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes serotype M2, strain
MGAS10270 hyaluronate lyase precursor
<400> 86
Met Val Tyr Phe Tyr Leu Val Asn Gln Ser Thr Phe Ile Ile Ser Phe
151015
Leu Tyr Trp Arg Asn Val Ser Val Asn Thr Tyr Phe Cys Thr His His
202530
Lys Gln Leu Leu Leu Tyr Ser Asn Leu Phe Leu Ser Phe Ala Met Ile
354045
Gly Gln Gly Thr Ala Ile Tyr Ala Asp Thr Leu Thr Ser Asn Ser Glu
505560
Pro Asn Asn Thr Tyr Phe Gln Thr Gln Thr Leu Thr Thr Thr Asp Ser
65707580
Glu Lys Lys Val Val Gln Pro Gln Gln Lys Asp Tyr Tyr Thr Glu Leu
859095
Leu Asp Gln Trp Asn Ser Ile Ile Ala Gly Asn Asp Ala Tyr Asp Lys
100105110
Thr Asn Pro Asp Met Val Thr Phe His Asn Lys Ala Glu Lys Asp Ala
115120125
Gln Asn Ile Ile Lys Ser Tyr Gln Gly Pro Asp His Glu Asn Arg Thr
130135140
Tyr Leu Trp Glu His Ala Lys Asp Tyr Ser Ala Ser Thr Asn Ile Thr
145150155160
Lys Thr Tyr Arg Asn Ile Glu Lys Ile Ala Lys Gln Ile Thr Asn Pro
165170175
Glu Ser Cys Tyr Tyr Gln Asp Ser Lys Ala Ile Ala Ile Val Lys Asp
180185190
Gly Met Ala Phe Met Tyr Glu His Ala Tyr Asn Leu Asn Arg Glu Asn
195200205
His Gln Thr Thr Gly Lys Glu Asn Lys Glu Asn Trp Trp Val Tyr Glu
210215220
Ile Gly Thr Pro Arg Ala Ile Asn Asn Thr Leu Ser Leu Met Tyr Pro
225230235240
Tyr Phe Thr Gln Glu Glu Ile Leu Lys Tyr Thr Ala Pro Ile Glu Lys
245250255
Phe Val Pro Asp Pro Thr Arg Phe Arg Val Arg Ala Ala Asn Phe Ser
260265270
Pro Phe Glu Ala Asn Ser Gly Asn Leu Ile Asp Met Gly Arg Val Lys
275280285
Leu Ile Ser Gly Ile Leu Arg Lys Asp Asp Leu Glu Ile Ser Asp Thr
290295300
Ile Lys Ala Ile Glu Lys Val Phe Thr Leu Val Asp Glu Gly Asn Gly
305310315320
Phe Tyr Gln Asp Gly Ser Leu Ile Asp His Val Val Thr Asn Thr Gln
325330335
Ser Pro Leu Tyr Lys Lys Gly Ile Ala Tyr Thr Gly Ala Tyr Gly Asn
340345350
Val Leu Ile Asp Gly Leu Ser Gln Leu Ile Pro Ile Ile Gln Lys Thr
355360365
Lys Ser Pro Ile Glu Ala Asp Lys Met Ala Thr Ile Tyr His Trp Ile
370375380
Asn His Ser Phe Phe Pro Ile Ile Val Arg Gly Glu Met Met Asp Met
385390395400
Thr Arg Gly Arg Ser Ile Ser Arg Phe Asn Ala Gln Ser His Val Ala
405410415
Gly Ile Glu Ala Leu Arg Ala Ile Leu Arg Ile Ala Asp Met Ser Glu
420425430
Glu Pro His Arg Leu Glu Leu Lys Thr Arg Ile Lys Thr Leu Val Thr
435440445
Gln Gly Asn Ala Phe Tyr Asn Val Tyr Asp Asn Leu Lys Thr Tyr His
450455460
Asp Ile Lys Leu Met Lys Glu Leu Leu Ser Asp Thr Ser Val Pro Val
465470475480
Gln Lys Leu Asp Ser Tyr Val Ala Ser Phe Asn Ser Met Asp Lys Leu
485490495
Ala Leu Tyr Asn Asn Lys His Asp Phe Ala Phe Gly Leu Ser Met Phe
500505510
Ser Asn Arg Thr Gln Asn Tyr Glu Ala Met Asn Asn Glu Asn Leu His
515520525
Gly Trp Phe Thr Ser Asp Gly Met Phe Tyr Leu Tyr Asn Asn Asp Leu
530535540
Gly His Tyr Ser Glu Asn Tyr Trp Ala Thr Val Asn Pro Tyr Arg Leu
545550555560
Pro Gly Thr Thr Glu Thr Glu Gln Lys Pro Leu Glu Gly Thr Pro Glu
565570575
Asn Ile Lys Thr Asn Tyr Gln Gln Val Gly Met Thr Ser Leu Ser Asp
580585590
Asp Ala Phe Val Ala Ser Lys Lys Leu Asn Asn Thr Ser Ala Leu Ala
595600605
Ala Met Thr Phe Thr Asn Trp Asn Lys Ser Leu Thr Leu Asn Lys Gly
610615620
Trp Phe Ile Leu Gly Asn Lys Ile Ile Phe Val Gly Ser Asn Ile Lys
625630635640
Asn Gln Ser Ser His Lys Ala Tyr Thr Thr Ile Glu Gln Arg Lys Glu
645650655
Asn Gln Lys His Pro Tyr Cys Ser Tyr Val Asn Asn Gln Pro Val Asp
660665670
Leu Asn Asn Gln Leu Val Asp Phe Thr Asn Thr Lys Ser Ile Phe Leu
675680685
Glu Ser Asp Asp Pro Ala Gln Asn Ile Gly Tyr Tyr Phe Phe Lys Pro
690695700
Arg Thr Leu Ser Ile Ser Lys Ala Leu Gln Thr Gly Lys Trp Gln Asn
705710715720
Ile Lys Ala Asp Asp Lys Ser Pro Glu Ala Ile Lys Glu Val Ser Asn
725730735
Thr Phe Ile Thr Ile Met Gln Asn His Thr Gln Glu Gly Asp Arg Tyr
740745750
Ala Tyr Met Met Leu Pro Asn Met Thr Arg Gln Glu Phe Glu Thr Tyr
755760765
Ile Ser Lys Leu Asp Ile Asp Leu Leu Glu Asn Asn
770775780
<210> 87
<211> 868
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes serotype M4, strain
MGAS10750 hyaluronate lyase precursor
<400> 87
Met Asn Thr Tyr Phe Cys Thr His His Lys Gln Leu Leu Leu Tyr Ser
151015
Asn Leu Phe Leu Ser Phe Ala Met Met Gly Gln Gly Thr Ala Ile Tyr
202530
Ala Asp Thr Leu Thr Ser Asn Ser Lys Pro Asn Asn Thr Tyr Phe Gln
354045
Thr Gln Thr Leu Thr Thr Thr Asp Ser Glu Lys Lys Val Val Gln Pro
505560
Gln Gln Lys Asp Tyr Tyr Thr Glu Leu Leu Asp Gln Trp Asn Ser Ile
65707580
Ile Ala Gly Asn Asp Ala Tyr Asp Lys Thr Asn Pro Asp Met Val Thr
859095
Phe His Asn Lys Ala Glu Lys Asp Ala Gln Asn Ile Ile Lys Ser Tyr
100105110
Gln Glu Pro Asp His Glu Asn Arg Thr Tyr Leu Trp Glu His Ala Lys
115120125
Asp Tyr Ser Ala Ser Ala Asn Ile Thr Lys Thr Tyr Arg Asn Ile Glu
130135140
Lys Ile Ala Lys Gln Ile Thr Asn Pro Glu Ser Cys Tyr Tyr Gln Asp
145150155160
Ser Lys Ala Ile Ala Ile Val Lys Asp Gly Met Ala Phe Met Tyr Glu
165170175
His Ala Tyr Asn Leu Asp Arg Glu Asn His Gln Thr Thr Gly Lys Glu
180185190
Asn Lys Glu Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Arg Ala Ile
195200205
Asn Asn Thr Leu Ser Leu Met Tyr Pro Tyr Phe Thr Gln Glu Glu Ile
210215220
Leu Lys Tyr Thr Ala Pro Ile Glu Lys Phe Val Pro Asp Pro Thr Arg
225230235240
Phe Arg Val Arg Ala Ala Asn Phe Pro Pro Phe Glu Ala Asn Ser Gly
245250255
Asn Leu Ile Asp Met Gly Arg Val Lys Leu Ile Ser Gly Ile Leu Arg
260265270
Lys Asp Asp Leu Glu Ile Ser Asp Thr Ile Lys Ala Ile Glu Lys Val
275280285
Phe Thr Leu Val Asp Glu Gly Asn Gly Phe Tyr Gln Asp Gly Ser Leu
290295300
Ile Asp His Val Val Thr Asn Ala Gln Ser Pro Leu Tyr Lys Lys Gly
305310315320
Ile Ala Tyr Thr Gly Ala Tyr Gly Asn Val Leu Ile Asp Gly Leu Ser
325330335
Gln Leu Ile Pro Ile Ile Gln Lys Thr Lys Ser Pro Ile Glu Ala Asp
340345350
Lys Met Ala Thr Ile Tyr His Trp Ile Asn His Ser Phe Phe Pro Ile
355360365
Ile Val Arg Gly Glu Met Met Asp Met Thr Arg Gly Arg Ser Ile Ser
370375380
Arg Phe Asn Ala Gln Ser His Val Ala Gly Ile Glu Ala Leu Arg Ala
385390395400
Ile Leu Arg Ile Ala Asp Met Ser Glu Glu Pro His Arg Leu Ala Leu
405410415
Lys Thr Arg Ile Lys Thr Leu Val Thr Gln Gly Asn Val Phe Tyr Asn
420425430
Val Tyr Asp Asn Leu Lys Thr Tyr His Asp Ile Lys Leu Met Lys Glu
435440445
Leu Leu Ser Asp Thr Ser Val Pro Val Gln Lys Leu Asp Ser Tyr Val
450455460
Ala Ser Phe Asn Ser Met Asp Lys Leu Ala Leu Tyr Asn Asn Lys His
465470475480
Asp Phe Ala Phe Gly Leu Ser Met Phe Ser Asn Arg Thr Gln Asn Tyr
485490495
Glu Ala Met Asn Asn Glu Asn Leu His Gly Trp Phe Thr Ser Asp Gly
500505510
Met Phe Tyr Leu Tyr Asn Asn Asp Leu Gly His Tyr Ser Glu Asn Tyr
515520525
Trp Ala Thr Val Asn Pro Tyr Arg Leu Pro Gly Thr Thr Glu Thr Glu
530535540
Gln Lys Pro Leu Glu Gly Thr Pro Glu Asn Ile Lys Thr Asn Tyr Gln
545550555560
Gln Val Gly Met Thr Ser Leu Ser Asp Asp Ala Phe Val Ala Ser Lys
565570575
Lys Leu Asn Asn Thr Ser Ala Leu Ala Ala Met Thr Phe Thr Asn Trp
580585590
Asn Lys Ser Leu Thr Leu Asn Lys Gly Trp Phe Ile Leu Gly Asn Lys
595600605
Ile Ile Phe Val Gly Ser Asn Ile Lys Asn Gln Ser Ser His Lys Ala
610615620
Tyr Thr Thr Ile Glu Gln Arg Lys Glu Asn Gln Lys His Pro Tyr Cys
625630635640
Ser Tyr Val Asn Asn Gln Pro Val Asp Leu Asn Asn Gln Leu Val Asp
645650655
Phe Thr Asn Thr Lys Ser Ile Phe Leu Glu Ser Asp Asp Pro Ala Gln
660665670
Asn Ile Gly Tyr Tyr Phe Phe Lys Pro Thr Thr Leu Ser Ile Ser Lys
675680685
Ala Leu Gln Thr Gly Lys Trp Gln Asn Ile Lys Ala Asp Asp Lys Ser
690695700
Pro Glu Ala Ile Lys Glu Val Ser Asn Thr Phe Ile Thr Ile Met Gln
705710715720
Asn His Thr Gln Asp Gly Asp Arg Tyr Ala Tyr Met Met Leu Pro Asn
725730735
Met Thr Arg Gln Glu Phe Glu Thr Tyr Ile Ser Lys Leu Asp Ile Asp
740745750
Leu Leu Glu Asn Asn Asp Lys Leu Ala Ala Val Tyr Asp His Asp Ser
755760765
Gln Gln Met His Val Ile His Tyr Glu Lys Lys Ala Thr Thr Phe Ser
770775780
Asn His Asn Leu Ser His Gln Gly Phe Tyr Ser Phe Pro His Pro Val
785790795800
Lys Gln Asn Gln Gln Gln Lys Leu Ala His Gln Gly Ile Ala Ala Lys
805810815
Asn Asn Ala Leu Asn Ser His Lys Ile Pro His Lys Arg Gln Arg Arg
820825830
Leu Pro Arg Thr Gly Tyr Gln Ser Ser Ser Leu Glu Phe Leu Gly Gly
835840845
Ala Leu Val Ala Ser Phe Asn His Ile Thr Lys Pro Phe Arg Lys Lys
850855860
Asp Leu Arg Ile
865
<210> 88
<211> 828
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes serotype M6, strain
MGAS10394 hyaluronate lyase precursor
<400> 88
Met Val Tyr Phe Tyr Leu Val Asp Gln Phe Thr Phe Ile Ile Ser Phe
151015
Leu Tyr Trp Arg Asn Leu Ser Val Asn Thr Tyr Phe Cys Thr His His
202530
Lys Gln Leu Leu Leu Tyr Ser Asn Leu Phe Leu Ser Phe Ala Met Met
354045
Gly Gln Gly Thr Ala Ile Tyr Ala Asp Thr Leu Thr Ser Asn Ser Glu
505560
Pro Asn Asn Thr Tyr Phe Gln Thr Gln Thr Leu Thr Thr Thr Asp Ser
65707580
Glu Lys Lys Val Val Gln Pro Gln Gln Lys Asp Tyr Tyr Thr Glu Leu
859095
Leu Asp Gln Trp Asn Ser Ile Ile Ala Gly Asn Asp Ala Tyr Asp Lys
100105110
Thr Asn Pro Asp Met Val Thr Phe His Asn Lys Ala Glu Lys Asp Ala
115120125
Gln Asn Ile Ile Lys Ser Tyr Gln Gly Pro Asp His Glu Asn Arg Thr
130135140
Tyr Leu Trp Glu His Ala Lys Asp Tyr Ser Ala Ser Thr Asn Ile Thr
145150155160
Lys Thr Tyr Arg Asn Ile Glu Lys Ile Ala Lys Gln Ile Thr Asn Pro
165170175
Glu Ser Cys Tyr Tyr Gln Asp Ser Lys Ala Ile Ala Ile Val Lys Asp
180185190
Gly Met Ala Phe Met Tyr Glu His Ala Tyr Asn Leu Asp Arg Glu Asn
195200205
His Gln Thr Thr Gly Lys Glu Asn Lys Glu Asn Trp Trp Val Tyr Glu
210215220
Ile Gly Thr Pro Arg Ala Ile Asn Asn Thr Leu Ser Leu Met Tyr Pro
225230235240
Tyr Phe Thr Gln Glu Glu Ile Leu Lys Tyr Thr Ala Pro Ile Glu Lys
245250255
Phe Val Pro Asp Pro Thr Arg Phe Arg Val Arg Ala Ala Asn Phe Ser
260265270
Pro Phe Glu Ala Asn Ser Gly Asn Leu Ile Asp Met Gly Arg Val Lys
275280285
Leu Ile Ser Gly Ile Leu Arg Lys Asp Asp Leu Glu Ile Ser Asp Thr
290295300
Ile Lys Ala Ile Glu Lys Val Phe Thr Leu Val Asp Glu Gly Asn Gly
305310315320
Phe Tyr Gln Asp Gly Ser Leu Ile Asp His Val Val Thr Asn Ala Gln
325330335
Ser Pro Leu Tyr Lys Lys Gly Ile Ala Tyr Thr Gly Ala Tyr Gly Asn
340345350
Val Leu Ile Asp Gly Leu Ser Gln Leu Ile Pro Ile Ile Gln Lys Thr
355360365
Lys Ser Pro Ile Glu Ala Asp Lys Met Ala Thr Ile Tyr His Trp Ile
370375380
Asn His Ser Phe Phe Pro Ile Ile Val Arg Gly Glu Met Met Asp Met
385390395400
Thr Arg Gly Arg Ser Ile Ser Arg Phe Asn Ala Gln Ser His Val Ala
405410415
Gly Ile Glu Ala Leu Arg Ala Ile Leu Arg Ile Ala Asp Met Ser Glu
420425430
Glu Pro His Arg Leu Ala Leu Lys Thr Arg Ile Lys Thr Leu Val Thr
435440445
Gln Gly Asn Ala Phe Tyr Asn Val Tyr Asp Asn Leu Lys Thr Tyr His
450455460
Asp Ile Lys Leu Met Lys Glu Leu Leu Ser Asp Thr Phe Val Pro Val
465470475480
Gln Lys Leu Asp Ser Tyr Val Ala Ser Phe Asn Ser Met Asp Lys Leu
485490495
Ala Leu Tyr Asn Asn Lys His Asp Phe Ala Phe Gly Leu Ser Met Phe
500505510
Ser Asn Arg Thr Gln Asn Tyr Glu Ala Met Asn Asn Glu Asn Leu His
515520525
Gly Trp Phe Thr Ser Asp Gly Met Phe Tyr Leu Tyr Asn Asn Asp Leu
530535540
Gly His Tyr Ser Glu Asn Tyr Trp Ala Thr Val Asn Pro Tyr Arg Leu
545550555560
Pro Gly Thr Thr Glu Thr Glu Gln Lys Pro Leu Glu Gly Thr Pro Glu
565570575
Asn Ile Lys Thr Asp Tyr Gln Gln Val Gly Met Thr Ser Leu Ser Asp
580585590
Asp Ala Phe Val Ala Ser Lys Lys Leu Asn Asn Thr Ser Ala Leu Ala
595600605
Ala Met Thr Phe Thr Asn Trp Asn Lys Ser Leu Thr Leu Asn Lys Gly
610615 620
Trp Phe Ile Leu Gly Asn Lys Ile Ile Phe Val Gly Ser Asn Ile Lys
625630635640
Asn Gln Ser Ser His Lys Ala Tyr Thr Thr Ile Glu Gln Arg Lys Glu
645650655
Asn Gln Lys His Pro Tyr Cys Ser Tyr Val Asn Asn Gln Pro Val Asp
660665670
Leu Asn Asn Gln Leu Val Asp Phe Thr Asn Thr Lys Ser Ile Phe Leu
675680685
Glu Ser Asp Asp Pro Ala Gln Asn Ile Gly Tyr Tyr Phe Phe Lys Pro
690695700
Thr Thr Leu Ser Ile Ser Lys Ala Leu Gln Thr Gly Lys Trp Gln Asn
705710715720
Ile Lys Ala Asp Asp Lys Ser Pro Glu Ala Ile Lys Glu Val Ser Asn
725730735
Thr Phe Ile Thr Ile Met Gln Asn His Thr Gln Asp Gly Asp Arg Tyr
740745750
Ala Tyr Met Met Leu Pro Asn Met Thr Arg Gln Glu Phe Glu Thr Tyr
755760765
Ile Ser Lys Leu Asp Ile Asp Leu Leu Glu Asn Asn Asp Lys Leu Ala
770775780
Ala Val Tyr Asp His Asp Ser Gln Gln Met His Val Ile His Tyr Glu
785790795800
Lys Lys Ala Thr Met Phe Ser Asn His Asn Leu Ser His Gln Gly Phe
805810815
Tyr Ser Phe Pro His Pro Val Lys Gln Asn Gln Gln
820825
<210> 89
<211> 556
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Staphylococcus aureus subsp. aureus strain MRSA252
hyaluronan lyase 2
<400> 89
Met Val Tyr Phe Tyr Leu Val Asn Gln Ser Thr Phe Ile Ile Ser Phe
151015
Leu Tyr Trp Arg Asn Leu Ser Val Asn Thr Tyr Phe Cys Thr His His
202530
Lys Gln Leu Leu Leu Tyr Ser Asn Leu Phe Leu Ser Phe Ala Met Met
354045
Gly Gln Gly Thr Ala Ile Tyr Ala Asp Thr Leu Thr Ser Asn Ser Glu
505560
Pro Asn Asn Thr Tyr Phe Gln Thr Gln Thr Leu Thr Thr Thr Asp Ser
65707580
Glu Lys Lys Val Val Gln Pro Gln Gln Lys Asp Tyr Tyr Thr Glu Leu
859095
Leu Asp Gln Trp Asn Ser Ile Ile Ala Gly Asn Asp Ala Tyr Asp Lys
100105110
Thr Asn Pro Asp Met Val Thr Phe His Asn Lys Ala Glu Lys Asp Ala
115120125
Gln Asn Ile Ile Lys Ser Tyr Gln Gly Pro Asp His Glu Asn Arg Thr
130135140
Tyr Leu Gly Asn Met Gln Arg Ile Ile Pro Leu Leu Leu Ile Ser Arg
145150155160
Lys Leu Thr Ala Ile Leu Lys Lys Ile Ser Lys Met Lys Ser Leu Met
165170175
Glu Asp Ser Thr Ile Ser Thr Asn Gly Leu Thr Gln Gln Leu Lys Ile
180185190
Tyr Asn Asp Met Asp Arg Val Thr Tyr His Asn Lys Gly Leu Asp Phe
195200205
Ala Phe Gly Leu Ser Met Thr Ser Lys Asn Val Ala Arg Tyr Glu Ser
210215220
Ile Asn Gly Glu Asn Leu Lys Gly Trp His Thr Gly Ala Gly Met Ser
225230235240
Tyr Leu Tyr Asn Ser Asp Val Lys His Tyr Arg Asp Asn Phe Trp Ala
245250255
Thr Ala Asp Met Lys Arg Leu Ala Gly Thr Thr Thr Leu Asp Asn Glu
260265270
Glu Pro Lys Ser Thr Asp Val Lys Lys Ser Ser Lys Thr Phe Val Gly
275280285
Gly Thr Lys Phe Asp Asp Gln His Ala Ser Ile Gly Met Asp Phe Glu
290295300
Asn Gln Asp Lys Thr Leu Thr Ala Lys Lys Ser Tyr Phe Ile Leu Asn
305310315320
Asp Lys Ile Val Phe Leu Gly Thr Gly Ile Lys Ser Thr Asp Ser Ser
325330335
Lys Asn Pro Val Thr Thr Ile Glu Asn Arg Lys Ala Asn Asp Tyr Lys
340345350
Leu Tyr Lys Asp Asp Thr Gln Thr Thr Asn Ser Asp Asn Gln Glu Thr
355360365
Asn Ser Leu Phe Leu Glu Ser Thr Asn Ser Thr Gln Asn Asn Ile Gly
370375380
Tyr His Phe Leu Asn Glu Ser Lys Ile Thr Val Lys Lys Glu Ser His
385390395400
Thr Gly Lys Trp Ser Asp Ile Asn Lys Ser Gln Lys Asp Ile Gln Lys
405410415
Thr Asp Glu Tyr Tyr Glu Val Thr Gln Lys His Ser Asn Thr Asp Ser
420425430
Lys Tyr Ala Tyr Val Leu Tyr Pro Gly Leu Ser Lys Asp Val Phe Lys
435440445
Ser Lys Ala Ser Lys Val Thr Val Val Lys Gln Glu Asp Asp Phe His
450455460
Val Val Lys Asp Asn Glu Ser Val Trp Ala Gly Ile Asn Tyr Ser Asp
465470475480
Ser Ala Lys Thr Phe Glu Ile Asn Asn Thr Lys Val Glu Val Lys Ala
485490495
Lys Gly Met Phe Ile Leu Thr Lys Lys Asp Asp Asn Thr Tyr Glu Cys
500505510
Ser Phe Tyr Asn Pro Glu Ser Thr Asn Ser Val Ser Asp Ile Glu Ser
515520525
Lys Ile Ser Met Thr Gly Tyr Ser Ile Ile Asn Lys Asn Thr Ser Thr
530535540
Ser Asn Glu Ser Gly Val Arg Phe Glu Leu Thr Lys
545550555
<210> 90
<211> 635
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes strain MGAS9429 hyaluronate
lyase precursor
<400> 90
Met Ala Phe Met Tyr Glu His Ala Tyr Asn Leu Asn Arg Glu Asn His
151015
Gln Thr Thr Gly Lys Glu Asn Lys Glu Asn Trp Trp Val Tyr Glu Ile
202530
Gly Thr Pro Arg Ala Ile Asn Asn Thr Leu Ser Leu Met Tyr Pro Tyr
354045
Phe Thr Gln Glu Glu Ile Leu Lys Tyr Thr Ala Pro Ile Glu Lys Phe
505560
Val Pro Asp Pro Thr Arg Phe Arg Val Arg Ala Ala Asn Phe Ser Pro
65707580
Phe Glu Ala Ser Ser Gly Asn Leu Ile Asp Met Gly Arg Val Lys Leu
859095
Ile Ser Gly Ile Leu Arg Lys Asp Asp Leu Glu Ile Ser Asp Thr Ile
100105110
Lys Ala Ile Glu Lys Val Phe Thr Leu Val Asp Glu Gly Asn Gly Phe
115120125
Tyr Gln Asp Gly Ser Leu Ile Asp His Val Val Thr Asn Ala Gln Ser
130135140
Pro Leu Tyr Lys Lys Gly Ile Ala Tyr Thr Gly Ala Tyr Gly Asn Val
145150155160
Leu Ile Asp Gly Leu Ser Gln Leu Ile Pro Ile Ile Gln Lys Thr Lys
165170175
Ser Pro Ile Glu Ala Asp Lys Met Ala Thr Ile Tyr His Trp Ile Asn
180185190
His Ser Phe Phe Pro Ile Ile Val Arg Gly Glu Met Met Asp Met Thr
195200205
Arg Gly Arg Ser Ile Ser Arg Phe Asn Ala Gln Ser His Val Ala Gly
210215220
Ile Glu Ala Leu Arg Ala Ile Leu Arg Ile Ala Asp Met Ser Glu Glu
225230235240
Pro His Arg Leu Ala Leu Lys Thr Arg Ile Lys Thr Leu Val Thr Gln
245250255
Gly Asn Ala Phe Tyr Asn Val Tyr Asp Asn Leu Lys Thr Tyr His Asp
260265270
Ile Lys Leu Met Lys Glu Leu Leu Ser Asp Thr Ser Val Pro Val Gln
275280285
Lys Leu Asp Ser Tyr Val Ala Ser Phe Asn Ser Met Asp Lys Leu Ala
290295300
Leu Tyr Asn Asn Lys His Asp Phe Ala Phe Gly Leu Ser Met Phe Ser
305310315320
Asn Arg Thr Gln Asn Tyr Glu Ala Met Asn Asn Glu Asn Leu His Gly
325330335
Trp Phe Thr Ser Asp Gly Met Phe Tyr Leu Tyr Asn Asn Asp Leu Gly
340345350
His Tyr Ser Glu Asn Tyr Trp Ala Thr Val Asn Pro Tyr Arg Leu Pro
355360365
Gly Thr Thr Glu Thr Glu Gln Lys Pro Leu Glu Gly Thr Pro Glu Asn
370375380
Ile Lys Thr Asn Tyr Gln Gln Val Gly Met Thr Ser Leu Ser Asp Asp
385390395400
Ala Phe Val Ala Ser Lys Lys Leu Asn Asn Thr Ser Ala Leu Ala Ala
405410415
Met Thr Phe Thr Asn Trp Asn Lys Ser Leu Thr Leu Asn Lys Gly Trp
420425430
Phe Ile Leu Gly Asn Lys Ile Ile Phe Val Gly Ser Asn Ile Lys Asn
435440445
Gln Ser Ser His Lys Ala Tyr Thr Thr Ile Glu Gln Arg Lys Glu Asn
450455460
Gln Lys His Pro Tyr Cys Ser Tyr Val Asn Asn Gln Pro Val Asp Leu
465470475480
Asn Asn Gln Leu Val Asp Phe Thr Asn Thr Lys Ser Ile Phe Leu Glu
485490495
Ser Asp Asp Pro Ala Gln Asn Ile Gly Tyr Tyr Phe Phe Lys Pro Thr
500505510
Thr Leu Ser Ile Ser Lys Ala Leu Gln Thr Gly Lys Trp Gln Asn Ile
515520525
Lys Ala Asp Asp Lys Ser Pro Glu Ala Ile Lys Glu Val Ser Asn Thr
530535540
Phe Ile Thr Ile Met Gln Asn His Thr Gln Asp Gly Asp Arg Tyr Ala
545550555560
Tyr Met Met Leu Pro Asn Met Thr Arg Gln Glu Phe Glu Thr Tyr Ile
565570575
Ser Lys Leu Asp Ile Asp Leu Leu Glu Asn Asn Asp Lys Leu Ala Ala
580585590
Val Tyr Asp His Asp Ser Gln Gln Met His Val Ile His Tyr Glu Lys
595600605
Lys Ala Thr Met Phe Ser Asn His Asn Leu Ser His Gln Gly Phe Tyr
610615620
Ser Phe Pro His Pro Val Lys Gln Asn Gln Gln
625630635
<210> 91
<211> 828
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes serotype M12, strain
MGAS9429 hyaluronate lyase precursor
<400> 91
Met Val Tyr Phe Tyr Leu Val Asn Gln Ser Thr Phe Ile Ile Ser Phe
151015
Leu Tyr Trp Arg Asn Leu Ser Val Asn Thr Tyr Phe Cys Thr His His
202530
Lys Gln Leu Leu Leu Tyr Ser Asn Leu Phe Leu Ser Phe Ala Met Met
354045
Gly Gln Gly Thr Ala Ile Tyr Ala Asp Thr Leu Thr Ser Asn Ser Glu
505560
Pro Asn Asn Thr Tyr Phe Gln Thr Gln Thr Leu Thr Thr Thr Asp Ser
65707580
Glu Lys Lys Val Val Gln Pro Gln Gln Lys Asp Tyr Tyr Thr Glu Leu
859095
Leu Asp Gln Trp Asn Ser Ile Ile Ala Gly Asn Asp Ala Tyr Val Lys
100105110
Thr Asn Pro Asp Met Val Thr Phe His Asn Lys Ala Glu Lys Asp Ala
115120 125
Gln Asn Ile Ile Lys Ser Tyr Gln Gly Pro Asp His Glu Asn Arg Thr
130135140
Tyr Leu Trp Glu His Ala Lys Asp Tyr Ser Ala Ser Thr Asn Ile Thr
145150155160
Lys Thr Tyr Arg Asn Ile Glu Lys Ile Ala Lys Gln Ile Thr Asn Pro
165170175
Glu Ser Cys Tyr Tyr Gln Asp Ser Lys Ala Ile Ala Ile Val Lys Asp
180185190
Gly Met Ala Phe Met Tyr Glu His Ala Tyr Asn Leu Asn Arg Glu Asn
195200205
His Gln Thr Thr Gly Lys Glu Asn Lys Glu Asn Trp Trp Val Tyr Glu
210215220
Ile Gly Thr Pro Arg Ala Ile Asn Asn Thr Leu Ser Leu Met Tyr Pro
225230235240
Tyr Phe Thr Gln Glu Glu Ile Leu Lys Tyr Thr Ala Pro Ile Glu Lys
245250255
Phe Val Pro Asp Pro Thr Arg Phe Arg Val Arg Ala Ala Asn Phe Ser
260265270
Pro Phe Glu Ala Ser Ser Gly Asn Leu Ile Asp Met Gly Arg Val Lys
275280285
Leu Ile Ser Gly Ile Leu Arg Lys Asp Asp Leu Glu Ile Ser Asp Thr
290295300
Ile Lys Ala Ile Glu Lys Val Phe Thr Leu Val Asp Glu Gly Asn Gly
305310315320
Phe Tyr Gln Asp Gly Ser Leu Ile Asp His Val Val Thr Asn Ala Gln
325330335
Ser Pro Leu Tyr Lys Lys Gly Ile Ala Tyr Thr Gly Ala Tyr Gly Asn
340345350
Val Leu Ile Asp Gly Leu Ser Gln Leu Ile Pro Ile Ile Gln Lys Thr
355360365
Lys Ser Pro Ile Glu Ala Asp Lys Met Ala Thr Ile Tyr His Trp Ile
370375380
Asn His Ser Phe Phe Pro Ile Ile Val Arg Gly Glu Met Met Asp Met
385390395400
Thr Arg Gly Arg Ser Ile Ser Arg Phe Asn Ala Gln Ser His Val Ala
405410415
Gly Ile Glu Ala Leu Arg Ala Ile Leu Arg Ile Ala Asp Met Ser Glu
420425430
Glu Pro His Arg Leu Ala Leu Lys Thr Arg Ile Lys Thr Leu Val Thr
435 440445
Gln Gly Asn Ala Phe Tyr Asn Val Tyr Asp Asn Leu Lys Thr Tyr His
450455460
Asp Ile Lys Leu Met Lys Glu Leu Leu Ser Asp Thr Ser Val Pro Val
465470475480
Gln Lys Leu Asp Ser Tyr Val Ala Ser Phe Asn Ser Met Asp Lys Leu
485490495
Ala Leu Tyr Asn Asn Lys His Asp Phe Ala Phe Gly Leu Ser Met Phe
500505510
Ser Asn Arg Thr Gln Asn Tyr Glu Ala Met Asn Asn Glu Asn Leu His
515520525
Gly Trp Phe Thr Ser Asp Gly Met Phe Tyr Leu Tyr Asn Asn Asp Leu
530535540
Gly His Tyr Ser Glu Asn Tyr Trp Ala Thr Val Asn Pro Tyr Arg Leu
545550555560
Pro Gly Thr Thr Glu Thr Glu Gln Lys Pro Leu Glu Gly Thr Pro Glu
565570575
Asn Ile Lys Thr Asn Tyr Gln Gln Val Gly Met Thr Ser Leu Ser Asp
580585590
Asp Ala Phe Val Ala Ser Lys Lys Leu Asn Asn Thr Ser Ala Leu Ala
595600605
Ala Met Thr Phe Thr Asn Trp Asn Lys Ser Leu Thr Leu Asn Lys Gly
610615620
Trp Phe Ile Leu Gly Asn Lys Ile Ile Phe Val Gly Ser Asn Ile Lys
625630635640
Asn Gln Ser Ser His Lys Ala Tyr Thr Thr Ile Glu Gln Arg Lys Glu
645650655
Asn Gln Lys His Pro Tyr Cys Ser Tyr Val Asn Asn Gln Pro Val Asp
660665670
Leu Asn Asn Gln Leu Val Asp Phe Thr Asn Thr Lys Ser Ile Phe Leu
675680685
Glu Ser Asp Asp Pro Ala Gln Asn Ile Gly Tyr Tyr Phe Phe Lys Pro
690695700
Thr Thr Leu Ser Ile Ser Lys Ala Leu Gln Thr Gly Lys Trp Gln Asn
705710715720
Ile Lys Ala Asp Asp Lys Ser Pro Glu Ala Ile Lys Glu Val Ser Asn
725730735
Thr Phe Ile Thr Ile Met Gln Asn His Thr Gln Asp Gly Asp Arg Tyr
740745750
Ala Tyr Met Met Leu Pro Asn Met Thr Arg Gln Glu Phe Glu Thr Tyr
755760765
Ile Ser Lys Leu Asp Ile Asp Leu Leu Glu Asn Asn Asp Lys Leu Ala
770775780
Ala Val Tyr Asp His Asp Ser Gln Gln Met His Val Ile His Tyr Glu
785790795800
Lys Lys Ala Thr Met Phe Ser Asn His Asn Leu Ser His Gln Gly Phe
805810815
Tyr Ser Phe Pro His Pro Val Lys Gln Asn Gln Gln
820825
<210> 92
<211> 828
<212> PRT
<213> Streptococcus pyogenes
<220>
<223> Streptococcus pyogenes serotype M28, strain
MGAS6180
<400> 92
Met Val Tyr Phe Tyr Leu Val Asn Gln Phe Thr Phe Ile Ile Ser Phe
151015
Leu Tyr Arg Arg Asn Leu Ser Val Asn Thr Tyr Phe Cys Thr His His
202530
Lys Gln Leu Leu Leu Tyr Ser Asn Leu Phe Leu Ser Phe Ala Met Met
354045
Gly Gln Gly Thr Ala Ile Tyr Ala Asp Thr Leu Thr Ser Asn Ser Glu
505560
Pro Asn Asn Thr Tyr Phe Gln Thr Gln Met Leu Thr Thr Thr Asp Ser
65707580
Glu Lys Lys Val Val Gln Pro Gln Gln Lys Asp Tyr Tyr Thr Glu Leu
859095
Leu Asp Gln Trp Asn Ser Ile Ile Ala Gly Asn Asp Ala Tyr Asp Lys
100105110
Thr Asn Pro Asp Met Val Thr Phe His Asn Lys Ala Glu Lys Asp Ala
115120125
Gln Asn Ile Ile Lys Ser Tyr Gln Gly Pro Asp His Glu Asn Arg Thr
130135140
Tyr Leu Trp Glu His Ala Lys Asp Tyr Ser Ala Ser Ala Asn Ile Thr
145150155160
Lys Thr Tyr Arg Asn Ile Glu Lys Ile Ala Lys Gln Ile Thr Asn Pro
165170175
Glu Ser Cys Tyr Tyr Gln Asp Ser Lys Ala Ile Ala Ile Val Lys Asp
180185190
Gly Met Ala Phe Met Tyr Glu His Ala Tyr Asn Leu Asp Arg Glu Asn
195200205
His Gln Thr Thr Gly Lys Glu Asn Lys Glu Asn Trp Trp Val Tyr Glu
210215220
Ile Gly Thr Pro Arg Ala Ile Asn Asn Thr Leu Ser Leu Met Tyr Pro
225230235240
Tyr Phe Thr Gln Glu Glu Ile Leu Lys Tyr Thr Ala Pro Ile Glu Lys
245250255
Phe Val Pro Asp Pro Thr Arg Phe Arg Val Arg Ala Ala Asn Phe Ser
260265270
Pro Phe Glu Ala Asn Ser Gly Asn Leu Ile Asp Met Gly Arg Val Lys
275280285
Leu Ile Ser Gly Ile Leu Arg Lys Asp Asp Leu Glu Ile Ser Asp Thr
290295300
Ile Lys Ala Ile Glu Lys Val Phe Thr Leu Val Asp Glu Gly Asn Gly
305310315320
Phe Tyr Gln Asp Gly Ser Leu Ile Asp His Val Val Thr Asn Ala Gln
325330335
Ser Pro Leu Tyr Lys Lys Gly Ile Ala Tyr Thr Gly Ala Tyr Gly Asn
340345350
Val Leu Ile Asp Gly Leu Ser Gln Leu Ile Pro Ile Ile Gln Lys Thr
355360365
Lys Ser Ser Ile Glu Ala Asp Lys Met Ala Thr Ile Tyr His Trp Ile
370375380
Asn His Ser Phe Phe Pro Ile Ile Val Arg Gly Glu Met Met Asp Met
385390395400
Thr Arg Gly Arg Ser Ile Ser Arg Phe Asn Ala Gln Ser His Val Ala
405410415
Gly Ile Glu Ala Leu Arg Ala Ile Leu Arg Ile Ala Asp Met Ser Glu
420425430
Glu Pro His Arg Leu Ala Leu Lys Thr Arg Ile Lys Thr Leu Val Thr
435440445
Gln Gly Asn Ala Phe Tyr Asn Val Tyr Asp Asn Leu Lys Thr Tyr His
450455460
Asp Ile Lys Leu Met Lys Glu Leu Leu Ser Asp Thr Ser Val Pro Val
465470475480
Gln Lys Leu Asp Ser Tyr Val Ala Ser Phe Asn Ser Met Asp Lys Leu
485490495
Ala Leu Tyr Asn Asn Lys His Asp Phe Ala Phe Gly Leu Ser Met Phe
500505510
Ser Asn Arg Thr Gln Asn Tyr Glu Ala Met Asn Asn Glu Asn Leu His
515520525
Gly Trp Phe Thr Ser Asp Gly Met Phe Tyr Leu Tyr Asn Asn Asp Leu
530535540
Gly His Tyr Ser Glu Asn Tyr Trp Ala Thr Val Asn Pro Tyr Arg Leu
545550555560
Pro Gly Thr Thr Glu Thr Glu Gln Lys Pro Leu Glu Gly Thr Pro Glu
565570575
Asn Ile Lys Thr Asn Tyr Gln Gln Val Gly Met Thr Ser Leu Ser Asp
580585590
Asp Ala Phe Val Ala Ser Lys Lys Leu Asn Asn Thr Ser Ala Leu Ala
595600605
Ala Met Thr Phe Thr Asn Trp Asn Lys Ser Leu Thr Leu Asn Lys Gly
610615620
Trp Phe Ile Leu Gly Asn Lys Ile Ile Phe Val Gly Ser Asn Ile Lys
625630635640
Asn Gln Ser Ser His Lys Ala Tyr Thr Thr Ile Glu Gln Arg Lys Glu
645650655
Asn Gln Lys His Pro Tyr His Ala Tyr Val Asn Asn Gln Pro Val Asp
660665670
Leu Asn Asn Gln Leu Val Asp Phe Thr Asn Thr Lys Ser Ile Phe Leu
675680685
Glu Ser Asp Asp Ser Ala Gln Asn Ile Gly Tyr Tyr Phe Phe Lys Pro
690695700
Thr Thr Leu Ser Ile Ser Lys Ala Leu Gln Thr Gly Lys Trp Gln Asn
705710715720
Ile Lys Ala Asp Asp Lys Ser Pro Glu Ala Ile Lys Glu Val Ser Asn
725730735
Thr Phe Ile Thr Ile Met Gln Asn His Thr Gln Asp Gly Asp Arg Tyr
740745750
Ala Tyr Met Met Leu Pro Asn Met Thr Arg Gln Glu Phe Glu Thr Tyr
755760765
Ile Ser Lys Leu Asp Ile Asp Leu Leu Glu Asn Asn Asp Lys Leu Ala
770775780
Ala Val Tyr Asp His Asp Ser Gln Gln Met His Val Ile His Tyr Glu
785790795800
Lys Lys Ala Thr Met Phe Ser Asn His Asn Leu Ser His Gln Gly Phe
805810815
Tyr Ser Phe Pro His Pro Val Lys Gln Asn Gln Gln
820825
<210> 93
<211> 522
<212> PRT
<213> Streptococcus suis
<220>
<223> Streptococcus suis 05ZYH33 hyaluronidase
<400> 93
Met Gly Phe Phe Ile Ser Gln Ser Lys Gln His Tyr Gly Ile Arg Lys
151015
Tyr Lys Val Gly Val Cys Ser Ala Leu Ile Ala Leu Ser Ile Leu Gly
202530
Thr Arg Val Ala Ala Asn Gln Leu Pro Ser Thr Glu Thr Ala Ser Pro
354045
Gln Ser Ser Gln Leu Val Glu Thr Thr Pro Glu Thr Thr Glu Ala Val
505560
Asn Leu Thr Thr Glu Ala Val Met Thr Ser Glu Val Ser Ser Glu Val
65707580
Ser Pro Val Thr Ser Thr Glu Thr Gln Pro Ser Ser Thr Ala Ala Glu
859095
Thr Leu Ala Ser Pro Gln Ala Val Gln Ala Thr Lys Glu Glu Glu Lys
100105110
Asn Leu Val Ala Asn Gly Glu Phe Ala Ser Thr Thr Ala Ala Ser Gly
115120125
Asn Trp Ala Asp Pro Ala Ala Thr Asn Trp Glu Thr Trp Ile Pro Ala
130135140
Asn Val Lys Lys Glu Asn Gly Gln Val Arg Ile Asp Glu Gly Arg Leu
145150155160
His Ile Ser Ser Thr Ala Ser Tyr Arg Val Ala Val His Gln Thr Val
165170175
Asp Val Asp Pro Asn Lys Arg Tyr Leu Phe Ser Tyr Asn Val Glu Thr
180185190
Lys Asp Leu Lys Gly Ser Gly Val Arg Val Arg Leu Arg Ser Leu Thr
195200205
Ala Glu Gly Lys Asp Leu Ser Pro Gln Glu Phe Ala Tyr Thr Pro Tyr
210215220
Lys Asn Gly Ser Gln Ala Glu His Ile Glu Gln Ile Leu Thr Val Ser
225230235240
Pro Glu Thr Arg Lys Leu Lys Val Glu Leu Phe Phe Glu Asn Ser Val
245250255
Gly Gln Ala Trp Leu Asp Asn Ile Ser Leu Val Glu Tyr Val Glu Lys
260265270
Thr Pro Glu Thr Pro Glu Pro Ser Leu Glu Leu Val Gln Pro Glu Thr
275280285
Gly Gln Ile Ser Leu Ala Ser Asn Lys Val Tyr Leu Pro Val Arg Pro
290295300
Asp Leu Thr Tyr Arg Ile Ala Asp Ala Ala Val Ala Ile Val Glu Lys
305310315320
Asn Met Ile Arg Pro Leu Ala Ala Gly Lys Thr Gln Val Asp Val Tyr
325330335
Asp Lys Asp Thr Lys Leu Ser Ser Phe Glu Leu Thr Val Thr Glu His
340345350
Gln Ala Thr Val Phe Asp Thr Leu Arg Asn Asn Trp Glu Asp Ile Ser
355360365
Leu Ala Asn Lys Arg Tyr Gln Ser Asn Asp Thr Gln Met Lys Ala Phe
370375380
Leu Gly Arg Leu Asp Ala Gly Val Ala Ser Ser Leu Lys Lys Trp Val
385390395400
Glu Pro Thr Asn Gln Gly Lys Thr Ile Phe Asn Asp Ile Asp Phe Ser
405410415
Lys Ser Ser His Leu Thr Thr Val Tyr Arg Arg Leu Glu Gln Met Ala
420425430
Gln Val Val Glu Asn Pro Asp Ser Ala Tyr Tyr His Asp Arg Ser Leu
435440445
Ile Asp Leu Val Arg Lys Gly Met Asn Trp Leu Tyr Thr Asn Val Tyr
450455460
Asn Glu Asn Lys Ser Ile Asp Gly Asn Trp Trp Asp Tyr Glu Ile Gly
465470475480
Thr Pro Arg Ala Val Val Asn Thr Leu Ile Tyr Met His Pro Tyr Phe
485490495
Ser Gln Glu Glu Ile Leu Thr Tyr Thr Lys Pro Ile Ser Lys Phe Val
500505510
Pro Asp Pro Thr Thr Ile Ser Val Lys His
515520
<210> 94
<211> 1164
<212> PRT
<213> Streptococcus suis
<220>
<223> Streptococcus suis hyaluronidase
<400> 94
Met Gly Phe Phe Ile Ser Gln Ser Lys Gln His Tyr Gly Ile Arg Lys
151015
Tyr Lys Val Gly Val Cys Ser Ala Leu Ile Ala Leu Ser Ile Leu Gly
202530
Thr Arg Val Ala Ala Asn Gln Leu Pro Ser Thr Glu Thr Ala Ser Pro
354045
Gln Ser Ser Gln Leu Val Glu Thr Thr Pro Glu Thr Thr Glu Ala Val
505560
Met Thr Ser Glu Val Ser Ser Glu Val Ser Pro Val Thr Ser Thr Glu
65707580
Thr Gln Pro Ser Ser Thr Thr Ala Glu Thr Leu Ala Ser Pro Gln Ala
859095
Val Gln Ala Thr Lys Glu Glu Lys Asn Leu Val Ala Asn Gly Glu Phe
100105110
Ile Ser Thr Thr Ala Pro Ser Gly Asn Trp Lys Glu Leu Ala Ala Thr
115120125
Asn Trp Glu Thr Trp Ile Pro Ala Asn Val Lys Lys Glu Asn Gly Gln
130135140
Val Arg Ile Asp Glu Gly Arg Leu His Ile Ser Ser Thr Ala Ser Tyr
145150155160
Arg Val Ala Val His Gln Thr Val Asp Val Asp Pro Asn Lys Arg Tyr
165170175
Leu Phe Ser Tyr Asp Val Glu Thr Lys Asp Leu Lys Gly Ser Gly Val
180185190
Arg Val Arg Leu Arg Ser Leu Thr Ala Glu Gly Lys Asp Leu Ser Pro
195200205
Gln Glu Phe Ala Tyr Thr Pro Tyr Lys Asn Gly Ser Gln Ala Glu His
210215220
Ile Glu Gln Ile Leu Thr Val Ser Pro Glu Thr Arg Lys Leu Lys Val
225230235240
Glu Leu Phe Phe Glu Asn Ser Val Gly Gln Ala Trp Leu Asp Asn Ile
245250255
Ser Leu Val Glu Tyr Val Glu Lys Thr Pro Glu Thr Pro Glu Gln Ser
260265270
Pro Glu Leu Val Gln Pro Glu Thr Gly Gln Ile Ser Leu Ala Ser Asn
275280285
Lys Val Tyr Leu Pro Val Arg Pro Asp Leu Thr Tyr Arg Ile Ala Asp
290295300
Ala Ala Val Ala Thr Val Glu Lys Asn Met Ile Arg Pro Leu Ala Ala
305310315320
Gly Lys Thr Gln Val Asp Val Tyr Asp Lys Asp Thr Lys Leu Ser Ser
325330335
Phe Glu Leu Ile Val Thr Glu His Gln Ala Thr Val Phe Asp Thr Leu
340345350
Arg Asn Asn Trp Glu Asp Ile Ser Leu Ala Asn Lys Arg Tyr Gln Ser
355360365
Asn Asp Ala Gln Met Lys Ala Phe Leu Gly Arg Leu Asp Ala Gly Val
370375380
Ala Ser Ser Leu Glu Lys Trp Val Glu Pro Thr Glu Gln Ser Lys Thr
385390395400
Ile Phe Asn Asp Ile Asp Phe Ser Lys Ser Ser His Leu Thr Thr Val
405410415
Tyr Arg Arg Leu Glu Gln Met Ala Gln Val Val Glu Asn Pro Asp Ser
420425430
Ala Tyr Tyr His Asp Arg Ser Leu Ile Asp Leu Val Arg Lys Gly Met
435440445
Asn Trp Leu Tyr Ala Asn Val Tyr Asn Glu Asn Lys Ser Ile Asp Gly
450455460
Asn Trp Trp Asp Tyr Glu Ile Gly Thr Ser Arg Ala Val Val Asn Thr
465470475480
Leu Ile Tyr Met His Pro Tyr Phe Ser Gln Glu Glu Ile Leu Thr Tyr
485490495
Thr Lys Pro Ile Ser Lys Phe Val Pro Asp Pro Thr Thr Ile Arg Lys
500505510
Thr Leu Thr Asn Pro Val Pro Ala Val Gly Gly Asn Gln Thr Asp Leu
515520525
Ser Lys Val Ala Ile Leu Glu Gly Ala Leu Arg Glu Asp Ala Asp Arg
530535540
Val Arg Ala Gly Ala Gln Gly Leu Thr Thr Ile Met Lys Phe Val Asp
545550555560
Lys Gly Glu Gly Phe Tyr Arg Asp Gly Ser Phe Ile Asp His Thr Asn
565570575
Val Ala Tyr Thr Gly Ala Tyr Gly Asn Val Leu Ile Glu Gly Phe Ser
580585590
Gln Leu Leu Pro Val Ile Gln Pro Thr Glu Phe Ala Leu Lys Glu Glu
595600605
Gln Thr Asn Ile Leu Tyr Glu Trp Ile Glu Lys Ala Phe Met Pro Ile
610615620
Leu Val Arg Gly Glu Leu Met Asp Met Thr Arg Gly Arg Ser Ile Ser
625630635640
Arg Ala Thr Gly Glu Ser His Val Gln Ala Met Glu Ile Leu Arg Ser
645650655
Leu Val Arg Ile Ala Glu Ser Ala Gln Pro Glu Gln Lys Thr Lys Leu
660665670
Leu Ser Phe Val Lys Ala Gln Leu Thr Ser Asp Thr Phe Tyr Asp Ser
675680685
Tyr Arg Ser Leu Lys Ser Tyr Lys Asp Ile Asp Leu Val Asn Lys Leu
690695700
Leu Ala Asp Asn Gln Ile Pro Ala Glu Val Asp Lys Asp Tyr Ile Ala
705710715720
Ala Phe Asn Asn Met Asp Lys Phe Val Tyr Arg Ser Ala Gln Glu Gly
725730735
Phe Thr Phe Ala Leu Ser Met Tyr Ser Ser Arg Thr Gln Asn Tyr Glu
740745750
Asp Met Asn Asn Glu Asn Arg Lys Gly Trp Tyr Thr Ala Asp Gly Met
755760765
Val Tyr Leu Tyr Asn Asp Asp Leu Ser His Tyr Ser Asn His Tyr Trp
770775780
Ala Thr Val Asp Pro Tyr Arg Leu Pro Gly Thr Thr Thr Thr Lys Asp
785790795800
Lys Arg Glu Asp Gly Ser Gly Glu Val Thr Leu Ala Ser Asp Phe Val
805810815
Gly Ala Ser Gln Leu Gly Asn Arg Leu Ala Thr Ile Ala Met Asp Phe
820825830
Asn Asn Trp Asn Asn Ser Leu Thr Ala Arg Lys Ala Trp Ile Val Leu
835840845
Gly Asn Lys Ile Val Phe Leu Gly Thr Asp Ile Gln His Gln Ser Ala
850855860
Gln Gly Ala Glu Thr Thr Ile Glu Asn Arg Lys Leu Leu Thr Gly Glu
865870875880
Lys Tyr Ser Tyr Tyr Ile Asn Gly Gln Pro Val Asp Leu Ser Lys Glu
885890895
Val Val Thr Asp Lys Thr Gln Ser Phe Tyr Met Thr Asn Gly Lys Asp
900905910
Asn Gln Ser Ile Gly Tyr Val Phe Leu Asn Gln Leu Pro Thr His Ala
915920925
Lys Leu Asp Gln Arg Thr Gly Lys Trp Ser Asp Ile Asn Tyr Asn Gln
930935940
Ser Lys Glu Glu Val Ser Asn Ser Phe Val Ser Leu Trp His Glu His
945950955960
Ala Gln Thr Ser Ser Asn Tyr Ala Tyr Val Leu Val Pro Asn Gln Ser
965970975
Met Glu Lys Val Asn Gln Ala Ala Ala Ser Val Lys Leu Leu His Gln
980985990
Asp Arg Asp Leu Gln Val Val Tyr Asp Gln Glu Gln Asn Val Trp Gly
99510001005
Val Val Lys Tyr Thr Asp Thr Ala Tyr Lys Leu Thr Asp Asp Ile Thr
101010151020
Leu Thr Asp Ala Gly Leu Tyr Thr Ile Gln Lys Val Glu Gly Gly Tyr
1025103010351040
Arg Ile Ala Phe Tyr Asn Pro Ser Thr Arg Thr Val Lys Asn Gly Ile
104510501055
Glu Leu Thr Lys Ala Gly Ser Ser Leu Thr Val Glu Met Glu Pro Thr
106010651070
Ala Ala Tyr Pro Ser Thr Val Trp Lys Val Thr Met Pro Glu Gly Ser
107510801085
Asp Lys Gln Thr Gly Ser Val Glu Lys Thr Glu Lys Glu Glu Lys Gln
109010951100
Leu Lys Glu Asn Gln Pro Ser Ser Glu Val Lys Gln Val Val His His
1105111011151120
Ala Ala Glu Lys Thr Lys Pro Ser Lys Pro Arg Leu Pro Gln Thr Gly
112511301135
Glu Glu Ala Ser Leu Gly Leu Gly Phe Leu Gly Leu Leu Thr Leu Gly
114011451150
Ala Val Val Asp Phe Lys Cys Arg Arg Ser His Ser
11551160
<210> 95
<211> 1164
<212> PRT
<213> Streptococcus suis
<220>
<223> Streptococcus suis ST3 hyaluronidase
<400> 95
Met Gly Phe Phe Ile Ser Gln Ser Lys Gln His Tyr Gly Ile Arg Lys
151015
Tyr Lys Val Gly Val Cys Ser Ala Leu Ile Ala Leu Ser Ile Leu Gly
202530
Thr Arg Val Ala Ala Asn Gln Leu Pro Ser Thr Glu Thr Ala Ser Pro
354045
Gln Ser Ser Gln Leu Val Glu Thr Thr Pro Glu Thr Thr Glu Ala Val
505560
Met Thr Ser Glu Val Ser Ser Glu Val Ser Pro Val Thr Ser Thr Glu
65707580
Thr Gln Pro Ser Ser Thr Thr Ala Glu Thr Leu Ala Ser Pro Gln Ala
859095
Val Gln Ala Thr Lys Glu Glu Lys Asn Leu Val Ala Asn Gly Glu Phe
100105110
Ile Ser Thr Thr Ala Pro Ser Gly Asn Trp Lys Glu Leu Ala Ala Thr
115120125
Asn Trp Glu Thr Trp Ile Pro Ala Asn Val Lys Lys Glu Asn Gly Gln
130135140
Val Arg Ile Asp Glu Gly Arg Leu His Ile Ser Ser Thr Ala Ser Tyr
145150155160
Arg Val Ala Val His Gln Thr Val Asp Val Asp Pro Asn Lys Arg Tyr
165170175
Leu Phe Ser Tyr Asp Val Glu Thr Lys Asp Leu Lys Gly Ser Gly Val
180185190
Arg Val Arg Leu Arg Ser Leu Thr Ala Glu Gly Lys Asp Leu Ser Pro
195200205
Gln Glu Phe Ala Tyr Thr Pro Tyr Lys Asn Gly Ser Gln Ala Glu His
210215220
Ile Glu Gln Ile Leu Thr Val Ser Pro Glu Thr Arg Lys Leu Lys Val
225230235240
Glu Leu Phe Phe Glu Asn Ser Val Gly Gln Ala Trp Leu Asp Asn Ile
245250255
Ser Leu Val Glu Tyr Val Glu Lys Thr Pro Glu Thr Pro Glu Gln Ser
260265270
Pro Glu Leu Val Gln Pro Glu Thr Gly Gln Ile Ser Leu Ala Ser Asn
275280285
Lys Val Tyr Leu Pro Val Arg Pro Asp Leu Thr Tyr Arg Ile Ala Asp
290295300
Ala Ala Val Ala Thr Val Glu Lys Asn Met Ile Arg Pro Leu Ala Ala
305310315320
Gly Lys Thr Gln Val Asp Val Tyr Asp Lys Asp Thr Lys Leu Ser Ser
325330335
Phe Glu Leu Ile Val Thr Glu His Gln Ala Thr Val Phe Asp Thr Leu
340345350
Arg Asn Asn Trp Glu Asp Ile Ser Leu Ala Asn Lys Arg Tyr Gln Ser
355360365
Asn Asp Ala Gln Met Lys Ala Phe Leu Gly Arg Leu Asp Ala Gly Val
370375380
Ala Ser Ser Leu Glu Lys Trp Val Glu Pro Thr Glu Gln Ser Lys Thr
385390395400
Ile Phe Asn Asp Ile Asp Phe Ser Lys Ser Ser His Leu Thr Thr Val
405410415
Tyr Arg Arg Leu Glu Gln Met Ala Gln Val Val Glu Asn Pro Asp Ser
420425430
Ala Tyr Tyr His Asp Arg Ser Leu Ile Asp Leu Val Arg Lys Gly Met
435440445
Asn Trp Leu Tyr Thr Asn Val Tyr Asn Glu Asn Lys Ser Ile Asp Gly
450455460
Asn Trp Trp Asp Tyr Glu Ile Gly Thr Pro Arg Ala Val Val Asn Thr
465470475480
Leu Ile Tyr Met His Pro Tyr Phe Ser Gln Glu Glu Ile Leu Thr Tyr
485490495
Thr Lys Pro Ile Ser Lys Phe Val Pro Asp Pro Thr Thr Ile Arg Lys
500505510
Thr Leu Thr Asn Pro Val Pro Ala Val Gly Gly Asn Gln Thr Asp Leu
515520525
Ser Lys Val Ala Ile Leu Glu Gly Ala Leu Arg Glu Asp Ala Asp Arg
530535540
Val Arg Ala Gly Ala Gln Gly Leu Thr Thr Ile Met Lys Phe Val Asp
545550555560
Lys Gly Glu Gly Phe Tyr Arg Asp Gly Ser Phe Ile Asp His Thr Asn
565570575
Val Ala Tyr Thr Gly Ala Tyr Gly Asn Val Leu Ile Glu Gly Phe Ser
580585590
Gln Leu Leu Pro Val Ile Gln Pro Thr Glu Phe Ala Leu Lys Glu Glu
595600605
Gln Thr Asn Ile Leu Tyr Glu Trp Ile Glu Lys Ala Phe Met Pro Ile
610615620
Leu Val Arg Gly Glu Leu Met Asp Met Thr Arg Gly Arg Ser Ile Ser
625630635640
Arg Ala Thr Gly Glu Ser His Val Gln Ala Met Glu Ile Leu Arg Ser
645650655
Leu Val Arg Ile Ala Glu Ser Ala Gln Pro Glu Gln Lys Thr Lys Leu
660665670
Leu Ser Phe Val Lys Ala Gln Leu Thr Ser Asp Thr Phe Tyr Asp Ser
675680685
Tyr Arg Ser Leu Lys Ser Tyr Lys Asp Ile Asp Leu Val Asn Lys Leu
690695700
Leu Ala Asp Asn Gln Ile Pro Ala Glu Val Asp Lys Asp Tyr Ile Ala
705710715720
Ala Phe Asn Asn Met Asp Lys Phe Val Tyr Arg Ser Ala Gln Glu Gly
725730735
Phe Thr Phe Ala Leu Ser Met Tyr Ser Ser Arg Thr Gln Asn Tyr Glu
740745750
Asp Met Asn Asn Glu Asn Arg Lys Gly Trp Tyr Thr Ala Asp Gly Met
755760765
Val Tyr Leu Tyr Asn Asp Asp Leu Ser His Tyr Ser Asn His Tyr Trp
770775780
Ala Thr Val Asp Pro Tyr Arg Leu Pro Gly Thr Thr Thr Thr Lys Asp
785790795800
Lys Arg Glu Asp Gly Ser Gly Glu Val Thr Leu Ala Ser Asp Phe Val
805810815
Gly Ala Ser Gln Leu Gly Asn Arg Leu Ala Thr Ile Ala Met Asp Phe
820825830
Asn Asn Trp Asn Asn Ser Leu Thr Ala Arg Lys Ala Trp Ile Val Leu
835840845
Gly Asn Lys Ile Val Phe Leu Gly Thr Asp Ile Gln His Gln Ser Ala
850855860
Gln Gly Ala Glu Thr Thr Ile Glu Asn Arg Lys Leu Leu Thr Gly Glu
865870875880
Lys Tyr Ser Tyr Tyr Ile Asn Gly Gln Pro Val Asp Leu Ser Lys Glu
885890895
Val Val Thr Asp Lys Thr Gln Ser Phe Tyr Met Thr Asn Gly Lys Asp
900905910
Asn Gln Ser Ile Gly Tyr Val Phe Leu Asn Gln Leu Pro Thr His Ala
915920925
Lys Leu Asp Gln Arg Thr Gly Lys Trp Ser Asp Ile Asn Tyr Asn Gln
930935940
Ser Lys Glu Glu Val Ser Asn Ser Phe Val Ser Leu Trp His Glu His
945950955960
Ala Gln Thr Ser Ser Asn Tyr Ala Tyr Val Leu Val Pro Asn Gln Ser
965970975
Met Glu Lys Val Asn Gln Ala Ala Ala Ser Val Lys Leu Leu His Gln
980985990
Asp Arg Asp Leu Gln Val Val Tyr Asp Gln Glu Gln Asn Val Trp Gly
99510001005
Val Val Lys Tyr Thr Asp Thr Ala Tyr Lys Leu Thr Asp Asp Ile Thr
101010151020
Leu Thr Asp Ala Gly Leu Tyr Thr Ile Gln Lys Val Glu Gly Gly Tyr
10251030 10351040
Arg Ile Ala Phe Tyr Asn Pro Ser Thr Arg Thr Val Lys Asn Gly Ile
104510501055
Glu Leu Thr Lys Ala Gly Ser Ser Leu Thr Val Glu Met Glu Pro Thr
106010651070
Ala Ala Tyr Pro Ser Thr Val Trp Lys Val Thr Met Pro Glu Gly Ser
107510801085
Asp Lys Gln Thr Gly Ser Val Glu Lys Thr Glu Lys Glu Glu Lys Gln
109010951100
Leu Lys Glu Asn Gln Pro Ser Ser Glu Val Lys Gln Val Val His His
1105111011151120
Ala Ala Glu Lys Thr Lys Pro Ser Lys Pro Arg Leu Pro Gln Thr Gly
112511301135
Glu Glu Ala Ser Leu Gly Leu Gly Phe Leu Gly Leu Leu Thr Leu Gly
114011451150
Ala Val Val Asp Phe Lys Cys Arg Arg Ser His Ser
11551160
<210> 96
<211> 802
<212> PRT
<213> Vibrio fischeri
<220>
<223> Vibrio fischeri strain ATCC 700601/ES114
hyaluronate lyase precursor
<400> 96
Met Tyr Met Ile Lys Lys His Arg Leu Asn Thr Ile Ala Leu Ser Met
151015
Leu Phe Leu Phe Thr Gly Asn Ala Tyr Ala Ala Lys Asn Thr Gln Thr
202530
Pro Gln Tyr Leu Pro Ser Asp Phe Glu Gln Val Arg Glu Asn Trp Ala
354045
Glu Asn Tyr Leu Gly Asp Pro Ala Ile Thr Phe Asp Gln Thr Leu Lys
505560
Asn Met Val Thr Ser Thr Asn Ser Ser Ala Gln Lys His Trp Asp Ser
65707580
Met Thr Pro Gln Pro Asn Ala Ser Gly Ile Trp Asp Asp Leu Pro Leu
859095
Ile Asp Lys Asp Thr Thr Leu Gly Pro Asn Ile Arg Asn Ser Tyr Gln
100105110
Arg Leu Phe Thr Met Ala Lys Ala Tyr Arg Leu Arg Asp Gly Asn Leu
115120125
Glu Asn Asn Gln Leu Met Leu Asn Asp Ile Met Thr Ala Met Asn Tyr
130135140
Ile Asn Gln Asn Phe Tyr Phe Val Asn Gln Leu Glu Tyr Gly Asn Trp
145150155160
Trp Gln Trp Glu Leu Ala Ile Pro Lys Asp Ile His Asn Ile Leu Val
165170175
Leu Leu Phe Asp Asp Ile Lys Asp Asn Tyr Gln Thr Ile Ile Thr Asn
180185190
His Leu Asn Ala Thr Arg Tyr Phe Thr Pro Asp Pro Thr His Leu Gly
195200205
Val Ser Pro Gly Ala Ala Glu Ser Thr Asn Pro Asn Tyr Arg Glu Ser
210215220
Thr Gly Gly Asn Arg Thr Asp Asn Ala Gln Val Val Leu Ile Arg Gly
225230235240
Met Leu Glu Asn Asn Ser Glu Glu Ile Ser Gln Ala Ile Ala Ala Leu
245250255
Pro Ala Val Ile Glu Tyr Val Ser Glu Gly Asp Gly Tyr Tyr Thr Asp
260265270
Gly Ser Phe Leu Gln His Ser Asp Ile Ala Tyr Asn Gly Thr Tyr Gly
275280285
Asn Val Leu Leu Gly Gly Leu Gly Ile Gln Met Asn Ala Val Ala Gly
290295300
Ser Pro Trp Ser Met Asp Asn Gln Thr Ile Ser Asn Val Tyr Asn Ile
305310315320
Ile Asn Gln Ser Tyr Glu Pro Leu Leu Tyr Lys Gly Ala Met Met Asp
325330335
Met Val Asn Gly Arg Ser Ile Ser Arg Ser Ala Glu Gln Asn His Asp
340345350
Val Gly Leu Asn Ile Val Asn Ser Met Leu Phe Tyr Thr Asn Gly Pro
355360365
Asp Ser Asp Lys Asn Lys Gln Leu Ser Ser Leu Ile Lys Thr Gln Ile
370375380
Thr Asp Asp Thr Tyr Gln Asn Phe Phe Asp Lys Ile Tyr Tyr Val Ser
385390395400
Thr Tyr Gln Ala Ala Gln His Ile Val Asn Asp Pro Thr Val Ser Leu
405410415
Lys Asp Pro Leu Ile Gly Asn Phe Ser Tyr Pro Ser Met Asp Arg Ile
420425430
Val His Arg Arg Thr Asp Trp Ala Phe Ala Leu Ala Met His Ser Tyr
435440445
Arg Ile Gly Asn Tyr Glu Cys Met Asn Gly Glu Asn Leu Lys Gly Trp
450455460
Phe Thr Gly Asp Gly Met Ile Tyr Leu Tyr Asn Asp Gln Leu Asp His
465470475480
Tyr Thr Gly Tyr Trp Pro Thr Val Asn Ala Ser Arg Met Pro Gly Thr
485490495
Thr Val Asp Ser Gln Ile Met Ala Asp Cys Ser Gly Glu Arg Val Gly
500505510
Gly Asn Val Asn Thr Asn Met Gln Trp Val Gly Ser Thr Ser Leu Asn
515520525
Asn Tyr Gly Ile Ala Gly Met Gln Phe Tyr Asn Trp Ser Asp Thr Leu
530535540
Ser Ala Tyr Lys Ser Trp Phe Met Phe Asp Asn Glu Val Val Met Leu
545550555560
Gly Ser Asn Ile Lys Asp Gln Ser Asn Ala Asn Asn Ile Thr Thr Ile
565570575
Glu Asn Arg Lys Arg Leu Ala Glu Thr Lys Leu Phe Ile Asp Gly Thr
580585590
Glu Gln Ala Ala Leu Pro Tyr Gln Gly Ala Pro Ala Thr Phe Ser Ile
595600605
Arg Asn Lys Thr Leu Ala Asn Ser Asp Leu Ser Tyr Val Met Leu Thr
610615620
Pro Lys Thr Ile Ser Ile Ser Gln Asn Asp Val Asp Gly Asn Trp Ser
625630635640
Asp Ile Gly Asn Ser Lys Gly Asp Val Ser Asp Ser Tyr Leu Gln Ala
645650655
Thr Leu Thr Gln Val Asp Gln Ala Asp Tyr Gln Tyr Ala Leu Leu Pro
660665670
Asn Gln Asn Asn Asp Thr Val Gln Asn Tyr Ala Gln His Pro Asp Val
675680685
Thr Val Leu Arg Gln Asp Glu Gln Ala His Ala Val Gln Glu Asn Thr
690695700
Leu Asn Ile Ile Ala Ala Asn Asn Trp Lys Asn Asn Pro Val Asn Ile
705710715720
Thr Asp Thr Ile Thr Leu Asn Ser Met Met Gly Phe Met Ile Lys Glu
725730735
Glu Ser Ser Asn Thr Phe Thr Val Ala Val Ser Glu Pro Ile Gln Thr
740745750
Ile Asp Ser Val Asn Phe Thr Phe Asp Lys Gln Gly Ile Val Ile Lys
755760765
Glu Asp Ile Glu Asn Arg Val Val Leu Asn Gly Thr Thr Leu Thr Ile
770775780
Asn Thr Ser Gly Leu Gln Gly Gln Ser Tyr Ser Phe Gln Val Thr Ile
785790795800
Gln Asp
<210> 97
<211> 517
<212> PRT
<213> Synechococcus sp.
<220>
<223> Synechococcus sp. RCC307 neutral invertase-like
protein
<400> 97
Met Gly Ala Pro Ala Ile Pro Lys Val Pro Arg Ser Pro Ser Lys Ser
151015
Glu His Thr Thr Arg Pro Asn Ser Gly Glu Ser Glu Val Val Arg Gln
202530
Ala Glu Glu Leu Phe Glu Gln Thr Leu Val Asn Val Arg Gly Gln Leu
354045
Ala Gly Ala Val Ala Ala Leu Glu Ser Ser Val His Asp Ser Glu Leu
505560
Asn Tyr Gly Glu Ile Phe Leu Arg Asp Asn Val Pro Val Met Val Tyr
65707580
Leu Leu Leu Arg Gly Arg Phe Glu Ile Val Arg His Phe Leu Asp Leu
859095
Cys Leu Glu Leu Gln Ser Arg Ser Tyr Arg Thr Arg Gly Val Phe Pro
100105110
Thr Ser Phe Val Glu Glu Asp Asp Lys Ile Leu Ala Asp Tyr Gly Gln
115120125
Arg Ser Ile Gly Arg Ile Thr Ser Val Asp Ala Ser Leu Trp Trp Pro
130135140
Val Leu Cys Trp Met Tyr Val Arg Ala Ser Gly Asp Thr Ser Tyr Gly
145150155160
Thr Ser Pro Lys Val Gln Arg Ala Val Gln Leu Leu Leu Asp Leu Val
165170175
Leu Gln Pro Ser Phe Tyr Glu Pro Pro Val Leu Phe Val Pro Asp Cys
180185190
Ala Phe Met Ile Asp Arg Pro Met Asp Val Trp Gly Ala Pro Leu Glu
195200205
Val Glu Val Leu Leu Phe Gly Cys Leu Lys Ser Cys Cys Gln Leu Met
210215220
Ser Leu Val Glu Gly Gly Gly His Gly Gly Pro Leu Ile Gln Gln Arg
225230235 240
Leu Glu Leu Thr Arg Thr Trp Met Arg Asp Leu Arg Val Tyr Leu Leu
245250255
Asn His Tyr Trp Val Thr Ser Lys Thr Met Gln Val Leu Arg Arg Arg
260265270
Pro Thr Glu Gln Tyr Gly Asp Tyr Gln Ser Arg Asn Glu Phe Asn Val
275280285
Gln Pro Glu Val Ile Pro His Trp Leu Gln Glu Trp Leu Asp Asp Arg
290295300
Gly Gly Tyr Leu Ile Gly Asn Met Arg Thr Gly Arg Pro Asp Phe Arg
305310315320
Phe Tyr Ser Leu Gly Asn Ala Leu Gly Ser Leu Phe Gly Leu Leu Thr
325330335
Gly Pro Gln Gln Leu Ala Leu Phe Arg Leu Val Ile His Asn Arg Gln
340345350
His Leu Met Ala Glu Met Pro Met Arg Ile Cys His Pro Pro Met Asp
355360365
Gln Asp Glu Trp Ile Thr Asn Thr Gly Met Asp Pro Lys Asn Trp Pro
370375380
Trp Ser Tyr His Asn Gly Gly His Trp Pro Ser Leu Leu Trp Pro Met
385390395400
Ala Ala Ala Val Leu Met His Gln Arg Leu Tyr Pro Asn Asp Asp Leu
405410415
Leu Leu Leu Gly Gln Thr Arg Thr Met Leu Glu Glu Cys Tyr Trp Gln
420425430
Gln Leu Asn Gln Leu Pro Arg Gln Gln Trp Ala Glu Tyr Phe Asp Gly
435440445
Pro Thr Gly Thr Trp Val Gly Gln Gln Ala Arg Ile Asn Gln Thr Trp
450455460
Thr Ile Val Gly Phe Leu Leu Leu His His Leu Met Arg Lys Ala Pro
465470475480
Gln Asp Val Lys Leu Leu Asp Leu Asp Asp Val Gly Pro Leu Arg Leu
485490495
Ser Phe Gln Asp Gln His Glu Lys Ser Ser Thr Asp Glu Arg Lys Ser
500505510
Phe Leu Lys Asn Tyr
515
<210> 98
<211> 1021
<212> PRT
<213> Proteus vulgaris
<220>
<223> Proteus vulgaris chondroitin-sulfate-ABC endolyase
<400> 98
Met Pro Ile Phe Arg Phe Thr Ala Leu Ala Met Thr Leu Gly Leu Leu
151015
Ser Ala Pro Tyr Asn Ala Met Ala Ala Thr Ser Asn Pro Ala Phe Asp
202530
Pro Lys Asn Leu Met Gln Ser Glu Ile Tyr His Phe Ala Gln Asn Asn
354045
Pro Leu Ala Asp Phe Ser Ser Asp Lys Asn Ser Ile Leu Thr Leu Ser
505560
Asp Lys Arg Ser Ile Met Gly Asn Gln Ser Leu Leu Trp Lys Trp Lys
65707580
Gly Gly Ser Ser Phe Thr Leu His Lys Lys Leu Ile Val Pro Thr Asp
859095
Lys Glu Ala Ser Lys Ala Trp Gly Arg Ser Ser Thr Pro Val Phe Ser
100105110
Phe Trp Leu Tyr Asn Glu Lys Pro Ile Asp Gly Tyr Leu Thr Ile Asp
115120125
Phe Gly Glu Lys Leu Ile Ser Thr Ser Glu Ala Gln Ala Gly Phe Lys
130135140
Val Lys Leu Asp Phe Thr Gly Trp Arg Ala Val Gly Val Ser Leu Asn
145150155160
Asn Asp Leu Glu Asn Arg Glu Met Thr Leu Asn Ala Thr Asn Thr Ser
165170175
Ser Asp Gly Thr Gln Asp Ser Ile Gly Arg Ser Leu Gly Ala Lys Val
180185190
Asp Ser Ile Arg Phe Lys Ala Pro Ser Asn Val Ser Gln Gly Glu Ile
195200205
Tyr Ile Asp Arg Ile Met Phe Ser Val Asp Asp Ala Arg Tyr Gln Trp
210215220
Ser Asp Tyr Gln Val Lys Thr Arg Leu Ser Glu Pro Glu Ile Gln Phe
225230235240
His Asn Val Lys Pro Gln Leu Pro Val Thr Pro Glu Asn Leu Ala Ala
245250255
Ile Asp Leu Ile Arg Gln Arg Leu Ile Asn Glu Phe Val Gly Gly Glu
260265270
Lys Glu Thr Asn Leu Ala Leu Glu Glu Asn Ile Ser Lys Leu Lys Ser
275280285
Asp Phe Asp Ala Leu Asn Ile His Thr Leu Ala Asn Gly Gly Thr Gln
290295300
Gly Arg His Leu Ile Thr Asp Lys Gln Ile Ile Ile Tyr Gln Pro Glu
305310315320
Asn Leu Asn Ser Gln Asp Lys Gln Leu Phe Asp Asn Tyr Val Ile Leu
325330335
Gly Asn Tyr Thr Thr Leu Met Phe Asn Ile Ser Arg Ala Tyr Val Leu
340345350
Glu Lys Asp Pro Thr Gln Lys Ala Gln Leu Lys Gln Met Tyr Leu Leu
355360365
Met Thr Lys His Leu Leu Asp Gln Gly Phe Val Lys Gly Ser Ala Leu
370375380
Val Thr Thr His His Trp Gly Tyr Ser Ser Arg Trp Trp Tyr Ile Ser
385390395400
Thr Leu Leu Met Ser Asp Ala Leu Lys Glu Ala Asn Leu Gln Thr Gln
405410415
Val Tyr Asp Ser Leu Leu Trp Tyr Ser Arg Glu Phe Lys Ser Ser Phe
420425430
Asp Met Lys Val Ser Ala Asp Ser Ser Asp Leu Asp Tyr Phe Asn Thr
435440445
Leu Ser Arg Gln His Leu Ala Leu Leu Leu Leu Glu Pro Asp Asp Gln
450455460
Lys Arg Ile Asn Leu Val Asn Thr Phe Ser His Tyr Ile Thr Gly Ala
465470475480
Leu Thr Gln Val Pro Pro Gly Gly Lys Asp Gly Leu Arg Pro Asp Gly
485490495
Thr Ala Trp Arg His Glu Gly Asn Tyr Pro Gly Tyr Ser Phe Pro Ala
500505510
Phe Lys Asn Ala Ser Gln Leu Ile Tyr Leu Leu Arg Asp Thr Pro Phe
515520525
Ser Val Gly Glu Ser Gly Trp Asn Asn Leu Lys Lys Ala Met Val Ser
530535540
Ala Trp Ile Tyr Ser Asn Pro Glu Val Gly Leu Pro Leu Ala Gly Arg
545550555560
His Pro Phe Asn Ser Pro Ser Leu Lys Ser Val Ala Gln Gly Tyr Tyr
565570575
Trp Leu Ala Met Ser Ala Lys Ser Ser Pro Asp Lys Thr Leu Ala Ser
580585590
Ile Tyr Leu Ala Ile Ser Asp Lys Thr Gln Asn Glu Ser Thr Ala Ile
595600605
Phe Gly Glu Thr Ile Thr Pro Ala Ser Leu Pro Gln Gly Phe Tyr Ala
610615620
Phe Asn Gly Gly Ala Phe Gly Ile His Arg Trp Gln Asp Lys Met Val
625630635640
Thr Leu Lys Ala Tyr Asn Thr Asn Val Trp Ser Ser Glu Ile Tyr Asn
645650655
Lys Asp Asn Arg Tyr Gly Arg Tyr Gln Ser His Gly Val Ala Gln Ile
660665670
Val Ser Asn Gly Ser Gln Leu Ser Gln Gly Tyr Gln Gln Glu Gly Trp
675680685
Asp Trp Asn Arg Met Glu Gly Ala Thr Thr Ile His Leu Pro Leu Lys
690695700
Asp Leu Asp Ser Pro Lys Pro His Thr Leu Met Gln Arg Gly Glu Arg
705710715720
Gly Phe Ser Gly Thr Ser Ser Leu Glu Gly Gln Tyr Gly Met Met Ala
725730735
Phe Asn Leu Ile Tyr Pro Ala Asn Leu Glu Arg Phe Asp Pro Asn Phe
740745750
Thr Ala Lys Lys Ser Val Leu Ala Ala Asp Asn His Leu Ile Phe Ile
755760765
Gly Ser Asn Ile Asn Ser Ser Asp Lys Asn Lys Asn Val Glu Thr Thr
770775780
Leu Phe Gln His Ala Ile Thr Pro Thr Leu Asn Thr Leu Trp Ile Asn
785790795800
Gly Gln Lys Ile Glu Asn Met Pro Tyr Gln Thr Thr Leu Gln Gln Gly
805810815
Asp Trp Leu Ile Asp Ser Asn Gly Asn Gly Tyr Leu Ile Thr Gln Ala
820825830
Glu Lys Val Asn Val Ser Arg Gln His Gln Val Ser Ala Glu Asn Lys
835840845
Asn Arg Gln Pro Thr Glu Gly Asn Phe Ser Ser Ala Trp Ile Asp His
850855860
Ser Thr Arg Pro Lys Asp Ala Ser Tyr Glu Tyr Met Val Phe Leu Asp
865870875880
Ala Thr Pro Glu Lys Met Gly Glu Met Ala Gln Lys Phe Arg Glu Asn
885890895
Asn Gly Leu Tyr Gln Val Leu Arg Lys Asp Lys Asp Val His Ile Ile
900905910
Leu Asp Lys Leu Ser Asn Val Thr Gly Tyr Ala Phe Tyr Gln Pro Ala
915920925
Ser Ile Glu Asp Lys Trp Ile Lys Lys Val Asn Lys Pro Ala Ile Val
930935940
Met Thr His Arg Gln Lys Asp Thr Leu Ile Val Ser Ala Val Thr Pro
945950955960
Asp Leu Asn Met Thr Arg Gln Lys Ala Ala Thr Pro Val Thr Ile Asn
965970975
Val Thr Ile Asn Gly Lys Trp Gln Ser Ala Asp Lys Asn Ser Glu Val
980985990
Lys Tyr Gln Val Ser Gly Asp Asn Thr Glu Leu Thr Phe Thr Ser Tyr
99510001005
Phe Gly Ile Pro Gln Glu Ile Lys Leu Ser Pro Leu Pro
101010151020
<210> 99
<211> 684
<212> PRT
<213> Pedobacter heparinus
<220>
<223> Pedobacter heparinus DSM 2366 chondroitin AC lyase
<400> 99
Pro Ala Leu Leu Ile Ala Gln Gln Thr Gly Thr Ala Glu Leu Ile Met
151015
Lys Arg Val Met Leu Asp Leu Lys Lys Pro Leu Arg Asn Met Asp Lys
202530
Val Ala Glu Lys Asn Leu Asn Thr Leu Gln Pro Asp Gly Ser Trp Lys
354045
Asp Val Pro Tyr Lys Asp Asp Ala Met Thr Asn Trp Leu Pro Asn Asn
505560
His Leu Leu Gln Leu Glu Thr Ile Ile Gln Ala Tyr Ile Glu Lys Asp
65707580
Ser His Tyr Tyr Gly Asp Asp Lys Val Phe Asp Gln Ile Ser Lys Ala
859095
Phe Lys Tyr Trp Tyr Asp Ser Asp Pro Lys Ser Arg Asn Trp Trp His
100105110
Asn Glu Ile Ala Thr Pro Gln Ala Leu Gly Glu Met Leu Ile Leu Met
115120125
Arg Tyr Gly Lys Lys Pro Leu Asp Glu Ala Leu Val His Lys Leu Thr
130135140
Glu Arg Met Lys Arg Gly Glu Pro Glu Lys Lys Thr Gly Ala Asn Lys
145150155160
Thr Asp Ile Ala Leu His Tyr Phe Tyr Arg Ala Leu Leu Thr Ser Asp
165170175
Glu Ala Leu Leu Ser Phe Ala Val Lys Glu Leu Phe Tyr Pro Val Gln
180185190
Phe Val His Tyr Glu Glu Gly Leu Gln Tyr Asp Tyr Ser Tyr Leu Gln
195200205
His Gly Pro Gln Leu Gln Ile Ser Ser Tyr Gly Ala Val Phe Ile Thr
210215220
Gly Val Leu Lys Leu Ala Asn Tyr Val Arg Asp Thr Pro Tyr Ala Leu
225230235240
Ser Thr Glu Lys Leu Ala Ile Phe Ser Lys Tyr Tyr Arg Asp Ser Tyr
245250255
Leu Lys Ala Ile Arg Gly Ser Tyr Met Asp Phe Asn Val Glu Gly Arg
260265270
Gly Val Ser Arg Pro Asp Ile Leu Asn Lys Lys Ala Glu Lys Lys Arg
275280285
Leu Leu Val Ala Lys Met Ile Asp Leu Lys His Thr Glu Glu Trp Ala
290295300
Asp Ala Ile Ala Arg Thr Asp Ser Thr Val Ala Ala Gly Tyr Lys Ile
305310315320
Glu Pro Tyr His His Gln Phe Trp Asn Gly Asp Tyr Val Gln His Leu
325330335
Arg Pro Ala Tyr Ser Phe Asn Val Arg Met Val Ser Lys Arg Thr Arg
340345350
Arg Ser Glu Ser Gly Asn Lys Glu Asn Leu Leu Gly Arg Tyr Leu Ser
355360365
Asp Gly Ala Thr Asn Ile Gln Leu Arg Gly Pro Glu Tyr Tyr Asn Ile
370375380
Met Pro Val Trp Glu Trp Asp Lys Ile Pro Gly Ile Thr Ser Arg Asp
385390395400
Tyr Leu Thr Asp Arg Pro Leu Thr Lys Leu Trp Gly Glu Gln Gly Ser
405410415
Asn Asp Phe Ala Gly Gly Val Ser Asp Gly Val Tyr Gly Ala Ser Ala
420425430
Tyr Ala Leu Asp Tyr Asp Ser Leu Gln Ala Lys Lys Ala Trp Phe Phe
435440445
Phe Asp Lys Glu Ile Val Cys Leu Gly Ala Gly Ile Asn Ser Asn Ala
450455460
Pro Glu Asn Ile Thr Thr Thr Leu Asn Gln Ser Trp Leu Asn Gly Pro
465470475480
Val Ile Ser Thr Ala Gly Lys Thr Gly Arg Gly Lys Ile Thr Thr Phe
485490495
Lys Ala Gln Gly Gln Phe Trp Leu Leu His Asp Ala Ile Gly Tyr Tyr
500505510
Phe Pro Glu Gly Ala Asn Leu Ser Leu Ser Thr Gln Ser Gln Lys Gly
515520525
Asn Trp Phe His Ile Asn Asn Ser His Ser Lys Asp Glu Val Ser Gly
530535540
Asp Val Phe Lys Leu Trp Ile Asn His Gly Ala Arg Pro Glu Asn Ala
545550555560
Gln Tyr Ala Tyr Ile Val Leu Pro Gly Ile Asn Lys Pro Glu Glu Ile
565570575
Lys Lys Tyr Asn Gly Thr Ala Pro Lys Val Leu Ala Asn Thr Asn Gln
580585590
Leu Gln Ala Val Tyr His Gln Gln Leu Asp Met Val Gln Ala Ile Phe
595600605
Tyr Thr Ala Gly Lys Leu Ser Val Ala Gly Ile Glu Ile Glu Thr Asp
610615620
Lys Pro Cys Ala Val Leu Ile Lys His Ile Asn Gly Lys Gln Val Ile
625630635640
Trp Ala Ala Asp Pro Leu Gln Lys Glu Lys Thr Ala Val Leu Ser Ile
645650655
Arg Asp Leu Lys Thr Gly Lys Thr Asn Arg Val Lys Ile Asp Phe Pro
660665670
Gln Gln Glu Phe Ala Gly Ala Thr Val Glu Leu Lys
675680
<210> 100
<211> 844
<212> PRT
<213> Victivallis vadensis
<220>
<223> Victivallis vadensis ATCC BAA-548 chondroitin AC
lyase
<400> 100
Met His Arg Lys Ile Val Phe Pro Leu Phe Val Leu Leu Phe Thr Ala
151015
Phe Ala Ala Phe Ala Ala Ser Gln Pro Gln Trp Lys Trp Arg Gln Ser
202530
Lys Tyr Cys Arg Ile Thr Glu His Ala Gly Lys Lys Leu Leu Thr Val
354045
Ala Ile Pro Ala Asp Ala Pro Glu Ile Ser Arg Arg Asn Thr Ala Asp
505560
Thr Pro Val Gly Leu Thr Cys Phe Glu Gly Gln Pro Ile Glu Phe Ser
65707580
Ile Arg Leu Arg Asn Ser Gly Ile Ser Arg Pro Asp Asn Leu His Asn
859095
Gly Ile Lys Phe Gln Leu Tyr Phe Arg Asp Gly Asn Gly Thr Glu Arg
100105110
Trp Thr Gln Ala Glu Ile Pro His Glu Pro Phe Pro Trp Arg Arg Phe
115120125
Arg Phe Ser Glu Arg Ile Pro Ala Asp Ala Thr Ser Gly Thr Leu Arg
130135140
Leu Gly Leu Gln Gly Ser Ser Gly Asn Val Glu Phe Asp Leu Asp Ser
145150155160
Leu Gln Ile Arg Pro Leu Asp Pro Glu Leu Ser Pro Val Pro Pro Thr
165170175
Pro Glu Gln Ile Arg Glu Cys Glu Leu Ile Glu Ser Arg Leu Arg Ala
180185190
Gly Leu Pro Ala Gln Gln Pro Pro Pro Gly Pro Glu Val Lys Lys Leu
195200205
Leu Glu Arg Gln Asn Gly Asp Gly Thr Phe Arg Asp Leu Asp Tyr Ser
210215220
Ala Arg Asn Arg Ser Ile Trp Pro Ala Ala Arg His Leu Lys Arg Thr
225230235240
Phe Glu Leu Ala Leu Ala Arg Ala Thr Pro Gly His Ala Leu Tyr Arg
245250255
Asp Pro Ala Ala Gly Glu Ala Val Arg Lys Ala Val Ala Trp Trp Ala
260265270
Glu Arg Gln Pro Gln Asn Gly Asn Trp Trp Trp Asn Asp Met Tyr Val
275280285
Pro Lys Ile Leu Gly Asn Ile Leu Leu Leu Ser Pro Glu Leu Phe Pro
290295300
Asp Gly Pro Arg Arg Arg Ala Ala Leu Asn Val Cys Arg Gln Ala Cys
305310315320
Phe Leu Ser Arg Tyr Thr Gly Asn Asn Arg Val Phe Ile Ala Ala Asn
325330335
Ile Phe Cys Arg Ala Leu Leu Glu Arg Asn Leu Pro Val Met Asp Arg
340345350
Ala Ala Ala Val Leu Ser Glu Glu Ile Arg Phe Ala Pro Ala Glu His
355360365
Lys Thr Ala Trp Ser Phe Gly Gly Ile Arg Ala Asp Gly Cys Tyr His
370375380
Gln His Gly Pro Gln Ile Gln Phe Gly Asn Tyr Gly Gly Glu Phe Leu
385390395400
Ala Asn Ile Ala Tyr Trp Ser Asn Ile Leu Lys Glu Thr His Trp Glu
405410415
Leu Ser Pro Glu Gln Trp Arg Ile Met Arg His Leu Thr Phe Asn Gly
420425430
Phe Gln Trp Val Leu Trp Arg Gly Arg Met Asp Leu Leu Ala Cys Gly
435440445
Arg Gln Leu Gly Arg Asn Ala Ala Glu Thr Lys Gly Glu Arg Thr Leu
450455460
Asn Ala Phe Ala Gln Leu Arg Asn Ala Asp Pro Gly Asp Arg Ala Pro
465470475480
Tyr Asp Ala Ala Leu Arg Arg Asn Arg Asp Gly Glu Asn Thr Leu Thr
485490495
Gly Asn Arg His Phe Trp Asn Ser Asp Tyr Met Val His Arg Arg Pro
500505510
Thr Trp Tyr Ala Ser Val Arg Met Asn Ser Val Arg Val Arg Pro Ile
515520525
Glu Asp Asp Thr Asn Trp Asp Asn Ala Leu Gly Arg Tyr Phe Ser Asp
530535540
Gly Ala Cys Leu Val Met Arg Ser Gly Arg Glu Tyr Glu Asn Ile Thr
545550555560
Ala Cys Trp Asp Trp Thr Arg Leu Pro Gly Thr Thr Leu Pro Lys Thr
565570575
Pro Val Tyr Thr Gly Glu Asp Ala Arg Arg Phe Gly Leu Lys Ile Gly
580585590
Gly Gly Asp Leu Pro Arg Trp Thr His Ser Arg Asn Trp Arg Gln Leu
595600605
Gly Glu Thr Gly Phe Val Gly Gly Val Thr Asp Gly Glu Arg Gly Ala
610615620
Ala Val Tyr Thr Gln Asp Leu Asp Gly Val Arg Ala Arg Lys Ala Trp
625630635640
Phe Phe Asp Arg Asp Ala Ile Tyr Cys Leu Gly Ser Gly Ile Thr Ser
645650655
Thr Ser Pro Tyr Glu Val Ala Thr Thr Val Asn Ser Cys Leu Arg Asn
660665670
Gly Glu Ile Gln Gln Gly Asp Gly Trp Phe Arg His Asp Gly Ile Gly
675680685
Tyr Arg Gly Glu Asn Leu Lys Leu Thr Ala Gly Pro Arg Thr Gly Asp
690695700
Trp Arg Tyr Val Glu Gly Gly Leu Thr Arg Pro Val Pro Glu Thr Lys
705710715720
Glu Leu Phe Thr Leu Thr Val Glu His Gly Val Lys Pro Arg Asn Ala
725730735
Ser Tyr Ile Tyr Thr Ile Leu Pro Gly Ala Thr Pro Glu Glu Thr Ala
740745750
Gly Thr Pro Pro Gly Arg Val Leu Arg Asn Thr Pro Glu Cys Gln Ala
755760765
Val Glu Phe Ala Asp Gly Val Arg Ala Ala Ile Phe Tyr Glu Pro Gly
770775780
Arg Leu Asp Asp Phe Glu Thr Asp Thr Pro Gly Val Phe Leu Ile Gly
785790795800
Lys Gly Thr Val His Ala Ala Asp Pro Thr Gly Arg His Ser Ser Phe
805810815
Thr Leu Lys Leu Asn Gly Val Ser Arg Lys Val Pro Leu Pro Ala Gly
820825830
Glu Phe Ala Gly Gln Ser Val Lys Ile Val Leu Lys
835840
<210> 101
<211> 510
<212> PRT
<213> Pan troglodyte
<220>
<223> Chimpanzee PH20
<400> 101
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
5055 60
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Val Thr Gly Gln Asp Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Gln Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Val Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Ser Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Asp
485490495
Leu Cys Asp Leu Tyr Leu Val Pro Thr Ser Tyr Leu Ile Leu
500505510
<210> 102
<211> 512
<212> PRT
<213> Macaca mulatta
<220>
<223> Rhesus Monkey PH20
<400> 102
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Ile Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asn Glu Pro Leu Asp Met Ser Leu Phe Thr Leu Met Gly Ser Pro Arg
65707580
Ile Asn Ile Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Leu Thr Thr Gly Val Thr Val His Gly
100105110
Gly Ile Pro Gln Lys Val Ser Leu Gln Asp His Leu Asp Lys Ser Lys
115120125
Gln Asp Ile Leu Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Pro Gln Ala Thr Asp Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Met Leu Glu Thr Ile Lys Leu Gly Arg
195200205
Ser Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Arg Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asp
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Val Val
260265270
Val Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Asn Pro Leu Pro Val Phe Val Tyr Ala
290295300
Arg Leu Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Arg Glu Glu
305310315320
Leu Val Ser Thr Leu Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Ser Leu Ser Ile Thr Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Thr Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asp Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Asp Ile Arg Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val His Gly Lys Pro Thr Val Glu Asp Leu Glu Glu Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Thr Asn Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Ser Leu Lys Pro Pro Val Glu Thr Glu Gly Ser Pro Pro
465470475480
Ile Phe Tyr Asn Thr Ser Ser Ser Thr Val Ser Thr Thr Met Phe Ile
485490495
Trp Arg Leu Glu Val Trp Asp Gln Gly Ile Ser Arg Ile Gly Phe Phe
500505510
<210> 103
<211> 505
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-505
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 103
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu Ile Ile Ser Ser
500505
<210> 104
<211> 503
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-503
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 104
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu Ile Ile
500
<210> 105
<211> 501
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-501
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 105
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu
500
<210> 106
<211> 499
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-499
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 106
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu
<210> 107
<211> 497
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-497
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 107
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
85 9095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser
<210> 108
<211> 495
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-495
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 108
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
15 1015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile
485490495
<210> 109
<211> 493
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-493
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 109
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met
485490
<210> 110
<211> 491
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-491
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 110
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala
485490
<210> 111
<211> 489
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-489
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 111
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu
485
<210> 112
<211> 490
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-490
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 112
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315 320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser
485490
<210> 113
<211> 487
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-487
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 113
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser
485
<210> 114
<211> 485
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-485
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 114
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser
485
<210> 115
<211> 484
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-484
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 115
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390 395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala
<210> 116
<211> 476
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-476
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 116
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
6570 7580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu
465470475
<210> 117
<211> 475
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-475
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 117
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr
465470475
<210> 118
<211> 474
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-474
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 118
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu
465470
<210> 119
<211> 473
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-473
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 119
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250 255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met
465470
<210> 120
<211> 472
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-472
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 120
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro
465470
<210> 121
<211> 471
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-471
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 121
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro
465470
<210> 122
<211> 470
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-470
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 122
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180 185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys
465470
<210> 123
<211> 469
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-469
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 123
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu
465
<210> 124
<211> 468
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-468
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 124
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe
465
<210> 125
<211> 466
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-466
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 125
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345 350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp
465
<210> 126
<211> 465
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-465
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 126
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile
465
<210> 127
<211> 464
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-464
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 127
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
<210> 128
<211> 462
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-462
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 128
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly
450455460
<210> 129
<211> 460
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-460
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 129
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala
450455460
<210> 130
<211> 458
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-458
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 130
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys
450455
<210> 131
<211> 456
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-456
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 131
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp
450455
<210> 132
<211> 454
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-454
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 132
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
15 1015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala
450
<210> 133
<211> 452
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-452
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 133
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr
450
<210> 134
<211> 450
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-450
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 134
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys
450
<210> 135
<211> 508
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-508
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 135
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu Ile Ile Ser Ser Val Ala Ser
500505
<210> 136
<211> 506
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-506
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 136
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu Ile Ile Ser Ser Val
500505
<210> 137
<211> 504
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-504
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 137
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu Ile Ile Ser
500
<210> 138
<211> 502
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-502
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 138
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe Leu Ile
500
<210> 139
<211> 500
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-500
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 139
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile Leu Phe
500
<210> 140
<211> 498
<212> PRT
<213> Homo sapiens
<220>
<223> HuPH20 precursor 1-498
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 140
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
Ser Ile
<210> 141
<211> 496
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-496
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 141
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
485490495
<210> 142
<211> 494
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-494
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 142
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe
485490
<210> 143
<211> 492
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-492
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 143
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
15 1015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr Leu Ser Ala Thr
485490
<210> 144
<211> 488
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-488
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 144
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro Ser Thr
485
<210> 145
<211> 486
<212> PRT
<213> Homo sapiens
<220>
<223> precursor soluble human PH20, amino acid residues
1-486
<220>
<221> SIGNAL
<222> (1)...(35)
<223> signal sequence
<400> 145
Met Gly Val Leu Lys Phe Lys His Ile Phe Phe Arg Ser Phe Val Lys
151015
Ser Ser Gly Val Ser Gln Ile Val Phe Thr Phe Leu Leu Ile Pro Cys
202530
Cys Leu Thr Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro
354045
Phe Leu Trp Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe
505560
Asp Glu Pro Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg
65707580
Ile Asn Ala Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu
859095
Gly Tyr Tyr Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly
100105110
Gly Ile Pro Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys
115120125
Lys Asp Ile Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val
130135140
Ile Asp Trp Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro
145150155160
Lys Asp Val Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn
165170175
Val Gln Leu Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe
180185190
Glu Lys Ala Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys
195200205
Leu Leu Arg Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys
210215220
Tyr Asn His His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn
225230235240
Val Glu Ile Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser
245250255
Thr Ala Leu Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val
260265270
Ala Ala Thr Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val
275280285
Ser Lys Ile Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr
290295300
Arg Ile Val Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu
305310315320
Leu Val Tyr Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile
325330335
Val Ile Trp Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu
340345350
Leu Leu Asp Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn
355360365
Val Thr Leu Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln
370375380
Gly Val Cys Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu
385390395400
Asn Pro Asp Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr
405410415
Val Arg Gly Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys
420425430
Phe Tyr Cys Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp
435440445
Val Lys Asp Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
450455460
Ile Asp Ala Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile
465470475480
Phe Tyr Asn Ala Ser Pro
485
<210> 146
<211> 472
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-507
<400> 146
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310 315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile Ile Ser Ser Val Ala
465470
<210> 147
<211> 470
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-505
<400> 147
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425 430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile Ile Ser Ser
465470
<210> 148
<211> 468
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-503
<400> 148
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile Ile
465
<210> 149
<211> 466
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-501
<400> 149
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu
465
<210> 150
<211> 464
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-499
<400> 150
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
<210> 151
<211> 462
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-497
<400> 151
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser
450455460
<210> 152
<211> 460
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-495
<400> 152
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile
450455460
<210> 153
<211> 458
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-493
<400> 153
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
1 51015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met
450455
<210> 154
<211> 456
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-491
<400> 154
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65 707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala
450455
<210> 155
<211> 454
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-489
<400> 155
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
6570 7580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu
450
<210> 156
<211> 455
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-490
<400> 156
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser
450455
<210> 157
<211> 452
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-487
<400> 157
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser
450
<210> 158
<211> 450
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-485
<400> 158
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser
450
<210> 159
<211> 449
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-484
<400> 159
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala
<210> 160
<211> 441
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-476
<400> 160
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu
435440
<210> 161
<211> 440
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-475
<400> 161
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
8590 95
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr
435440
<210> 162
<211> 439
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-474
<400> 162
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu
435
<210> 163
<211> 438
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-473
<400> 163
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met
435
<210> 164
<211> 437
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-472
<400> 164
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro
435
<210> 165
<211> 436
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-471
<400> 165
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390 395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro
435
<210> 166
<211> 435
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-470
<400> 166
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys
435
<210> 167
<211> 434
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-469
<400> 167
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu
<210> 168
<211> 433
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-468
<400> 168
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe
<210> 169
<211> 431
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-466
<400> 169
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265 270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp
420425430
<210> 170
<211> 430
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-465
<400> 170
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225 230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile
420425430
<210> 171
<211> 429
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-464
<400> 171
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys
420425
<210> 172
<211> 427
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-462
<400> 172
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly
420425
<210> 173
<211> 425
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-460
<400> 173
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala
420425
<210> 174
<211> 423
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-458
<400> 174
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys
420
<210> 175
<211> 421
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-456
<400> 175
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp
420
<210> 176
<211> 419
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-454
<400> 176
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390 395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala
<210> 177
<211> 417
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-452
<400> 177
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr
<210> 178
<211> 415
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-450
<400> 178
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155 160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys
405410415
<210> 179
<211> 473
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-508
<400> 179
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile Ile Ser Ser Val Ala Ser
465470
<210> 180
<211> 471
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-506
<400> 180
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370 375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile Ile Ser Ser Val
465470
<210> 181
<211> 469
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-504
<400> 181
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235 240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile Ile Ser
465
<210> 182
<211> 467
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-502
<400> 182
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe Leu Ile
465
<210> 183
<211> 465
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-500
<400> 183
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile Leu
450455460
Phe
465
<210> 184
<211> 463
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-498
<400> 184
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val Ser Ile
450455460
<210> 185
<211> 461
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-496
<400> 185
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe Ile Val
450455460
<210> 186
<211> 459
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-494
<400> 186
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr Met Phe
450455
<210> 187
<211> 457
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-492
<400> 187
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
657075 80
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr Leu Ser Ala Thr
450455
<210> 188
<211> 453
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-488
<400> 188
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro Ser Thr
450
<210> 189
<211> 451
<212> PRT
<213> Homo sapiens
<220>
<223> mature soluble human PH20, amino acid residues
36-486
<400> 189
Leu Asn Phe Arg Ala Pro Pro Val Ile Pro Asn Val Pro Phe Leu Trp
151015
Ala Trp Asn Ala Pro Ser Glu Phe Cys Leu Gly Lys Phe Asp Glu Pro
202530
Leu Asp Met Ser Leu Phe Ser Phe Ile Gly Ser Pro Arg Ile Asn Ala
354045
Thr Gly Gln Gly Val Thr Ile Phe Tyr Val Asp Arg Leu Gly Tyr Tyr
505560
Pro Tyr Ile Asp Ser Ile Thr Gly Val Thr Val Asn Gly Gly Ile Pro
65707580
Gln Lys Ile Ser Leu Gln Asp His Leu Asp Lys Ala Lys Lys Asp Ile
859095
Thr Phe Tyr Met Pro Val Asp Asn Leu Gly Met Ala Val Ile Asp Trp
100105110
Glu Glu Trp Arg Pro Thr Trp Ala Arg Asn Trp Lys Pro Lys Asp Val
115120125
Tyr Lys Asn Arg Ser Ile Glu Leu Val Gln Gln Gln Asn Val Gln Leu
130135140
Ser Leu Thr Glu Ala Thr Glu Lys Ala Lys Gln Glu Phe Glu Lys Ala
145150155160
Gly Lys Asp Phe Leu Val Glu Thr Ile Lys Leu Gly Lys Leu Leu Arg
165170175
Pro Asn His Leu Trp Gly Tyr Tyr Leu Phe Pro Asp Cys Tyr Asn His
180185190
His Tyr Lys Lys Pro Gly Tyr Asn Gly Ser Cys Phe Asn Val Glu Ile
195200205
Lys Arg Asn Asp Asp Leu Ser Trp Leu Trp Asn Glu Ser Thr Ala Leu
210215220
Tyr Pro Ser Ile Tyr Leu Asn Thr Gln Gln Ser Pro Val Ala Ala Thr
225230235240
Leu Tyr Val Arg Asn Arg Val Arg Glu Ala Ile Arg Val Ser Lys Ile
245250255
Pro Asp Ala Lys Ser Pro Leu Pro Val Phe Ala Tyr Thr Arg Ile Val
260265270
Phe Thr Asp Gln Val Leu Lys Phe Leu Ser Gln Asp Glu Leu Val Tyr
275280285
Thr Phe Gly Glu Thr Val Ala Leu Gly Ala Ser Gly Ile Val Ile Trp
290295300
Gly Thr Leu Ser Ile Met Arg Ser Met Lys Ser Cys Leu Leu Leu Asp
305310315320
Asn Tyr Met Glu Thr Ile Leu Asn Pro Tyr Ile Ile Asn Val Thr Leu
325330335
Ala Ala Lys Met Cys Ser Gln Val Leu Cys Gln Glu Gln Gly Val Cys
340345350
Ile Arg Lys Asn Trp Asn Ser Ser Asp Tyr Leu His Leu Asn Pro Asp
355360365
Asn Phe Ala Ile Gln Leu Glu Lys Gly Gly Lys Phe Thr Val Arg Gly
370375380
Lys Pro Thr Leu Glu Asp Leu Glu Gln Phe Ser Glu Lys Phe Tyr Cys
385390395400
Ser Cys Tyr Ser Thr Leu Ser Cys Lys Glu Lys Ala Asp Val Lys Asp
405410415
Thr Asp Ala Val Asp Val Cys Ile Ala Asp Gly Val Cys Ile Asp Ala
420425430
Phe Leu Lys Pro Pro Met Glu Thr Glu Glu Pro Gln Ile Phe Tyr Asn
435440445
Ala Ser Pro
450
<210> 190
<211> 2105
<212> DNA
<213> Bos taurus
<220>
<223> cow PH20 DNA
<400> 190
ggtttatctc tgttcttggt gaggagacag acagaattga ctgctgtgct catccgcgag 60
ggtaaatgtg ctcagctctt tatggagtag tggagacggg cagagatgac aagatgaagc120
aacttgcaaa acattcctaa atacgaagga agaagaatat ttaaatgtaa atcatcatta180
ttcattttta tccatcaaag tggcttcatt ctgtgttcat atcttgcatc aaatattagg240
tacaccaaag cgtgtaggag aaaaaagtgc ctttcacagt catcgctctt tgtgatgaga300
atgctgaggc gccaccatat ctcctttcgg agctttgctg ggtctagcgg aacaccccag360
gcagtgttca ccttccttct gcttccgtgt tgtttggctc tggacttcag agcaccccct420
cttatttcaa acacttcttt cctctgggcc tggaatgccc cagttgaacg ttgtgttaac480
agaagatttc aactacctcc agatctgaga ctcttctctg taaaaggaag cccccagaaa540
agtgctaccg gacaatttat tacattattt tatgctgata gacttggcta ctatcctcat600
atagatgaaa aaacaggcaa aaccgtattc ggaggaattc cccagttggg aaacttaaaa660
agtcatatgg agaaagcaaa aaatgacatt gcctattaca taccaaatga cagcgtgggc720
ttggcggtca ttgactggga aaactggagg cctacctggg caagaaactg gaaacctaaa780
gatgtttaca gggatgagtc agttgagttg gttctgcaaa aaaatccgca actcagtttc840
ccagaggctt ccaagattgc aaaagtggat tttgagacag caggaaagag tttcatgcaa900
gagactttaa aactgggaaa attacttcgg ccaaatcact tatggggtta ttatcttttt960
cctgattgtt acaatcataa tcataaccaa cctacttaca atggaaattg ccctgatgta1020
gaaaaaagga gaaatgatga tctcgagtgg ttgtggaagg aaagcactgc ccttttccct1080
tctgtttatt tgaatatcag gttaaaatct actcaaaatg ctgccttgta tgttcgtaat1140
cgtgtccagg aagccattcg gttgtctaaa atagcgagtg tcgaaagtcc acttccggtt1200
tttgtatatg cccgtccagt ttttactgat gggtcttcaa catatctttc tcagggtgac1260
cttgtgaatt cggttggtga gatcgtttct ctaggtgcct ctgggattat aatgtggggc1320
agtctcaatc taagcttatc tatgcaatct tgcatgaacc taggcactta cttgaacact1380
acactgaatc cttacataat caacgtcacc ctagccgcca aaatgtgcag ccaagtgctt1440
tgccacaatg aaggagtgtg tacaaggaaa cactggaatt caagcgacta tcttcacctg1500
aacccaatga attttgctat tcaaactggg gaaggtggaa aatacacagt acctgggaca1560
gtcacacttg aagacttgca aaagttttct gatacatttt attgcagttg ttatgccaac1620
atccactgta agaagagagt tgatataaaa aatgttcata gtgttaacgt gtgtatggca1680
gaagacattt gtatagacag ccctgtgaag ttacaaccca gtgatcattc ctccagccag1740
gaggcatcta ctaccacctt cagcagtatc tcaccctcca ctacaactgc cacagtatct1800
ccatgtactc ctgagaaaca ctcccctgag tgcctcaaag tcaggtgttc ggaagtcatc1860
cccaacgtca cccaaaaggc gtgtcaaagt gttaaattga agaacatttc ctatcagtca1920
cctattcaaa atattaaaaa tcaaacaacc tattaaaatt aaattcagta aaaaaaaaaa1980
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa2040
aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaag aaaaaaaaaa2100
aaaaa2105
<210> 191
<211> 1971
<212> DNA
<213> Bos taurus
<220>
<223> cow Hyal1 DNA
<400> 191
ttggtgcgcc tggtgccaga cttaaggaac agaatcttgc tgatgcctgc acaggccctc 60
gccctggggt caggaagttt ggagaatgag gcctttcagc cttgaggttt ccctacacct120
gccctgggct atggcagccc acttgcttcc tgtctgcacc ctgttcctga acttgctcag180
catgacccaa ggctcccggg accctgtggt ccccaaccag cccttcacta ccatctggaa240
tgccaacacc gagtggtgta tgaagaaaca cggcgtggac gtagacatca gtatctttga300
tgtggtgacc aacccggggc agaccttccg cggccctaac atgaccattt tctacagctc360
ccagctgggt acctaccctt actatacatc tgctggggag cctgtgtttg gtggcctgcc420
ccagaatgcc agcctgaatg cccacctggc ccgcacattc caggacatcc tggctgccat480
gcctgagcct cgcttctcag ggctggcagt cattgactgg gaggcatggc gcccgcgctg540
ggccttcaac tgggacacca aggacattta ccggcagcgc tcacgggcat tggtacagaa600
gcagcaccca gactggctag ctcctcgggt ggaggccgca gctcaggacc agttcgaggg660
ggctgcagag gagtggatgg caggcaccct caagctggga caagcactgc gccctcaggg720
cctctggggc ttctataatt tccctgagtg ctacaactat gactttaaaa gtcccaacta780
tacaggccgg tgtccactaa acatctgtgc ccagaatgac cagctcgggt ggctgtgggg840
ccagagccgt gccctctacc ccagcatcta cctgcctgca gcactggagg gcacgaagaa900
gacacagatg ttcgtgcagc accgtgtggc tgaggcattc cgtgtggcag cgggtgcggg960
ggaccccaag ctgccggtgc tgccctacat gcagctcttc tacgacatga ctaaccactt1020
tctgcccgcg gaggagctgg agcacagcct gggggagagt gcagcccagg gtgcagcggg1080
agtggtgctc tgggtgagct ggctgagcac aagcaccaag gaatcatgcc aggccatcaa1140
ggagtatgtg gacacgacgc tgggaccctc catcctgaat gtgaccagcg gggctcgtct1200
gtgcagtcag gtcctatgct ccggccatgg ccgttgtgcc cggcgcccca gttaccccaa1260
ggcccgcctc atcctcaact ccaccagttt ttccatcaag cctacacctg gtggtgggcc1320
cctgacccta caaggtgccc tctcgctcga ggatcggttg cggatggcag tggagttcga1380
atgtcgctgc taccgtgggt ggagggggac acggtgtgag cagtggggca tgtggtgatt1440
ggcatgggca cgcactgagt acctgatgca agctgggcct ggctaggtag ggctttccca1500
agtccaggca gtcacaggag tcatggttac agtcagaagt ccactcagcc agtgtcatga1560
gcatacacca gtgtgcacac ctgcttacag accaagatag ctgcataagg acacggtgtg1620
agcagtgggg catatgctga ttggcatggg cacacactga gtacctgatg caatctgggc1680
ctggctaggg ctttcccaag tccaggcagt cacaggagtc atggttaggc atccagtcac1740
aggagtcatg tcaggcatcc tgccgacaga gtcaaaaata cttcctctgg agacactgag1800
tcagtcttca aacagaagca gtcacaagca ctgacattcg ggacttccct ggccatccag1860
tggttaagac acggagcttc cactgcaggg ggcacgggca gagactaaga tcacgaatgc1920
taagcggtgc ggttaaacaa ataacaaata aataaactga cattcactgg g1971
<210> 192
<211> 1912
<212> DNA
<213> Bos taurus
<220>
<223> cow Hyal2 DNA
<400> 192
caagtcgccg gcgggctgcc caaagggcag gagctggcgc gaatagcttg gctagagact 60
taccccggga aggagggagg ccgccgacct actgggccga cggactccca cacagttcct120
gagctggtgc ctggcaggtg acactgactt cctgcagccc ccagcatgtg gacaggcctg180
ggccccgccg tcacactggc cctggtgttg gtggtggcat gggccacgga gctgaagccc240
acagcaccac ccatcttcac gggccggccc tttgtggtcg catgggatgt gcccacacag300
gactgtggcc cgcgccacaa gatgccattg gacccaaagg acatgaaggc ctttgatgtt360
caggcttcac ctaacgaggg ttttgtaaat cagaacatca ccatcttcta ccgtgaccgg420
ctgggcatgt atccacactt caattcggtg gggaggtcag tacatggtgg tgtgccacag480
aatggcagcc tctgggtaca cctggagatg ctgaagggac acgtggaaca ctacattcgt540
acacaggagc ctgcagggct ggcagtcatc gactgggagg actggcggcc agtgtgggtg600
cgcaactggc aggacaagga tgtgtaccgc cgattatcac gccatttggt agccattcgc660
caccctgatt ggccaccaga gcgcgtagcc aaggaggcgc agtatgagtt tgagttcgct720
gcacggcagt tcatgctgga gacattgcga tttgtcaagg cgtttcggcc tcggcaccta780
tggggcttct acctcttccc tgactgttac aaccatgatt atgtgcagaa ctgggagacc840
tatacaggcc gctgccctga tgttgaggtc tcccgaaatg accagctggc ctggctctgg900
gccgagagca cggccctctt cccctctgtc tacttggaag agacactggc ttcctccact960
cacggccgca actttgtcag ctttcgtgtc caggaggctc ttcgcgtggc tgacgtccac1020
catgccaacc atgcactccc cgtctacgtc ttcacgaggc ccacctatag ccgtggactc1080
acagggctta gcgagatgga tctcatctcc accattggtg agagtgctgc cctgggtgca1140
gctggcgtca tcctctgggg tgacgcaggg tttaccacca gcaacgagac ctgccgacgc1200
ctcaaggatt atctgactcg gtcattggta ccctatgtcg tcaatgtgtc ctgggctgcc1260
cagtactgca gctgggccca gtgccatggc catgggcgct gtgtgcgccg ggaccccaac1320
gctcacacct tcctgcacct cagtgccagc agcttccgtc tagtgcctag ccacgcacct1380
gatgagccgc ggctgcgacc agagggggaa ctcagttggg ccgaccgcaa ccacctacag1440
atgcactttc gctgccagtg ctacttaggc tggggcggtg agcaatgcca gtgggaccgc1500
aggcgggcag ctgggggtgc cagtggggcc tgggctgggt cccacctcac tggcctgctg1560
gcagtggcag tcctggcctt cacctagact ttgtaagggt ctctcaccca gctgccacgc1620
cagctggcct ctgccacaag gggtctgtca ggcatgtagg agcctgcaag gggtggacaa1680
accagagtct ggaggggcag agccctctgg gatgcctggt aggatgtcct taccagctcc1740
caccccctgt tctaaggggg aggggcagtc ccctggaagg ccccgtctct ccctgccaga1800
gaggaagagg ggcacagctg ggccggggag gacctgaccc tactcccctg cccctggata1860
gtttattatt attattttgg ggtctctttt gtaaattaaa tataaaacaa ct1912
<210> 193
<211> 1537
<212> DNA
<213> Ovis aries
<220>
<223> sheep Hyal2 DNA
<400> 193
gcaaatgaca ctgacttcct gcagccccca gcatgtggac aggcctgggc cccgccgtca 60
cactggccct ggtgttggtg gtggcatggg ccacagagct gaagcccaca gcaccaccca120
tcttcacggg ccggcccttt gtggttgcat gggatgtgcc cacacaggac tgtggcccac180
gccacaagat gccattggac ccaaaggaca tgaaggcctt tgatgtgcag gcctcaccta240
acgagggttt tgtaaatcag aacatcacca tcttctaccg tgaccggctg ggcatgtatc300
cacacttcaa ctcggtgggg aggtcagtcc atggtggtgt gccacagaat ggcagcctct360
gggtacacct ggagatgctg aagggacacg tggaacacta cattcgtaca caggagcctg420
cagggctggc agtcatcgac tgggaggact ggcggccagt gtgggtgcgc aactggcagg480
acaaggatgt gtaccgccga ttatcacgcc agttggtggc cagtcaccac cccgattggc540
caccagagcg catagtcaag gaggcgcagt atgagtttga gttcgctgca cggcagttca600
tgctggagac actgcgattt gtcaaggcgt ttcggcctcg gcacctatgg ggcttctacc660
tcttccctga ctgttacaac catgattatg tgcaaaactg ggagacctat acaggccgct720
gccctgatgt tgaggtctcc cgaaatgacc agctgtcctg gctctgggcc gagagcacag780
ccctcttccc ctctgtctac ctggaagaga cgctggcttc ctccactcac ggccgcaact840
ttgtcagctt tcgtgtccag gaggctcttc gcgtggctga cgtccaccat gccaaccatg900
cactcccagt ctacgtcttc acgaggccca cctacagccg tggactcaca gggcttagcg960
agatggatct catctccacc attggtgaga gtgctgccct gggtgcagcc ggcgtcatcc1020
tctggggtga cgcagggttt accaccagca acgagacctg ccgacgcctc aaggattatc1080
tgactcggtc actggtaccc tatgtcgtca atgtgtcctg ggctgcccag tactgcagct1140
gggcccagtg ccatggccat gggcgctgtg tgcgccggga ccccaacgct cacaccttcc1200
tgcacctcag tgccagcagc ttccgtctag tgcctagcca cgcacctgat gagccgcggc1260
tgcgaccaga gggggagctc agttgggccg accgcaacca cctacagacg cactttcgct1320
gccagtgcta cttaggctgg ggcggtgagc agtgccagtg ggaccgcagg cgggcagctg1380
ggggtgccag tggggcctgg gctgggtccc acctcactgg cctgctggca gtggcagtcc1440
tggccttcac ctggacttcg taagggtctc acccagctgc caggccagct ggcctctgcc1500
acaaggggtc tgccaggcat gtagcagccc acaaggg1537
<210> 194
<211> 1967
<212> DNA
<213> Ovis aries
<220>
<223> sheep hyaluronidase DNA
<400> 194
actcctgttt atctctgttc ttggtgagga gacagacaga attgactgct gtgctcatcc 60
accaggttac agatgaagca acttgcaaaa cattcctaaa tacgaaggaa gaagagtatt120
taaacgtaaa tcatcattat tcatttttat ccatcaaagt agcttcattc tgtgttccta180
tcttgcatca aatattaggt aaaccaaagt gtgtaggaga aaaaagtgct tttcatagtc240
atcgctcttt gtgaagagaa tgctaaggcg ccgccatatc tcctttagga gctttgttgg300
ggccagtgga acaccccagg cggcgctcgc cttccttctg cttccatgtt ggttggctct360
ggacttcaga gcaccccctc ttatttcaaa cacttctttc ctctgggcct ggaatgcccc420
agctgaacgt tgtgttaaaa tctttaaact acctccagat ctgagactct tctctgtaaa480
aggaagcccc caaaaaagtg ctacgggaca atttattaca ttattttatg ctgatagact540
tggctactat cctcatatag atgaaaaaac aggcaacacc gtatatggag gaattcccca600
gttgggaaac ttaaaaaatc atttggaaaa agccaaaaaa gacattgcct attatatacc660
aaatgacagc gtgggcttgg cggtcattga ctgggaaaac tggaggccta cctgggcaag720
aaactggaaa cctaaagatg tttacaggga tgagtctgtt gagttggttc tgcaaaaaaa780
tccacaactc agtttcccag aggcttccaa gattgcaaaa gtggattttg agacagcagg840
aaagagtttc atgcaagaga ctttaaaact gggaaaatta cttcggccaa atcacttatg900
gggttattat ctttttcctg attgttacaa tcataattat aaccagccta cttacaatgg960
aaattgctct gatttagaaa aaaggagaaa tgatgatctc gactggttgt ggaaggaaag1020
cactgccctt ttcccttctg tttatttgaa tatcaagtta aaatctactc caaaagctgc1080
cttctatgtt cgtaatcgtg tccaggaagc cattcggttg tctaaaatag cgagtgttga1140
aagtccactt ccggtttttg tatatcaccg tccagttttt actgatgggt cttcaacata1200
cctttctcag ggtgaccttg tgaattcggt tggtgagatc gttgctctag gtgcctctgg1260
gattataatg tggggcagtc tcaatctaag cctaactatg caatcttgca tgaacctagg1320
caattacttg aacactacac tgaatcctta cataatcaac gtcaccctag cagccaaaat1380
gtgcagccaa gtgctttgcc acgatgaagg agtgtgtaca aggaaacaat ggaattcaag1440
cgactatctt cacctgaacc caatgaattt tgctattcaa actgggaaag gtggaaaata1500
cacagtacct gggaaagtca cacttgaaga cctgcaaacg ttttctgata aattttattg1560
cagttgttat gccaacatca actgtaagaa gagagttgat ataaaaaatg ttcatagtgt1620
taatgtatgt atggcagaag acatttgtat agagggccct gtgaagttac aacccagtga1680
tcattcctct agccagaatg aggcatctac taccaccgtc agcagtatct caccctctac1740
tacagccacc acagtatctc catgtactcc tgagaaacag tcccctgagt gcctcaaagt1800
caggtgtttg gaagccatcg ccaacgtcac ccaaacgggg tgtcaaggtg ttaaatggaa1860
gaacacttcc agtcagtcaa gtattcaaaa tattaaaaat caaacaacct attaaaatat1920
aaattcagtg cttattaaga aaaaaaaaaa aaaaaaaaaa aaaaaaa1967
<210> 195
<211> 552
<212> PRT
<213> Homo sapiens
<220>
<223> human hyaluronan synthase 2 gi4885391
<400> 195
Met His Cys Glu Arg Phe Leu Cys Ile Leu Arg Ile Ile Gly Thr Thr
151015
Leu Phe Gly Val Ser Leu Leu Leu Gly Ile Thr Ala Ala Tyr Ile Val
202530
Gly Tyr Gln Phe Ile Gln Thr Asp Asn Tyr Tyr Phe Ser Phe Gly Leu
354045
Tyr Gly Ala Phe Leu Ala Ser His Leu Ile Ile Gln Ser Leu Phe Ala
505560
Phe Leu Glu His Arg Lys Met Lys Lys Ser Leu Glu Thr Pro Ile Lys
65707580
Leu Asn Lys Thr Val Ala Leu Cys Ile Ala Ala Tyr Gln Glu Asp Pro
859095
Asp Tyr Leu Arg Lys Cys Leu Gln Ser Val Lys Arg Leu Thr Tyr Pro
100105110
Gly Ile Lys Val Val Met Val Ile Asp Gly Asn Ser Glu Asp Asp Leu
115120125
Tyr Met Met Asp Ile Phe Ser Glu Val Met Gly Arg Asp Lys Ser Ala
130135140
Thr Tyr Ile Trp Lys Asn Asn Phe His Glu Lys Gly Pro Gly Glu Thr
145150155160
Asp Glu Ser His Lys Glu Ser Ser Gln His Val Thr Gln Leu Val Leu
165170175
Ser Asn Lys Ser Ile Cys Ile Met Gln Lys Trp Gly Gly Lys Arg Glu
180185190
Val Met Tyr Thr Ala Phe Arg Ala Leu Gly Arg Ser Val Asp Tyr Val
195200205
Gln Val Cys Asp Ser Asp Thr Met Leu Asp Pro Ala Ser Ser Val Glu
210215220
Met Val Lys Val Leu Glu Glu Asp Pro Met Val Gly Gly Val Gly Gly
225230235240
Asp Val Gln Ile Leu Asn Lys Tyr Asp Ser Trp Ile Ser Phe Leu Ser
245250255
Ser Val Arg Tyr Trp Met Ala Phe Asn Ile Glu Arg Ala Cys Gln Ser
260265270
Tyr Phe Gly Cys Val Gln Cys Ile Ser Gly Pro Leu Gly Met Tyr Arg
275280285
Asn Ser Leu Leu His Glu Phe Val Glu Asp Trp Tyr Asn Gln Glu Phe
290295300
Met Gly Asn Gln Cys Ser Phe Gly Asp Asp Arg His Leu Thr Asn Arg
305310315320
Val Leu Ser Leu Gly Tyr Ala Thr Lys Tyr Thr Ala Arg Ser Lys Cys
325330335
Leu Thr Glu Thr Pro Ile Glu Tyr Leu Arg Trp Leu Asn Gln Gln Thr
340345350
Arg Trp Ser Lys Ser Tyr Phe Arg Glu Trp Leu Tyr Asn Ala Met Trp
355360365
Phe His Lys His His Leu Trp Met Thr Tyr Glu Ala Ile Ile Thr Gly
370375380
Phe Phe Pro Phe Phe Leu Ile Ala Thr Val Ile Gln Leu Phe Tyr Arg
385390395400
Gly Lys Ile Trp Asn Ile Leu Leu Phe Leu Leu Thr Val Gln Leu Val
405410415
Gly Leu Ile Lys Ser Ser Phe Ala Ser Cys Leu Arg Gly Asn Ile Val
420425430
Met Val Phe Met Ser Leu Tyr Ser Val Leu Tyr Met Ser Ser Leu Leu
435440445
Pro Ala Lys Met Phe Ala Ile Ala Thr Ile Asn Lys Ala Gly Trp Gly
450455460
Thr Ser Gly Arg Lys Thr Ile Val Val Asn Phe Ile Gly Leu Ile Pro
465470475480
Val Ser Val Trp Phe Thr Ile Leu Leu Gly Gly Val Ile Phe Thr Ile
485490495
Tyr Lys Glu Ser Lys Arg Pro Phe Ser Glu Ser Lys Gln Thr Val Leu
500505510
Ile Val Gly Thr Leu Leu Tyr Ala Cys Tyr Trp Val Met Leu Leu Thr
515520525
Leu Tyr Val Val Leu Ile Asn Lys Cys Gly Arg Arg Lys Lys Gly Gln
530535540
Gln Tyr Asp Met Val Leu Asp Val
545550
<210> 196
<211> 1849
<212> DNA
<213> Artificial Sequence
<220>
<223> N-terminal His6-tagged hHAS2 cDNA
<400> 196
gtgcgaacgg gcgtcttgtc tgctgcagcc aagcttgggc tgcaggtcga cggatccgtt 60
aaccctagcc accatgcatc accatcacca tcacggcgga ggcggatcag ggcattgtga120
gaggtttcta tgtatcctga gaataattgg aaccacactc tttggagtct ctctcctcct180
tggaatcaca gctgcttata ttgttggcta ccagtttatc caaacggata attactattt240
ctcttttgga ctgtatggtg cctttttggc atcacacctc atcatccaaa gcctgtttgc300
ctttttggag caccgaaaaa tgaaaaaatc cctagaaacc cccataaagt tgaacaaaac360
agttgccctt tgcatcgctg cctatcaaga agatccagac tacttaagga aatgtttgca420
atctgtgaaa aggctaacct accctgggat taaagttgtc atggtcatag atgggaactc480
agaagatgac ctttacatga tggacatctt cagtgaagtc atgggcagag acaaatcagc540
cacttatatc tggaagaaca acttccacga aaagggtccc ggtgagacag atgagtcaca600
taaagaaagc tcgcaacacg taacgcaatt ggtcttgtcc aacaaaagta tctgcatcat660
gcaaaaatgg ggtggaaaaa gagaagtcat gtacacagcc ttcagagcac tgggacgaag720
tgtggattat gtacaggttt gtgattcaga cactatgctt gacccagcct catctgtgga780
gatggtaaaa gttttagaag aagatcccat ggttggaggt gttgggggag atgtccagat840
tttaaacaag tacgattcct ggatctcatt cctcagcagt gtaagatatt ggatggcttt900
taatatagaa agggcctgtc agtcttattt tgggtgtgtt cagtgcatta gtggacctct960
gggaatgtac agaaactcct tgttgcatga gtttgtggaa gattggtaca atcaagaatt1020
tatgggcaac caatgtagct ttggtgatga caggcatctc acgaaccggg tgctgagcct1080
gggctatgca acaaaataca cagctcgatc taagtgcctt actgaaacac ctatagaata1140
tctcagatgg ctaaaccagc agacccgttg gagcaagtcc tacttccgag aatggctgta1200
caatgcaatg tggtttcaca aacatcactt gtggatgacc tacgaagcga ttatcactgg1260
attctttcct ttctttctca ttgccacagt aatccagctc ttctaccggg gtaaaatttg1320
gaacattctc ctcttcttgt taactgtcca gctagtaggt ctcataaaat catcttttgc1380
cagctgcctt agaggaaata tcgtcatggt cttcatgtct ctctactcag tgttatacat1440
gtcgagttta cttcccgcca agatgtttgc aattgcaaca ataaacaaag ctgggtgggg1500
cacatcagga aggaaaacca ttgttgttaa tttcatagga ctcattccag tatcagtttg1560
gtttacaatc ctcctgggtg gtgtgatttt caccatttat aaggagtcta aaaggccatt1620
ttcagaatcc aaacagacag ttctaattgt tggaacgttg ctctatgcat gctattgggt1680
catgcttttg acgctgtatg tagttctcat caataagtgt ggcaggcgga agaagggaca1740
acaatatgac atggtgcttg atgtatgagc ggcctcgaga gatcccctca ggatatagta1800
gtttcgcttt tgcataggga gggggaaatg tagtctatgc aattttttt1849
<210> 197
<211> 6419
<212> DNA
<213> Artificial Sequence
<220>
<223> pLXRN
<400> 197
ttttgaaaga ccccacccgt aggtggcaag ctagcttaag taacgccact ttgcaaggca 60
tggaaaaata cataactgag aatagaaaag ttcagatcaa ggtcaggaac aaagaaacag120
ctgaatacca aacaggatat ctgtggtaag cggttcctgc cccggctcag ggccaagaac180
agatgagaca gctgagtgat gggccaaaca ggatatctgt ggtaagcagt tcctgccccg240
gctcggggcc aagaacagat ggtccccaga tgcggtccag ccctcagcag tttctagtga300
atcatcagat gtttccaggg tgccccaagg acctgaaaat gaccctgtac cttatttgaa360
ctaaccaatc agttcgcttc tcgcttctgt tcgcgcgctt ccgctctccg agctcaataa420
aagagcccac aacccctcac tcggcgcgcc agtcttccga tagactgcgt cgcccgggta480
cccgtattcc caataaagcc tcttgctgtt tgcatccgaa tcgtggtctc gctgttcctt540
gggagggtct cctctgagtg attgactacc cacgacgggg gtctttcatt tgggggctcg600
tccgggattt ggagacccct gcccagggac caccgaccca ccaccgggag gtaagctggc660
cagcaactta tctgtgtctg tccgattgtc tagtgtctat gtttgatgtt atgcgcctgc720
gtctgtacta gttagctaac tagctctgta tctggcggac ccgtggtgga actgacgagt780
tctgaacacc cggccgcaac cctgggagac gtcccaggga ctttgggggc cgtttttgtg840
gcccgacctg aggaagggag tcgatgtgga atccgacccc gtcaggatat gtggttctgg900
taggagacga gaacctaaaa cagttcccgc ctccgtctga atttttgctt tcggtttgga960
accgaagccg cgcgtcttgt ctgctgcagc caagcttggg ctgcaggtcg acggatccgt1020
taaccctagg ctcgagagat cccctcagga tatagtagtt tcgcttttgc atagggaggg1080
ggaaatgtag tcttatgcaa tactcttgta gtcttgcaac atggtaacga tgagttagca1140
acatgcctta caaggagaga aaaagcaccg tgcatgccga ttggtggaag taaggtggta1200
cgatcgtgcc ttattaggaa ggcaacagac gggtctgaca tggattggac gaaccactga1260
attccgcatt gcagagatat tgtatttaag tgcctagctc gatacagcaa acgccatttg1320
accattcacc acattggtgt gcacctccaa gcttcacgct gccgcaagca ctcagggcgc1380
aagggctgct aaaggaagcg gaacacgtag aaagccagtc cgcagaaacg gtgctgaccc1440
cggatgaatg tcagctactg ggctatctgg acaagggaaa acgcaagcgc aaagagaaag1500
caggtagctt gcagtgggct tacatggcga tagctagact gggcggtttt atggacagca1560
agcgaaccgg aattgccagc tggggcgccc tctggtaagg ttgggaagcc ctgcaaagta1620
aactggatgg ctttcttgcc gccaaggatc tgatggcgca ggggatcaag atctgatcaa1680
gagacaggat gaggatcgtt tcgcatgatt gaacaagatg gattgcacgc aggttctccg1740
gccgcttggg tggagaggct attcggctat gactgggcac aacagacaat cggctgctct1800
gatgccgccg tgttccggct gtcagcgcag gggcgcccgg ttctttttgt caagaccgac1860
ctgtccggtg ccctgaatga actgcaggac gaggcagcgc ggctatcgtg gctggccacg1920
acgggcgttc cttgcgcagc tgtgctcgac gttgtcactg aagcgggaag ggactggctg1980
ctattgggcg aagtgccggg gcaggatctc ctgtcatctc accttgctcc tgccgagaaa2040
gtatccatca tggctgatgc aatgcggcgg ctgcatacgc ttgatccggc tacctgccca2100
ttcgaccacc aagcgaaaca tcgcatcgag cgagcacgta ctcggatgga agccggtctt2160
gtcgatcagg atgatctgga cgaagagcat caggggctcg cgccagccga actgttcgcc2220
aggctcaagg cgcgcatgcc cgacggcgag gatctcgtcg tgacccatgg cgatgcctgc2280
ttgccgaata tcatggtgga aaatggccgc ttttctggat tcatcgactg tggccggctg2340
ggtgtggcgg accgctatca ggacatagcg ttggctaccc gtgatattgc tgaagagctt2400
ggcggcgaat gggctgaccg cttcctcgtg ctttacggta tcgccgctcc cgattcgcag2460
cgcatcgcct tctatcgcct tcttgacgag ttcttctgag cgggactctg gggttcgaaa2520
tgaccgacca agcgacgccc aacctgccat cacgagattt cgattccacc gccgccttct2580
atgaaaggtt gggcttcgga atcgttttcc gggacgccgg ctggatgatc ctccagcgcg2640
gggatctcat gctggagttc ttcgcccacc ccaaccctgg ccctattatt gggtggacta2700
accatggggg gaattgccgc tggaatagga acagggacta ctgctctaat ggccactcag2760
caattccagc agctccaagc cgcagtacag gatgatctca gggaggttga aaaatcaatc2820
tctaacctag aaaagtctct cacttccctg tctgaagttg tcctacagaa tcgaaggggc2880
ctagacttgt tatttctaaa agaaggaggg ctgtgtgctg ctctaaaaga agaatgttgc2940
ttctatgcgg accacacagg actagtgaga gacagcatgg ccaaattgag agagaggctt3000
aatcagagac agaaactgtt tgagtcaact caaggatggt ttgagggact gtttaacaga3060
tccccttggt ttaccacctt gatatctacc attatgggac ccctcattgt actcctaatg3120
attttgctct tcggaccctg cattcttaat cgattagtcc aatttgttaa agacaggata3180
tcagtggtcc aggctctagt tttgactcaa caatatcacc agctgaagcc tatagagtac3240
gagccataga taaaataaaa gattttattt agtctccaga aaaagggggg aatgaaagac3300
cccacctgta ggtttggcaa gctagcttaa gtaacgccat tttgcaaggc atggaaaaat3360
acataactga gaatagagaa gttcagatca aggtcaggaa cagatggaac agctgaatat3420
gggccaaaca ggatatctgt ggtaagcagt tcctgccccg gctcagggcc aagaacagat3480
ggaacagctg aatatgggcc aaacaggata tctgtggtaa gcagttcctg ccccggctca3540
gggccaagaa cagatggtcc ccagatgcgg tccagccctc agcagtttct agagaaccat3600
cagatgtttc cagggtgccc caaggacctg aaatgaccct gtgccttatt tgaactaacc3660
aatcagttcg cttctcgctt ctgttcgcgc gcttctgctc cccgagctca ataaaagagc3720
ccacaacccc tcactcgggg cgccagtcct ccgattgact gagtcgcccg ggtacccgtg3780
tatccaataa accctcttgc agttgcatcc gacttgtggt ctcgctgttc cttgggaggg3840
tctcctctga gtgattgact acccgtcagc gggggtcttt catttggggg ctcgtccggg3900
atcgggagac ccctgcccag ggaccaccga cccaccaccg ggaggtaagc tggctgcctc3960
gcgcgtttcg gtgatgacgg tgaaaacctc tgacacatgc agctcccgga gacggtcaca4020
gcttgtctgt aagcggatgc cgggagcaga caagcccgtc agggcgcgtc agcgggtgtt4080
ggcgggtgtc ggggcgcagc catgacccag tcacgtagcg atagcggagt gtatactggc4140
ttaactatgc ggcatcagag cagattgtac tgagagtgca ccatatgcgg tgtgaaatac4200
cgcacagatg cgtaaggaga aaataccgca tcaggcgctc ttccgcttcc tcgctcactg4260
actcgctgcg ctcggtcgtt cggctgcggc gagcggtatc agctcactca aaggcggtaa4320
tacggttatc cacagaatca ggggataacg caggaaagaa catgtgagca aaaggccagc4380
aaaaggccag gaaccgtaaa aaggccgcgt tgctggcgtt tttccatagg ctccgccccc4440
ctgacgagca tcacaaaaat cgacgctcaa gtcagaggtg gcgaaacccg acaggactat4500
aaagatacca ggcgtttccc cctggaagct ccctcgtgcg ctctcctgtt ccgaccctgc4560
cgcttaccgg atacctgtcc gcctttctcc cttcgggaag cgtggcgctt tctcatagct4620
cacgctgtag gtatctcagt tcggtgtagg tcgttcgctc caagctgggc tgtgtgcacg4680
aaccccccgt tcagcccgac cgctgcgcct tatccggtaa ctatcgtctt gagtccaacc4740
cggtaagaca cgacttatcg ccactggcag cagccactgg taacaggatt agcagagcga4800
ggtatgtagg cggtgctaca gagttcttga agtggtggcc taactacggc tacactagaa4860
ggacagtatt tggtatctgc gctctgctga agccagttac cttcggaaaa agagttggta4920
gctcttgatc cggcaaacaa accaccgctg gtagcggtgg tttttttgtt tgcaagcagc4980
agattacgcg cagaaaaaaa ggatctcaag aagatccttt gatcttttct acggggtctg5040
acgctcagtg gaacgaaaac tcacgttaag ggattttggt catgagatta tcaaaaagga5100
tcttcaccta gatcctttta aattaaaaat gaagttttaa atcaatctaa agtatatatg5160
agtaaacttg gtctgacagt taccaatgct taatcagtga ggcacctatc tcagcgatct5220
gtctatttcg ttcatccata gttgcctgac tccccgtcgt gtagataact acgatacggg5280
agggcttacc atctggcccc agtgctgcaa tgataccgcg agacccacgc tcaccggctc5340
cagatttatc agcaataaac cagccagccg gaagggccga gcgcagaagt ggtcctgcaa5400
ctttatccgc ctccatccag tctattaatt gttgccggga agctagagta agtagttcgc5460
cagttaatag tttgcgcaac gttgttgcca ttgctgcagg catcgtggtg tcacgctcgt5520
cgtttggtat ggcttcattc agctccggtt cccaacgatc aaggcgagtt acatgatccc5580
ccatgttgtg caaaaaagcg gttagctcct tcggtcctcc gatcgttgtc agaagtaagt5640
tggccgcagt gttatcactc atggttatgg cagcactgca taattctctt actgtcatgc5700
catccgtaag atgcttttct gtgactggtg agtactcaac caagtcattc tgagaatagt5760
gtatgcggcg accgagttgc tcttgcccgg cgtcaacacg ggataatacc gcgccacata5820
gcagaacttt aaaagtgctc atcattggaa aacgttcttc ggggcgaaaa ctctcaagga5880
tcttaccgct gttgagatcc agttcgatgt aacccactcg tgcacccaac tgatcttcag5940
catcttttac tttcaccagc gtttctgggt gagcaaaaac aggaaggcaa aatgccgcaa6000
aaaagggaat aagggcgaca cggaaatgtt gaatactcat actcttcctt tttcaatatt6060
attgaagcat ttatcagggt tattgtctca tgagcggata catatttgaa tgtatttaga6120
aaaataaaca aataggggtt ccgcgcacat ttccccgaaa agtgccacct gacgtctaag6180
aaaccattat tatcatgaca ttaacctata aaaataggcg tatcacgagg ccctttcgtc6240
ttcaaagaat tgctagcaat tgctagcaat tgctagcaat tcataccaga tcaccgaaaa6300
ctgtcctcca aatgtgtccc cctcacactc ccaaattcgc gggcttctgc ctcttagacc6360
actctaccct attccccaca ctcaccggag ccaaagccgc ggcccttccg tttctttgc6419
<210> 198
<211> 6507
<212> DNA
<213> Artificial Sequence
<220>
<223> pVSV-G envelope vector
<400> 198
gcggccgctc tagagagctt ggcccattgc atacgttgta tccatatcat aatatgtaca 60
tttatattgg ctcatgtcca acattaccgc catgttgaca ttgattattg actagttatt120
aatagtaatc aattacgggg tcattagttc atagcccata tatggagttc cgcgttacat180
aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa240
taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg300
agtatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg ccaagtacgc360
cccctattga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag tacatgacct420
tatgggactt tcctacttgg cagtacatct acgtattagt catcgctatt accatggtga480
tgcggttttg gcagtacatc aatgggcgtg gatagcggtt tgactcacgg ggatttccaa540
gtctccaccc cattgacgtc aatgggagtt tgttttggca ccaaaatcaa cgggactttc600
caaaatgtcg taacaactcc gccccattga cgcaaatggg cggtaggcgt gtacggtggg660
aggtctatat aagcagagct cgtttagtga accgtcagat cgcctggaga cgccatccac720
gctgttttga cctccataga agacaccggg accgatccag cctccggtcg accgatcctg780
agaacttcag ggtgagtttg gggacccttg attgttcttt ctttttcgct attgtaaaat840
tcatgttata tggagggggc aaagttttca gggtgttgtt tagaatggga agatgtccct900
tgtatcacca tggaccctca tgataatttt gtttctttca ctttctactc tgttgacaac960
cattgtctcc tcttattttc ttttcatttt ctgtaacttt ttcgttaaac tttagcttgc1020
atttgtaacg aatttttaaa ttcacttttg tttatttgtc agattgtaag tactttctct1080
aatcactttt ttttcaaggc aatcagggta tattatattg tacttcagca cagttttaga1140
gaacaattgt tataattaaa tgataaggta gaatatttct gcatataaat tctggctggc1200
gtggaaatat tcttattggt agaaacaact acaccctggt catcatcctg cctttctctt1260
tatggttaca atgatataca ctgtttgaga tgaggataaa atactctgag tccaaaccgg1320
gcccctctgc taaccatgtt catgccttct tctctttcct acagctcctg ggcaacgtgc1380
tggttgttgt gctgtctcat cattttggca aagaattcct cgacggatcc ctcgaggaat1440
tctgacacta tgaagtgcct tttgtactta gcctttttat tcattggggt gaattgcaag1500
ttcaccatag tttttccaca caaccaaaaa ggaaactgga aaaatgttcc ttctaattac1560
cattattgcc cgtcaagctc agatttaaat tggcataatg acttaatagg cacagcctta1620
caagtcaaaa tgcccaagag tcacaaggct attcaagcag acggttggat gtgtcatgct1680
tccaaatggg tcactacttg tgatttccgc tggtatggac cgaagtatat aacacattcc1740
atccgatcct tcactccatc tgtagaacaa tgcaaggaaa gcattgaaca aacgaaacaa1800
ggaacttggc tgaatccagg cttccctcct caaagttgtg gatatgcaac tgtgacggat1860
gccgaagcag tgattgtcca ggtgactcct caccatgtgc tggttgatga atacacagga1920
gaatgggttg attcacagtt catcaacgga aaatgcagca attacatatg ccccactgtc1980
cataactcta caacctggca ttctgactat aaggtcaaag ggctatgtga ttctaacctc2040
atttccatgg acatcacctt cttctcagag gacggagagc tatcatccct gggaaaggag2100
ggcacagggt tcagaagtaa ctactttgct tatgaaactg gaggcaaggc ctgcaaaatg2160
caatactgca agcattgggg agtcagactc ccatcaggtg tctggttcga gatggctgat2220
aaggatctct ttgctgcagc cagattccct gaatgcccag aagggtcaag tatctctgct2280
ccatctcaga cctcagtgga tgtaagtcta attcaggacg ttgagaggat cttggattat2340
tccctctgcc aagaaacctg gagcaaaatc agagcgggtc ttccaatctc tccagtggat2400
ctcagctatc ttgctcctaa aaacccagga accggtcctg ctttcaccat aatcaatggt2460
accctaaaat actttgagac cagatacatc agagtcgata ttgctgctcc aatcctctca2520
agaatggtcg gaatgatcag tggaactacc acagaaaggg aactgtggga tgactgggca2580
ccatatgaag acgtggaaat tggacccaat ggagttctga ggaccagttc aggatataag2640
tttcctttat acatgattgg acatggtatg ttggactccg atcttcatct tagctcaaag2700
gctcaggtgt tcgaacatcc tcacattcaa gacgctgctt cgcaacttcc tgatgatgag2760
agtttatttt ttggtgatac tgggctatcc aaaaatccaa tcgagcttgt agaaggttgg2820
ttcagtagtt ggaaaagctc tattgcctct tttttcttta tcatagggtt aatcattgga2880
ctattcttgg ttctccgagt tggtatccat ctttgcatta aattaaagca caccaagaaa2940
agacagattt atacagacat agagatgaac cgacttggaa agtaactcaa atcctgcaca3000
acagattctt catgtttgga ccaaatcaac ttgtgatacc atgctcaaag aggcctcaat3060
tatatttgag tttttaattt ttatgaaaaa aaaaaaaaaa aacggaattc ctcgagggat3120
ccgtcgagga attcactcct caggtgcagg ctgcctatca gaaggtggtg gctggtgtgg3180
ccaatgccct ggctcacaaa taccactgag atctttttcc ctctgccaaa aattatgggg3240
acatcatgaa gccccttgag catctgactt ctggctaata aaggaaattt attttcattg3300
caatagtgtg ttggaatttt ttgtgtctct cactcggaag gacatatggg agggcaaatc3360
atttaaaaca tcagaatgag tatttggttt agagtttggc aacatatgcc catatgctgg3420
ctgccatgaa caaaggttgg ctataaagag gtcatcagta tatgaaacag ccccctgctg3480
tccattcctt attccataga aaagccttga cttgaggtta gatttttttt atattttgtt3540
ttgtgttatt tttttcttta acatccctaa aattttcctt acatgtttta ctagccagat3600
ttttcctcct ctcctgacta ctcccagtca tagctgtccc tcttctctta tggagatccc3660
tcgacggatc ggccgcaatt cgtaatcatg tcatagctgt ttcctgtgtg aaattgttat3720
ccgctcacaa ttccacacaa catacgagcc ggaagcataa agtgtaaagc ctggggtgcc3780
taatgagtga gctaactcac attaattgcg ttgcgctcac tgcccgcttt ccagtcggga3840
aacctgtcgt gccagctgca ttaatgaatc ggccaacgcg cggggagagg cggtttgcgt3900
attgggcgct cttccgcttc ctcgctcact gactcgctgc gctcggtcgt tcggctgcgg3960
cgagcggtat cagctcactc aaaggcggta atacggttat ccacagaatc aggggataac4020
gcaggaaaga acatgtgagc aaaaggccag caaaaggcca ggaaccgtaa aaaggccgcg4080
ttgctggcgt ttttccatag gctccgcccc cctgacgagc atcacaaaaa tcgacgctca4140
agtcagaggt ggcgaaaccc gacaggacta taaagatacc aggcgtttcc ccctggaagc4200
tccctcgtgc gctctcctgt tccgaccctg ccgcttaccg gatacctgtc cgcctttctc4260
ccttcgggaa gcgtggcgct ttctcatagc tcacgctgta ggtatctcag ttcggtgtag4320
gtcgttcgct ccaagctggg ctgtgtgcac gaaccccccg ttcagcccga ccgctgcgcc4380
ttatccggta actatcgtct tgagtccaac ccggtaagac acgacttatc gccactggca4440
gcagccactg gtaacaggat tagcagagcg aggtatgtag gcggtgctac agagttcttg4500
aagtggtggc ctaactacgg ctacactaga agaacagtat ttggtatctg cgctctgctg4560
aagccagtta ccttcggaaa aagagttggt agctcttgat ccggcaaaca aaccaccgct4620
ggtagcggtg gtttttttgt ttgcaagcag cagattacgc gcagaaaaaa aggatctcaa4680
gaagatcctt tgatcttttc tacggggtct gacgctcagt ggaacgaaaa ctcacgttaa4740
gggattttgg tcatgagatt atcaaaaagg atcttcacct agatcctttt aaattaaaaa4800
tgaagtttta aatcaatcta aagtatatat gagtaaactt ggtctgacag ttaccaatgc4860
ttaatcagtg aggcacctat ctcagcgatc tgtctatttc gttcatccat agttgcctga4920
ctccccgtcg tgtagataac tacgatacgg gagggcttac catctggccc cagtgctgca4980
atgataccgc gagacccacg ctcaccggct ccagatttat cagcaataaa ccagccagcc5040
ggaagggccg agcgcagaag tggtcctgca actttatccg cctccatcca gtctattaat5100
tgttgccggg aagctagagt aagtagttcg ccagttaata gtttgcgcaa cgttgttgcc5160
attgctacag gcatcgtggt gtcacgctcg tcgtttggta tggcttcatt cagctccggt5220
tcccaacgat caaggcgagt tacatgatcc cccatgttgt gcaaaaaagc ggttagctcc5280
ttcggtcctc cgatcgttgt cagaagtaag ttggccgcag tgttatcact catggttatg5340
gcagcactgc ataattctct tactgtcatg ccatccgtaa gatgcttttc tgtgactggt5400
gagtactcaa ccaagtcatt ctgagaatag tgtatgcggc gaccgagttg ctcttgcccg5460
gcgtcaatac gggataatac cgcgccacat agcagaactt taaaagtgct catcattgga5520
aaacgttctt cggggcgaaa actctcaagg atcttaccgc tgttgagatc cagttcgatg5580
taacccactc gtgcacccaa ctgatcttca gcatctttta ctttcaccag cgtttctggg5640
tgagcaaaaa caggaaggca aaatgccgca aaaaagggaa taagggcgac acggaaatgt5700
tgaatactca tactcttcct ttttcaatat tattgaagca tttatcaggg ttattgtctc5760
atgagcggat acatatttga atgtatttag aaaaataaac aaataggggt tccgcgcaca5820
tttccccgaa aagtgccacc taaattgtaa gcgttaatat tttgttaaaa ttcgcgttaa5880
atttttgtta aatcagctca ttttttaacc aataggccga aatcggcaaa atcccttata5940
aatcaaaaga atagaccgag atagggttga gtgttgttcc agtttggaac aagagtccac6000
tattaaagaa cgtggactcc aacgtcaaag ggcgaaaaac cgtctatcag ggcgatggcc6060
cactacgtga accatcaccc taatcaagtt ttttggggtc gaggtgccgt aaagcactaa6120
atcggaaccc taaagggagc ccccgattta gagcttgacg gggaaagccg gcgaacgtgg6180
cgagaaagga agggaagaaa gcgaaaggag cgggcgctag ggcgctggca agtgtagcgg6240
tcacgctgcg cgtaaccacc acacccgccg cgcttaatgc gccgctacag ggcgcgtccc6300
attcgccatt caggctgcgc aactgttggg aagggcgatc ggtgcgggcc tcttcgctat6360
tacgccagct ggcgaaaggg ggatgtgctg caaggcgatt aagttgggta acgccagggt6420
tttcccagtc acgacgttgt aaaacgacgg ccagtgagcg cgcgtaatac gactcactat6480
agggcgaatt ggagctccac cgcggtg6507
<210> 199
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> pLXSN 5' primer (1398-1420)
<400> 199
cccttgaacc tcctcgttcg acc23
<210> 200
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> pLXSN 3' primer (1537-1515)
<400> 200
gagcctgggg actttccaca ccc23
<210> 201
<211> 8092
<212> DNA
<213> Artificial Sequence
<220>
<223> pLXRN-hHAS2
<400> 201
ttttgaaaga ccccacccgt aggtggcaag ctagcttaag taacgccact ttgcaaggca 60
tggaaaaata cataactgag aatagaaaag ttcagatcaa ggtcaggaac aaagaaacag120
ctgaatacca aacaggatat ctgtggtaag cggttcctgc cccggctcag ggccaagaac180
agatgagaca gctgagtgat gggccaaaca ggatatctgt ggtaagcagt tcctgccccg240
gctcggggcc aagaacagat ggtccccaga tgcggtccag ccctcagcag tttctagtga300
atcatcagat gtttccaggg tgccccaagg acctgaaaat gaccctgtac cttatttgaa360
ctaaccaatc agttcgcttc tcgcttctgt tcgcgcgctt ccgctctccg agctcaataa420
aagagcccac aacccctcac tcggcgcgcc agtcttccga tagactgcgt cgcccgggta480
cccgtattcc caataaagcc tcttgctgtt tgcatccgaa tcgtggtctc gctgttcctt540
gggagggtct cctctgagtg attgactacc cacgacgggg gtctttcatt tgggggctcg600
tccgggattt ggagacccct gcccagggac caccgaccca ccaccgggag gtaagctggc660
cagcaactta tctgtgtctg tccgattgtc tagtgtctat gtttgatgtt atgcgcctgc720
gtctgtacta gttagctaac tagctctgta tctggcggac ccgtggtgga actgacgagt780
tctgaacacc cggccgcaac cctgggagac gtcccaggga ctttgggggc cgtttttgtg840
gcccgacctg aggaagggag tcgatgtgga atccgacccc gtcaggatat gtggttctgg900
taggagacga gaacctaaaa cagttcccgc ctccgtctga atttttgctt tcggtttgga960
accgaagccg cgcgtcttgt ctgctgcagc caagcttggg ctgcaggtcg acggatccgt1020
taaccctagc caccatgcat caccatcacc atcacggcgg aggcggatca gggcattgtg1080
agaggtttct atgtatcctg agaataattg gaaccacact ctttggagtc tctctcctcc1140
ttggaatcac agctgcttat attgttggct accagtttat ccaaacggat aattactatt1200
tctcttttgg actgtatggt gcctttttgg catcacacct catcatccaa agcctgtttg1260
cctttttgga gcaccgaaaa atgaaaaaat ccctagaaac ccccataaag ttgaacaaaa1320
cagttgccct ttgcatcgct gcctatcaag aagatccaga ctacttaagg aaatgtttgc1380
aatctgtgaa aaggctaacc taccctggga ttaaagttgt catggtcata gatgggaact1440
cagaagatga cctttacatg atggacatct tcagtgaagt catgggcaga gacaaatcag1500
ccacttatat ctggaagaac aacttccacg aaaagggtcc cggtgagaca gatgagtcac1560
ataaagaaag ctcgcaacac gtaacgcaat tggtcttgtc caacaaaagt atctgcatca1620
tgcaaaaatg gggtggaaaa agagaagtca tgtacacagc cttcagagca ctgggacgaa1680
gtgtggatta tgtacaggtt tgtgattcag acactatgct tgacccagcc tcatctgtgg1740
agatggtaaa agttttagaa gaagatccca tggttggagg tgttggggga gatgtccaga1800
ttttaaacaa gtacgattcc tggatctcat tcctcagcag tgtaagatat tggatggctt1860
ttaatataga aagggcctgt cagtcttatt ttgggtgtgt tcagtgcatt agtggacctc1920
tgggaatgta cagaaactcc ttgttgcatg agtttgtgga agattggtac aatcaagaat1980
ttatgggcaa ccaatgtagc tttggtgatg acaggcatct cacgaaccgg gtgctgagcc2040
tgggctatgc aacaaaatac acagctcgat ctaagtgcct tactgaaaca cctatagaat2100
atctcagatg gctaaaccag cagacccgtt ggagcaagtc ctacttccga gaatggctgt2160
acaatgcaat gtggtttcac aaacatcact tgtggatgac ctacgaagcg attatcactg2220
gattctttcc tttctttctc attgccacag taatccagct cttctaccgg ggtaaaattt2280
ggaacattct cctcttcttg ttaactgtcc agctagtagg tctcataaaa tcatcttttg2340
ccagctgcct tagaggaaat atcgtcatgg tcttcatgtc tctctactca gtgttataca2400
tgtcgagttt acttcccgcc aagatgtttg caattgcaac aataaacaaa gctgggtggg2460
gcacatcagg aaggaaaacc attgttgtta atttcatagg actcattcca gtatcagttt2520
ggtttacaat cctcctgggt ggtgtgattt tcaccattta taaggagtct aaaaggccat2580
tttcagaatc caaacagaca gttctaattg ttggaacgtt gctctatgca tgctattggg2640
tcatgctttt gacgctgtat gtagttctca tcaataagtg tggcaggcgg aagaagggac2700
aacaatatga catggtgctt gatgtatgag cggcctcgag agatcccctc aggatatagt2760
agtttcgctt ttgcataggg agggggaaat gtagtcttat gcaatactct tgtagtcttg2820
caacatggta acgatgagtt agcaacatgc cttacaagga gagaaaaagc accgtgcatg2880
ccgattggtg gaagtaaggt ggtacgatcg tgccttatta ggaaggcaac agacgggtct2940
gacatggatt ggacgaacca ctgaattccg cattgcagag atattgtatt taagtgccta3000
gctcgataca gcaaacgcca tttgaccatt caccacattg gtgtgcacct ccaagcttca3060
cgctgccgca agcactcagg gcgcaagggc tgctaaagga agcggaacac gtagaaagcc3120
agtccgcaga aacggtgctg accccggatg aatgtcagct actgggctat ctggacaagg3180
gaaaacgcaa gcgcaaagag aaagcaggta gcttgcagtg ggcttacatg gcgatagcta3240
gactgggcgg ttttatggac agcaagcgaa ccggaattgc cagctggggc gccctctggt3300
aaggttggga agccctgcaa agtaaactgg atggctttct tgccgccaag gatctgatgg3360
cgcaggggat caagatctga tcaagagaca ggatgaggat cgtttcgcat gattgaacaa3420
gatggattgc acgcaggttc tccggccgct tgggtggaga ggctattcgg ctatgactgg3480
gcacaacaga caatcggctg ctctgatgcc gccgtgttcc ggctgtcagc gcaggggcgc3540
ccggttcttt ttgtcaagac cgacctgtcc ggtgccctga atgaactgca ggacgaggca3600
gcgcggctat cgtggctggc cacgacgggc gttccttgcg cagctgtgct cgacgttgtc3660
actgaagcgg gaagggactg gctgctattg ggcgaagtgc cggggcagga tctcctgtca3720
tctcaccttg ctcctgccga gaaagtatcc atcatggctg atgcaatgcg gcggctgcat3780
acgcttgatc cggctacctg cccattcgac caccaagcga aacatcgcat cgagcgagca3840
cgtactcgga tggaagccgg tcttgtcgat caggatgatc tggacgaaga gcatcagggg3900
ctcgcgccag ccgaactgtt cgccaggctc aaggcgcgca tgcccgacgg cgaggatctc3960
gtcgtgaccc atggcgatgc ctgcttgccg aatatcatgg tggaaaatgg ccgcttttct4020
ggattcatcg actgtggccg gctgggtgtg gcggaccgct atcaggacat agcgttggct4080
acccgtgata ttgctgaaga gcttggcggc gaatgggctg accgcttcct cgtgctttac4140
ggtatcgccg ctcccgattc gcagcgcatc gccttctatc gccttcttga cgagttcttc4200
tgagcgggac tctggggttc gaaatgaccg accaagcgac gcccaacctg ccatcacgag4260
atttcgattc caccgccgcc ttctatgaaa ggttgggctt cggaatcgtt ttccgggacg4320
ccggctggat gatcctccag cgcggggatc tcatgctgga gttcttcgcc caccccaacc4380
ctggccctat tattgggtgg actaaccatg gggggaattg ccgctggaat aggaacaggg4440
actactgctc taatggccac tcagcaattc cagcagctcc aagccgcagt acaggatgat4500
ctcagggagg ttgaaaaatc aatctctaac ctagaaaagt ctctcacttc cctgtctgaa4560
gttgtcctac agaatcgaag gggcctagac ttgttatttc taaaagaagg agggctgtgt4620
gctgctctaa aagaagaatg ttgcttctat gcggaccaca caggactagt gagagacagc4680
atggccaaat tgagagagag gcttaatcag agacagaaac tgtttgagtc aactcaagga4740
tggtttgagg gactgtttaa cagatcccct tggtttacca ccttgatatc taccattatg4800
ggacccctca ttgtactcct aatgattttg ctcttcggac cctgcattct taatcgatta4860
gtccaatttg ttaaagacag gatatcagtg gtccaggctc tagttttgac tcaacaatat4920
caccagctga agcctataga gtacgagcca tagataaaat aaaagatttt atttagtctc4980
cagaaaaagg ggggaatgaa agaccccacc tgtaggtttg gcaagctagc ttaagtaacg5040
ccattttgca aggcatggaa aaatacataa ctgagaatag agaagttcag atcaaggtca5100
ggaacagatg gaacagctga atatgggcca aacaggatat ctgtggtaag cagttcctgc5160
cccggctcag ggccaagaac agatggaaca gctgaatatg ggccaaacag gatatctgtg5220
gtaagcagtt cctgccccgg ctcagggcca agaacagatg gtccccagat gcggtccagc5280
cctcagcagt ttctagagaa ccatcagatg tttccagggt gccccaagga cctgaaatga5340
ccctgtgcct tatttgaact aaccaatcag ttcgcttctc gcttctgttc gcgcgcttct5400
gctccccgag ctcaataaaa gagcccacaa cccctcactc ggggcgccag tcctccgatt5460
gactgagtcg cccgggtacc cgtgtatcca ataaaccctc ttgcagttgc atccgacttg5520
tggtctcgct gttccttggg agggtctcct ctgagtgatt gactacccgt cagcgggggt5580
ctttcatttg ggggctcgtc cgggatcggg agacccctgc ccagggacca ccgacccacc5640
accgggaggt aagctggctg cctcgcgcgt ttcggtgatg acggtgaaaa cctctgacac5700
atgcagctcc cggagacggt cacagcttgt ctgtaagcgg atgccgggag cagacaagcc5760
cgtcagggcg cgtcagcggg tgttggcggg tgtcggggcg cagccatgac ccagtcacgt5820
agcgatagcg gagtgtatac tggcttaact atgcggcatc agagcagatt gtactgagag5880
tgcaccatat gcggtgtgaa ataccgcaca gatgcgtaag gagaaaatac cgcatcaggc5940
gctcttccgc ttcctcgctc actgactcgc tgcgctcggt cgttcggctg cggcgagcgg6000
tatcagctca ctcaaaggcg gtaatacggt tatccacaga atcaggggat aacgcaggaa6060
agaacatgtg agcaaaaggc cagcaaaagg ccaggaaccg taaaaaggcc gcgttgctgg6120
cgtttttcca taggctccgc ccccctgacg agcatcacaa aaatcgacgc tcaagtcaga6180
ggtggcgaaa cccgacagga ctataaagat accaggcgtt tccccctgga agctccctcg6240
tgcgctctcc tgttccgacc ctgccgctta ccggatacct gtccgccttt ctcccttcgg6300
gaagcgtggc gctttctcat agctcacgct gtaggtatct cagttcggtg taggtcgttc6360
gctccaagct gggctgtgtg cacgaacccc ccgttcagcc cgaccgctgc gccttatccg6420
gtaactatcg tcttgagtcc aacccggtaa gacacgactt atcgccactg gcagcagcca6480
ctggtaacag gattagcaga gcgaggtatg taggcggtgc tacagagttc ttgaagtggt6540
ggcctaacta cggctacact agaaggacag tatttggtat ctgcgctctg ctgaagccag6600
ttaccttcgg aaaaagagtt ggtagctctt gatccggcaa acaaaccacc gctggtagcg6660
gtggtttttt tgtttgcaag cagcagatta cgcgcagaaa aaaaggatct caagaagatc6720
ctttgatctt ttctacgggg tctgacgctc agtggaacga aaactcacgt taagggattt6780
tggtcatgag attatcaaaa aggatcttca cctagatcct tttaaattaa aaatgaagtt6840
ttaaatcaat ctaaagtata tatgagtaaa cttggtctga cagttaccaa tgcttaatca6900
gtgaggcacc tatctcagcg atctgtctat ttcgttcatc catagttgcc tgactccccg6960
tcgtgtagat aactacgata cgggagggct taccatctgg ccccagtgct gcaatgatac7020
cgcgagaccc acgctcaccg gctccagatt tatcagcaat aaaccagcca gccggaaggg7080
ccgagcgcag aagtggtcct gcaactttat ccgcctccat ccagtctatt aattgttgcc7140
gggaagctag agtaagtagt tcgccagtta atagtttgcg caacgttgtt gccattgctg7200
caggcatcgt ggtgtcacgc tcgtcgtttg gtatggcttc attcagctcc ggttcccaac7260
gatcaaggcg agttacatga tcccccatgt tgtgcaaaaa agcggttagc tccttcggtc7320
ctccgatcgt tgtcagaagt aagttggccg cagtgttatc actcatggtt atggcagcac7380
tgcataattc tcttactgtc atgccatccg taagatgctt ttctgtgact ggtgagtact7440
caaccaagtc attctgagaa tagtgtatgc ggcgaccgag ttgctcttgc ccggcgtcaa7500
cacgggataa taccgcgcca catagcagaa ctttaaaagt gctcatcatt ggaaaacgtt7560
cttcggggcg aaaactctca aggatcttac cgctgttgag atccagttcg atgtaaccca7620
ctcgtgcacc caactgatct tcagcatctt ttactttcac cagcgtttct gggtgagcaa7680
aaacaggaag gcaaaatgcc gcaaaaaagg gaataagggc gacacggaaa tgttgaatac7740
tcatactctt cctttttcaa tattattgaa gcatttatca gggttattgt ctcatgagcg7800
gatacatatt tgaatgtatt tagaaaaata aacaaatagg ggttccgcgc acatttcccc7860
gaaaagtgcc acctgacgtc taagaaacca ttattatcat gacattaacc tataaaaata7920
ggcgtatcac gaggcccttt cgtcttcaag aattcatacc agatcaccga aaactgtcct7980
ccaaatgtgt ccccctcaca ctcccaaatt cgcgggcttc tgcctcttag accactctac8040
cctattcccc acactcaccg gagccaaagc cgcggccctt ccgtttcttt gc8092
<210> 202
<211> 657
<212> PRT
<213> Homo sapiens
<220>
<223> recombinant human aggrecan G1-IGD-G2 domains,
Val20-Gly676 of Accession No. NP_037359
<400> 202
Val Glu Thr Ser Asp His Asp Asn Ser Leu Ser Val Ser Ile Pro Gln
151015
Pro Ser Pro Leu Arg Val Leu Leu Gly Thr Ser Leu Thr Ile Pro Cys
202530
Tyr Phe Ile Asp Pro Met His Pro Val Thr Thr Ala Pro Ser Thr Ala
354045
Pro Leu Ala Pro Arg Ile Lys Trp Ser Arg Val Ser Lys Glu Lys Glu
505560
Val Val Leu Leu Val Ala Thr Glu Gly Arg Val Arg Val Asn Ser Ala
65 707580
Tyr Gln Asp Lys Val Ser Leu Pro Asn Tyr Pro Ala Ile Pro Ser Asp
859095
Ala Thr Leu Glu Val Gln Ser Leu Arg Ser Asn Asp Ser Gly Val Tyr
100105110
Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Glu Ala Thr Leu Glu
115120125
Val Val Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile Ser Thr Arg
130135140
Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu Gln Asn Ser
145150155160
Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr Glu Asp Gly
165170175
Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr Val Arg Tyr
180185190
Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys Asp Glu Phe
195200205
Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu Thr Tyr Asp
210215220
Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe Tyr Ala Thr
225230235240
Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu Cys Arg Arg
245250255
Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu Ala Trp Gln
260265270
Ala Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp Arg Ser Val
275280285
Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly Asn Leu Leu
290295300
Gly Val Arg Thr Val Tyr Val His Ala Asn Gln Thr Gly Tyr Pro Asp
305310315320
Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu Asp Phe Val
325330335
Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Glu Asp Ile Thr
340345350
Val Gln Thr Val Thr Trp Pro Asp Met Glu Leu Pro Leu Pro Arg Asn
355360365
Ile Thr Glu Gly Glu Ala Arg Gly Ser Val Ile Leu Thr Val Lys Pro
370375380
Ile Phe Glu Val Ser Pro Ser Pro Leu Glu Pro Glu Glu Pro Phe Thr
385390395400
Phe Ala Pro Glu Ile Gly Ala Thr Ala Phe Ala Glu Val Glu Asn Glu
405410415
Thr Gly Glu Ala Thr Arg Pro Trp Gly Phe Pro Thr Pro Gly Leu Gly
420425430
Pro Ala Thr Ala Phe Thr Ser Glu Asp Leu Val Val Gln Val Thr Ala
435440445
Val Pro Gly Gln Pro His Leu Pro Gly Gly Val Val Phe His Tyr Arg
450455460
Pro Gly Pro Thr Arg Tyr Ser Leu Thr Phe Glu Glu Ala Gln Gln Ala
465470475480
Cys Leu Arg Thr Gly Ala Val Ile Ala Ser Pro Glu Gln Leu Gln Ala
485490495
Ala Tyr Glu Ala Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Arg Asp
500505510
Gln Thr Val Arg Tyr Pro Ile Val Ser Pro Arg Thr Pro Cys Val Gly
515520525
Asp Lys Asp Ser Ser Pro Gly Val Arg Thr Tyr Gly Val Arg Pro Ser
530535540
Thr Glu Thr Tyr Asp Val Tyr Cys Phe Val Asp Arg Leu Glu Gly Glu
545550555560
Val Phe Phe Ala Thr Arg Leu Glu Gln Phe Thr Phe Gln Glu Ala Leu
565570575
Glu Phe Cys Glu Ser His Asn Ala Thr Leu Ala Thr Thr Gly Gln Leu
580585590
Tyr Ala Ala Trp Ser Arg Gly Leu Asp Lys Cys Tyr Ala Gly Trp Leu
595600605
Ala Asp Gly Ser Leu Arg Tyr Pro Ile Val Thr Pro Arg Pro Ala Cys
610615620
Gly Gly Asp Lys Pro Gly Val Arg Thr Val Tyr Leu Tyr Pro Asn Gln
625630635640
Thr Gly Leu Pro Asp Pro Leu Ser Arg His His Ala Phe Cys Phe Arg
645650655
Gly
<210> 203
<211> 669
<212> DNA
<213> Homo sapiens
<220>
<223> cDNA fragment of human IgG1 heavy chain
<400> 203
acatgcccac cgtgcccagc acctgaactc ctggggggac cgtcagtctt cctcttcccc 60
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg120
gacgtgagcc acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg180
cataatgcca agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc240
gtcctcaccg tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc300
aacaaagccc tcccagcccc catcgagaaa accatctcca aagccaaagg gcagccccga360
gaaccacagg tgtacaccct gcccccatcc cgggatgagc tgaccaagaa ccaggtcagc420
ctgacctgcc tggtcaaagg cttctatccc agcgacatcg ccgtggagtg ggagagcaat480
gggcagccgg agaacaacta caagaccacg cctcccgtgc tggactccga cggccccttc540
ttcctctaca gcaagctcac cgtggacaag agcaggtggc agcaggggaa cgtcttctca600
tgctccgtga tgcatgaggc tctgcacaac cactacacgc agaagagcct ctccctgtct660
ccgggtaaa669
<210> 204
<211> 223
<212> PRT
<213> Homo sapiens
<220>
<223> fragment of IgG1 heavy chain
<400> 204
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
151015
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
202530
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
354045
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
505560
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
65707580
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
859095
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
100105110
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
115120125
Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
130135140
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
145150155160
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
165170 175
Asp Gly Pro Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
180185190
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
195200205
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
210215220
<210> 205
<211> 1439
<212> DNA
<213> Homo sapiens
<220>
<223> human Tumor necrosis factor-stimulated gene-6
(TSG-6) preprotein-encoding DNA GI No. 315139000
<400> 205
agtcacattt cagccactgc tctgagaatt tgtgagcagc ccctaacagg ctgttacttc 60
actacaactg acgatatgat catcttaatt tacttatttc tcttgctatg ggaagacact120
caaggatggg gattcaagga tggaattttt cataactcca tatggcttga acgagcagcc180
ggtgtgtacc acagagaagc acggtctggc aaatacaagc tcacctacgc agaagctaag240
gcggtgtgtg aatttgaagg cggccatctc gcaacttaca agcagctaga ggcagccaga300
aaaattggat ttcatgtctg tgctgctgga tggatggcta agggcagagt tggatacccc360
attgtgaagc cagggcccaa ctgtggattt ggaaaaactg gcattattga ttatggaatc420
cgtctcaata ggagtgaaag atgggatgcc tattgctaca acccacacgc aaaggagtgt480
ggtggcgtct ttacagatcc aaagcaaatt tttaaatctc caggcttccc aaatgagtac540
gaagataacc aaatctgcta ctggcacatt agactcaagt atggtcagcg tattcacctg600
agttttttag attttgacct tgaagatgac ccaggttgct tggctgatta tgttgaaata660
tatgacagtt acgatgatgt ccatggcttt gtgggaagat actgtggaga tgagcttcca720
gatgacatca tcagtacagg aaatgtcatg accttgaagt ttctaagtga tgcttcagtg780
acagctggag gtttccaaat caaatatgtt gcaatggatc ctgtatccaa atccagtcaa840
ggaaaaaata caagtactac ttctactgga aataaaaact ttttagctgg aagatttagc900
cacttataaa aaaaaaaaaa aggatgatca aaacacacag tgtttatgtt ggaatctttt960
ggaactcctt tgatctcact gttattatta acatttattt attatttttc taaatgtgaa1020
agcaatacat aatttaggga aaattggaaa atataggaaa ctttaaacga gaaaatgaaa1080
cctctcataa tcccactgca tagaaataac aagcgttaac attttcatat ttttttcttt1140
cagtcatttt tctatttgtg gtatatgtat atatgtacct atatgtattt gcatttgaaa1200
ttttggaatc ctgctctatg tacagttttg tattatactt tttaaatctt gaactttata1260
aacattttct gaaatcattg attattctac aaaaacatga ttttaaacag ctgtaaaata1320
ttctatgata tgaatgtttt atgcattatt taagcctgtc tctattgttg gaatttcagg1380
tcattttcat aaatattgtt gcaataaata tccttgaaca cacaaaaaaa aaaaaaaaa1439
<210> 206
<211> 277
<212> PRT
<213> Homo sapiens
<220>
<223> human Tumor necrosis factor-stimulated gene-6
(TSG-6) preprotein, P98066
<220>
<221> SIGNAL
<222> (1)...(17)
<223> signal sequence
<400> 206
Met Ile Ile Leu Ile Tyr Leu Phe Leu Leu Leu Trp Glu Asp Thr Gln
151015
Gly Trp Gly Phe Lys Asp Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Arg Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Gln
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Glu Asp Asn Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu Asp Asp Pro Gly Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Asp Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Ala Met Asp Pro Val Ser Lys Ser Ser Gln Gly
245250255
Lys Asn Thr Ser Thr Thr Ser Thr Gly Asn Lys Asn Phe Leu Ala Gly
260265270
Arg Phe Ser His Leu
275
<210> 207
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> human TSG-6 aa residues 35-129
<400> 207
Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys Leu Thr
151015
Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His Leu Ala
202530
Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His Val Cys
354045
Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile Val Lys
505560
Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp Tyr Gly
65707580
Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr Asn
859095
<210> 208
<211> 12
<212> DNA
<213> Artificial Sequence
<220>
<223> 12 bp sequence
<400> 208
gacaaaactc ac12
<210> 209
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> 4 amino acid peptide
<400> 209
Asp Lys Thr His
1
<210> 210
<211> 22
<212> PRT
<213> Homo sapiens
<220>
<223> IgK signal peptide
<400> 210
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
151015
Leu Pro Gly Ala Arg Gly
20
<210> 211
<211> 1059
<212> DNA
<213> Artificial Sequence
<220>
<223> TSG-6-LM-Fc fusion protein - Codon optimized DNA
Seq. used for protein expression
<400> 211
gctagcatgg acatgcgtgt gccagctcag ctgctgggac tgctgctgct gtggctgcct 60
ggagctagag gagcagatat cgcaggcgtg taccacaggg aggcacggtc cggaaagtac120
aaactgacct atgctgaagc aaaggccgtg tgcgagttcg aaggcggaca cctggctaca180
tataagcagc tggaggccgc tcgcaaaatc gggtttcacg tgtgcgcagc cggttggatg240
gcaaaggggc gagtcggtta ccccattgtg aaaccaggcc ccaactgtgg cttcggaaag300
actggcatca ttgactatgg aatcagactg aaccgcagcg agcgatggga cgcatactgc360
tataataccg gtgataagac tcacacctgc cccccttgtc ctgccccaga actgctgggg420
ggtccttccg tgttcctgtt tccacccaag ccaaaagaca ccctgatgat ttctaggaca480
cctgaggtca cttgcgtggt cgtggacgtg agtcacgaag atccagaagt caagtttaac540
tggtacgtgg atggcgtcga agtgcataat gccaagacaa aacctcgtga ggaacagtac600
aattctactt atagggtcgt gagtgtcctg accgtgctgc atcaggattg gctgaacggg660
aaggagtata agtgcaaagt gtcaaataag gctctgcccg cacctatcga gaaaacaatt720
tccaaggcca aaggccagcc acgggaaccc caggtgtaca ctctgcctcc atccagagag780
gaaatgacca aaaaccaggt cagcctgaca tgtctggtga aggggttcta tccaagcgac840
atcgctgtgg agtgggaatc taatggtcag cccgagaaca attacaagac cacaccccct900
gtcctggact ccgatggcag cttctttctg tattcaaagc tgacagtgga taaatcccgc960
tggcagcagg gaaacgtctt ctcctgtagc gtgatgcatg aggctctgca caatcattac1020
actcagaagt ctctgagtct gtcaccaggg aaaggatcc1059
<210> 212
<211> 349
<212> PRT
<213> Artificial Sequence
<220>
<223> Peptide sequence for TSG-6-LM-Fc fusion protein
<400> 212
Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Pro
151015
Gly Ala Arg Gly Ala Asp Ile Ala Gly Val Tyr His Arg Glu Ala Arg
202530
Ser Gly Lys Tyr Lys Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu
354045
Phe Glu Gly Gly His Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg
505560
Lys Ile Gly Phe His Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg
65707580
Val Gly Tyr Pro Ile Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys
859095
Thr Gly Ile Ile Asp Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp
100105110
Asp Ala Tyr Cys Tyr Asn Thr Gly Asp Lys Thr His Thr Cys Pro Pro
115120125
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
130135140
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
145150155160
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
165170175
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
180185190
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
195200205
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
210215220
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
225230235240
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
245250255
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
260265270
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
275280285
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
290295300
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
305310315320
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
325330335
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Ser
340345
<210> 213
<211> 5540
<212> DNA
<213> Artificial Sequence
<220>
<223> pHZ24-TSG-6-LM-Fc (DNA)
<400> 213
tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagc720
tcgtttagtg aaccgtcaga tcactagaag ctttattgcg gtagtttatc acagttaaat780
tgctaacgca gtcagtgctt ctgacacaac agtctcgaac ttaagctgca gaagttggtc840
gtgaggcact gggcaggtaa gtatcaaggt tacaagacag gtttaaggag accaatagaa900
actgggcttg tcgagacaga gaagactctt gcgtttctga taggcaccta ttggtcttac960
tgacatccac tttgcctttc tctccacagg tgtccactcc cagttcaatt acagctctta1020
aggctagagt acttaatacg actcactata ggctagcatg gacatgcgtg tgccagctca1080
gctgctggga ctgctgctgc tgtggctgcc tggagctaga ggagcagata tcgcaggcgt1140
gtaccacagg gaggcacggt ccggaaagta caaactgacc tatgctgaag caaaggccgt1200
gtgcgagttc gaaggcggac acctggctac atataagcag ctggaggccg ctcgcaaaat1260
cgggtttcac gtgtgcgcag ccggttggat ggcaaagggg cgagtcggtt accccattgt1320
gaaaccaggc cccaactgtg gcttcggaaa gactggcatc attgactatg gaatcagact1380
gaaccgcagc gagcgatggg acgcatactg ctataatacc ggtgataaga ctcacacctg1440
ccccccttgt cctgccccag aactgctggg gggtccttcc gtgttcctgt ttccacccaa1500
gccaaaagac accctgatga tttctaggac acctgaggtc acttgcgtgg tcgtggacgt1560
gagtcacgaa gatccagaag tcaagtttaa ctggtacgtg gatggcgtcg aagtgcataa1620
tgccaagaca aaacctcgtg aggaacagta caattctact tatagggtcg tgagtgtcct1680
gaccgtgctg catcaggatt ggctgaacgg gaaggagtat aagtgcaaag tgtcaaataa1740
ggctctgccc gcacctatcg agaaaacaat ttccaaggcc aaaggccagc cacgggaacc1800
ccaggtgtac actctgcctc catccagaga ggaaatgacc aaaaaccagg tcagcctgac1860
atgtctggtg aaggggttct atccaagcga catcgctgtg gagtgggaat ctaatggtca1920
gcccgagaac aattacaaga ccacaccccc tgtcctggac tccgatggca gcttctttct1980
gtattcaaag ctgacagtgg ataaatcccg ctggcagcag ggaaacgtct tctcctgtag2040
cgtgatgcat gaggctctgc acaatcatta cactcagaag tctctgagtc tgtcaccagg2100
gaaaggatcc tagtaagaat tcctcgagag atctatagct aacgcccctc tccctccccc2160
ccccctaacg ttactggccg aagccgcttg gaataaggcc ggtgtgcgtt tgtctatatg2220
ttattttcca ccatattgcc gtcttttggc aatgtgaggg cccggaaacc tggccctgtc2280
ttcttgacga gcattcctag gggtctttcc cctctcgcca aaggaatgca aggtctgttg2340
aatgtcgtga aggaagcagt tcctctggaa gcttcttgaa gacaaacaac gtctgtagcg2400
accctttgca ggcagcggaa ccccccacct ggcgacaggt gcctctgcgg ccaaaagcca2460
cgtgtataag atacacctgc aaaggcggca caaccccagt gccacgttgt gagttggata2520
gttgtggaaa gagtcaaatg gctctcctca agcgtattca acaaggggct gaaggatgcc2580
cagaaggtac cccattgtat gggatctgat ctggggcctc ggtgcacatg ctttacatgt2640
gtttagtcga ggttaaaaaa acgtctaggc cccccgaacc acggggacgt ggttttcctt2700
tgaaaaacac gatgataagc ttgccacaac ccacagcggc cgctgccatc atggttcgac2760
cattgaactg catcgtcgcc gtgtcccaaa atatggggat tggcaagaac ggagacctac2820
cctggcctcc gctcaggaac gagttcaagt acttccaaag aatgaccaca acctcttcag2880
tggaaggtaa acagaatctg gtgattatgg gtaggaaaac ctggttctcc attcctgaga2940
agaatcgacc tttaaaggac agaattaata tagttctcag tagagaactc aaagaaccac3000
cacgaggagc tcattttctt gccaaaagtt tggatgatgc cttaagactt attgaacaac3060
cggaattggc aagtaaagta gacatggttt ggatagtcgg aggcagttct gtttaccagg3120
aagccatgaa tcaaccaggc cacctcagac tctttgtgac aaggatcatg caggaatttg3180
aaagtgacac gtttttccca gaaattgatt tggggaaata taaacttctc ccagaatacc3240
caggcgtcct ctctgaggtc caggaggaaa aaggcatcaa gtataagttt gaagtctacg3300
agaagaaaga ctaaacgcgt ggtacctcta gagtcgacct gggcggccgc ttcgagcaga3360
catgataaga tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg3420
ctttatttgt gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa3480
acaagttaac aacaacaatt gcattcattt tatgtttcag gttcaggggg agatgtggga3540
ggttttttaa agcaagtaaa acctctacaa atgtggtaaa atcgataagt atccgggctg3600
gcgtaatagc gaagaggccc gcaccgatcg cccttcccaa cagttgcgca gcctgaatgg3660
cgaatggacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc3720
gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt3780
ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc3840
cgatttagtg ctttacggca cctcgacccc aaaaaacttg attagggtga tggttcacgt3900
agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt3960
aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggt ctattctttt4020
gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa4080
aaatttaacg cgaattttaa caaaatatta acgcttacaa tttcctgatg cggtattttc4140
tccttacgca tctgtgcggt atttcacacc gcatatggtg cactctcagt acaatctgct4200
ctgatgccgc atagttaagc cagccccgac acccgccaac acccgctgac gcgccctgac4260
gggcttgtct gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca4320
tgtgtcagag gttttcaccg tcatcaccga aacgcgcgag acgaaagggc ctcgtgatac4380
gcctattttt ataggttaat gtcatgataa taatggtttc ttagacgtca ggtggcactt4440
ttcggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat tcaaatatgt4500
atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta4560
tgagtattca acatttccgt gtcgccctta ttcccttttt tgcggcattt tgccttcctg4620
tttttgctca cccagaaacg ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac4680
gagtgggtta catcgaactg gatctcaaca gcggtaagat ccttgagagt tttcgccccg4740
aagaacgttt tccaatgatg agcactttta aagttctgct atgtggcgcg gtattatccc4800
gtattgacgc cgggcaagag caactcggtc gccgcataca ctattctcag aatgacttgg4860
ttgagtactc accagtcaca gaaaagcatc ttacggatgg catgacagta agagaattat4920
gcagtgctgc cataaccatg agtgataaca ctgcggccaa cttacttctg acaacgatcg4980
gaggaccgaa ggagctaacc gcttttttgc acaacatggg ggatcatgta actcgccttg5040
atcgttggga accggagctg aatgaagcca taccaaacga cgagcgtgac accacgatgc5100
ctgtagcaat ggcaacaacg ttgcgcaaac tattaactgg cgaactactt actctagctt5160
cccggcaaca attaatagac tggatggagg cggataaagt tgcaggacca cttctgcgct5220
cggcccttcc ggctggctgg tttattgctg ataaatctgg agccggtgag cgtgggtctc5280
gcggtatcat tgcagcactg gggccagatg gtaagccctc ccgtatcgta gttatctaca5340
cgacggggag tcaggcaact atggatgaac gaaatagaca gatcgctgag ataggtgcct5400
cactgattaa gcattggtaa ctgtcagacc aagtttactc atatatactt tagattgatt5460
taaaacttca tttttaattt aaaaggatct aggtgaagat cctttttgat aatctcatga5520
ccaaaatccc ttaacgtgag5540
<210> 214
<211> 1059
<212> DNA
<213> Artificial Sequence
<220>
<223> TSG-6-LM-Fc/deltaHep (DNA)
<400> 214
gctagcatgg acatgcgtgt gccagctcag ctgctgggac tgctgctgct gtggctgcct 60
ggagctagag gagcagatat cgcaggcgtg taccacaggg aggcacggtc cggaaagtac120
aaactgacct atgctgaagc agcggccgtg tgcgagttcg aaggcggaca cctggctaca180
tatgcgcagc tggaggccgc tcgcgcaatc gggtttcacg tgtgcgcagc cggttggatg240
gcaaaggggc gagtcggtta ccccattgtg aaaccaggcc ccaactgtgg cttcggaaag300
actggcatca ttgactatgg aatcagactg aaccgcagcg agcgatggga cgcatactgc360
tataataccg gtgataagac tcacacctgc cccccttgtc ctgccccaga actgctgggg420
ggtccttccg tgttcctgtt tccacccaag ccaaaagaca ccctgatgat ttctaggaca480
cctgaggtca cttgcgtggt cgtggacgtg agtcacgaag atccagaagt caagtttaac540
tggtacgtgg atggcgtcga agtgcataat gccaagacaa aacctcgtga ggaacagtac600
aattctactt atagggtcgt gagtgtcctg accgtgctgc atcaggattg gctgaacggg660
aaggagtata agtgcaaagt gtcaaataag gctctgcccg cacctatcga gaaaacaatt720
tccaaggcca aaggccagcc acgggaaccc caggtgtaca ctctgcctcc atccagagag780
gaaatgacca aaaaccaggt cagcctgaca tgtctggtga aggggttcta tccaagcgac840
atcgctgtgg agtgggaatc taatggtcag cccgagaaca attacaagac cacaccccct900
gtcctggact ccgatggcag cttctttctg tattcaaagc tgacagtgga taaatcccgc960
tggcagcagg gaaacgtctt ctcctgtagc gtgatgcatg aggctctgca caatcattac1020
actcagaagt ctctgagtct gtcaccaggg aaaggatcc1059
<210> 215
<211> 349
<212> PRT
<213> Artificial Sequence
<220>
<223> TSG-6-LM-Fc/deltaHep (protein)
<400> 215
Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Pro
151015
Gly Ala Arg Gly Ala Asp Ile Ala Gly Val Tyr His Arg Glu Ala Arg
202530
Ser Gly Lys Tyr Lys Leu Thr Tyr Ala Glu Ala Ala Ala Val Cys Glu
354045
Phe Glu Gly Gly His Leu Ala Thr Tyr Ala Gln Leu Glu Ala Ala Arg
505560
Ala Ile Gly Phe His Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg
65707580
Val Gly Tyr Pro Ile Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys
859095
Thr Gly Ile Ile Asp Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp
100105110
Asp Ala Tyr Cys Tyr Asn Thr Gly Asp Lys Thr His Thr Cys Pro Pro
115120125
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro
130135140
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr
145150155160
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn
165170175
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
180185190
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val
195200205
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser
210215220
Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys
225230235240
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu
245250255
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe
260265270
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
275280285
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe
290295300
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly
305310315320
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
325330335
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Ser
340345
<210> 216
<211> 285
<212> DNA
<213> Homo sapiens
<220>
<223> TSG-6 preprotein, DNA encoding aa 35-129 (285 bp)
<400> 216
gccggtgtgt accacagaga agcacggtct ggcaaataca agctcaccta cgcagaagct 60
aaggcggtgt gtgaatttga aggcggccat ctcgcaactt acaagcagct agaggcagcc120
agaaaaattg gatttcatgt ctgtgctgct ggatggatgg ctaagggcag agttggatac180
cccattgtga agccagggcc caactgtgga tttggaaaaa ctggcattat tgattatgga240
atccgtctca ataggagtga aagatgggat gcctattgct acaac285
<210> 217
<211> 1059
<212> DNA
<213> Artificial Sequence
<220>
<223> TSG-6-LM-Fc fusion protein encoding DNA
<400> 217
gctagcatgg acatgcgcgt acctgctcag ttgttggggc tcttgctgct gtggttgccc 60
ggggcacgtg gggcagatat cgccggtgtg taccacagag aagcacggtc tggcaaatac120
aagctcacct acgcagaagc taaggcggtg tgtgaatttg aaggcggcca tctcgcaact180
tacaagcagc tagaggcagc cagaaaaatt ggatttcatg tctgtgctgc tggatggatg240
gctaagggca gagttggata ccccattgtg aagccagggc ccaactgtgg atttggaaaa300
actggcatta ttgattatgg aatccgtctc aataggagtg aaagatggga tgcctattgc360
tacaacaccg gtgacaaaac tcacacatgc ccaccgtgcc cagcacctga actcctgggg420
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc480
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac540
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac600
aacagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc660
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc720
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag780
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac840
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc900
gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg960
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcacg aggctctgca caaccactac1020
acgcagaaga gcctctccct gtctccgggt aaaggatcc1059
<210> 218
<211> 5540
<212> DNA
<213> Artificial Sequence
<220>
<223> pHZ24-TSG-6-LM-Fc/deltaHep (DNA)
<400> 218
tcaatattgg ccattagcca tattattcat tggttatata gcataaatca atattggcta 60
ttggccattg catacgttgt atctatatca taatatgtac atttatattg gctcatgtcc120
aatatgaccg ccatgttggc attgattatt gactagttat taatagtaat caattacggg180
gtcattagtt catagcccat atatggagtt ccgcgttaca taacttacgg taaatggccc240
gcctggctga ccgcccaacg acccccgccc attgacgtca ataatgacgt atgttcccat300
agtaacgcca atagggactt tccattgacg tcaatgggtg gagtatttac ggtaaactgc360
ccacttggca gtacatcaag tgtatcatat gccaagtccg ccccctattg acgtcaatga420
cggtaaatgg cccgcctggc attatgccca gtacatgacc ttacgggact ttcctacttg480
gcagtacatc tacgtattag tcatcgctat taccatggtg atgcggtttt ggcagtacac540
caatgggcgt ggatagcggt ttgactcacg gggatttcca agtctccacc ccattgacgt600
caatgggagt ttgttttggc accaaaatca acgggacttt ccaaaatgtc gtaataaccc660
cgccccgttg acgcaaatgg gcggtaggcg tgtacggtgg gaggtctata taagcagagc720
tcgtttagtg aaccgtcaga tcactagaag ctttattgcg gtagtttatc acagttaaat780
tgctaacgca gtcagtgctt ctgacacaac agtctcgaac ttaagctgca gaagttggtc840
gtgaggcact gggcaggtaa gtatcaaggt tacaagacag gtttaaggag accaatagaa900
actgggcttg tcgagacaga gaagactctt gcgtttctga taggcaccta ttggtcttac960
tgacatccac tttgcctttc tctccacagg tgtccactcc cagttcaatt acagctctta1020
aggctagagt acttaatacg actcactata ggctagcatg gacatgcgtg tgccagctca1080
gctgctggga ctgctgctgc tgtggctgcc tggagctaga ggagcagata tcgcaggcgt1140
gtaccacagg gaggcacggt ccggaaagta caaactgacc tatgctgaag cagcggccgt1200
gtgcgagttc gaaggcggac acctggctac atatgcgcag ctggaggccg ctcgcgcaat1260
cgggtttcac gtgtgcgcag ccggttggat ggcaaagggg cgagtcggtt accccattgt1320
gaaaccaggc cccaactgtg gcttcggaaa gactggcatc attgactatg gaatcagact1380
gaaccgcagc gagcgatggg acgcatactg ctataatacc ggtgataaga ctcacacctg1440
ccccccttgt cctgccccag aactgctggg gggtccttcc gtgttcctgt ttccacccaa1500
gccaaaagac accctgatga tttctaggac acctgaggtc acttgcgtgg tcgtggacgt1560
gagtcacgaa gatccagaag tcaagtttaa ctggtacgtg gatggcgtcg aagtgcataa1620
tgccaagaca aaacctcgtg aggaacagta caattctact tatagggtcg tgagtgtcct1680
gaccgtgctg catcaggatt ggctgaacgg gaaggagtat aagtgcaaag tgtcaaataa1740
ggctctgccc gcacctatcg agaaaacaat ttccaaggcc aaaggccagc cacgggaacc1800
ccaggtgtac actctgcctc catccagaga ggaaatgacc aaaaaccagg tcagcctgac1860
atgtctggtg aaggggttct atccaagcga catcgctgtg gagtgggaat ctaatggtca1920
gcccgagaac aattacaaga ccacaccccc tgtcctggac tccgatggca gcttctttct1980
gtattcaaag ctgacagtgg ataaatcccg ctggcagcag ggaaacgtct tctcctgtag2040
cgtgatgcat gaggctctgc acaatcatta cactcagaag tctctgagtc tgtcaccagg2100
gaaaggatcc tagtaagaat tcctcgagag atctatagct aacgcccctc tccctccccc2160
ccccctaacg ttactggccg aagccgcttg gaataaggcc ggtgtgcgtt tgtctatatg2220
ttattttcca ccatattgcc gtcttttggc aatgtgaggg cccggaaacc tggccctgtc2280
ttcttgacga gcattcctag gggtctttcc cctctcgcca aaggaatgca aggtctgttg2340
aatgtcgtga aggaagcagt tcctctggaa gcttcttgaa gacaaacaac gtctgtagcg2400
accctttgca ggcagcggaa ccccccacct ggcgacaggt gcctctgcgg ccaaaagcca2460
cgtgtataag atacacctgc aaaggcggca caaccccagt gccacgttgt gagttggata2520
gttgtggaaa gagtcaaatg gctctcctca agcgtattca acaaggggct gaaggatgcc2580
cagaaggtac cccattgtat gggatctgat ctggggcctc ggtgcacatg ctttacatgt2640
gtttagtcga ggttaaaaaa acgtctaggc cccccgaacc acggggacgt ggttttcctt2700
tgaaaaacac gatgataagc ttgccacaac ccacagcggc cgctgccatc atggttcgac2760
cattgaactg catcgtcgcc gtgtcccaaa atatggggat tggcaagaac ggagacctac2820
cctggcctcc gctcaggaac gagttcaagt acttccaaag aatgaccaca acctcttcag2880
tggaaggtaa acagaatctg gtgattatgg gtaggaaaac ctggttctcc attcctgaga2940
agaatcgacc tttaaaggac agaattaata tagttctcag tagagaactc aaagaaccac3000
cacgaggagc tcattttctt gccaaaagtt tggatgatgc cttaagactt attgaacaac3060
cggaattggc aagtaaagta gacatggttt ggatagtcgg aggcagttct gtttaccagg3120
aagccatgaa tcaaccaggc cacctcagac tctttgtgac aaggatcatg caggaatttg3180
aaagtgacac gtttttccca gaaattgatt tggggaaata taaacttctc ccagaatacc3240
caggcgtcct ctctgaggtc caggaggaaa aaggcatcaa gtataagttt gaagtctacg3300
agaagaaaga ctaaacgcgt ggtacctcta gagtcgacct gggcggccgc ttcgagcaga3360
catgataaga tacattgatg agtttggaca aaccacaact agaatgcagt gaaaaaaatg3420
ctttatttgt gaaatttgtg atgctattgc tttatttgta accattataa gctgcaataa3480
acaagttaac aacaacaatt gcattcattt tatgtttcag gttcaggggg agatgtggga3540
ggttttttaa agcaagtaaa acctctacaa atgtggtaaa atcgataagt atccgggctg3600
gcgtaatagc gaagaggccc gcaccgatcg cccttcccaa cagttgcgca gcctgaatgg3660
cgaatggacg cgccctgtag cggcgcatta agcgcggcgg gtgtggtggt tacgcgcagc3720
gtgaccgcta cacttgccag cgccctagcg cccgctcctt tcgctttctt cccttccttt3780
ctcgccacgt tcgccggctt tccccgtcaa gctctaaatc gggggctccc tttagggttc3840
cgatttagtg ctttacggca cctcgacccc aaaaaacttg attagggtga tggttcacgt3900
agtgggccat cgccctgata gacggttttt cgccctttga cgttggagtc cacgttcttt3960
aatagtggac tcttgttcca aactggaaca acactcaacc ctatctcggt ctattctttt4020
gatttataag ggattttgcc gatttcggcc tattggttaa aaaatgagct gatttaacaa4080
aaatttaacg cgaattttaa caaaatatta acgcttacaa tttcctgatg cggtattttc4140
tccttacgca tctgtgcggt atttcacacc gcatatggtg cactctcagt acaatctgct4200
ctgatgccgc atagttaagc cagccccgac acccgccaac acccgctgac gcgccctgac4260
gggcttgtct gctcccggca tccgcttaca gacaagctgt gaccgtctcc gggagctgca4320
tgtgtcagag gttttcaccg tcatcaccga aacgcgcgag acgaaagggc ctcgtgatac4380
gcctattttt ataggttaat gtcatgataa taatggtttc ttagacgtca ggtggcactt4440
ttcggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat tcaaatatgt4500
atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta4560
tgagtattca acatttccgt gtcgccctta ttcccttttt tgcggcattt tgccttcctg4620
tttttgctca cccagaaacg ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac4680
gagtgggtta catcgaactg gatctcaaca gcggtaagat ccttgagagt tttcgccccg4740
aagaacgttt tccaatgatg agcactttta aagttctgct atgtggcgcg gtattatccc4800
gtattgacgc cgggcaagag caactcggtc gccgcataca ctattctcag aatgacttgg4860
ttgagtactc accagtcaca gaaaagcatc ttacggatgg catgacagta agagaattat4920
gcagtgctgc cataaccatg agtgataaca ctgcggccaa cttacttctg acaacgatcg4980
gaggaccgaa ggagctaacc gcttttttgc acaacatggg ggatcatgta actcgccttg5040
atcgttggga accggagctg aatgaagcca taccaaacga cgagcgtgac accacgatgc5100
ctgtagcaat ggcaacaacg ttgcgcaaac tattaactgg cgaactactt actctagctt5160
cccggcaaca attaatagac tggatggagg cggataaagt tgcaggacca cttctgcgct5220
cggcccttcc ggctggctgg tttattgctg ataaatctgg agccggtgag cgtgggtctc5280
gcggtatcat tgcagcactg gggccagatg gtaagccctc ccgtatcgta gttatctaca5340
cgacggggag tcaggcaact atggatgaac gaaatagaca gatcgctgag ataggtgcct5400
cactgattaa gcattggtaa ctgtcagacc aagtttactc atatatactt tagattgatt5460
taaaacttca tttttaattt aaaaggatct aggtgaagat cctttttgat aatctcatga5520
ccaaaatccc ttaacgtgag5540
<210> 219
<211> 2116
<212> DNA
<213> Homo sapiens
<220>
<223> HAS1 (DNA)
<400> 219
cggagagaag agagagcccg gccagaccca ctgcgatgag acagcaggac gcgcccaagc 60
ccactcctgc agcctgccgc tgctccggcc tggcccggag ggtgctgacc atcgccttcg120
ccctgctcat cctgggcctc atgacctggg cctacgccgc cggggtgccg ctggcctccg180
atcgctacgg cctcctggcc ttcggcctct acggggcctt cctttcagcg cacctggtgg240
cgcagagcct cttcgcgtac ctggagcacc ggcgggtggc ggcggcggcg cgggggccgc300
tggatgcagc caccgcgcgc agtgtggcgc tgaccatctc cgcctaccag gaggaccccg360
cgtacctgcg ccagtgcctg gcgtccgccc gcgccctgct gtacccgcgc gcgcggctgc420
gcgtcctcat ggtggtggat ggcaaccgcg ccgaggacct ctacatggtc gacatgttcc480
gcgaggtctt cgctgacgag gaccccgcca cgtacgtgtg ggacggcaac taccaccagc540
cctgggaacc cgcggcggcg ggcgcggtgg gcgccggagc ctatcgggag gtggaggcgg600
aggatcctgg gcggctggca gtggaggcgc tggtgaggac tcgcaggtgc gtgtgcgtgg660
cgcagcgctg gggcggcaag cgcgaggtca tgtacacagc cttcaaggcg ctcggagatt720
cggtggacta cgtgcaggtc tgtgactcgg acacaaggtt ggaccccatg gcactgctgg780
agctcgtgcg ggtactggac gaggaccccc gggtaggggc tgttggtggg gacgtgcgga840
tccttaaccc tctggactcc tgggtcagct tcctaagcag cctgcgatac tgggtagcct900
tcaatgtgga gcgggcttgt cagagctact tccactgtgt atcctgcatc agcggtcctc960
taggcctata taggaataac ctcttgcagc agtttcttga ggcctggtac aaccagaagt1020
tcctgggtac ccactgtact tttggggatg accggcacct caccaaccgc atgctcagca1080
tgggttatgc taccaagtac acctccaggt cccgctgcta ctcagagacg ccctcgtcct1140
tcctgcggtg gctgagccag cagacacgct ggtccaagtc gtacttccgt gagtggctgt1200
acaacgcgct ctggtggcac cggcaccatg cgtggatgac ctacgaggcg gtggtctccg1260
gcctgttccc cttcttcgtg gcggccactg tgctgcgtct gttctacgcg ggccgccctt1320
gggcgctgct gtgggtgctg ctgtgcgtgc agggcgtggc actggccaag gcggccttcg1380
cggcctggct gcggggctgc ctgcgcatgg tgcttctgtc gctctacgcg cccctctaca1440
tgtgtggcct cctgcctgcc aagttcctgg cgctagtcac catgaaccag agtggctggg1500
gcacctcggg ccggcggaag ctggccgcta actacgtccc tctgctgccc ctggcgctct1560
gggcgctgct gctgcttggg ggcctggtcc gcagcgtagc acacgaggcc agggccgact1620
ggagcggccc ttcccgcgca gccgaggcct accacttggc cgcgggggcc ggcgcctacg1680
tgggctactg ggtggccatg ttgacgctgt actgggtggg cgtgcggagg ctttgccggc1740
ggcggaccgg gggctaccgc gtccaggtgt gagtccagcc acgcggatgc cgcctcaagg1800
gtcttcaggg gaggccagag gagagctgct gggccccgag ccacgaactt gctgggtggt1860
tctctgggcc tcagtttccc tcctctgcaa aacgaggggg tcagcccaag attcttcagt1920
ctggactata ttgggactgg gacttctggg tctccaggga gggtatttat tggtcagggt1980
gtgggatctg aggagtggag ggaaagggtc ctgctttctc ctcgttctta tttaatctcc2040
atttctactg tgtgatcagg atgtaataaa gaattttatt tattttcaaa aaaaaaaaaa2100
aaaaaaaaaa aaaaaa 2116
<210> 220
<211> 3275
<212> DNA
<213> Homo sapiens
<220>
<223> HAS2 (DNA)
<400> 220
gaagtcaaga cgtctggaaa gaattaccca gtcctggctt cgagcagccc attgaaccag 60
agacttgaaa cagccccagc caaagacttt tctcccaatt ctgcgcttcc tgggttctgc120
tgagtcttcc acaggctttt tttttttttt tttttttttt taagacgaaa aagagatttt180
ctgttatcgg gggcagaaag actgaagccc aaaaaaaaaa aaaaaaaaaa aagaaaagaa240
aagaaaaaag aaaagttaat ttatttttaa agcataattt ttttaagaat tagactgaag300
tgcaacggaa acataaagag aatattagtg aaattatttt ttaaagtggg gaagaatcaa360
acatttaaga ctcccctatc ctttttaaat gttgttttta aatttcttat tttttttggc420
cggtcgtctc aaattcatct gatctcttat tacctcaatt ttggaaactg cccgccaccg480
accctccggg accacacaga caggctgagg acgactttat gaccaagagc tgaacaagat540
gcattgtgag aggtttctat gtatcctgag aataattgga accacactct ttggagtctc600
tctcctcctt ggaatcacag ctgcttatat tgttggctac cagtttatcc aaacggataa660
ttactatttc tcttttggac tgtatggtgc ctttttggca tcacacctca tcatccaaag720
cctgtttgcc tttttggagc accgaaaaat gaaaaaatcc ctagaaaccc ccataaagtt780
gaacaaaaca gttgcccttt gcatcgctgc ctatcaagaa gatccagact acttaaggaa840
atgtttgcaa tctgtgaaaa ggctaaccta ccctgggatt aaagttgtca tggtcataga900
tgggaactca gaagatgacc tttacatgat ggacatcttc agtgaagtca tgggcagaga960
caaatcagcc acttatatct ggaagaacaa cttccacgaa aagggtcccg gtgagacaga1020
tgagtcacat aaagaaagct cgcaacacgt aacgcaattg gtcttgtcca acaaaagtat1080
ctgcatcatg caaaaatggg gtggaaaaag agaagtcatg tacacagcct tcagagcact1140
gggacgaagt gtggattatg tacaggtttg tgattcagac actatgcttg acccagcctc1200
atctgtggag atggtaaaag ttttagaaga agatcccatg gttggaggtg ttgggggaga1260
tgtccagatt ttaaacaagt acgattcctg gatctcattc ctcagcagtg taagatattg1320
gatggctttt aatatagaaa gggcctgtca gtcttatttt gggtgtgttc agtgcattag1380
tggacctctg ggaatgtaca gaaactcctt gttgcatgag tttgtggaag attggtacaa1440
tcaagaattt atgggcaacc aatgtagctt tggtgatgac aggcatctca cgaaccgggt1500
gctgagcctg ggctatgcaa caaaatacac agctcgatct aagtgcctta ctgaaacacc1560
tatagaatat ctcagatggc taaaccagca gacccgttgg agcaagtcct acttccgaga1620
atggctgtac aatgcaatgt ggtttcacaa acatcacttg tggatgacct acgaagcgat1680
tatcactgga ttctttcctt tctttctcat tgccacagta atccagctct tctaccgggg1740
taaaatttgg aacattctcc tcttcttgtt aactgtccag ctagtaggtc tcataaaatc1800
atcttttgcc agctgcctta gaggaaatat cgtcatggtc ttcatgtctc tctactcagt1860
gttatacatg tcgagtttac ttcccgccaa gatgtttgca attgcaacaa taaacaaagc1920
tgggtggggc acatcaggaa ggaaaaccat tgttgttaat ttcataggac tcattccagt1980
atcagtttgg tttacaatcc tcctgggtgg tgtgattttc accatttata aggagtctaa2040
aaggccattt tcagaatcca aacagacagt tctaattgtt ggaacgttgc tctatgcatg2100
ctattgggtc atgcttttga cgctgtatgt agttctcatc aataagtgtg gcaggcggaa2160
gaagggacaa caatatgaca tggtgcttga tgtatgatct tccatgtttt gacgtttgca2220
gtcacacaca acaccttagt tcctctaggg gctgtacagt attgtggcat cagataatgc2280
caccaaagga gacatatcac tgctgctggg acttgaacaa agacatttat atgggtttat2340
tttcattctg ccaaagtaaa acaatacatc aacaagaaga aactcagatt taacctgtta2400
tttctatgaa aatgggatga attctttgtt tatgcacttt ttccttactg tgcatccgcc2460
tgaaagtgtt ttgccctata tacctcacta gccatgcttt atgtgggtta tcatggaaga2520
aaaggatttt ggaaactcaa ggaaaagttc tttcaaccta tacaacctaa cttatggact2580
gttttgatag atgataattt ttttttttta ggaaggattt tctttttaac tttaccaaat2640
gaaatgccaa aggaagtttt aaaggccgtt ggctgtgctg tattttgata taattgtact2700
gtgtttttaa attttgtatg ccaatcttaa agacaaattt tgcatattct ctattttact2760
tttctgccaa aataaacctg ttcttccttt tttaaaataa aataagttct taaaaaattt2820
atacttaaaa aatcctgccc aaaatgtgaa gcttggttga ctgatgttca tgatagaaag2880
aataaaatgt ttctctctct ctacctttta aaattgaata gtttatttct gtgaaagaag2940
tatttaaact ttcaatattt taactttttg tttttatttc ttttagaaaa ggccaatata3000
cctatcacac tttggaagta aaaatacaca ctttcgtgtg tacctaaaaa aaaaatcgtt3060
gaaaatcaag gccaaaggta gtgcaatttt ttcattaaga tttaaaaaaa agggaatgat3120
agtctttgaa agaaaacagt aggcatccag cactggacaa aacatgggta tcaaagatga3180
ataatctttg gagattctgg cagtgttttc ccagaacaag tcaagtggaa agtggagaaa3240
ttatctgtat aattttggac acatacaatg cagtt3275
<210> 221
<211> 4220
<212> DNA
<213> Homo sapiens
<220>
<223> HAS3 (DNA)
<400> 221
gagtgcgttc gcggctgctt tgacctggtg ggcgccgcct ccggcactgc accgaggcgg 60
ggcgccagcg cccaggttgc tgggctggcc ttggcgcccc cttcccctac ccagagcgca120
ggcaggcagg ggggtcccgc cgcgcccctt cagcatatgc cggtgcagct gacgacagcc180
ctgcgtgtgg tgggcaccag cctgtttgcc ctggcagtgc tgggtggcat cctggcagcc240
tatgtgacgg gctaccagtt catccacacg gaaaagcact acctgtcctt cggcctgtac300
ggcgccatcc tgggcctgca cctgctcatt cagagccttt ttgccttcct ggagcaccgg360
cgcatgcgac gtgccggcca ggccctgaag ctgccctccc cgcggcgggg ctcggtggca420
ctgtgcattg ccgcatacca ggaggaccct gactacttgc gcaagtgcct gcgctcggcc480
cagcgcatct ccttccctga cctcaaggtg gtcatggtgg tggatggcaa ccgccaggag540
gacgcctaca tgctggacat cttccacgag gtgctgggcg gcaccgagca ggccggcttc600
tttgtgtggc gcagcaactt ccatgaggca ggcgagggtg agacggaggc cagcctgcag660
gagggcatgg accgtgtgcg ggatgtggtg cgggccagca ccttctcgtg catcatgcag720
aagtggggag gcaagcgcga ggtcatgtac acggccttca aggccctcgg cgattcggtg780
gactacatcc aggtgtgcga ctctgacact gtgctggatc cagcctgcac catcgagatg840
cttcgagtcc tggaggagga tccccaagta gggggagtcg ggggagatgt ccagatcctc900
aacaagtacg actcatggat ttccttcctg agcagcgtgc ggtactggat ggccttcaac960
gtggagcggg cctgccagtc ctactttggc tgtgtgcagt gtattagtgg gcccttgggc1020
atgtaccgca acagcctcct ccagcagttc ctggaggact ggtaccatca gaagttccta1080
ggcagcaagt gcagcttcgg ggatgaccgg cacctcacca accgagtcct gagccttggc1140
taccgaacta agtataccgc gcgctccaag tgcctcacag agacccccac taagtacctc1200
cggtggctca accagcaaac ccgctggagc aagtcttact tccgggagtg gctctacaac1260
tctctgtggt tccataagca ccacctctgg atgacctacg agtcagtggt cacgggtttc1320
ttccccttct tcctcattgc cacggttata cagcttttct accggggccg catctggaac1380
attctcctct tcctgctgac ggtgcagctg gtgggcatta tcaaggccac ctacgcctgc1440
ttccttcggg gcaatgcaga gatgatcttc atgtccctct actccctcct ctatatgtcc1500
agccttctgc cggccaagat ctttgccatt gctaccatca acaaatctgg ctggggcacc1560
tctggccgaa aaaccattgt ggtgaacttc attggcctca ttcctgtgtc catctgggtg1620
gcagttctcc tgggagggct ggcctacaca gcttattgcc aggacctgtt cagtgagaca1680
gagctagcct tccttgtctc tggggctata ctgtatggct gctactgggt ggccctcctc1740
atgctatatc tggccatcat cgcccggcga tgtgggaaga agccggagca gtacagcttg1800
gcttttgctg aggtgtgaca tggcccccaa gcagagcggg taaagtgcaa tgggtaaggg1860
agggaagggg aatggaagag aaaagacagg gtgggaggga ggagggagtg ctgtgtttta1920
gtctcttaat ggtccaaagg acaaatctaa aatgcaaaga acggtgatgt agtatggcct1980
gacagctctg tttagaggag gcaacactga tcccccagat gcagggctgc aggggattct2040
gtgttttcag actgcctgtc tgcttgcatc tgcacatagg cagtagcctc ctcctgggct2100
ccagagggca ctcagaagtt gtgctaaacc aagttaagtc ccattcagtg gcaacttgtg2160
ataggtacct gagtgacggc aacctgcgga aggaggttct cccagcccat ctgaacacaa2220
ccagaggtgg caggagaatt tctactgagc gagctgggcc ggttagtgta tgtcaccccc2280
accccacccc taagtagtca tcaatgcaat aagattgcgc ctgagataca aggcccagaa2340
gcctgatctt tgggcatcag aaaacagggt ccaggaatgg tgctttatgt gagatacccc2400
actccacatc aacattccag ggatgagcca aaccagcagg gagttagcac tgaactgctt2460
ttaaaagtgc acattaaaaa ggaaagtttg ccaggaggaa caaagagatt gtggtggtgc2520
taaaggaggc cataagctac acagaggcct tgggtgttcc acctggaaac tgctcagacg2580
tctagatggg ttcttagctt gtctgtgatc tctgctgggg agataaaaag attaagcccc2640
aacatgttca gaaaagaagt gaagtcttgg gtattttaac ctgtatactc ttgaattcct2700
ctcaaattca gctctgatct gaggctaaga cacactcccc acttcacttt cttcaaagcc2760
acattttttg aggtatcact gcagtcacct cttctaccct catcatcata ggtaaggttt2820
tcaaggtggc aattggggcg gagccccggc tcttatagaa gcttcagcag gaggcaagcg2880
tgttctcagc acatatggga actatgagga gcctctgatc aaattggcta caatcttgga2940
gctgcttgga cggattcctt ggcagccggg ttagcatgtg tgactttcag gctactgttc3000
ttgacaatca tctccaatgg aaagcttttc agtgttccca aagtgaactc tcaaatccaa3060
aatggttatc tttgagacca tccattctcc tcagtggctt ctccagggaa ttcttacagc3120
caagttgtga cagtcactgc atttgcctgc ttctttccag aaaccaaact aggagatgaa3180
actggttcct acatcctaag gttcttgctt tctctctcat gcctcctgag gctgtttttg3240
gctgttttcc ctctgctgct tttggggaat gaggggaagc cattttccag tgacttgcaa3300
tccaggctgt tctcagcgtt ttgagtttaa aacctgggat cctgactaag cctttgactt3360
aagggttgct tgcttgccct ccaaatgtcc tttctcagag gggccagcta acccgtgcag3420
aaccagcact aaggtggaca gcagacaaga gggcaagcct ctagtgtacc aagtgcttcc3480
tacaaagacg caaggtgtgc tctgagccac agatgggcaa accctggtgc tttccttcat3540
ctcccacgaa ctcaagggtt ttccaggtgt agctaacagt tgccacatca cacagacctc3600
gagtttctgg taagactgct ggttgacatc agacccaacc catgaaggct ggaaggcagc3660
aggcatttgc taaggcagct gatccaggca atcgttctgc tggccaagaa gttaaactat3720
tttgagcatt agaatggagg aaatccggtc agccaagtgc agagttcaga cttcgctaag3780
ggcttgtttt tcttcagcat ttacttgaag attaatgtag gatgacaggc tctcctggct3840
gtcctaccat cagctctgcc ttgcactgtg gtcgtcaact ttcctcaaat caaaaacagg3900
caggtacagg tagtgggctc acaacgtttg acctcgactg gtttttctaa gttattttgt3960
acatttttca gcagcaaaac caaactgggt cttcagcttt atccccgttt cttgcaaggg4020
aagagccttt atacaattgg acgcattttg gtttttcctc attgagaatt caaatcctct4080
tttgtattgt ttctacaata atttgtaaac atatttattt ttacctgctt tttttttttt4140
ttttaatttt caggtcaagt tttttatact gcacttattt gtcaaaataa agattctcac4200
atatgccggt tatctcgaaa4220
<210> 222
<211> 260
<212> PRT
<213> Homo sapiens
<220>
<223> mature human Tumor necrosis factor-stimulated
gene-6 (TSG-6) protein P98066
<400> 222
Trp Gly Phe Lys Asp Gly Ile Phe His Asn Ser Ile Trp Leu Glu Arg
151015
Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys Leu
202530
Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His Leu
354045
Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His Val
505560
Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile Val
65707580
Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp Tyr
859095
Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr Asn
100105110
Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Gln Ile
115120125
Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Glu Asp Asn Gln Ile Cys
130135140
Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser Phe
145150155160
Leu Asp Phe Asp Leu Glu Asp Asp Pro Gly Cys Leu Ala Asp Tyr Val
165170175
Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg Tyr
180185190
Cys Gly Asp Glu Leu Pro Asp Asp Ile Ile Ser Thr Gly Asn Val Met
195200205
Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe Gln
210215220
Ile Lys Tyr Val Ala Met Asp Pro Val Ser Lys Ser Ser Gln Gly Lys
225230235240
Asn Thr Ser Thr Thr Ser Thr Gly Asn Lys Asn Phe Leu Ala Gly Arg
245250255
Phe Ser His Leu
260
<210> 223
<211> 2570
<212> PRT
<213> Homo sapiens
<220>
<223> Stabilin-1 protein Q9NY15
<400> 223
Met Ala Gly Pro Arg Gly Leu Leu Pro Leu Cys Leu Leu Ala Phe Cys
151015
Leu Ala Gly Phe Ser Phe Val Arg Gly Gln Val Leu Phe Lys Gly Cys
202530
Asp Val Lys Thr Thr Phe Val Thr His Val Pro Cys Thr Ser Cys Ala
354045
Ala Ile Lys Lys Gln Thr Cys Pro Ser Gly Trp Leu Arg Glu Leu Pro
505560
Asp Gln Ile Thr Gln Asp Cys Arg Tyr Glu Val Gln Leu Gly Gly Ser
65707580
Met Val Ser Met Ser Gly Cys Arg Arg Lys Cys Arg Lys Gln Val Val
859095
Gln Lys Ala Cys Cys Pro Gly Tyr Trp Gly Ser Arg Cys His Glu Cys
100105110
Pro Gly Gly Ala Glu Thr Pro Cys Asn Gly His Gly Thr Cys Leu Asp
115120125
Gly Met Asp Arg Asn Gly Thr Cys Val Cys Gln Glu Asn Phe Arg Gly
130135140
Ser Ala Cys Gln Glu Cys Gln Asp Pro Asn Arg Phe Gly Pro Asp Cys
145150155160
Gln Ser Val Cys Ser Cys Val His Gly Val Cys Asn His Gly Pro Arg
165170175
Gly Asp Gly Ser Cys Leu Cys Phe Ala Gly Tyr Thr Gly Pro His Cys
180185190
Asp Gln Glu Leu Pro Val Cys Gln Glu Leu Arg Cys Pro Gln Asn Thr
195200205
Gln Cys Ser Ala Glu Ala Pro Ser Cys Arg Cys Leu Pro Gly Tyr Thr
210215220
Gln Gln Gly Ser Glu Cys Arg Ala Pro Asn Pro Cys Trp Pro Ser Pro
225230235240
Cys Ser Leu Leu Ala Gln Cys Ser Val Ser Pro Lys Gly Gln Ala Gln
245250255
Cys His Cys Pro Glu Asn Tyr His Gly Asp Gly Met Val Cys Leu Pro
260265270
Lys Asp Pro Cys Thr Asp Asn Leu Gly Gly Cys Pro Ser Asn Ser Thr
275280285
Leu Cys Val Tyr Gln Lys Pro Gly Gln Ala Phe Cys Thr Cys Arg Pro
290295300
Gly Leu Val Ser Ile Asn Ser Asn Ala Ser Ala Gly Cys Phe Ala Phe
305310315320
Cys Ser Pro Phe Ser Cys Asp Arg Ser Ala Thr Cys Gln Val Thr Ala
325330335
Asp Gly Lys Thr Ser Cys Val Cys Arg Glu Ser Glu Val Gly Asp Gly
340345350
Arg Ala Cys Tyr Gly His Leu Leu His Glu Val Gln Lys Ala Thr Gln
355360365
Thr Gly Arg Val Phe Leu Gln Leu Arg Val Ala Val Ala Met Met Asp
370375380
Gln Gly Cys Arg Glu Ile Leu Thr Thr Ala Gly Pro Phe Thr Val Leu
385390395400
Val Pro Ser Val Ser Ser Phe Ser Ser Arg Thr Met Asn Ala Ser Leu
405410415
Ala Gln Gln Leu Cys Arg Gln His Ile Ile Ala Gly Gln His Ile Leu
420425430
Glu Asp Thr Arg Thr Gln Gln Thr Arg Arg Trp Trp Thr Leu Ala Gly
435440445
Gln Glu Ile Thr Val Thr Phe Asn Gln Phe Thr Lys Tyr Ser Tyr Lys
450455460
Tyr Lys Asp Gln Pro Gln Gln Thr Phe Asn Ile Tyr Lys Ala Asn Asn
465470475480
Ile Ala Ala Asn Gly Val Phe His Val Val Thr Gly Leu Arg Trp Gln
485490495
Ala Pro Ser Gly Thr Pro Gly Asp Pro Lys Arg Thr Ile Gly Gln Ile
500505510
Leu Ala Ser Thr Glu Ala Phe Ser Arg Phe Glu Thr Ile Leu Glu Asn
515520525
Cys Gly Leu Pro Ser Ile Leu Asp Gly Pro Gly Pro Phe Thr Val Phe
530535540
Ala Pro Ser Asn Glu Ala Val Asp Ser Leu Arg Asp Gly Arg Leu Ile
545550555560
Tyr Leu Phe Thr Ala Gly Leu Ser Lys Leu Gln Glu Leu Val Arg Tyr
565570575
His Ile Tyr Asn His Gly Gln Leu Thr Val Glu Lys Leu Ile Ser Lys
580585590
Gly Arg Ile Leu Thr Met Ala Asn Gln Val Leu Ala Val Asn Ile Ser
595600605
Glu Glu Gly Arg Ile Leu Leu Gly Pro Glu Gly Val Pro Leu Gln Arg
610615620
Val Asp Val Met Ala Ala Asn Gly Val Ile His Met Leu Asp Gly Ile
625630635640
Leu Leu Pro Pro Thr Ile Leu Pro Ile Leu Pro Lys His Cys Ser Glu
645650655
Glu Gln His Lys Ile Val Ala Gly Ser Cys Val Asp Cys Gln Ala Leu
660665670
Asn Thr Ser Thr Cys Pro Pro Asn Ser Val Lys Leu Asp Ile Phe Pro
675680685
Lys Glu Cys Val Tyr Ile His Asp Pro Thr Gly Leu Asn Val Leu Lys
690695700
Lys Gly Cys Ala Ser Tyr Cys Asn Gln Thr Ile Met Glu Gln Gly Cys
705710715720
Cys Lys Gly Phe Phe Gly Pro Asp Cys Thr Gln Cys Pro Gly Gly Phe
725730735
Ser Asn Pro Cys Tyr Gly Lys Gly Asn Cys Ser Asp Gly Ile Gln Gly
740745750
Asn Gly Ala Cys Leu Cys Phe Pro Asp Tyr Lys Gly Ile Ala Cys His
755760765
Ile Cys Ser Asn Pro Asn Lys His Gly Glu Gln Cys Gln Glu Asp Cys
770775780
Gly Cys Val His Gly Leu Cys Asp Asn Arg Pro Gly Ser Gly Gly Val
785790795800
Cys Gln Gln Gly Thr Cys Ala Pro Gly Phe Ser Gly Arg Phe Cys Asn
805810815
Glu Ser Met Gly Asp Cys Gly Pro Thr Gly Leu Ala Gln His Cys His
820825830
Leu His Ala Arg Cys Val Ser Gln Glu Gly Val Ala Arg Cys Arg Cys
835840845
Leu Asp Gly Phe Glu Gly Asp Gly Phe Ser Cys Thr Pro Ser Asn Pro
850855860
Cys Ser His Pro Asp Arg Gly Gly Cys Ser Glu Asn Ala Glu Cys Val
865870875880
Pro Gly Ser Leu Gly Thr His His Cys Thr Cys His Lys Gly Trp Ser
885890895
Gly Asp Gly Arg Val Cys Val Ala Ile Asp Glu Cys Glu Leu Asp Met
900905910
Arg Gly Gly Cys His Thr Asp Ala Leu Cys Ser Tyr Val Gly Pro Gly
915920925
Gln Ser Arg Cys Thr Cys Lys Leu Gly Phe Ala Gly Asp Gly Tyr Gln
930935940
Cys Ser Pro Ile Asp Pro Cys Arg Ala Gly Asn Gly Gly Cys His Gly
945950955960
Leu Ala Thr Cys Arg Ala Val Gly Gly Gly Gln Arg Val Cys Thr Cys
965970975
Pro Pro Gly Phe Gly Gly Asp Gly Phe Ser Cys Tyr Gly Asp Ile Phe
980985990
Arg Glu Leu Glu Ala Asn Ala His Phe Ser Ile Phe Tyr Gln Trp Leu
99510001005
Lys Ser Ala Gly Ile Thr Leu Pro Ala Asp Arg Arg Val Thr Ala Leu
101010151020
Val Pro Ser Glu Ala Ala Val Arg Gln Leu Ser Pro Glu Asp Arg Ala
1025103010351040
Phe Trp Leu Gln Pro Arg Thr Leu Pro Asn Leu Val Arg Ala His Phe
104510501055
Leu Gln Gly Ala Leu Phe Glu Glu Glu Leu Ala Arg Leu Gly Gly Gln
106010651070
Glu Val Ala Thr Leu Asn Pro Thr Thr Arg Trp Glu Ile Arg Asn Ile
107510801085
Ser Gly Arg Val Trp Val Gln Asn Ala Ser Val Asp Val Ala Asp Leu
109010951100
Leu Ala Thr Asn Gly Val Leu His Ile Leu Ser Gln Val Leu Leu Pro
1105111011151120
Pro Arg Gly Asp Val Pro Gly Gly Gln Gly Leu Leu Gln Gln Leu Asp
112511301135
Leu Val Pro Ala Phe Ser Leu Phe Arg Glu Leu Leu Gln His His Gly
114011451150
Leu Val Pro Gln Ile Glu Ala Ala Thr Ala Tyr Thr Ile Phe Val Pro
115511601165
Thr Asn Arg Ser Leu Glu Ala Gln Gly Asn Ser Ser His Leu Asp Ala
117011751180
Asp Thr Val Arg His His Val Val Leu Gly Glu Ala Leu Ser Met Glu
1185119011951200
Thr Leu Arg Lys Gly Gly His Arg Asn Ser Leu Leu Gly Pro Ala His
120512101215
Trp Ile Val Phe Tyr Asn His Ser Gly Gln Pro Glu Val Asn His Val
122012251230
Pro Leu Glu Gly Pro Met Leu Glu Ala Pro Gly Arg Ser Leu Ile Gly
123512401245
Leu Ser Gly Val Leu Thr Val Gly Ser Ser Arg Cys Leu His Ser His
125012551260
Ala Glu Ala Leu Arg Glu Lys Cys Val Asn Cys Thr Arg Arg Phe Arg
1265127012751280
Cys Thr Gln Gly Phe Gln Leu Gln Asp Thr Pro Arg Lys Ser Cys Val
128512901295
Tyr Arg Ser Gly Phe Ser Phe Ser Arg Gly Cys Ser Tyr Thr Cys Ala
130013051310
Lys Lys Ile Gln Val Pro Asp Cys Cys Pro Gly Phe Phe Gly Thr Leu
131513201325
Cys Glu Pro Cys Pro Gly Gly Leu Gly Gly Val Cys Ser Gly His Gly
133013351340
Gln Cys Gln Asp Arg Phe Leu Gly Ser Gly Glu Cys His Cys His Glu
1345135013551360
Gly Phe His Gly Thr Ala Cys Glu Val Cys Glu Leu Gly Arg Tyr Gly
136513701375
Pro Asn Cys Thr Gly Val Cys Asp Cys Ala His Gly Leu Cys Gln Glu
138013851390
Gly Leu Gln Gly Asp Gly Ser Cys Val Cys Asn Val Gly Trp Gln Gly
139514001405
Leu Arg Cys Asp Gln Lys Ile Thr Ser Pro Gln Cys Pro Arg Lys Cys
141014151420
Asp Pro Asn Ala Asn Cys Val Gln Asp Ser Ala Gly Ala Ser Thr Cys
1425143014351440
Ala Cys Ala Ala Gly Tyr Ser Gly Asn Gly Ile Phe Cys Ser Glu Val
144514501455
Asp Pro Cys Ala His Gly His Gly Gly Cys Ser Pro His Ala Asn Cys
146014651470
Thr Lys Val Ala Pro Gly Gln Arg Thr Cys Thr Cys Gln Asp Gly Tyr
147514801485
Met Gly Asp Gly Glu Leu Cys Gln Glu Ile Asn Ser Cys Leu Ile His
149014951500
His Gly Gly Cys His Ile His Ala Glu Cys Ile Pro Thr Gly Pro Gln
1505151015151520
Gln Val Ser Cys Ser Cys Arg Glu Gly Tyr Ser Gly Asp Gly Ile Arg
152515301535
Thr Cys Glu Leu Leu Asp Pro Cys Ser Lys Asn Asn Gly Gly Cys Ser
154015451550
Pro Tyr Ala Thr Cys Lys Ser Thr Gly Asp Gly Gln Arg Thr Cys Thr
155515601565
Cys Asp Thr Ala His Thr Val Gly Asp Gly Leu Thr Cys Arg Ala Arg
157015751580
Val Gly Leu Glu Leu Leu Arg Asp Lys His Ala Ser Phe Phe Ser Leu
1585159015951600
Arg Leu Leu Glu Tyr Lys Glu Leu Lys Gly Asp Gly Pro Phe Thr Ile
160516101615
Phe Val Pro His Ala Asp Leu Met Ser Asn Leu Ser Gln Asp Glu Leu
162016251630
Ala Arg Ile Arg Ala His Arg Gln Leu Val Phe Arg Tyr His Val Val
163516401645
Gly Cys Arg Arg Leu Arg Ser Glu Asp Leu Leu Glu Gln Gly Tyr Ala
165016551660
Thr Ala Leu Ser Gly His Pro Leu Arg Phe Ser Glu Arg Glu Gly Ser
1665167016751680
Ile Tyr Leu Asn Asp Phe Ala Arg Val Val Ser Ser Asp His Glu Ala
168516901695
Val Asn Gly Ile Leu His Phe Ile Asp Arg Val Leu Leu Pro Pro Glu
170017051710
Ala Leu His Trp Glu Pro Asp Asp Ala Pro Ile Pro Arg Arg Asn Val
171517201725
Thr Ala Ala Ala Gln Gly Phe Gly Tyr Lys Ile Phe Ser Gly Leu Leu
173017351740
Lys Val Ala Gly Leu Leu Pro Leu Leu Arg Glu Ala Ser His Arg Pro
1745175017551760
Phe Thr Met Leu Trp Pro Thr Asp Ala Ala Phe Arg Ala Leu Pro Pro
176517701775
Asp Arg Gln Ala Trp Leu Tyr His Glu Asp His Arg Asp Lys Leu Ala
178017851790
Ala Ile Leu Arg Gly His Met Ile Arg Asn Val Glu Ala Leu Ala Ser
179518001805
Asp Leu Pro Asn Leu Gly Pro Leu Arg Thr Met His Gly Thr Pro Ile
181018151820
Ser Phe Ser Cys Ser Arg Thr Arg Ala Gly Glu Leu Met Val Gly Glu
1825183018351840
Asp Asp Ala Arg Ile Val Gln Arg His Leu Pro Phe Glu Gly Gly Leu
184518501855
Ala Tyr Gly Ile Asp Gln Leu Leu Glu Pro Pro Gly Leu Gly Ala Arg
186018651870
Cys Asp His Phe Glu Thr Arg Pro Leu Arg Leu Asn Thr Cys Ser Ile
187518801885
Cys Gly Leu Glu Pro Pro Cys Pro Glu Gly Ser Gln Glu Gln Gly Ser
189018951900
Pro Glu Ala Cys Trp Arg Phe Tyr Pro Lys Phe Trp Thr Ser Pro Pro
1905191019151920
Leu His Ser Leu Gly Leu Arg Ser Val Trp Val His Pro Ser Leu Trp
192519301935
Gly Arg Pro Gln Gly Leu Gly Arg Gly Cys His Arg Asn Cys Val Thr
194019451950
Thr Thr Trp Lys Pro Ser Cys Cys Pro Gly His Tyr Gly Ser Glu Cys
195519601965
Gln Ala Cys Pro Gly Gly Pro Ser Ser Pro Cys Ser Asp Arg Gly Val
197019751980
Cys Met Asp Gly Met Ser Gly Ser Gly Gln Cys Leu Cys Arg Ser Gly
1985199019952000
Phe Ala Gly Thr Ala Cys Glu Leu Cys Ala Pro Gly Ala Phe Gly Pro
200520102015
His Cys Gln Ala Cys Arg Cys Thr Val His Gly Arg Cys Asp Glu Gly
202020252030
Leu Gly Gly Ser Gly Ser Cys Phe Cys Asp Glu Gly Trp Thr Gly Pro
203520402045
Arg Cys Glu Val Gln Leu Glu Leu Gln Pro Val Cys Thr Pro Pro Cys
205020552060
Ala Pro Glu Ala Val Cys Arg Ala Gly Asn Ser Cys Glu Cys Ser Leu
2065207020752080
Gly Tyr Glu Gly Asp Gly Arg Val Cys Thr Val Ala Asp Leu Cys Gln
208520902095
Asp Gly His Gly Gly Cys Ser Glu His Ala Asn Cys Ser Gln Val Gly
210021052110
Thr Met Val Thr Cys Thr Cys Leu Pro Asp Tyr Glu Gly Asp Gly Trp
211521202125
Ser Cys Arg Ala Arg Asn Pro Cys Thr Asp Gly His Arg Gly Gly Cys
213021352140
Ser Glu His Ala Asn Cys Leu Ser Thr Gly Leu Asn Thr Arg Arg Cys
2145215021552160
Glu Cys His Ala Gly Tyr Val Gly Asp Gly Leu Gln Cys Leu Glu Glu
216521702175
Ser Glu Pro Pro Val Asp Arg Cys Leu Gly Gln Pro Pro Pro Cys His
218021852190
Ser Asp Ala Met Cys Thr Asp Leu His Phe Gln Glu Lys Arg Ala Gly
219522002205
Val Phe His Leu Gln Ala Thr Ser Gly Pro Tyr Gly Leu Asn Phe Ser
221022152220
Glu Ala Glu Ala Ala Cys Glu Ala Gln Gly Ala Val Leu Ala Ser Phe
2225223022352240
Pro Gln Leu Ser Ala Ala Gln Gln Leu Gly Phe His Leu Cys Leu Met
224522502255
Gly Trp Leu Ala Asn Gly Ser Thr Ala His Pro Val Val Phe Pro Val
226022652270
Ala Asp Cys Gly Asn Gly Arg Val Gly Ile Val Ser Leu Gly Ala Arg
227522802285
Lys Asn Leu Ser Glu Arg Trp Asp Ala Tyr Cys Phe Arg Val Gln Asp
229022952300
Val Ala Cys Arg Cys Arg Asn Gly Phe Val Gly Asp Gly Ile Ser Thr
2305231023152320
Cys Asn Gly Lys Leu Leu Asp Val Leu Ala Ala Thr Ala Asn Phe Ser
232523302335
Thr Phe Tyr Gly Met Leu Leu Gly Tyr Ala Asn Ala Thr Gln Arg Gly
234023452350
Leu Asp Phe Leu Asp Phe Leu Asp Asp Glu Leu Thr Tyr Lys Thr Leu
235523602365
Phe Val Pro Val Asn Glu Gly Phe Val Asp Asn Met Thr Leu Ser Gly
237023752380
Pro Asp Leu Glu Leu His Ala Ser Asn Ala Thr Leu Leu Ser Ala Asn
2385239023952400
Ala Ser Gln Gly Lys Leu Leu Pro Ala His Ser Gly Leu Ser Leu Ile
240524102415
Ile Ser Asp Ala Gly Pro Asp Asn Ser Ser Trp Ala Pro Val Ala Pro
242024252430
Gly Thr Val Val Val Ser Arg Ile Ile Val Trp Asp Ile Met Ala Phe
243524402445
Asn Gly Ile Ile His Ala Leu Ala Ser Pro Leu Leu Ala Pro Pro Gln
245024552460
Pro Gln Ala Val Leu Ala Pro Glu Ala Pro Pro Val Ala Ala Gly Val
2465247024752480
Gly Ala Val Leu Ala Ala Gly Ala Leu Leu Gly Leu Val Ala Gly Ala
248524902495
Leu Tyr Leu Arg Ala Arg Gly Lys Pro Met Gly Phe Gly Phe Ser Ala
250025052510
Phe Gln Ala Glu Asp Asp Ala Asp Asp Asp Phe Ser Pro Trp Gln Glu
251525202525
Gly Thr Asn Pro Thr Leu Val Ser Val Pro Asn Pro Val Phe Gly Ser
253025352540
Asp Thr Phe Cys Glu Pro Phe Asp Asp Ser Leu Leu Glu Glu Asp Phe
2545255025552560
Pro Asp Thr Gln Arg Ile Leu Thr Val Lys
25652570
<210> 224
<211> 2551
<212> PRT
<213> Homo sapiens
<220>
<223> Stabilin-2 protein Q8WWQ8
<400> 224
Met Met Leu Gln His Leu Val Ile Phe Cys Leu Gly Leu Val Val Gln
151015
Asn Phe Cys Ser Pro Ala Glu Thr Thr Gly Gln Ala Arg Arg Cys Asp
202530
Arg Lys Ser Leu Leu Thr Ile Arg Thr Glu Cys Arg Ser Cys Ala Leu
354045
Asn Leu Gly Val Lys Cys Pro Asp Gly Tyr Thr Met Ile Thr Ser Gly
505560
Ser Val Gly Val Arg Asp Cys Arg Tyr Thr Phe Glu Val Arg Thr Tyr
65707580
Ser Leu Ser Leu Pro Gly Cys Arg His Ile Cys Arg Lys Asp Tyr Leu
859095
Gln Pro Arg Cys Cys Pro Gly Arg Trp Gly Pro Asp Cys Ile Glu Cys
100105110
Pro Gly Gly Ala Gly Ser Pro Cys Asn Gly Arg Gly Ser Cys Ala Glu
115120125
Gly Met Glu Gly Asn Gly Thr Cys Ser Cys Gln Glu Gly Phe Gly Gly
130135140
Thr Ala Cys Glu Thr Cys Ala Asp Asp Asn Leu Phe Gly Pro Ser Cys
145150155160
Ser Ser Val Cys Asn Cys Val His Gly Val Cys Asn Ser Gly Leu Asp
165170175
Gly Asp Gly Thr Cys Glu Cys Tyr Ser Ala Tyr Thr Gly Pro Lys Cys
180185190
Asp Lys Pro Ile Pro Glu Cys Ala Ala Leu Leu Cys Pro Glu Asn Ser
195200205
Arg Cys Ser Pro Ser Thr Glu Asp Glu Asn Lys Leu Glu Cys Lys Cys
210215220
Leu Pro Asn Tyr Arg Gly Asp Gly Lys Tyr Cys Asp Pro Ile Asn Pro
225230235240
Cys Leu Arg Lys Ile Cys His Pro His Ala His Cys Thr Tyr Leu Gly
245250255
Pro Asn Arg His Ser Cys Thr Cys Gln Glu Gly Tyr Arg Gly Asp Gly
260265270
Gln Val Cys Leu Pro Val Asp Pro Cys Gln Ile Asn Phe Gly Asn Cys
275280285
Pro Thr Lys Ser Thr Val Cys Lys Tyr Asp Gly Pro Gly Gln Ser His
290295300
Cys Glu Cys Lys Glu His Tyr Gln Asn Phe Val Pro Gly Val Gly Cys
305310315320
Ser Met Thr Asp Ile Cys Lys Ser Asp Asn Pro Cys His Arg Asn Ala
325330335
Asn Cys Thr Thr Val Ala Pro Gly Arg Thr Glu Cys Ile Cys Gln Lys
340345350
Gly Tyr Val Gly Asp Gly Leu Thr Cys Tyr Gly Asn Ile Met Glu Arg
355360365
Leu Arg Glu Leu Asn Thr Glu Pro Arg Gly Lys Trp Gln Gly Arg Leu
370375380
Thr Ser Phe Ile Ser Leu Leu Asp Lys Ala Tyr Ala Trp Pro Leu Ser
385390395400
Lys Leu Gly Pro Phe Thr Val Leu Leu Pro Thr Asp Lys Gly Leu Lys
405410415
Gly Phe Asn Val Asn Glu Leu Leu Val Asp Asn Lys Ala Ala Gln Tyr
420425430
Phe Val Lys Leu His Ile Ile Ala Gly Gln Met Asn Ile Glu Tyr Met
435440445
Asn Asn Thr Asp Met Phe Tyr Thr Leu Thr Gly Lys Ser Gly Glu Ile
450455460
Phe Asn Ser Asp Lys Asp Asn Gln Ile Lys Leu Lys Leu His Gly Gly
465470475480
Lys Lys Lys Val Lys Ile Ile Gln Gly Asp Ile Ile Ala Ser Asn Gly
485490495
Leu Leu His Ile Leu Asp Arg Ala Met Asp Lys Leu Glu Pro Thr Phe
500505510
Glu Ser Asn Asn Glu Gln Thr Ile Met Thr Met Leu Gln Pro Arg Tyr
515520525
Ser Lys Phe Arg Ser Leu Leu Glu Glu Thr Asn Leu Gly His Ala Leu
530535540
Asp Glu Asp Gly Val Gly Gly Pro Tyr Thr Ile Phe Val Pro Asn Asn
545550555560
Glu Ala Leu Asn Asn Met Lys Asp Gly Thr Leu Asp Tyr Leu Leu Ser
565570575
Pro Glu Gly Ser Arg Lys Leu Leu Glu Leu Val Arg Tyr His Ile Val
580585590
Pro Phe Thr Gln Leu Glu Val Ala Thr Leu Ile Ser Thr Pro His Ile
595600605
Arg Ser Met Ala Asn Gln Leu Ile Gln Phe Asn Thr Thr Asp Asn Gly
610615620
Gln Ile Leu Ala Asn Asp Val Ala Met Glu Glu Ile Glu Ile Thr Ala
625630635640
Lys Asn Gly Arg Ile Tyr Thr Leu Thr Gly Val Leu Ile Pro Pro Ser
645650655
Ile Val Pro Ile Leu Pro His Arg Cys Asp Glu Thr Lys Arg Glu Met
660665670
Lys Leu Gly Thr Cys Val Ser Cys Ser Leu Val Tyr Trp Ser Arg Cys
675680685
Pro Ala Asn Ser Glu Pro Thr Ala Leu Phe Thr His Arg Cys Val Tyr
690695700
Ser Gly Arg Phe Gly Ser Leu Lys Ser Gly Cys Ala Arg Tyr Cys Asn
705710715720
Ala Thr Val Lys Ile Pro Lys Cys Cys Lys Gly Phe Tyr Gly Pro Asp
725730735
Cys Asn Gln Cys Pro Gly Gly Phe Ser Asn Pro Cys Ser Gly Asn Gly
740745750
Gln Cys Ala Asp Ser Leu Gly Gly Asn Gly Thr Cys Ile Cys Glu Glu
755760765
Gly Phe Gln Gly Ser Gln Cys Gln Phe Cys Ser Asp Pro Asn Lys Tyr
770775780
Gly Pro Arg Cys Asn Lys Lys Cys Leu Cys Val His Gly Thr Cys Asn
785790795800
Asn Arg Ile Asp Ser Asp Gly Ala Cys Leu Thr Gly Thr Cys Arg Asp
805810815
Gly Ser Ala Gly Arg Leu Cys Asp Lys Gln Thr Ser Ala Cys Gly Pro
820825830
Tyr Val Gln Phe Cys His Ile His Ala Thr Cys Glu Tyr Ser Asn Gly
835840845
Thr Ala Ser Cys Ile Cys Lys Ala Gly Tyr Glu Gly Asp Gly Thr Leu
850855860
Cys Ser Glu Met Asp Pro Cys Thr Gly Leu Thr Pro Gly Gly Cys Ser
865870875880
Arg Asn Ala Glu Cys Ile Lys Thr Gly Thr Gly Thr His Thr Cys Val
885890895
Cys Gln Gln Gly Trp Thr Gly Asn Gly Arg Asp Cys Ser Glu Ile Asn
900905910
Asn Cys Leu Leu Pro Ser Ala Gly Gly Cys His Asp Asn Ala Ser Cys
915920925
Leu Tyr Val Gly Pro Gly Gln Asn Glu Cys Glu Cys Lys Lys Gly Phe
930935940
Arg Gly Asn Gly Ile Asp Cys Glu Pro Ile Thr Ser Cys Leu Glu Gln
945950955960
Thr Gly Lys Cys His Pro Leu Ala Ser Cys Gln Ser Thr Ser Ser Gly
965970975
Val Trp Ser Cys Val Cys Gln Glu Gly Tyr Glu Gly Asp Gly Phe Leu
980985990
Cys Tyr Gly Asn Ala Ala Val Glu Leu Ser Phe Leu Ser Glu Ala Ala
99510001005
Ile Phe Asn Arg Trp Ile Asn Asn Ala Ser Leu Gln Pro Thr Leu Ser
101010151020
Ala Thr Ser Asn Leu Thr Val Leu Val Pro Ser Gln Gln Ala Thr Glu
1025103010351040
Asp Met Asp Gln Asp Glu Lys Ser Phe Trp Leu Ser Gln Ser Asn Ile
104510501055
Pro Ala Leu Ile Lys Tyr His Met Leu Leu Gly Thr Tyr Arg Val Ala
106010651070
Asp Leu Gln Thr Leu Ser Ser Ser Asp Met Leu Ala Thr Ser Leu Gln
107510801085
Gly Asn Phe Leu His Leu Ala Lys Val Asp Gly Asn Ile Thr Ile Glu
109010951100
Gly Ala Ser Ile Val Asp Gly Asp Asn Ala Ala Thr Asn Gly Val Ile
1105111011151120
His Ile Ile Asn Lys Val Leu Val Pro Gln Arg Arg Leu Thr Gly Ser
112511301135
Leu Pro Asn Leu Leu Met Arg Leu Glu Gln Met Pro Asp Tyr Ser Ile
114011451150
Phe Arg Gly Tyr Ile Ile Gln Tyr Asn Leu Ala Asn Ala Ile Glu Ala
115511601165
Ala Asp Ala Tyr Thr Val Phe Ala Pro Asn Asn Asn Ala Ile Glu Asn
117011751180
Tyr Ile Arg Glu Lys Lys Val Leu Ser Leu Glu Glu Asp Val Leu Arg
1185119011951200
Tyr His Val Val Leu Glu Glu Lys Leu Leu Lys Asn Asp Leu His Asn
120512101215
Gly Met His Arg Glu Thr Met Leu Gly Phe Ser Tyr Phe Leu Ser Phe
1220 12251230
Phe Leu His Asn Asp Gln Leu Tyr Val Asn Glu Ala Pro Ile Asn Tyr
123512401245
Thr Asn Val Ala Thr Asp Lys Gly Val Ile His Gly Leu Gly Lys Val
125012551260
Leu Glu Ile Gln Lys Asn Arg Cys Asp Asn Asn Asp Thr Thr Ile Ile
1265127012751280
Arg Gly Arg Cys Arg Thr Cys Ser Ser Glu Leu Thr Cys Pro Phe Gly
128512901295
Thr Lys Ser Leu Gly Asn Glu Lys Arg Arg Cys Ile Tyr Thr Ser Tyr
130013051310
Phe Met Gly Arg Arg Thr Leu Phe Ile Gly Cys Gln Pro Lys Cys Val
131513201325
Arg Thr Val Ile Thr Arg Glu Cys Cys Ala Gly Phe Phe Gly Pro Gln
133013351340
Cys Gln Pro Cys Pro Gly Asn Ala Gln Asn Val Cys Phe Gly Asn Gly
1345135013551360
Ile Cys Leu Asp Gly Val Asn Gly Thr Gly Val Cys Glu Cys Gly Glu
136513701375
Gly Phe Ser Gly Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly
138013851390
Ile His Cys Asp Gln Ala Cys Ser Cys Val His Gly Arg Cys Asn Gln
139514001405
Gly Pro Leu Gly Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly
141014151420
Val His Cys Asp Asn Ala Thr Thr Glu Asp Asn Cys Asn Gly Thr Cys
1425143014351440
His Thr Ser Ala Asn Cys Leu Thr Asn Ser Asp Gly Thr Ala Ser Cys
144514501455
Lys Cys Ala Ala Gly Phe Gln Gly Asn Gly Thr Ile Cys Thr Ala Ile
146014651470
Asn Ala Cys Glu Ile Ser Asn Gly Gly Cys Ser Ala Lys Ala Asp Cys
147514801485
Lys Arg Thr Thr Pro Gly Arg Arg Val Cys Thr Cys Lys Ala Gly Tyr
149014951500
Thr Gly Asp Gly Ile Val Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn
1505151015151520
His Gly Gly Cys Asp Lys Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn
152515301535
Gln Ala Ala Cys Asn Cys Leu Pro Ala Tyr Thr Gly Asp Gly Lys Val
154015451550
Cys Thr Leu Ile Asn Val Cys Leu Thr Lys Asn Gly Gly Cys Ser Glu
155515601565
Phe Ala Ile Cys Asn His Thr Gly Gln Val Glu Arg Thr Cys Thr Cys
157015751580
Lys Pro Asn Tyr Ile Gly Asp Gly Phe Thr Cys Arg Gly Ser Ile Tyr
1585159015951600
Gln Glu Leu Pro Lys Asn Pro Lys Thr Ser Gln Tyr Phe Phe Gln Leu
160516101615
Gln Glu His Phe Val Lys Asp Leu Val Gly Pro Gly Pro Phe Thr Val
162016251630
Phe Ala Pro Leu Ser Ala Ala Phe Asp Glu Glu Ala Arg Val Lys Asp
163516401645
Trp Asp Lys Tyr Gly Leu Met Pro Gln Val Leu Arg Tyr His Val Val
165016551660
Ala Cys His Gln Leu Leu Leu Glu Asn Leu Lys Leu Ile Ser Asn Ala
1665167016751680
Thr Ser Leu Gln Gly Glu Pro Ile Val Ile Ser Val Ser Gln Ser Thr
168516901695
Val Tyr Ile Asn Asn Lys Ala Lys Ile Ile Ser Ser Asp Ile Ile Ser
170017051710
Thr Asn Gly Ile Val His Ile Ile Asp Lys Leu Leu Ser Pro Lys Asn
171517201725
Leu Leu Ile Thr Pro Lys Asp Asn Ser Gly Arg Ile Leu Gln Asn Leu
173017351740
Thr Thr Leu Ala Thr Asn Asn Gly Tyr Ile Lys Phe Ser Asn Leu Ile
1745175017551760
Gln Asp Ser Gly Leu Leu Ser Val Ile Thr Asp Pro Ile His Thr Pro
176517701775
Val Thr Leu Phe Trp Pro Thr Asp Gln Ala Leu His Ala Leu Pro Ala
178017851790
Glu Gln Gln Asp Phe Leu Phe Asn Gln Asp Asn Lys Asp Lys Leu Lys
179518001805
Glu Tyr Leu Lys Phe His Val Ile Arg Asp Ala Lys Val Leu Ala Val
181018151820
Asp Leu Pro Thr Ser Thr Ala Trp Lys Thr Leu Gln Gly Ser Glu Leu
1825183018351840
Ser Val Lys Cys Gly Ala Gly Arg Asp Ile Gly Asp Leu Phe Leu Asn
184518501855
Gly Gln Thr Cys Arg Ile Val Gln Arg Glu Leu Leu Phe Asp Leu Gly
186018651870
Val Ala Tyr Gly Ile Asp Cys Leu Leu Ile Asp Pro Thr Leu Gly Gly
187518801885
Arg Cys Asp Thr Phe Thr Thr Phe Asp Ala Ser Gly Glu Cys Gly Ser
189018951900
Cys Val Asn Thr Pro Ser Cys Pro Arg Trp Ser Lys Pro Lys Gly Val
1905191019151920
Lys Gln Lys Cys Leu Tyr Asn Leu Pro Phe Lys Arg Asn Leu Glu Gly
192519301935
Cys Arg Glu Arg Cys Ser Leu Val Ile Gln Ile Pro Arg Cys Cys Lys
194019451950
Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys Pro Gly Gly Pro Asp Ala
195519601965
Pro Cys Asn Asn Arg Gly Val Cys Leu Asp Gln Tyr Ser Ala Thr Gly
197019751980
Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly Thr Ala Cys Glu Met Cys
1985199019952000
Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu Pro Cys Gly Cys Ser Asp
200520102015
His Gly Gln Cys Asp Asp Gly Ile Thr Gly Ser Gly Gln Cys Leu Cys
202020252030
Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp Thr Gln Ala Val Leu Pro
203520402045
Ala Val Cys Thr Pro Pro Cys Ser Ala His Ala Thr Cys Lys Glu Asn
205020552060
Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu Gly Asp Gly Ile Thr Cys
2065207020752080
Thr Val Val Asp Phe Cys Lys Gln Asp Asn Gly Gly Cys Ala Lys Val
208520902095
Ala Arg Cys Ser Gln Lys Gly Thr Lys Val Ser Cys Ser Cys Gln Lys
210021052110
Gly Tyr Lys Gly Asp Gly His Ser Cys Thr Glu Ile Asp Pro Cys Ala
211521202125
Asp Gly Leu Asn Gly Gly Cys His Glu His Ala Thr Cys Lys Met Thr
213021352140
Gly Pro Gly Lys His Lys Cys Glu Cys Lys Ser His Tyr Val Gly Asp
2145215021552160
Gly Leu Asn Cys Glu Pro Glu Gln Leu Pro Ile Asp Arg Cys Leu Gln
216521702175
Asp Asn Gly Gln Cys His Ala Asp Ala Lys Cys Val Asp Leu His Phe
218021852190
Gln Asp Thr Thr Val Gly Val Phe His Leu Arg Ser Pro Leu Gly Gln
219522002205
Tyr Lys Leu Thr Phe Asp Lys Ala Arg Glu Ala Cys Ala Asn Glu Ala
221022152220
Ala Thr Met Ala Thr Tyr Asn Gln Leu Ser Tyr Ala Gln Lys Ala Lys
2225223022352240
Tyr His Leu Cys Ser Ala Gly Trp Leu Glu Thr Gly Arg Val Ala Tyr
224522502255
Pro Thr Ala Phe Ala Ser Gln Asn Cys Gly Ser Gly Val Val Gly Ile
226022652270
Val Asp Tyr Gly Pro Arg Pro Asn Lys Ser Glu Met Trp Asp Val Phe
227522802285
Cys Tyr Arg Met Lys Asp Val Asn Cys Thr Cys Lys Val Gly Tyr Val
229022952300
Gly Asp Gly Phe Ser Cys Ser Gly Asn Leu Leu Gln Val Leu Met Ser
2305231023152320
Phe Pro Ser Leu Thr Asn Phe Leu Thr Glu Val Leu Ala Tyr Ser Asn
232523302335
Ser Ser Ala Arg Gly Arg Ala Phe Leu Glu His Leu Thr Asp Leu Ser
234023452350
Ile Arg Gly Thr Leu Phe Val Pro Gln Asn Ser Gly Leu Gly Glu Asn
235523602365
Glu Thr Leu Ser Gly Arg Asp Ile Glu His His Leu Ala Asn Val Ser
237023752380
Met Phe Phe Tyr Asn Asp Leu Val Asn Gly Thr Thr Leu Gln Thr Arg
2385239023952400
Leu Gly Ser Lys Leu Leu Ile Thr Ala Ser Gln Asp Pro Leu Gln Pro
240524102415
Thr Glu Thr Arg Phe Val Asp Gly Arg Ala Ile Leu Gln Trp Asp Ile
242024252430
Phe Ala Ser Asn Gly Ile Ile His Val Ile Ser Arg Pro Leu Lys Ala
243524402445
Pro Pro Ala Pro Val Thr Leu Thr His Thr Gly Leu Gly Ala Gly Ile
245024552460
Phe Phe Ala Ile Ile Leu Val Thr Gly Ala Val Ala Leu Ala Ala Tyr
2465247024752480
Ser Tyr Phe Arg Ile Asn Arg Arg Thr Ile Gly Phe Gln His Phe Glu
248524902495
Ser Glu Glu Asp Ile Asn Val Ala Ala Leu Gly Lys Gln Gln Pro Glu
250025052510
Asn Ile Ser Asn Pro Leu Tyr Glu Ser Thr Thr Ser Ala Pro Pro Glu
251525202525
Pro Ser Tyr Asp Pro Phe Thr Asp Ser Glu Glu Arg Gln Leu Glu Gly
253025352540
Asn Asp Pro Leu Arg Thr Leu
25452550
<210> 225
<211> 862
<212> PRT
<213> Homo sapiens
<220>
<223> CAB61358 protein
<400> 225
Gly Thr Ala Ser Cys Lys Cys Ala Ala Gly Phe Gln Gly Asn Gly Thr
151015
Ile Cys Thr Ala Ile Asn Ala Cys Glu Ile Ser Asn Gly Gly Cys Ser
202530
Ala Lys Ala Asp Cys Lys Arg Thr Thr Pro Gly Arg Arg Val Cys Thr
354045
Cys Lys Ala Gly Tyr Thr Gly Asp Gly Ile Val Cys Leu Glu Ile Asn
505560
Pro Cys Leu Glu Asn His Gly Gly Cys Asp Lys Asn Ala Glu Cys Thr
65707580
Gln Thr Gly Pro Asn Gln Ala Ala Cys Asn Cys Leu Pro Ala Tyr Thr
859095
Gly Asp Gly Lys Val Cys Thr Leu Ile Asn Val Cys Leu Thr Lys Asn
100105110
Gly Gly Cys Ser Glu Phe Ala Ile Cys Asn His Thr Gly Gln Val Glu
115120125
Arg Thr Cys Thr Cys Lys Pro Asn Tyr Ile Gly Asp Gly Phe Thr Cys
130135140
Arg Gly Ser Ile Tyr Gln Glu Leu Pro Lys Asn Pro Lys Thr Ser Gln
145150 155160
Tyr Phe Phe Gln Leu Gln Glu His Phe Val Lys Asp Leu Val Gly Pro
165170175
Gly Pro Phe Thr Val Phe Ala Pro Leu Ser Ala Ala Phe Asp Glu Glu
180185190
Ala Arg Val Lys Asp Trp Asp Lys Tyr Gly Leu Met Pro Gln Val Leu
195200205
Arg Tyr His Val Val Ala Cys His Gln Leu Leu Leu Glu Asn Leu Lys
210215220
Leu Ile Ser Asn Ala Thr Ser Leu Gln Gly Glu Pro Ile Val Ile Ser
225230235240
Val Ser Gln Ser Thr Val Tyr Ile Asn Asn Lys Ala Lys Ile Ile Ser
245250255
Ser Asp Ile Ile Ser Thr Asn Gly Ile Val His Ile Ile Asp Lys Leu
260265270
Leu Ser Pro Lys Asn Leu Leu Ile Thr Pro Lys Asp Asn Ser Gly Arg
275280285
Ile Leu Gln Asn Leu Thr Thr Leu Ala Thr Asn Asn Gly Tyr Ile Lys
290295300
Phe Ser Asn Leu Ile Gln Asp Ser Gly Leu Leu Ser Val Ile Thr Asp
305310315320
Pro Ile His Thr Pro Val Thr Leu Phe Trp Pro Thr Asp Gln Ala Leu
325330335
His Ala Leu Pro Ala Glu Gln Gln Asp Phe Leu Phe Asn Gln Asp Asn
340345350
Lys Asp Lys Leu Lys Glu Tyr Leu Lys Phe His Val Ile Arg Asp Ala
355360365
Lys Val Leu Ala Val Asp Leu Pro Thr Ser Thr Ala Trp Lys Thr Leu
370375380
Gln Gly Ser Glu Leu Ser Val Lys Cys Gly Ala Gly Arg Asp Ile Gly
385390395400
Asp Leu Phe Leu Asn Gly Gln Thr Cys Arg Ile Val Gln Arg Glu Leu
405410415
Leu Phe Asp Leu Gly Val Ala Tyr Gly Ile Asp Cys Leu Leu Ile Asp
420425430
Pro Thr Leu Gly Gly Arg Cys Asp Thr Phe Thr Thr Phe Asp Ala Ser
435440445
Gly Glu Cys Gly Ser Cys Val Asn Thr Pro Ser Cys Pro Arg Trp Ser
450455460
Lys Pro Lys Gly Val Lys Gln Lys Cys Leu Tyr Asn Leu Pro Phe Lys
465 470475480
Arg Asn Leu Glu Gly Cys Arg Glu Arg Cys Ser Leu Val Ile Gln Ile
485490495
Pro Arg Cys Cys Lys Gly Tyr Phe Gly Arg Asp Cys Gln Ala Cys Pro
500505510
Gly Gly Pro Asp Ala Pro Cys Asn Asn Arg Gly Val Cys Leu Asp Gln
515520525
Tyr Ser Ala Thr Gly Glu Cys Lys Cys Asn Thr Gly Phe Asn Gly Thr
530535540
Ala Cys Glu Met Cys Trp Pro Gly Arg Phe Gly Pro Asp Cys Leu Pro
545550555560
Cys Gly Cys Ser Asp His Gly Gln Cys Asp Asp Gly Ile Thr Gly Ser
565570575
Gly Gln Cys Leu Cys Glu Thr Gly Trp Thr Gly Pro Ser Cys Asp Thr
580585590
Gln Ala Val Leu Pro Ala Val Cys Thr Pro Pro Cys Ser Ala His Ala
595600605
Thr Cys Lys Glu Asn Asn Thr Cys Glu Cys Asn Leu Asp Tyr Glu Gly
610615620
Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln Asp Asn Gly
625630635640
Gly Cys Ala Lys Val Ala Arg Cys Ser Gln Lys Gly Thr Lys Val Ser
645650655
Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser Cys Thr Glu
660665670
Ile Asp Pro Cys Ala Asp Gly Leu Asn Gly Gly Cys His Glu His Ala
675680685
Thr Cys Lys Met Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys Ser
690695700
His Tyr Val Gly Asp Gly Leu Asn Cys Glu Pro Glu Gln Leu Pro Ile
705710715720
Asp Arg Cys Leu Gln Asp Asn Gly Gln Cys His Ala Asp Ala Lys Cys
725730735
Val Asp Leu His Phe Gln Asp Thr Thr Val Gly Val Phe His Leu Arg
740745750
Ser Pro Leu Gly Gln Tyr Lys Leu Thr Phe Asp Lys Ala Arg Glu Ala
755760765
Cys Ala Asn Glu Ala Ala Thr Met Ala Thr Tyr Asn Gln Leu Ser Tyr
770775780
Ala Gln Lys Ala Lys Tyr His Leu Cys Ser Ala Gly Trp Leu Glu Thr
785790795800
Gly Arg Val Ala Tyr Pro Thr Ala Phe Ala Ser Gln Asn Cys Gly Ser
805810815
Gly Val Val Gly Ile Val Asp Tyr Gly Pro Arg Pro Asn Lys Ser Glu
820825830
Met Trp Asp Val Phe Cys Tyr Arg Met Lys Gly Ser Ala Gly Leu Phe
835840845
Gln Gln Leu Ser Ser Arg Pro Cys Ile Ser Arg Thr Pro Asp
850855860
<210> 226
<211> 768
<212> PRT
<213> Homo sapiens
<220>
<223> KIAA0527 protein AB011099
<400> 226
Pro Arg Val Pro Gln Thr Gly Gly Gly Ser Leu Arg Pro Ala Ser Tyr
151015
Ser Pro Arg Leu Pro Ala Pro Ser Pro Ser Ala Pro Leu Tyr Pro Gln
202530
Ser Ala Arg Pro Ser Ala Ala Pro Phe Gly Thr Glu Val Ser Arg Cys
354045
Pro Ala Arg Arg Arg Ser Arg Val Thr Ala Ala Ser Ser Ala Pro Gln
505560
Arg Arg Pro Pro Gly Val Arg Arg Pro Arg Arg Ser Gly Ser Ala Ser
65707580
Arg Ala Ser Pro Gly Ser Pro Arg Ser Ser Leu Ser Ala Arg Pro Ala
859095
Arg Ser Leu Arg Phe Val Ser Arg Ala Gln Ser Ala Glu Pro Ser Gly
100105110
Ala Arg Trp Ala Val Ala Trp Ala Thr Pro Asn Ala Ala Arg Ala Leu
115120125
Thr Arg Val Arg Trp Pro Ala His Ser Arg Thr Met Thr Ala Glu Gly
130135140
Pro Ser Pro Pro Ala Arg Trp His Arg Arg Leu Pro Gly Leu Trp Ala
145150155160
Ala Ala Leu Leu Leu Leu Gly Leu Pro Arg Leu Ser Val Arg Ala Asp
165170175
Gly Lys Leu Phe Val Leu Glu Ser Gln Asn Gly Ser Gln Gly Leu Gln
180185190
Leu Glu Ala Ala Arg Leu Ser Cys Lys Ser Arg Gly Ala His Leu Ala
195200205
Ser Ala Asp Glu Leu Arg Arg Val Val Gln Asp Cys Ser Phe Ala Val
210215220
Cys Thr Thr Gly Trp Leu Ala Asp Gly Thr Leu Gly Thr Thr Val Cys
225230235240
Ser Lys Gly Ser Gly Glu Gln Gln Ile Met Arg Ala Val Asp Val Arg
245250255
Ile Glu Ser Asn Pro Val Pro Gly Gly Thr Tyr Ser Ala Leu Cys Ile
260265270
Lys Asp Glu Glu Lys Pro Cys Gly Asp Pro Pro Ser Phe Pro His Thr
275280285
Ile Leu Gln Gly Arg Thr Gly Leu Glu Met Gly Asp Glu Leu Leu Tyr
290295300
Val Cys Ala Pro Gly His Ile Met Gly His Arg Glu Thr Ala Phe Thr
305310315320
Leu Leu Cys Asn Ser Cys Gly Glu Trp Tyr Gly Leu Val Gln Ala Cys
325330335
Gly Lys Asp Glu Ala Glu Ala His Ile Asp Tyr Glu Asp Asn Phe Pro
340345350
Asp Asp Arg Ser Val Ser Phe Arg Glu Leu Met Glu Asp Ser Arg Thr
355360365
Glu Ala Asp Glu Asp Arg Gly Gln Gly Asp Ser Ser Glu Glu Ala Pro
370375380
Lys Gln Asp Arg Leu Val Ser Ile Ser Val Gly Arg Glu Asn Ile Ala
385390395400
Arg Asp Lys Val Phe Val Pro Thr Thr Gly Ser Pro Gly Ala Gly Ser
405410415
Ser Val Pro Ala Asp Ser Pro Gly Ser Arg Leu Leu Gln Lys His Leu
420425430
Phe Trp Phe Pro Ala Glu Ala Phe His Lys Pro Gly Leu Glu Lys Glu
435440445
Val Asp Asp Asp Thr Lys Lys Gln Phe Ser Ala Gly Asp Asn His Ser
450455460
Gly Val Lys Leu Val Pro Gly Glu Pro Glu Thr Lys Val Ile Tyr Gly
465470475480
Asn Thr Asp Gly Pro Ser Gly Pro Phe Val Gly Lys Asn Asp Ser Lys
485490495
Ala Gly Asp Pro Val Val Ser Ser Ser Asp Glu Ser Trp Leu Asp Gly
500505510
Tyr Pro Val Thr Asp Gly Ala Trp Arg Lys Thr Glu Ala Glu Glu Glu
515520525
Glu Asp Gly Asp Arg Gly Asp Gly Ser Val Gly Leu Asp Glu Asn Val
530535540
Leu Val Thr Pro Asp Gln Pro Ile Leu Val Glu Val Lys Lys Pro Lys
545550555560
Ser Ser Thr Leu Thr Pro Ser Glu Gly Met Thr His Ser Ser Val Leu
565570575
Pro Ser Gln Met Leu Asp Val Glu Ala Leu Ala Leu Arg Pro Val Asn
580585590
Ala Ser Glu Thr Glu Gly Ile Gly Asp Gly Asp Leu Thr Lys Tyr Gln
595600605
Ser Thr Leu Pro Trp Arg Phe Ile Thr Glu Glu Ser Pro Met Ala Thr
610615620
Leu Ser Tyr Glu Leu Thr Ser Ser Thr Leu Glu Ile Leu Thr Val Asn
625630635640
Thr Val Lys Gln Thr Pro Asn His Ile Pro Ser Thr Ile Met Ala Thr
645650655
Thr Gln Pro Pro Val Glu Thr Thr Val Pro Glu Ile Gln Asp Ser Phe
660665670
Pro Tyr Leu Leu Ser Glu Asp Phe Phe Gly Gln Glu Gly Pro Gly Pro
675680685
Gly Ala Ser Glu Glu Leu His Pro Thr Leu Glu Ser Cys Val Gly Asp
690695700
Gly Cys Pro Gly Leu Ser Arg Gly Pro Val Ile Ala Thr Ile Val Thr
705710715720
Val Leu Cys Leu Leu Leu Leu Leu Ala Gly Val Gly Met Val Trp Gly
725730735
Tyr Arg Lys Cys Gln His Lys Ser Ser Val Tyr Lys Leu Asn Val Gly
740745750
Gln Arg Gln Ala Arg His Tyr His Gln Gln Ile Glu Met Glu Lys Val
755760765
<210> 227
<211> 742
<212> PRT
<213> Homo sapiens
<220>
<223> CD44 protein P16070
<400> 227
Met Asp Lys Phe Trp Trp His Ala Ala Trp Gly Leu Cys Leu Val Pro
151015
Leu Ser Leu Ala Gln Ile Asp Leu Asn Ile Thr Cys Arg Phe Ala Gly
202530
Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg Thr Glu
354045
Ala Ala Asp Leu Cys Lys Ala Phe Asn Ser Thr Leu Pro Thr Met Ala
505560
Gln Met Glu Lys Ala Leu Ser Ile Gly Phe Glu Thr Cys Arg Tyr Gly
65707580
Phe Ile Glu Gly His Val Val Ile Pro Arg Ile His Pro Asn Ser Ile
859095
Cys Ala Ala Asn Asn Thr Gly Val Tyr Ile Leu Thr Ser Asn Thr Ser
100105110
Gln Tyr Asp Thr Tyr Cys Phe Asn Ala Ser Ala Pro Pro Glu Glu Asp
115120125
Cys Thr Ser Val Thr Asp Leu Pro Asn Ala Phe Asp Gly Pro Ile Thr
130135140
Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Val Gln Lys Gly Glu
145150155160
Tyr Arg Thr Asn Pro Glu Asp Ile Tyr Pro Ser Asn Pro Thr Asp Asp
165170175
Asp Val Ser Ser Gly Ser Ser Ser Glu Arg Ser Ser Thr Ser Gly Gly
180185190
Tyr Ile Phe Tyr Thr Phe Ser Thr Val His Pro Ile Pro Asp Glu Asp
195200205
Ser Pro Trp Ile Thr Asp Ser Thr Asp Arg Ile Pro Ala Thr Thr Leu
210215220
Met Ser Thr Ser Ala Thr Ala Thr Glu Thr Ala Thr Lys Arg Gln Glu
225230235240
Thr Trp Asp Trp Phe Ser Trp Leu Phe Leu Pro Ser Glu Ser Lys Asn
245250255
His Leu His Thr Thr Thr Gln Met Ala Gly Thr Ser Ser Asn Thr Ile
260265270
Ser Ala Gly Trp Glu Pro Asn Glu Glu Asn Glu Asp Glu Arg Asp Arg
275280285
His Leu Ser Phe Ser Gly Ser Gly Ile Asp Asp Asp Glu Asp Phe Ile
290295300
Ser Ser Thr Ile Ser Thr Thr Pro Arg Ala Phe Asp His Thr Lys Gln
305310315320
Asn Gln Asp Trp Thr Gln Trp Asn Pro Ser His Ser Asn Pro Glu Val
325330335
Leu Leu Gln Thr Thr Thr Arg Met Thr Asp Val Asp Arg Asn Gly Thr
340345350
Thr Ala Tyr Glu Gly Asn Trp Asn Pro Glu Ala His Pro Pro Leu Ile
355360365
His His Glu His His Glu Glu Glu Glu Thr Pro His Ser Thr Ser Thr
370375380
Ile Gln Ala Thr Pro Ser Ser Thr Thr Glu Glu Thr Ala Thr Gln Lys
385390395400
Glu Gln Trp Phe Gly Asn Arg Trp His Glu Gly Tyr Arg Gln Thr Pro
405410415
Lys Glu Asp Ser His Ser Thr Thr Gly Thr Ala Ala Ala Ser Ala His
420425430
Thr Ser His Pro Met Gln Gly Arg Thr Thr Pro Ser Pro Glu Asp Ser
435440445
Ser Trp Thr Asp Phe Phe Asn Pro Ile Ser His Pro Met Gly Arg Gly
450455460
His Gln Ala Gly Arg Arg Met Asp Met Asp Ser Ser His Ser Ile Thr
465470475480
Leu Gln Pro Thr Ala Asn Pro Asn Thr Gly Leu Val Glu Asp Leu Asp
485490495
Arg Thr Gly Pro Leu Ser Met Thr Thr Gln Gln Ser Asn Ser Gln Ser
500505510
Phe Ser Thr Ser His Glu Gly Leu Glu Glu Asp Lys Asp His Pro Thr
515520525
Thr Ser Thr Leu Thr Ser Ser Asn Arg Asn Asp Val Thr Gly Gly Arg
530535540
Arg Asp Pro Asn His Ser Glu Gly Ser Thr Thr Leu Leu Glu Gly Tyr
545550555560
Thr Ser His Tyr Pro His Thr Lys Glu Ser Arg Thr Phe Ile Pro Val
565570575
Thr Ser Ala Lys Thr Gly Ser Phe Gly Val Thr Ala Val Thr Val Gly
580585590
Asp Ser Asn Ser Asn Val Asn Arg Ser Leu Ser Gly Asp Gln Asp Thr
595600605
Phe His Pro Ser Gly Gly Ser His Thr Thr His Gly Ser Glu Ser Asp
610615620
Gly His Ser His Gly Ser Gln Glu Gly Gly Ala Asn Thr Thr Ser Gly
625630635640
Pro Ile Arg Thr Pro Gln Ile Pro Glu Trp Leu Ile Ile Leu Ala Ser
645650655
Leu Leu Ala Leu Ala Leu Ile Leu Ala Val Cys Ile Ala Val Asn Ser
660665670
Arg Arg Arg Cys Gly Gln Lys Lys Lys Leu Val Ile Asn Ser Gly Asn
675680685
Gly Ala Val Glu Asp Arg Lys Pro Ser Gly Leu Asn Gly Glu Ala Ser
690695700
Lys Ser Gln Glu Met Val His Leu Val Asn Lys Glu Ser Ser Glu Thr
705710715720
Pro Asp Gln Phe Met Thr Ala Asp Glu Thr Arg Asn Leu Gln Asn Val
725730735
Asp Met Lys Ile Gly Val
740
<210> 228
<211> 322
<212> PRT
<213> Homo sapiens
<220>
<223> Lymphatic vessel endothelial hyaluronic acid
receptor 1 LYVE-1
<400> 228
Met Ala Arg Cys Phe Ser Leu Val Leu Leu Leu Thr Ser Ile Trp Thr
151015
Thr Arg Leu Leu Val Gln Gly Ser Leu Arg Ala Glu Glu Leu Ser Ile
202530
Gln Val Ser Cys Arg Ile Met Gly Ile Thr Leu Val Ser Lys Lys Ala
354045
Asn Gln Gln Leu Asn Phe Thr Glu Ala Lys Glu Ala Cys Arg Leu Leu
505560
Gly Leu Ser Leu Ala Gly Lys Asp Gln Val Glu Thr Ala Leu Lys Ala
65707580
Ser Phe Glu Thr Cys Ser Tyr Gly Trp Val Gly Asp Gly Phe Val Val
859095
Ile Ser Arg Ile Ser Pro Asn Pro Lys Cys Gly Lys Asn Gly Val Gly
100105110
Val Leu Ile Trp Lys Val Pro Val Ser Arg Gln Phe Ala Ala Tyr Cys
115120125
Tyr Asn Ser Ser Asp Thr Trp Thr Asn Ser Cys Ile Pro Glu Ile Ile
130135140
Thr Thr Lys Asp Pro Ile Phe Asn Thr Gln Thr Ala Thr Gln Thr Thr
145150155160
Glu Phe Ile Val Ser Asp Ser Thr Tyr Ser Val Ala Ser Pro Tyr Ser
165170175
Thr Ile Pro Ala Pro Thr Thr Thr Pro Pro Ala Pro Ala Ser Thr Ser
180185190
Ile Pro Arg Arg Lys Lys Leu Ile Cys Val Thr Glu Val Phe Met Glu
195200205
Thr Ser Thr Met Ser Thr Glu Thr Glu Pro Phe Val Glu Asn Lys Ala
210215220
Ala Phe Lys Asn Glu Ala Ala Gly Phe Gly Gly Val Pro Thr Ala Leu
225230235240
Leu Val Leu Ala Leu Leu Phe Phe Gly Ala Ala Ala Gly Leu Gly Phe
245250255
Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pro Phe Thr Asn Lys Asn
260265270
Gln Gln Lys Glu Met Ile Glu Thr Lys Val Val Lys Glu Glu Lys Ala
275280285
Asn Asp Ser Asn Pro Asn Glu Glu Ser Lys Lys Thr Asp Lys Asn Pro
290295300
Glu Glu Ser Lys Ser Pro Ser Lys Thr Thr Val Arg Cys Leu Glu Ala
305310315320
Glu Val
<210> 229
<211> 354
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN1 Hyaluronan and proteoglycan link protein 1
P10915
<400> 229
Met Lys Ser Leu Leu Leu Leu Val Leu Ile Ser Ile Cys Trp Ala Asp
151015
His Leu Ser Asp Asn Tyr Thr Leu Asp His Asp Arg Ala Ile His Ile
202530
Gln Ala Glu Asn Gly Pro His Leu Leu Val Glu Ala Glu Gln Ala Lys
354045
Val Phe Ser His Arg Gly Gly Asn Val Thr Leu Pro Cys Lys Phe Tyr
505560
Arg Asp Pro Thr Ala Phe Gly Ser Gly Ile His Lys Ile Arg Ile Lys
65707580
Trp Thr Lys Leu Thr Ser Asp Tyr Leu Lys Glu Val Asp Val Phe Val
859095
Ser Met Gly Tyr His Lys Lys Thr Tyr Gly Gly Tyr Gln Gly Arg Val
100105110
Phe Leu Lys Gly Gly Ser Asp Ser Asp Ala Ser Leu Val Ile Thr Asp
115120125
Leu Thr Leu Glu Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile Glu Gly
130135140
Leu Glu Asp Asp Thr Val Val Val Ala Leu Asp Leu Gln Gly Val Val
145150155160
Phe Pro Tyr Phe Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe His Glu
165170175
Ala Gln Gln Ala Cys Leu Asp Gln Asp Ala Val Ile Ala Ser Phe Asp
180185190
Gln Leu Tyr Asp Ala Trp Arg Gly Gly Leu Asp Trp Cys Asn Ala Gly
195200205
Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro Arg Glu
210215220
Pro Cys Gly Gly Gln Asn Thr Val Pro Gly Val Arg Asn Tyr Gly Phe
225230235240
Trp Asp Lys Asp Lys Ser Arg Tyr Asp Val Phe Cys Phe Thr Ser Asn
245250255
Phe Asn Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu Thr Tyr
260265270
Asp Glu Ala Val Gln Ala Cys Leu Asn Asp Gly Ala Gln Ile Ala Lys
275280285
Val Gly Gln Ile Phe Ala Ala Trp Lys Ile Leu Gly Tyr Asp Arg Cys
290295300
Asp Ala Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ser Arg
305310315320
Pro Arg Arg Arg Cys Ser Pro Thr Glu Ala Ala Val Arg Phe Val Gly
325330335
Phe Pro Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe Arg Ala
340345350
Tyr Asn
<210> 230
<211> 340
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN2 Hyaluronan and proteoglycan link protein 2
Q9CZV7
<400> 230
Met Pro Gly Trp Leu Thr Leu Pro Thr Leu Cys Arg Phe Leu Leu Trp
151015
Ala Phe Thr Ile Phe His Lys Ala Gln Gly Asp Pro Ala Ser His Pro
202530
Gly Pro His Tyr Leu Leu Pro Pro Ile His Glu Val Ile His Ser His
354045
Arg Gly Ala Thr Ala Thr Leu Pro Cys Val Leu Gly Thr Thr Pro Pro
505560
Ser Tyr Lys Val Arg Trp Ser Lys Val Glu Pro Gly Glu Leu Arg Glu
65707580
Thr Leu Ile Leu Ile Thr Asn Gly Leu His Ala Arg Gly Tyr Gly Pro
859095
Leu Gly Gly Arg Ala Arg Met Arg Arg Gly His Arg Leu Asp Ala Ser
100105110
Leu Val Ile Ala Gly Val Arg Leu Glu Asp Glu Gly Arg Tyr Arg Cys
115120125
Glu Leu Ile Asn Gly Ile Glu Asp Glu Ser Val Ala Leu Thr Leu Ser
130 135140
Leu Glu Gly Val Val Phe Pro Tyr Gln Pro Ser Arg Gly Arg Tyr Gln
145150155160
Phe Asn Tyr Tyr Glu Ala Lys Gln Ala Cys Glu Glu Gln Asp Gly Arg
165170175
Leu Ala Thr Tyr Ser Gln Leu Tyr Gln Ala Trp Thr Glu Gly Leu Asp
180185190
Trp Cys Asn Ala Gly Trp Leu Leu Glu Gly Ser Val Arg Tyr Pro Val
195200205
Leu Thr Ala Arg Ala Pro Cys Gly Gly Arg Gly Arg Pro Gly Ile Arg
210215220
Ser Tyr Gly Pro Arg Asp Arg Met Arg Asp Arg Tyr Asp Ala Phe Cys
225230235240
Phe Thr Ser Ala Leu Ala Gly Gln Val Phe Phe Val Pro Gly Arg Leu
245250255
Thr Leu Ser Glu Ala His Ala Ala Cys Arg Arg Arg Gly Ala Val Val
260265270
Ala Lys Val Gly His Leu Tyr Ala Ala Trp Lys Phe Ser Gly Leu Asp
275280285
Gln Cys Asp Gly Gly Trp Leu Ala Asp Gly Ser Val Arg Phe Pro Ile
290295300
Thr Thr Pro Arg Pro Arg Cys Gly Gly Leu Pro Asp Pro Gly Val Arg
305310315320
Ser Phe Gly Phe Pro Arg Pro Gln Gln Ala Ala Tyr Gly Thr Tyr Cys
325330335
Tyr Ala Glu Asn
340
<210> 231
<211> 360
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN3 Hyaluronan and proteoglycan link protein 3
Q96S86
<400> 231
Met Gly Leu Leu Leu Leu Val Pro Leu Leu Leu Leu Pro Gly Ser Tyr
151015
Gly Leu Pro Phe Tyr Asn Gly Phe Tyr Tyr Ser Asn Ser Ala Asn Asp
202530
Gln Asn Leu Gly Asn Gly His Gly Lys Asp Leu Leu Asn Gly Val Lys
354045
Leu Val Val Glu Thr Pro Glu Glu Thr Leu Phe Thr Tyr Gln Gly Ala
505560
Ser Val Ile Leu Pro Cys Arg Tyr Arg Tyr Glu Pro Ala Leu Val Ser
65707580
Pro Arg Arg Val Arg Val Lys Trp Trp Lys Leu Ser Glu Asn Gly Ala
859095
Pro Glu Lys Asp Val Leu Val Ala Ile Gly Leu Arg His Arg Ser Phe
100105110
Gly Asp Tyr Gln Gly Arg Val His Leu Arg Gln Asp Lys Glu His Asp
115120125
Val Ser Leu Glu Ile Gln Asp Leu Arg Leu Glu Asp Tyr Gly Arg Tyr
130135140
Arg Cys Glu Val Ile Asp Gly Leu Glu Asp Glu Ser Gly Leu Val Glu
145150155160
Leu Glu Leu Arg Gly Val Val Phe Pro Tyr Gln Ser Pro Asn Gly Arg
165170175
Tyr Gln Phe Asn Phe His Glu Gly Gln Gln Val Cys Ala Glu Gln Ala
180185190
Ala Val Val Ala Ser Phe Glu Gln Leu Phe Arg Ala Trp Glu Glu Gly
195200205
Leu Asp Trp Cys Asn Ala Gly Trp Leu Gln Asp Ala Thr Val Gln Tyr
210215220
Pro Ile Met Leu Pro Arg Gln Pro Cys Gly Gly Pro Gly Leu Ala Pro
225230235240
Gly Val Arg Ser Tyr Gly Pro Arg His Arg Arg Leu His Arg Tyr Asp
245250255
Val Phe Cys Phe Ala Thr Ala Leu Lys Gly Arg Val Tyr Tyr Leu Glu
260265270
His Pro Glu Lys Leu Thr Leu Thr Glu Ala Arg Glu Ala Cys Gln Glu
275280285
Asp Asp Ala Thr Ile Ala Lys Val Gly Gln Leu Phe Ala Ala Trp Lys
290295300
Phe His Gly Leu Asp Arg Cys Asp Ala Gly Trp Leu Ala Asp Gly Ser
305310315320
Val Arg Tyr Pro Val Val His Pro His Pro Asn Cys Gly Pro Pro Glu
325330335
Pro Gly Val Arg Ser Phe Gly Phe Pro Asp Pro Gln Ser Arg Leu Tyr
340345350
Gly Val Tyr Cys Tyr Arg Gln His
355360
<210> 232
<211> 402
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN4 Hyaluronan and proteoglycan link protein 4
Q86UW8
<400> 232
Met Val Cys Ala Arg Ala Ala Leu Gly Pro Gly Ala Leu Trp Ala Ala
151015
Ala Trp Gly Val Leu Leu Leu Thr Ala Pro Ala Gly Ala Gln Arg Gly
202530
Arg Lys Lys Val Val His Val Leu Glu Gly Glu Ser Gly Ser Val Val
354045
Val Gln Thr Ala Pro Gly Gln Val Val Ser His Arg Gly Gly Thr Ile
505560
Val Leu Pro Cys Arg Tyr His Tyr Glu Ala Ala Ala His Gly His Asp
65707580
Gly Val Arg Leu Lys Trp Thr Lys Val Val Asp Pro Leu Ala Phe Thr
859095
Asp Val Phe Val Ala Leu Gly Pro Gln His Arg Ala Phe Gly Ser Tyr
100105110
Arg Gly Arg Ala Glu Leu Gln Gly Asp Gly Pro Gly Asp Ala Ser Leu
115120125
Val Leu Arg Asn Val Thr Leu Gln Asp Tyr Gly Arg Tyr Glu Cys Glu
130135140
Val Thr Asn Glu Leu Glu Asp Asp Ala Gly Met Val Lys Leu Asp Leu
145150155160
Glu Gly Val Val Phe Pro Tyr His Pro Arg Gly Gly Arg Tyr Lys Leu
165170175
Thr Phe Ala Glu Ala Gln Arg Ala Cys Ala Glu Gln Asp Gly Ile Leu
180185190
Ala Ser Ala Glu Gln Leu His Ala Ala Trp Arg Asp Gly Leu Asp Trp
195200205
Cys Asn Ala Gly Trp Leu Arg Asp Gly Ser Val Gln Tyr Pro Val Asn
210215220
Arg Pro Arg Glu Pro Cys Gly Gly Leu Gly Gly Thr Gly Ser Ala Gly
225230235240
Gly Gly Gly Asp Ala Asn Gly Gly Leu Arg Asn Tyr Gly Tyr Arg His
245250255
Asn Ala Glu Glu Arg Tyr Asp Ala Phe Cys Phe Thr Ser Asn Leu Pro
260265270
Gly Arg Val Phe Phe Leu Lys Pro Leu Arg Pro Val Pro Phe Ser Gly
275280285
Ala Ala Arg Ala Cys Ala Ala Arg Gly Ala Ala Val Ala Lys Val Gly
290295300
Gln Leu Phe Ala Ala Trp Lys Leu Gln Leu Leu Asp Arg Cys Thr Ala
305310315320
Gly Trp Leu Ala Asp Gly Ser Ala Arg Tyr Pro Ile Val Asn Pro Arg
325330335
Ala Arg Cys Gly Gly Arg Arg Pro Gly Val Arg Ser Leu Gly Phe Pro
340345350
Asp Ala Thr Arg Arg Leu Phe Gly Val Tyr Cys Tyr Arg Ala Pro Gly
355360365
Ala Pro Asp Pro Ala Pro Gly Gly Trp Gly Trp Gly Trp Ala Gly Gly
370375380
Gly Gly Trp Ala Gly Gly Ala Arg Asp Pro Ala Ala Trp Thr Pro Leu
385390395400
His Val
<210> 233
<211> 2431
<212> PRT
<213> Homo sapiens
<220>
<223> human Aggrecan protein P16112
<400> 233
Met Thr Thr Leu Leu Trp Val Phe Val Thr Leu Arg Val Ile Thr Ala
151015
Ala Val Thr Val Glu Thr Ser Asp His Asp Asn Ser Leu Ser Val Ser
202530
Ile Pro Gln Pro Ser Pro Leu Arg Val Leu Leu Gly Thr Ser Leu Thr
354045
Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val Thr Thr Ala Pro
505560
Ser Thr Ala Pro Leu Ala Pro Arg Ile Lys Trp Ser Arg Val Ser Lys
65707580
Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly Arg Val Arg Val
859095
Asn Ser Ala Tyr Gln Asp Lys Val Ser Leu Pro Asn Tyr Pro Ala Ile
100105110
Pro Ser Asp Ala Thr Leu Glu Val Gln Ser Leu Arg Ser Asn Asp Ser
115120125
Gly Val Tyr Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Glu Ala
130135140
Thr Leu Glu Val Val Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile
145150155160
Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
165170175
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
180185190
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
195200205
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
210215220
Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu
225230235240
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe
245250255
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu
260265270
Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu
275280285
Ala Trp Gln Ala Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
290295300
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
305310315320
Asn Leu Leu Gly Val Arg Thr Val Tyr Val His Ala Asn Gln Thr Gly
325330335
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
340345350
Asp Phe Val Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Glu
355360365
Asp Ile Thr Val Gln Thr Val Thr Trp Pro Asp Met Glu Leu Pro Leu
370375380
Pro Arg Asn Ile Thr Glu Gly Glu Ala Arg Gly Ser Val Ile Leu Thr
385390395400
Val Lys Pro Ile Phe Glu Val Ser Pro Ser Pro Leu Glu Pro Glu Glu
405410415
Pro Phe Thr Phe Ala Pro Glu Ile Gly Ala Thr Ala Phe Ala Glu Val
420425430
Glu Asn Glu Thr Gly Glu Ala Thr Arg Pro Trp Gly Phe Pro Thr Pro
435440445
Gly Leu Gly Pro Ala Thr Ala Phe Thr Ser Glu Asp Leu Val Val Gln
450455460
Val Thr Ala Val Pro Gly Gln Pro His Leu Pro Gly Gly Val Val Phe
465470475480
His Tyr Arg Pro Gly Pro Thr Arg Tyr Ser Leu Thr Phe Glu Glu Ala
485490495
Gln Gln Ala Cys Leu Arg Thr Gly Ala Val Ile Ala Ser Pro Glu Gln
500505510
Leu Gln Ala Ala Tyr Glu Ala Gly Tyr Glu Gln Cys Asp Ala Gly Trp
515520525
Leu Arg Asp Gln Thr Val Arg Tyr Pro Ile Val Ser Pro Arg Thr Pro
530535540
Cys Val Gly Asp Lys Asp Ser Ser Pro Gly Val Arg Thr Tyr Gly Val
545550555560
Arg Pro Ser Thr Glu Thr Tyr Asp Val Tyr Cys Phe Val Asp Arg Leu
565570575
Glu Gly Glu Val Phe Phe Ala Thr Arg Leu Glu Gln Phe Thr Phe Gln
580585590
Glu Ala Leu Glu Phe Cys Glu Ser His Asn Ala Thr Leu Ala Thr Thr
595600605
Gly Gln Leu Tyr Ala Ala Trp Ser Arg Gly Leu Asp Lys Cys Tyr Ala
610615620
Gly Trp Leu Ala Asp Gly Ser Leu Arg Tyr Pro Ile Val Thr Pro Arg
625630635640
Pro Ala Cys Gly Gly Asp Lys Pro Gly Val Arg Thr Val Tyr Leu Tyr
645650655
Pro Asn Gln Thr Gly Leu Pro Asp Pro Leu Ser Arg His His Ala Phe
660665670
Cys Phe Arg Gly Ile Ser Ala Val Pro Ser Pro Gly Glu Glu Glu Gly
675680685
Gly Thr Pro Thr Ser Pro Ser Gly Val Glu Glu Trp Ile Val Thr Gln
690695700
Val Val Pro Gly Val Ala Ala Val Pro Val Glu Glu Glu Thr Thr Ala
705710715720
Val Pro Ser Gly Glu Thr Thr Ala Ile Leu Glu Phe Thr Thr Glu Pro
725730735
Glu Asn Gln Thr Glu Trp Glu Pro Ala Tyr Thr Pro Val Gly Thr Ser
740745750
Pro Leu Pro Gly Ile Leu Pro Thr Trp Pro Pro Thr Gly Ala Ala Thr
755760765
Glu Glu Ser Thr Glu Gly Pro Ser Ala Thr Glu Val Pro Ser Ala Ser
770775780
Glu Glu Pro Ser Pro Ser Glu Val Pro Phe Pro Ser Glu Glu Pro Ser
785790795800
Pro Ser Glu Glu Pro Phe Pro Ser Val Arg Pro Phe Pro Ser Val Glu
805810815
Leu Phe Pro Ser Glu Glu Pro Phe Pro Ser Lys Glu Pro Ser Pro Ser
820825830
Glu Glu Pro Ser Ala Ser Glu Glu Pro Tyr Thr Pro Ser Pro Pro Val
835840845
Pro Ser Trp Thr Glu Leu Pro Ser Ser Gly Glu Glu Ser Gly Ala Pro
850855860
Asp Val Ser Gly Asp Phe Thr Gly Ser Gly Asp Val Ser Gly His Leu
865870875880
Asp Phe Ser Gly Gln Leu Ser Gly Asp Arg Ala Ser Gly Leu Pro Ser
885890895
Gly Asp Leu Asp Ser Ser Gly Leu Thr Ser Thr Val Gly Ser Gly Leu
900905910
Pro Val Glu Ser Gly Leu Pro Ser Gly Asp Glu Glu Arg Ile Glu Trp
915920925
Pro Ser Thr Pro Thr Val Gly Glu Leu Pro Ser Gly Ala Glu Ile Leu
930935940
Glu Gly Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu Pro Ser Gly
945950955960
Glu Val Leu Glu Thr Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu
965970975
Pro Ser Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val Glu Asp Ile
980985990
Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val
99510001005
Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala
101010151020
Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu
1025103010351040
Thr Thr Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu
104510501055
Val Leu Glu Thr Thr Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro
106010651070
Ser Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val Glu Asp Ile Ser
107510801085
Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu
109010951100
Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro
1105 111011151120
Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr
112511301135
Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val
114011451150
Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser
115511601165
Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly
117011751180
Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp
1185119011951200
Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly
120512101215
Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala
122012251230
Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu
123512401245
Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly
125012551260
Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu
1265127012751280
Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile
128512901295
Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val
130013051310
Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Ala Ala
131513201325
Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu
133013351340
Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Glu
1345135013551360
Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser Gly Leu Pro
136513701375
Ser Gly Glu Val Leu Glu Thr Ala Ala Pro Gly Val Glu Asp Ile Ser
138013851390
Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala Pro Gly Val Glu
139514001405
Glu Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr Thr Ala Pro
141014151420
Gly Val Asp Glu Ile Ser Gly Leu Pro Ser Gly Glu Val Leu Glu Thr
1425143014351440
Thr Ala Pro Gly Val Glu Glu Ile Ser Gly Leu Pro Ser Gly Glu Val
144514501455
Leu Glu Thr Ser Thr Ser Ala Val Gly Asp Leu Ser Gly Leu Pro Ser
146014651470
Gly Gly Glu Val Leu Glu Ile Ser Val Ser Gly Val Glu Asp Ile Ser
147514801485
Gly Leu Pro Ser Gly Glu Val Val Glu Thr Ser Ala Ser Gly Ile Glu
149014951500
Asp Val Ser Glu Leu Pro Ser Gly Glu Gly Leu Glu Thr Ser Ala Ser
1505151015151520
Gly Val Glu Asp Leu Ser Arg Leu Pro Ser Gly Glu Glu Val Leu Glu
152515301535
Ile Ser Ala Ser Gly Phe Gly Asp Leu Ser Gly Leu Pro Ser Gly Gly
154015451550
Glu Gly Leu Glu Thr Ser Ala Ser Glu Val Gly Thr Asp Leu Ser Gly
155515601565
Leu Pro Ser Gly Arg Glu Gly Leu Glu Thr Ser Ala Ser Gly Ala Glu
157015751580
Asp Leu Ser Gly Leu Pro Ser Gly Lys Glu Asp Leu Val Gly Ser Ala
1585159015951600
Ser Gly Asp Leu Asp Leu Gly Lys Leu Pro Ser Gly Thr Leu Gly Ser
160516101615
Gly Gln Ala Pro Glu Thr Ser Gly Leu Pro Ser Gly Phe Ser Gly Glu
162016251630
Tyr Ser Gly Val Asp Leu Gly Ser Gly Pro Pro Ser Gly Leu Pro Asp
163516401645
Phe Ser Gly Leu Pro Ser Gly Phe Pro Thr Val Ser Leu Val Asp Ser
165016551660
Thr Leu Val Glu Val Val Thr Ala Ser Thr Ala Ser Glu Leu Glu Gly
1665167016751680
Arg Gly Thr Ile Gly Ile Ser Gly Ala Gly Glu Ile Ser Gly Leu Pro
168516901695
Ser Ser Glu Leu Asp Ile Ser Gly Arg Ala Ser Gly Leu Pro Ser Gly
170017051710
Thr Glu Leu Ser Gly Gln Ala Ser Gly Ser Pro Asp Val Ser Gly Glu
171517201725
Ile Pro Gly Leu Phe Gly Val Ser Gly Gln Pro Ser Gly Phe Pro Asp
173017351740
Thr Ser Gly Glu Thr Ser Gly Val Thr Glu Leu Ser Gly Leu Ser Ser
1745175017551760
Gly Gln Pro Gly Ile Ser Gly Glu Ala Ser Gly Val Leu Tyr Gly Thr
176517701775
Ser Gln Pro Phe Gly Ile Thr Asp Leu Ser Gly Glu Thr Ser Gly Val
178017851790
Pro Asp Leu Ser Gly Gln Pro Ser Gly Leu Pro Gly Phe Ser Gly Ala
179518001805
Thr Ser Gly Val Pro Asp Leu Val Ser Gly Thr Thr Ser Gly Ser Gly
181018151820
Glu Ser Ser Gly Ile Thr Phe Val Asp Thr Ser Leu Val Glu Val Ala
1825183018351840
Pro Thr Thr Phe Lys Glu Glu Glu Gly Leu Gly Ser Val Glu Leu Ser
184518501855
Gly Leu Pro Ser Gly Glu Ala Asp Leu Ser Gly Lys Ser Gly Met Val
186018651870
Asp Val Ser Gly Gln Phe Ser Gly Thr Val Asp Ser Ser Gly Phe Thr
187518801885
Ser Gln Thr Pro Glu Phe Ser Gly Leu Pro Ser Gly Ile Ala Glu Val
189018951900
Ser Gly Glu Ser Ser Arg Ala Glu Ile Gly Ser Ser Leu Pro Ser Gly
1905191019151920
Ala Tyr Tyr Gly Ser Gly Thr Pro Ser Ser Phe Pro Thr Val Ser Leu
192519301935
Val Asp Arg Thr Leu Val Glu Ser Val Thr Gln Ala Pro Thr Ala Gln
194019451950
Glu Ala Gly Glu Gly Pro Ser Gly Ile Leu Glu Leu Ser Gly Ala His
195519601965
Ser Gly Ala Pro Asp Met Ser Gly Glu His Ser Gly Phe Leu Asp Leu
197019751980
Ser Gly Leu Gln Ser Gly Leu Ile Glu Pro Ser Gly Glu Pro Pro Gly
1985199019952000
Thr Pro Tyr Phe Ser Gly Asp Phe Ala Ser Thr Thr Asn Val Ser Gly
200520102015
Glu Ser Ser Val Ala Met Gly Thr Ser Gly Glu Ala Ser Gly Leu Pro
202020252030
Glu Val Thr Leu Ile Thr Ser Glu Phe Val Glu Gly Val Thr Glu Pro
203520402045
Thr Ile Ser Gln Glu Leu Gly Gln Arg Pro Pro Val Thr His Thr Pro
205020552060
Gln Leu Phe Glu Ser Ser Gly Lys Val Ser Thr Ala Gly Asp Ile Ser
2065207020752080
Gly Ala Thr Pro Val Leu Pro Gly Ser Gly Val Glu Val Ser Ser Val
208520902095
Pro Glu Ser Ser Ser Glu Thr Ser Ala Tyr Pro Glu Ala Gly Phe Gly
210021052110
Ala Ser Ala Ala Pro Glu Ala Ser Arg Glu Asp Ser Gly Ser Pro Asp
211521202125
Leu Ser Glu Thr Thr Ser Ala Phe His Glu Ala Asn Leu Glu Arg Ser
213021352140
Ser Gly Leu Gly Val Ser Gly Ser Thr Leu Thr Phe Gln Glu Gly Glu
2145215021552160
Ala Ser Ala Ala Pro Glu Val Ser Gly Glu Ser Thr Thr Thr Ser Asp
216521702175
Val Gly Thr Glu Ala Pro Gly Leu Pro Ser Ala Thr Pro Thr Ala Ser
218021852190
Gly Asp Arg Thr Glu Ile Ser Gly Asp Leu Ser Gly His Thr Ser Gln
219522002205
Leu Gly Val Val Ile Ser Thr Ser Ile Pro Glu Ser Glu Trp Thr Gln
221022152220
Gln Thr Gln Arg Pro Ala Glu Thr His Leu Glu Ile Glu Ser Ser Ser
2225223022352240
Leu Leu Tyr Ser Gly Glu Glu Thr His Thr Val Glu Thr Ala Thr Ser
224522502255
Pro Thr Asp Ala Ser Ile Pro Ala Ser Pro Glu Trp Lys Arg Glu Ser
226022652270
Glu Ser Thr Ala Ala Asp Gln Glu Val Cys Glu Glu Gly Trp Asn Lys
227522802285
Tyr Gln Gly His Cys Tyr Arg His Phe Pro Asp Arg Glu Thr Trp Val
229022952300
Asp Ala Glu Arg Arg Cys Arg Glu Gln Gln Ser His Leu Ser Ser Ile
2305231023152320
Val Thr Pro Glu Glu Gln Glu Phe Val Asn Asn Asn Ala Gln Asp Tyr
232523302335
Gln Trp Ile Gly Leu Asn Asp Arg Thr Ile Glu Gly Asp Phe Arg Trp
234023452350
Ser Asp Gly His Pro Met Gln Phe Glu Asn Trp Arg Pro Asn Gln Pro
235523602365
Asp Asn Phe Phe Ala Ala Gly Glu Asp Cys Val Val Met Ile Trp His
237023752380
Glu Lys Gly Glu Trp Asn Asp Val Pro Cys Asn Tyr His Leu Pro Phe
2385239023952400
Thr Cys Lys Lys Gly Thr Ala Thr Thr Tyr Lys Arg Arg Leu Gln Lys
240524102415
Arg Ser Ser Arg His Pro Arg Arg Ser Arg Pro Ser Thr Ala His
242024252430
<210> 234
<211> 911
<212> PRT
<213> Homo sapiens
<220>
<223> human Brevican protein Q96GW7
<400> 234
Met Ala Gln Leu Phe Leu Pro Leu Leu Ala Ala Leu Val Leu Ala Gln
151015
Ala Pro Ala Ala Leu Ala Asp Val Leu Glu Gly Asp Ser Ser Glu Asp
202530
Arg Ala Phe Arg Val Arg Ile Ala Gly Asp Ala Pro Leu Gln Gly Val
354045
Leu Gly Gly Ala Leu Thr Ile Pro Cys His Val His Tyr Leu Arg Pro
505560
Pro Pro Ser Arg Arg Ala Val Leu Gly Ser Pro Arg Val Lys Trp Thr
65707580
Phe Leu Ser Arg Gly Arg Glu Ala Glu Val Leu Val Ala Arg Gly Val
859095
Arg Val Lys Val Asn Glu Ala Tyr Arg Phe Arg Val Ala Leu Pro Ala
100105110
Tyr Pro Ala Ser Leu Thr Asp Val Ser Leu Ala Leu Ser Glu Leu Arg
115120125
Pro Asn Asp Ser Gly Ile Tyr Arg Cys Glu Val Gln His Gly Ile Asp
130135140
Asp Ser Ser Asp Ala Val Glu Val Lys Val Lys Gly Val Val Phe Leu
145150155160
Tyr Arg Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe Ser Gly Ala Gln
165170175
Glu Ala Cys Ala Arg Ile Gly Ala His Ile Ala Thr Pro Glu Gln Leu
180185190
Tyr Ala Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu
195200205
Ser Asp Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro Arg Glu Ala Cys
210215220
Tyr Gly Asp Met Asp Gly Phe Pro Gly Val Arg Asn Tyr Gly Val Val
225230235240
Asp Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Asp Leu Asn
245250255
Gly Glu Leu Phe Leu Gly Asp Pro Pro Glu Lys Leu Thr Leu Glu Glu
260265270
Ala Arg Ala Tyr Cys Gln Glu Arg Gly Ala Glu Ile Ala Thr Thr Gly
275280285
Gln Leu Tyr Ala Ala Trp Asp Gly Gly Leu Asp His Cys Ser Pro Gly
290295300
Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Val Thr Pro Ser Gln
305310315320
Arg Cys Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro
325330335
Asn Gln Thr Gly Phe Pro Asn Lys His Ser Arg Phe Asn Val Tyr Cys
340345350
Phe Arg Asp Ser Ala Gln Pro Ser Ala Ile Pro Glu Ala Ser Asn Pro
355360365
Ala Ser Asn Pro Ala Ser Asp Gly Leu Glu Ala Ile Val Thr Val Thr
370375380
Glu Thr Leu Glu Glu Leu Gln Leu Pro Gln Glu Ala Thr Glu Ser Glu
385390395400
Ser Arg Gly Ala Ile Tyr Ser Ile Pro Ile Met Glu Asp Gly Gly Gly
405410415
Gly Ser Ser Thr Pro Glu Asp Pro Ala Glu Ala Pro Arg Thr Leu Leu
420425430
Glu Phe Glu Thr Gln Ser Met Val Pro Pro Thr Gly Phe Ser Glu Glu
435440445
Glu Gly Lys Ala Leu Glu Glu Glu Glu Lys Tyr Glu Asp Glu Glu Glu
450455460
Lys Glu Glu Glu Glu Glu Glu Glu Glu Val Glu Asp Glu Ala Leu Trp
465470475 480
Ala Trp Pro Ser Glu Leu Ser Ser Pro Gly Pro Glu Ala Ser Leu Pro
485490495
Thr Glu Pro Ala Ala Gln Glu Glu Ser Leu Ser Gln Ala Pro Ala Arg
500505510
Ala Val Leu Gln Pro Gly Ala Ser Pro Leu Pro Asp Gly Glu Ser Glu
515520525
Ala Ser Arg Pro Pro Arg Val His Gly Pro Pro Thr Glu Thr Leu Pro
530535540
Thr Pro Arg Glu Arg Asn Leu Ala Ser Pro Ser Pro Ser Thr Leu Val
545550555560
Glu Ala Arg Glu Val Gly Glu Ala Thr Gly Gly Pro Glu Leu Ser Gly
565570575
Val Pro Arg Gly Glu Ser Glu Glu Thr Gly Ser Ser Glu Gly Ala Pro
580585590
Ser Leu Leu Pro Ala Thr Arg Ala Pro Glu Gly Thr Arg Glu Leu Glu
595600605
Ala Pro Ser Glu Asp Asn Ser Gly Arg Thr Ala Pro Ala Gly Thr Ser
610615620
Val Gln Ala Gln Pro Val Leu Pro Thr Asp Ser Ala Ser Arg Gly Gly
625630635640
Val Ala Val Val Pro Ala Ser Gly Asp Cys Val Pro Ser Pro Cys His
645650655
Asn Gly Gly Thr Cys Leu Glu Glu Glu Glu Gly Val Arg Cys Leu Cys
660665670
Leu Pro Gly Tyr Gly Gly Asp Leu Cys Asp Val Gly Leu Arg Phe Cys
675680685
Asn Pro Gly Trp Asp Ala Phe Gln Gly Ala Cys Tyr Lys His Phe Ser
690695700
Thr Arg Arg Ser Trp Glu Glu Ala Glu Thr Gln Cys Arg Met Tyr Gly
705710715720
Ala His Leu Ala Ser Ile Ser Thr Pro Glu Glu Gln Asp Phe Ile Asn
725730735
Asn Arg Tyr Arg Glu Tyr Gln Trp Ile Gly Leu Asn Asp Arg Thr Ile
740745750
Glu Gly Asp Phe Leu Trp Ser Asp Gly Val Pro Leu Leu Tyr Glu Asn
755760765
Trp Asn Pro Gly Gln Pro Asp Ser Tyr Phe Leu Ser Gly Glu Asn Cys
770775780
Val Val Met Val Trp His Asp Gln Gly Gln Trp Ser Asp Val Pro Cys
785790 795800
Asn Tyr His Leu Ser Tyr Thr Cys Lys Met Gly Leu Val Ser Cys Gly
805810815
Pro Pro Pro Glu Leu Pro Leu Ala Gln Val Phe Gly Arg Pro Arg Leu
820825830
Arg Tyr Glu Val Asp Thr Val Leu Arg Tyr Arg Cys Arg Glu Gly Leu
835840845
Ala Gln Arg Asn Leu Pro Leu Ile Arg Cys Gln Glu Asn Gly Arg Trp
850855860
Glu Ala Pro Gln Ile Ser Cys Val Pro Arg Arg Pro Ala Arg Ala Leu
865870875880
His Pro Glu Glu Asp Pro Glu Gly Arg Gln Gly Arg Leu Leu Gly Arg
885890895
Trp Lys Ala Leu Leu Ile Pro Pro Ser Ser Pro Met Pro Gly Pro
900905910
<210> 235
<211> 2376
<212> PRT
<213> Homo sapiens
<220>
<223> human Versican protein P13611
<400> 235
Met Phe Ile Asn Ile Lys Ser Ile Leu Trp Met Cys Ser Thr Leu Ile
151015
Val Thr His Ala Leu His Lys Val Lys Val Gly Lys Ser Pro Pro Val
202530
Arg Gly Ser Leu Ser Gly Lys Val Ser Leu Pro Cys His Phe Ser Thr
354045
Met Pro Thr Leu Pro Pro Ser Tyr Asn Thr Ser Glu Phe Leu Arg Ile
505560
Lys Trp Ser Lys Ile Glu Val Asp Lys Asn Gly Lys Asp Leu Lys Glu
65707580
Thr Thr Val Leu Val Ala Gln Asn Gly Asn Ile Lys Ile Gly Gln Asp
859095
Tyr Lys Gly Arg Val Ser Val Pro Thr His Pro Glu Ala Val Gly Asp
100105110
Ala Ser Leu Thr Val Val Lys Leu Leu Ala Ser Asp Ala Gly Leu Tyr
115120125
Arg Cys Asp Val Met Tyr Gly Ile Glu Asp Thr Gln Asp Thr Val Ser
130135140
Leu Thr Val Asp Gly Val Val Phe His Tyr Arg Ala Ala Thr Ser Arg
145150155160
Tyr Thr Leu Asn Phe Glu Ala Ala Gln Lys Ala Cys Leu Asp Val Gly
165170175
Ala Val Ile Ala Thr Pro Glu Gln Leu Phe Ala Ala Tyr Glu Asp Gly
180185190
Phe Glu Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr Val Arg Tyr
195200205
Pro Ile Arg Ala Pro Arg Val Gly Cys Tyr Gly Asp Lys Met Gly Lys
210215220
Ala Gly Val Arg Thr Tyr Gly Phe Arg Ser Pro Gln Glu Thr Tyr Asp
225230235240
Val Tyr Cys Tyr Val Asp His Leu Asp Gly Asp Val Phe His Leu Thr
245250255
Val Pro Ser Lys Phe Thr Phe Glu Glu Ala Ala Lys Glu Cys Glu Asn
260265270
Gln Asp Ala Arg Leu Ala Thr Val Gly Glu Leu Gln Ala Ala Trp Arg
275280285
Asn Gly Phe Asp Gln Cys Asp Tyr Gly Trp Leu Ser Asp Ala Ser Val
290295300
Arg His Pro Val Thr Val Ala Arg Ala Gln Cys Gly Gly Gly Leu Leu
305310315320
Gly Val Arg Thr Leu Tyr Arg Phe Glu Asn Gln Thr Gly Phe Pro Pro
325330335
Pro Asp Ser Arg Phe Asp Ala Tyr Cys Phe Lys Pro Lys Glu Ala Thr
340345350
Thr Ile Asp Leu Ser Ile Leu Ala Ile Asp Leu Tyr His Ser Glu Glu
355360365
Asn Glu Glu Glu Glu Glu Glu Cys Ala Asn Ala Thr Asp Val Thr Thr
370 375380
Thr Pro Ser Val Gln Tyr Ile Asn Gly Lys His Leu Val Thr Thr Val
385390395400
Pro Lys Asp Pro Glu Ala Ala Glu Ala Arg Arg Gly Gln Phe Glu Ser
405410415
Val Ala Pro Ser Gln Asn Phe Ser Asp Ser Ser Glu Ser Asp Thr His
420425430
Pro Phe Val Ile Ala Lys Thr Glu Leu Ser Thr Ala Val Gln Pro Asn
435440445
Glu Ser Thr Glu Thr Thr Glu Ser Leu Glu Val Thr Trp Lys Pro Glu
450455460
Thr Tyr Pro Glu Thr Ser Glu His Phe Ser Gly Gly Glu Pro Asp Val
465470475480
Phe Pro Thr Val Pro Phe His Glu Glu Phe Glu Ser Gly Thr Ala Lys
485490495
Lys Gly Ala Glu Ser Val Thr Glu Arg Asp Thr Glu Val Gly His Gln
500505510
Ala His Glu His Thr Glu Pro Val Ser Leu Phe Pro Glu Glu Ser Ser
515520525
Gly Glu Ile Ala Ile Asp Gln Glu Ser Gln Lys Ile Ala Phe Ala Arg
530535540
Ala Thr Glu Val Thr Phe Gly Glu Glu Val Glu Lys Ser Thr Ser Val
545550555560
Thr Tyr Thr Pro Thr Ile Val Pro Ser Ser Ala Ser Ala Tyr Val Ser
565570575
Glu Glu Glu Ala Val Thr Leu Ile Gly Asn Pro Trp Pro Asp Asp Leu
580585590
Leu Ser Thr Lys Glu Ser Trp Val Glu Ala Thr Pro Arg Gln Val Val
595600605
Glu Leu Ser Gly Ser Ser Ser Ile Pro Ile Thr Glu Gly Ser Gly Glu
610615620
Ala Glu Glu Asp Glu Asp Thr Met Phe Thr Met Val Thr Asp Leu Ser
625630635640
Gln Arg Asn Thr Thr Asp Thr Leu Ile Thr Leu Asp Thr Ser Arg Ile
645650655
Ile Thr Glu Ser Phe Phe Glu Val Pro Ala Thr Thr Ile Tyr Pro Val
660665670
Ser Glu Gln Pro Ser Ala Lys Val Val Pro Thr Lys Phe Val Ser Glu
675680685
Thr Asp Thr Ser Glu Trp Ile Ser Ser Thr Thr Val Glu Glu Lys Lys
690695700
Arg Lys Glu Glu Glu Gly Thr Thr Gly Thr Ala Ser Thr Phe Glu Val
705710715720
Tyr Ser Ser Thr Gln Arg Ser Asp Gln Leu Ile Leu Pro Phe Glu Leu
725730735
Glu Ser Pro Asn Val Ala Thr Ser Ser Asp Ser Gly Thr Arg Lys Ser
740745750
Phe Met Ser Leu Thr Thr Pro Thr Gln Ser Glu Arg Glu Met Thr Asp
755760765
Ser Thr Pro Val Phe Thr Glu Thr Asn Thr Leu Glu Asn Leu Gly Ala
770775780
Gln Thr Thr Glu His Ser Ser Ile His Gln Pro Gly Val Gln Glu Gly
785790795800
Leu Thr Thr Leu Pro Arg Ser Pro Ala Ser Val Phe Met Glu Gln Gly
805810815
Ser Gly Glu Ala Ala Ala Asp Pro Glu Thr Thr Thr Val Ser Ser Phe
820825830
Ser Leu Asn Val Glu Tyr Ala Ile Gln Ala Glu Lys Glu Val Ala Gly
835840845
Thr Leu Ser Pro His Val Glu Thr Thr Phe Ser Thr Glu Pro Thr Gly
850855860
Leu Val Leu Ser Thr Val Met Asp Arg Val Val Ala Glu Asn Ile Thr
865870875880
Gln Thr Ser Arg Glu Ile Val Ile Ser Glu Arg Leu Gly Glu Pro Asn
885890895
Tyr Gly Ala Glu Ile Arg Gly Phe Ser Thr Gly Phe Pro Leu Glu Glu
900905910
Asp Phe Ser Gly Asp Phe Arg Glu Tyr Ser Thr Val Ser His Pro Ile
915920925
Ala Lys Glu Glu Thr Val Met Met Glu Gly Ser Gly Asp Ala Ala Phe
930935940
Arg Asp Thr Gln Thr Ser Pro Ser Thr Val Pro Thr Ser Val His Ile
945950955960
Ser His Ile Ser Asp Ser Glu Gly Pro Ser Ser Thr Met Val Ser Thr
965970975
Ser Ala Phe Pro Trp Glu Glu Phe Thr Ser Ser Ala Glu Gly Ser Gly
980985990
Glu Gln Leu Val Thr Val Ser Ser Ser Val Val Pro Val Leu Pro Ser
99510001005
Ala Val Gln Lys Phe Ser Gly Thr Ala Ser Ser Ile Ile Asp Glu Gly
101010151020
Leu Gly Glu Val Gly Thr Val Asn Glu Ile Asp Arg Arg Ser Thr Ile
1025103010351040
Leu Pro Thr Ala Glu Val Glu Gly Thr Lys Ala Pro Val Glu Lys Glu
104510501055
Glu Val Lys Val Ser Gly Thr Val Ser Thr Asn Phe Pro Gln Thr Ile
106010651070
Glu Pro Ala Lys Leu Trp Ser Arg Gln Glu Val Asn Pro Val Arg Gln
107510801085
Glu Ile Glu Ser Glu Thr Thr Ser Glu Glu Gln Ile Gln Glu Glu Lys
109010951100
Ser Phe Glu Ser Pro Gln Asn Ser Pro Ala Thr Glu Gln Thr Ile Phe
1105111011151120
Asp Ser Gln Thr Phe Thr Glu Thr Glu Leu Lys Thr Thr Asp Tyr Ser
112511301135
Val Leu Thr Thr Lys Lys Thr Tyr Ser Asp Asp Lys Glu Met Lys Glu
114011451150
Glu Asp Thr Ser Leu Val Asn Met Ser Thr Pro Asp Pro Asp Ala Asn
115511601165
Gly Leu Glu Ser Tyr Thr Thr Leu Pro Glu Ala Thr Glu Lys Ser His
117011751180
Phe Phe Leu Ala Thr Ala Leu Val Thr Glu Ser Ile Pro Ala Glu His
1185119011951200
Val Val Thr Asp Ser Pro Ile Lys Lys Glu Glu Ser Thr Lys His Phe
120512101215
Pro Lys Gly Met Arg Pro Thr Ile Gln Glu Ser Asp Thr Glu Leu Leu
122012251230
Phe Ser Gly Leu Gly Ser Gly Glu Glu Val Leu Pro Thr Leu Pro Thr
123512401245
Glu Ser Val Asn Phe Thr Glu Val Glu Gln Ile Asn Asn Thr Leu Tyr
125012551260
Pro His Thr Ser Gln Val Glu Ser Thr Ser Ser Asp Lys Ile Glu Asp
1265127012751280
Phe Asn Arg Met Glu Asn Val Ala Lys Glu Val Gly Pro Leu Val Ser
128512901295
Gln Thr Asp Ile Phe Glu Gly Ser Gly Ser Val Thr Ser Thr Thr Leu
130013051310
Ile Glu Ile Leu Ser Asp Thr Gly Ala Glu Gly Pro Thr Val Ala Pro
131513201325
Leu Pro Phe Ser Thr Asp Ile Gly His Pro Gln Asn Gln Thr Val Arg
133013351340
Trp Ala Glu Glu Ile Gln Thr Ser Arg Pro Gln Thr Ile Thr Glu Gln
1345135013551360
Asp Ser Asn Lys Asn Ser Ser Thr Ala Glu Ile Asn Glu Thr Thr Thr
136513701375
Ser Ser Thr Asp Phe Leu Ala Arg Ala Tyr Gly Phe Glu Met Ala Lys
138013851390
Glu Phe Val Thr Ser Ala Pro Lys Pro Ser Asp Leu Tyr Tyr Glu Pro
139514001405
Ser Gly Glu Gly Ser Gly Glu Val Asp Ile Val Asp Ser Phe His Thr
141014151420
Ser Ala Thr Thr Gln Ala Thr Arg Gln Glu Ser Ser Thr Thr Phe Val
1425143014351440
Ser Asp Gly Ser Leu Glu Lys His Pro Glu Val Pro Ser Ala Lys Ala
144514501455
Val Thr Ala Asp Gly Phe Pro Thr Val Ser Val Met Leu Pro Leu His
146014651470
Ser Glu Gln Asn Lys Ser Ser Pro Asp Pro Thr Ser Thr Leu Ser Asn
147514801485
Thr Val Ser Tyr Glu Arg Ser Thr Asp Gly Ser Phe Gln Asp Arg Phe
149014951500
Arg Glu Phe Glu Asp Ser Thr Leu Lys Pro Asn Arg Lys Lys Pro Thr
1505151015151520
Glu Asn Ile Ile Ile Asp Leu Asp Lys Glu Asp Lys Asp Leu Ile Leu
152515301535
Thr Ile Thr Glu Ser Thr Ile Leu Glu Ile Leu Pro Glu Leu Thr Ser
154015451550
Asp Lys Asn Thr Ile Ile Asp Ile Asp His Thr Lys Pro Val Tyr Glu
155515601565
Asp Ile Leu Gly Met Gln Thr Asp Ile Asp Thr Glu Val Pro Ser Glu
157015751580
Pro His Asp Ser Asn Asp Glu Ser Asn Asp Asp Ser Thr Gln Val Gln
1585159015951600
Glu Ile Tyr Glu Ala Ala Val Asn Leu Ser Leu Thr Glu Glu Thr Phe
160516101615
Glu Gly Ser Ala Asp Val Leu Ala Ser Tyr Thr Gln Ala Thr His Asp
162016251630
Glu Ser Met Thr Tyr Glu Asp Arg Ser Gln Leu Asp His Met Gly Phe
163516401645
His Phe Thr Thr Gly Ile Pro Ala Pro Ser Thr Glu Thr Glu Leu Asp
165016551660
Val Leu Leu Pro Thr Ala Thr Ser Leu Pro Ile Pro Arg Lys Ser Ala
1665167016751680
Thr Val Ile Pro Glu Ile Glu Gly Ile Lys Ala Glu Ala Lys Ala Leu
168516901695
Asp Asp Met Phe Glu Ser Ser Thr Leu Ser Asp Gly Gln Ala Ile Ala
170017051710
Asp Gln Ser Glu Ile Ile Pro Thr Leu Gly Gln Phe Glu Arg Thr Gln
171517201725
Glu Glu Tyr Glu Asp Lys Lys His Ala Gly Pro Ser Phe Gln Pro Glu
173017351740
Phe Ser Ser Gly Ala Glu Glu Ala Leu Val Asp His Thr Pro Tyr Leu
1745175017551760
Ser Ile Ala Thr Thr His Leu Met Asp Gln Ser Val Thr Glu Val Pro
176517701775
Asp Val Met Glu Gly Ser Asn Pro Pro Tyr Tyr Thr Asp Thr Thr Leu
178017851790
Ala Val Ser Thr Phe Ala Lys Leu Ser Ser Gln Thr Pro Ser Ser Pro
179518001805
Leu Thr Ile Tyr Ser Gly Ser Glu Ala Ser Gly His Thr Glu Ile Pro
181018151820
Gln Pro Ser Ala Leu Pro Gly Ile Asp Val Gly Ser Ser Val Met Ser
182518301835 1840
Pro Gln Asp Ser Phe Lys Glu Ile His Val Asn Ile Glu Ala Thr Phe
184518501855
Lys Pro Ser Ser Glu Glu Tyr Leu His Ile Thr Glu Pro Pro Ser Leu
186018651870
Ser Pro Asp Thr Lys Leu Glu Pro Ser Glu Asp Asp Gly Lys Pro Glu
187518801885
Leu Leu Glu Glu Met Glu Ala Ser Pro Thr Glu Leu Ile Ala Val Glu
189018951900
Gly Thr Glu Ile Leu Gln Asp Phe Gln Asn Lys Thr Asp Gly Gln Val
1905191019151920
Ser Gly Glu Ala Ile Lys Met Phe Pro Thr Ile Lys Thr Pro Glu Ala
192519301935
Gly Thr Val Ile Thr Thr Ala Asp Glu Ile Glu Leu Glu Gly Ala Thr
194019451950
Gln Trp Pro His Ser Thr Ser Ala Ser Ala Thr Tyr Gly Val Glu Ala
195519601965
Gly Val Val Pro Trp Leu Ser Pro Gln Thr Ser Glu Arg Pro Thr Leu
197019751980
Ser Ser Ser Pro Glu Ile Asn Pro Glu Thr Gln Ala Ala Leu Ile Arg
1985199019952000
Gly Gln Asp Ser Thr Ile Ala Ala Ser Glu Gln Gln Val Ala Ala Arg
200520102015
Ile Leu Asp Ser Asn Asp Gln Ala Thr Val Asn Pro Val Glu Phe Asn
202020252030
Thr Glu Val Ala Thr Pro Pro Phe Ser Leu Leu Glu Thr Ser Asn Glu
203520402045
Thr Asp Phe Leu Ile Gly Ile Asn Glu Glu Ser Val Glu Gly Thr Ala
205020552060
Ile Tyr Leu Pro Gly Pro Asp Arg Cys Lys Met Asn Pro Cys Leu Asn
2065207020752080
Gly Gly Thr Cys Tyr Pro Thr Glu Thr Ser Tyr Val Cys Thr Cys Val
208520902095
Pro Gly Tyr Ser Gly Asp Gln Cys Glu Leu Asp Phe Asp Glu Cys His
210021052110
Ser Asn Pro Cys Arg Asn Gly Ala Thr Cys Val Asp Gly Phe Asn Thr
211521202125
Phe Arg Cys Leu Cys Leu Pro Ser Tyr Val Gly Ala Leu Cys Glu Gln
213021352140
Asp Thr Glu Thr Cys Asp Tyr Gly Trp His Lys Phe Gln Gly Gln Cys
21452150 21552160
Tyr Lys Tyr Phe Ala His Arg Arg Thr Trp Asp Ala Ala Glu Arg Glu
216521702175
Cys Arg Leu Gln Gly Ala His Leu Thr Ser Ile Leu Ser His Glu Glu
218021852190
Gln Met Phe Val Asn Arg Val Gly His Asp Tyr Gln Trp Ile Gly Leu
219522002205
Asn Asp Lys Met Phe Glu His Asp Phe Arg Trp Thr Asp Gly Ser Thr
221022152220
Leu Gln Tyr Glu Asn Trp Arg Pro Asn Gln Pro Asp Ser Phe Phe Ser
2225223022352240
Ala Gly Glu Asp Cys Val Val Ile Ile Trp His Glu Asn Gly Gln Trp
224522502255
Asn Asp Val Pro Cys Asn Tyr His Leu Thr Tyr Thr Cys Lys Lys Gly
226022652270
Thr Val Ala Cys Gly Gln Pro Pro Val Val Glu Asn Ala Lys Thr Phe
227522802285
Gly Lys Met Lys Pro Arg Tyr Glu Ile Asn Ser Leu Ile Arg Tyr His
229022952300
Cys Lys Asp Gly Phe Ile Gln Arg His Leu Pro Thr Ile Arg Cys Leu
2305231023152320
Gly Asn Gly Arg Trp Ala Ile Pro Lys Ile Thr Cys Met Asn Pro Ser
232523302335
Ala Tyr Gln Arg Thr Tyr Ser Met Lys Tyr Phe Lys Asn Ser Ser Ser
234023452350
Ala Lys Asp Asn Ser Ile Asn Thr Ser Lys His Asp His Arg Trp Ser
235523602365
Arg Arg Trp Gln Glu Ser Arg Arg
23702375
<210> 236
<211> 1321
<212> PRT
<213> Homo sapiens
<220>
<223> human Neurocan protein O15494
<400> 236
Met Gly Ala Pro Phe Val Trp Ala Leu Gly Leu Leu Met Leu Gln Met
151015
Leu Leu Phe Val Ala Gly Glu Gln Gly Thr Gln Asp Ile Thr Asp Ala
202530
Ser Glu Arg Gly Leu His Met Gln Lys Leu Gly Ser Gly Ser Val Gln
354045
Ala Ala Leu Ala Glu Leu Val Ala Leu Pro Cys Leu Phe Thr Leu Gln
505560
Pro Arg Pro Ser Ala Ala Arg Asp Ala Pro Arg Ile Lys Trp Thr Lys
65707580
Val Arg Thr Ala Ser Gly Gln Arg Gln Asp Leu Pro Ile Leu Val Ala
859095
Lys Asp Asn Val Val Arg Val Ala Lys Ser Trp Gln Gly Arg Val Ser
100105110
Leu Pro Ser Tyr Pro Arg Arg Arg Ala Asn Ala Thr Leu Leu Leu Gly
115120125
Pro Leu Arg Ala Ser Asp Ser Gly Leu Tyr Arg Cys Gln Val Val Arg
130135140
Gly Ile Glu Asp Glu Gln Asp Leu Val Pro Leu Glu Val Thr Gly Val
145150155160
Val Phe His Tyr Arg Ser Ala Arg Asp Arg Tyr Ala Leu Thr Phe Ala
165170175
Glu Ala Gln Glu Ala Cys Arg Leu Ser Ser Ala Ile Ile Ala Ala Pro
180185190
Arg His Leu Gln Ala Ala Phe Glu Asp Gly Phe Asp Asn Cys Asp Ala
195200205
Gly Trp Leu Ser Asp Arg Thr Val Arg Tyr Pro Ile Thr Gln Ser Arg
210215220
Pro Gly Cys Tyr Gly Asp Arg Ser Ser Leu Pro Gly Val Arg Ser Tyr
225230235240
Gly Arg Arg Asn Pro Gln Glu Leu Tyr Asp Val Tyr Cys Phe Ala Arg
245250255
Glu Leu Gly Gly Glu Val Phe Tyr Val Gly Pro Ala Arg Arg Leu Thr
260265270
Leu Ala Gly Ala Arg Ala Gln Cys Arg Arg Gln Gly Ala Ala Leu Ala
275280285
Ser Val Gly Gln Leu His Leu Ala Trp His Glu Gly Leu Asp Gln Cys
290295300
Asp Pro Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Gln Thr
305310315320
Pro Arg Arg Arg Cys Gly Gly Pro Ala Pro Gly Val Arg Thr Val Tyr
325330335
Arg Phe Ala Asn Arg Thr Gly Phe Pro Ser Pro Ala Glu Arg Phe Asp
340345350
Ala Tyr Cys Phe Arg Ala His His Pro Thr Ser Gln His Gly Asp Leu
355360365
Glu Thr Pro Ser Ser Gly Asp Glu Gly Glu Ile Leu Ser Ala Glu Gly
370375380
Pro Pro Val Arg Glu Leu Glu Pro Thr Leu Glu Glu Glu Glu Val Val
385390395400
Thr Pro Asp Phe Gln Glu Pro Leu Val Ser Ser Gly Glu Glu Glu Thr
405410415
Leu Ile Leu Glu Glu Lys Gln Glu Ser Gln Gln Thr Leu Ser Pro Thr
420425430
Pro Gly Asp Pro Met Leu Ala Ser Trp Pro Thr Gly Glu Val Trp Leu
435440445
Ser Thr Val Ala Pro Ser Pro Ser Asp Met Gly Ala Gly Thr Ala Ala
450455460
Ser Ser His Thr Glu Val Ala Pro Thr Asp Pro Met Pro Arg Arg Arg
465470475480
Gly Arg Phe Lys Gly Leu Asn Gly Arg Tyr Phe Gln Gln Gln Glu Pro
485490495
Glu Pro Gly Leu Gln Gly Gly Met Glu Ala Ser Ala Gln Pro Pro Thr
500505510
Ser Glu Ala Ala Val Asn Gln Met Glu Pro Pro Leu Ala Met Ala Val
515520525
Thr Glu Met Leu Gly Ser Gly Gln Ser Arg Ser Pro Trp Ala Asp Leu
530535540
Thr Asn Glu Val Asp Met Pro Gly Ala Gly Ser Ala Gly Gly Lys Ser
545550555560
Ser Pro Glu Pro Trp Leu Trp Pro Pro Thr Met Val Pro Pro Ser Ile
565570575
Ser Gly His Ser Arg Ala Pro Val Leu Glu Leu Glu Lys Ala Glu Gly
580585590
Pro Ser Ala Arg Pro Ala Thr Pro Asp Leu Phe Trp Ser Pro Leu Glu
595600605
Ala Thr Val Ser Ala Pro Ser Pro Ala Pro Trp Glu Ala Phe Pro Val
610615620
Ala Thr Ser Pro Asp Leu Pro Met Met Ala Met Leu Arg Gly Pro Lys
625630635640
Glu Trp Met Leu Pro His Pro Thr Pro Ile Ser Thr Glu Ala Asn Arg
645650655
Val Glu Ala His Gly Glu Ala Thr Ala Thr Ala Pro Pro Ser Pro Ala
660665670
Ala Glu Thr Lys Val Tyr Ser Leu Pro Leu Ser Leu Thr Pro Thr Gly
675680685
Gln Gly Gly Glu Ala Met Pro Thr Thr Pro Glu Ser Pro Arg Ala Asp
690695700
Phe Arg Glu Thr Gly Glu Thr Ser Pro Ala Gln Val Asn Lys Ala Glu
705710715720
His Ser Ser Ser Ser Pro Trp Pro Ser Val Asn Arg Asn Val Ala Val
725730735
Gly Phe Val Pro Thr Glu Thr Ala Thr Glu Pro Thr Gly Leu Arg Gly
740745750
Ile Pro Gly Ser Glu Ser Gly Val Phe Asp Thr Ala Glu Ser Pro Thr
755760765
Ser Gly Leu Gln Ala Thr Val Asp Glu Val Gln Asp Pro Trp Pro Ser
770775780
Val Tyr Ser Lys Gly Leu Asp Ala Ser Ser Pro Ser Ala Pro Leu Gly
785790795800
Ser Pro Gly Val Phe Leu Val Pro Lys Val Thr Pro Asn Leu Glu Pro
805810815
Trp Val Ala Thr Asp Glu Gly Pro Thr Val Asn Pro Met Asp Ser Thr
820825830
Val Thr Pro Ala Pro Ser Asp Ala Ser Gly Ile Trp Glu Pro Gly Ser
835840845
Gln Val Phe Glu Glu Ala Glu Ser Thr Thr Leu Ser Pro Gln Val Ala
850855860
Leu Asp Thr Ser Ile Val Thr Pro Leu Thr Thr Leu Glu Gln Gly Asp
865870875880
Lys Val Gly Val Pro Ala Met Ser Thr Leu Gly Ser Ser Ser Ser Gln
885890895
Pro His Pro Glu Pro Glu Asp Gln Val Glu Thr Gln Gly Thr Ser Gly
900905910
Ala Ser Val Pro Pro His Gln Ser Ser Pro Leu Gly Lys Pro Ala Val
915920925
Pro Pro Gly Thr Pro Thr Ala Ala Ser Val Gly Glu Ser Ala Ser Val
930935940
Ser Ser Gly Glu Pro Thr Val Pro Trp Asp Pro Ser Ser Thr Leu Leu
945950955960
Pro Val Thr Leu Gly Ile Glu Asp Phe Glu Leu Glu Val Leu Ala Gly
965970975
Ser Pro Gly Val Glu Ser Phe Trp Glu Glu Val Ala Ser Gly Glu Glu
980985990
Pro Ala Leu Pro Gly Thr Pro Met Asn Ala Gly Ala Glu Glu Val His
99510001005
Ser Asp Pro Cys Glu Asn Asn Pro Cys Leu His Gly Gly Thr Cys Asn
101010151020
Ala Asn Gly Thr Met Tyr Gly Cys Ser Cys Asp Gln Gly Phe Ala Gly
1025103010351040
Glu Asn Cys Glu Ile Asp Ile Asp Asp Cys Leu Cys Ser Pro Cys Glu
104510501055
Asn Gly Gly Thr Cys Ile Asp Glu Val Asn Gly Phe Val Cys Leu Cys
106010651070
Leu Pro Ser Tyr Gly Gly Ser Phe Cys Glu Lys Asp Thr Glu Gly Cys
107510801085
Asp Arg Gly Trp His Lys Phe Gln Gly His Cys Tyr Arg Tyr Phe Ala
109010951100
His Arg Arg Ala Trp Glu Asp Ala Glu Lys Asp Cys Arg Arg Arg Ser
1105111011151120
Gly His Leu Thr Ser Val His Ser Pro Glu Glu His Ser Phe Ile Asn
112511301135
Ser Phe Gly His Glu Asn Thr Trp Ile Gly Leu Asn Asp Arg Ile Val
114011451150
Glu Arg Asp Phe Gln Trp Thr Asp Asn Thr Gly Leu Gln Phe Glu Asn
115511601165
Trp Arg Glu Asn Gln Pro Asp Asn Phe Phe Ala Gly Gly Glu Asp Cys
117011751180
Val Val Met Val Ala His Glu Ser Gly Arg Trp Asn Asp Val Pro Cys
1185119011951200
Asn Tyr Asn Leu Pro Tyr Val Cys Lys Lys Gly Thr Val Leu Cys Gly
120512101215
Pro Pro Pro Ala Val Glu Asn Ala Ser Leu Ile Gly Ala Arg Lys Ala
122012251230
Lys Tyr Asn Val His Ala Thr Val Arg Tyr Gln Cys Asn Glu Gly Phe
123512401245
Ala Gln His His Val Ala Thr Ile Arg Cys Arg Ser Asn Gly Lys Trp
125012551260
Asp Arg Pro Gln Ile Val Cys Thr Lys Pro Arg Arg Ser His Arg Met
1265127012751280
Arg Arg His His His His His Gln His His His Gln His His His His
128512901295
Lys Ser Arg Lys Glu Arg Arg Lys His Lys Lys His Pro Thr Glu Asp
130013051310
Trp Glu Lys Asp Glu Gly Asn Phe Cys
13151320
<210> 237
<211> 2316
<212> PRT
<213> Rattus norvegicus
<220>
<223> rat Phosphacan Q62656
<400> 237
Met Arg Ile Leu Gln Ser Phe Leu Ala Cys Val Gln Leu Leu Cys Val
151015
Cys Arg Leu Asp Trp Ala Tyr Gly Tyr Tyr Arg Gln Gln Arg Lys Leu
202530
Val Glu Glu Ile Gly Trp Ser Tyr Thr Gly Ala Leu Asn Gln Lys Asn
354045
Trp Gly Lys Lys Tyr Pro Ile Cys Asn Ser Pro Lys Gln Ser Pro Ile
505560
Asn Ile Asp Glu Asp Leu Thr Gln Val Asn Val Asn Leu Lys Lys Leu
65707580
Lys Phe Gln Gly Trp Glu Lys Pro Ser Leu Glu Asn Thr Phe Ile His
859095
Asn Thr Gly Lys Thr Val Glu Ile Asn Leu Thr Asn Asp Tyr Tyr Leu
100105110
Ser Gly Gly Leu Ser Glu Lys Val Phe Lys Ala Ser Lys Met Thr Phe
115120125
His Trp Gly Lys Cys Asn Val Ser Ser Glu Gly Ser Glu His Ser Leu
130135140
Glu Gly Gln Lys Phe Pro Leu Glu Met Gln Ile Tyr Cys Phe Asp Ala
145150155160
Asp Arg Phe Ser Ser Phe Glu Glu Thr Val Lys Gly Lys Gly Arg Leu
165170175
Arg Ala Leu Ser Ile Leu Phe Glu Ile Gly Val Glu Glu Asn Leu Asp
180185190
Tyr Lys Ala Ile Ile Asp Gly Thr Glu Ser Val Ser Arg Phe Gly Lys
195200205
Gln Ala Ala Leu Asp Pro Phe Ile Leu Gln Asn Leu Leu Pro Asn Ser
210215220
Thr Asp Lys Tyr Tyr Ile Tyr Asn Gly Ser Leu Thr Ser Pro Pro Cys
225230235240
Thr Asp Thr Val Glu Trp Ile Val Phe Lys Asp Thr Val Ser Ile Ser
245250255
Glu Ser Gln Leu Ala Val Phe Cys Glu Val Leu Thr Met Gln Gln Ser
260265270
Gly Tyr Val Met Leu Met Asp Tyr Leu Gln Asn Asn Phe Arg Glu Gln
275280285
Gln Tyr Lys Phe Ser Arg Gln Val Phe Ser Ser Tyr Thr Gly Lys Glu
290295300
Glu Ile His Glu Ala Val Cys Ser Ser Glu Pro Glu Asn Val Gln Ala
305310315320
Asp Pro Glu Asn Tyr Thr Ser Leu Leu Ile Thr Trp Glu Arg Pro Arg
325330335
Val Val Tyr Asp Thr Met Ile Glu Lys Phe Ala Val Leu Tyr Gln Pro
340345350
Leu Glu Gly Asn Asp Gln Thr Lys His Glu Phe Leu Thr Asp Gly Tyr
355360365
Gln Asp Leu Gly Ala Ile Leu Asn Asn Leu Ile Pro Asn Met Ser Tyr
370375380
Val Leu Gln Ile Val Ala Ile Cys Ser Asn Gly Leu Tyr Gly Lys Tyr
385390395400
Ser Asp Gln Leu Ile Val Asp Met Pro Thr Glu Asp Ala Glu Leu Asp
405410415
Leu Phe Pro Glu Leu Ile Gly Thr Glu Glu Ile Ile Lys Glu Glu Asn
420425430
Tyr Gly Lys Gly Asn Glu Glu Asp Thr Gly Leu Asn Pro Gly Arg Asp
435440445
Ser Ala Thr Asn Gln Ile Arg Lys Lys Glu Pro Gln Val Ser Thr Thr
450455460
Thr His Tyr Asn His Met Gly Thr Lys Tyr Asn Glu Ala Lys Thr Asn
465470475480
Arg Ser Pro Thr Arg Gly Ser Glu Phe Ser Gly Lys Ser Asp Val Leu
485490495
Asn Thr Ser Leu Asn Pro Thr Ser Gln Gln Val Ala Glu Phe Asn Pro
500505510
Glu Arg Glu Met Ser Leu Pro Ser Gln Ile Gly Thr Asn Leu Pro Pro
515520525
His Ser Val Glu Gly Thr Ser Ala Ser Leu Asn Ser Gly Ser Lys Thr
530535540
Leu Leu Val Phe Pro Gln Met Asn Leu Ser Gly Thr Ala Glu Ser Leu
545550555560
Asn Met Val Ser Ile Thr Glu Tyr Lys Glu Val Ser Ala Asp Leu Ser
565570575
Glu Glu Glu Asn Leu Leu Thr Asp Phe Lys Leu Asp Ser Gly Ala Asp
580585590
Asp Ser Ser Gly Ser Ser Pro Ala Ser Ser Thr Val Pro Phe Ser Thr
595600605
Asp Asn Leu Ser His Gly Tyr Thr Ser Ser Ser Asp Thr Pro Glu Ala
610615620
Val Thr Tyr Asp Val Leu Arg Pro Glu Ser Thr Arg Asn Ala Leu Glu
625630635640
Asp Ser Ala Pro Ser Gly Ser Glu Glu Ser Leu Lys Asp Pro Ser Leu
645650655
Glu Gly Ser Val Trp Phe Pro Gly Ser Thr Asp Leu Thr Thr Gln Ser
660665670
Glu Thr Gly Ser Gly Arg Glu Gly Phe Leu Gln Val Asn Ser Thr Asp
675680685
Phe Gln Val Asp Glu Ser Arg Glu Thr Thr Glu Thr Phe Ser Pro Asp
690695700
Ala Thr Ala Ser Arg Gly Pro Ser Val Thr Asp Met Glu Met Pro His
705710715720
Tyr Ser Thr Phe Ala Tyr Pro Pro Thr Glu Val Thr Ser His Ala Phe
725730735
Thr Pro Ser Ser Arg Pro Leu Asp Leu Ala Pro Thr Ser Asn Ile Leu
740745750
His Ser Gln Thr Thr Gln Pro Val Tyr Asn Gly Glu Thr Pro Leu Gln
755760765
Pro Ser Tyr Ser Ser Glu Val Phe Pro Leu Val Thr Pro Leu Leu Leu
770775780
Asp Asn Gln Thr Leu Asn Thr Thr Pro Ala Ala Ser Ser Ser Asp Ser
785790795800
Ala Leu His Ala Thr Pro Val Phe Pro Ser Val Gly Val Ser Phe Asp
805810815
Ser Ile Leu Ser Ser Tyr Asp Asp Ala Pro Leu Leu Pro Phe Ser Ser
820825830
Ala Ser Phe Ser Ser Asp Leu Phe His His Leu His Thr Val Ser Gln
835840845
Thr Leu Pro Gln Val Thr Ser Ala Ala Glu Arg Asp Glu Leu Ser Leu
850855860
His Ala Ser Leu Leu Val Ala Gly Gly Asp Leu Leu Leu Glu Pro Ser
865870875880
Leu Val Gln Tyr Ser Asp Val Met Ser His Gln Val Thr Ile His Ala
885890895
Ala Ser Asp Thr Leu Glu Phe Gly Ser Glu Ser Ala Val Leu Tyr Lys
900905910
Thr Ser Met Val Ser Gln Ile Glu Ser Pro Ser Ser Asp Val Val Met
915920925
His Ala Tyr Ser Ser Gly Pro Glu Thr Ser Tyr Ala Ile Glu Gly Ser
930935940
His His Val Leu Thr Val Ser Ser Ser Ser Ala Ile Pro Val His Asp
945950955960
Ser Val Gly Val Ala Asp Gln Gly Ser Leu Leu Ile Asn Pro Ser His
965970975
Ile Ser Leu Pro Glu Ser Ser Phe Ile Thr Pro Thr Ala Ser Leu Leu
980985990
Gln Leu Pro Pro Ala Leu Ser Gly Asp Gly Glu Trp Ser Gly Ala Ser
99510001005
Ser Asp Ser Glu Leu Leu Leu Pro Asp Thr Asp Gly Leu Arg Thr Leu
101010151020
Asn Met Ser Ser Pro Val Ser Val Ala Asp Phe Thr Tyr Thr Thr Ser
1025103010351040
Val Ser Gly Asp Asp Ile Lys Pro Leu Ser Lys Gly Glu Met Met Tyr
104510501055
Gly Asn Glu Thr Glu Leu Lys Met Ser Ser Phe Ser Asp Met Ala Tyr
106010651070
Pro Ser Lys Ser Thr Val Val Pro Lys Met Ser Asp Ile Val Asn Lys
107510801085
Trp Ser Glu Ser Leu Lys Glu Thr Ser Val Ser Val Ser Ser Ile Asn
109010951100
Ser Val Phe Thr Glu Ser Leu Val Tyr Pro Ile Thr Lys Val Phe Asp
1105111011151120
Gln Glu Ile Ser Arg Val Pro Glu Ile Ile Phe Pro Val Lys Pro Thr
112511301135
His Thr Ala Ser Gln Ala Ser Gly Asp Thr Trp Leu Lys Pro Gly Leu
114011451150
Ser Thr Asn Ser Glu Pro Ala Leu Ser Asp Thr Ala Ser Ser Glu Val
115511601165
Ser His Pro Ser Thr Gln Pro Leu Leu Tyr Glu Ala Ala Ser Pro Phe
117011751180
Asn Thr Glu Ala Leu Leu Gln Pro Ser Phe Pro Ala Ser Asp Val Asp
1185119011951200
Thr Leu Leu Lys Thr Ala Leu Pro Ser Gly Pro Arg Asp Pro Val Leu
120512101215
Thr Glu Thr Pro Met Val Glu Gln Ser Ser Ser Ser Val Ser Leu Pro
122012251230
Leu Ala Ser Glu Ser Ala Ser Ser Lys Ser Thr Leu His Phe Thr Ser
123512401245
Val Pro Val Leu Asn Met Ser Pro Ser Asp Val His Pro Thr Ser Leu
125012551260
Gln Arg Leu Thr Val Pro His Ser Arg Glu Glu Tyr Phe Glu Gln Gly
1265127012751280
Leu Leu Lys Ser Lys Ser Pro Gln Gln Val Leu Pro Ser Leu His Ser
128512901295
His Asp Glu Phe Phe Gln Thr Ala His Leu Asp Ile Ser Gln Ala Tyr
130013051310
Pro Pro Lys Gly Arg His Ala Phe Ala Thr Pro Ile Leu Ser Ile Asn
131513201325
Glu Pro Gln Asn Thr Leu Ile Asn Arg Leu Val Tyr Ser Glu Asp Ile
133013351340
Phe Met His Pro Glu Ile Ser Ile Thr Asp Lys Ala Leu Thr Gly Leu
1345135013551360
Pro Thr Thr Val Ser Asp Val Leu Ile Ala Thr Asp His Ser Val Pro
136513701375
Leu Gly Ser Gly Pro Ile Ser Met Thr Thr Val Ser Pro Asn Arg Asp
138013851390
Asp Ser Val Thr Thr Thr Lys Leu Leu Leu Pro Ser Lys Ala Thr Ser
139514001405
Lys Pro Thr His Ser Ala Arg Ser Asp Ala Asp Leu Val Gly Gly Gly
141014151420
Glu Asp Gly Asp Asp Tyr Asp Asp Asp Asp Tyr Asp Asp Ile Asp Ser
1425143014351440
Asp Arg Phe Pro Val Asn Lys Cys Met Ser Cys Ser Pro Tyr Arg Glu
144514501455
Ser Gln Glu Lys Val Met Asn Asp Ser Asp Thr Gln Glu Ser Ser Leu
146014651470
Val Asp Gln Ser Asp Pro Ile Ser His Leu Leu Ser Glu Asn Thr Glu
147514801485
Glu Glu Asn Gly Gly Thr Gly Val Thr Arg Val Asp Lys Ser Pro Asp
149014951500
Lys Ser Pro Pro Pro Ser Met Leu Pro Gln Lys His Asn Asp Gly Arg
1505151015151520
Glu Asp Arg Asp Ile Gln Met Gly Ser Ala Val Leu Pro His Thr Pro
152515301535
Gly Ser Lys Ala Trp Ala Val Leu Thr Ser Asp Glu Glu Ser Gly Ser
154015451550
Gly Gln Gly Thr Ser Asp Ser Leu Asn Asp Asn Glu Thr Ser Thr Asp
155515601565
Phe Ser Phe Pro Asp Val Asn Glu Lys Asp Ala Asp Gly Val Leu Glu
157015751580
Ala Asp Asp Thr Gly Ile Ala Pro Gly Ser Pro Arg Ser Ser Thr Pro
1585159015951600
Ser Val Thr Ser Gly His Ser Gly Val Ser Asn Ser Ser Glu Ala Glu
160516101615
Ala Ser Asn Ser Ser His Glu Ser Arg Ile Gly Leu Ala Glu Gly Leu
162016251630
Glu Ser Glu Lys Lys Ala Val Ile Pro Leu Val Ile Val Ser Ala Leu
163516401645
Thr Phe Ile Cys Leu Val Val Leu Val Gly Ile Leu Ile Tyr Trp Arg
165016551660
Lys Cys Phe Gln Thr Ala His Phe Tyr Leu Glu Asp Asn Thr Ser Pro
1665167016751680
Arg Val Ile Ser Thr Pro Pro Thr Pro Ile Phe Pro Ile Ser Asp Asp
168516901695
Ile Gly Ala Ile Pro Ile Lys His Phe Pro Lys His Val Ala Asp Leu
170017051710
His Ala Ser Asn Gly Phe Thr Glu Glu Phe Glu Thr Leu Lys Glu Phe
171517201725
Tyr Gln Glu Val Gln Ser Cys Thr Val Asp Leu Gly Ile Thr Ala Asp
173017351740
Ser Ser Asn His Pro Asp Asn Lys His Lys Asn Arg Tyr Val Asn Ile
1745175017551760
Val Ala Tyr Asp His Ser Arg Val Lys Leu Thr Gln Leu Ala Glu Lys
176517701775
Asp Gly Lys Leu Thr Asp Tyr Ile Asn Ala Asn Tyr Val Asp Gly Tyr
178017851790
Asn Arg Pro Lys Ala Tyr Ile Ala Ala Gln Gly Pro Leu Lys Ser Thr
179518001805
Ala Glu Asp Phe Trp Arg Met Ile Trp Glu His Asn Val Glu Val Ile
181018151820
Val Met Ile Thr Asn Leu Val Glu Lys Gly Arg Arg Lys Cys Asp Gln
1825183018351840
Tyr Trp Pro Thr Asp Gly Ser Glu Glu Tyr Gly Ser Phe Leu Val Asn
184518501855
Gln Lys Asn Val Gln Val Leu Ala Tyr Tyr Thr Val Arg Asn Phe Thr
186018651870
Leu Arg Asn Thr Lys Ile Lys Lys Gly Ser Gln Lys Gly Arg Ser Ser
187518801885
Gly Arg Leu Val Thr Gln Tyr His Tyr Thr Gln Trp Pro Asp Met Gly
189018951900
Val Pro Glu Tyr Ser Leu Pro Val Leu Ala Phe Val Arg Lys Thr Ala
1905191019151920
Gln Ala Lys Arg His Ala Val Gly Pro Val Val Val His Cys Ser Ala
192519301935
Gly Val Gly Arg Thr Gly Thr Tyr Ile Val Leu Asp Ser Met Leu Gln
194019451950
Gln Ile Gln His Glu Gly Thr Val Asn Ile Phe Gly Phe Leu Lys His
195519601965
Ile Arg Ser Gln Arg Asn Tyr Leu Val Gln Thr Glu Glu Gln Tyr Val
197019751980
Phe Ile His Asp Thr Leu Val Glu Ala Ile Leu Ser Lys Glu Thr Glu
1985199019952000
Val Pro Asp Ser His Ile His Ser Tyr Val Asn Thr Leu Leu Ile Pro
200520102015
Gly Pro Ser Gly Lys Thr Lys Leu Glu Lys Gln Phe Gln Leu Leu Ser
202020252030
Gln Ser Asn Ile Leu Gln Ser Asp Tyr Ser Thr Ala Leu Lys Gln Cys
203520402045
Asn Arg Glu Lys Asn Arg Thr Ser Ser Ile Ile Pro Val Glu Arg Ser
205020552060
Arg Val Gly Ile Ser Ser Leu Ser Gly Glu Gly Thr Asp Tyr Ile Asn
2065207020752080
Ala Ser Tyr Ile Met Gly Tyr Tyr Gln Ser Asn Glu Phe Ile Ile Thr
208520902095
Gln His Pro Leu Leu His Thr Ile Lys Asp Phe Trp Arg Met Ile Trp
210021052110
Asp His Asn Ala Gln Leu Val Val Met Ile Pro Asp Gly Gln Asn Met
211521202125
Ala Glu Asp Glu Phe Val Tyr Trp Pro Asn Lys Asp Glu Pro Ile Asn
213021352140
Cys Glu Ser Phe Lys Val Thr Leu Met Ser Glu Glu His Lys Cys Leu
2145215021552160
Ser Asn Glu Glu Lys Leu Ile Val Gln Asp Phe Ile Leu Glu Ala Thr
216521702175
Gln Asp Asp Tyr Val Leu Glu Val Arg His Phe Gln Cys Pro Lys Trp
218021852190
Pro Asn Pro Asp Ser Pro Ile Ser Lys Thr Phe Glu Leu Ile Ser Ile
219522002205
Ile Lys Glu Glu Ala Ala Asn Arg Asp Gly Pro Met Ile Val His Asp
221022152220
Glu His Gly Gly Val Thr Ala Gly Thr Phe Cys Ala Leu Thr Thr Leu
2225223022352240
Met His Gln Leu Glu Lys Glu Asn Ser Met Asp Val Tyr Gln Val Ala
224522502255
Lys Met Ile Asn Leu Met Arg Pro Gly Val Phe Thr Asp Ile Glu Gln
226022652270
Tyr Gln Phe Leu Tyr Lys Val Val Leu Ser Leu Val Ser Thr Arg Gln
227522802285
Glu Glu Asn Pro Ser Thr Ser Leu Asp Ser Asn Gly Ala Ala Leu Pro
229022952300
Asp Gly Asn Ile Ala Glu Ser Leu Glu Ser Leu Val
230523102315
<210> 238
<211> 382
<212> PRT
<213> Homo sapiens
<220>
<223> Layilin Isoform 1Q6UX15
<400> 238
Met Arg Pro Gly Thr Ala Leu Gln Ala Val Leu Leu Ala Val Leu Leu
151015
Val Gly Leu Arg Ala Ala Thr Gly Arg Leu Leu Ser Ala Ser Asp Leu
202530
Asp Leu Arg Gly Gly Gln Pro Val Cys Arg Gly Gly Thr Gln Arg Pro
354045
Cys Tyr Lys Val Ile Tyr Phe His Asp Thr Ser Arg Arg Leu Asn Phe
505560
Glu Glu Ala Lys Glu Ala Cys Arg Arg Asp Gly Gly Gln Leu Val Ser
65707580
Ile Glu Ser Glu Asp Glu Gln Lys Leu Ile Glu Lys Phe Ile Glu Asn
859095
Leu Leu Pro Ser Asp Gly Asp Phe Trp Ile Gly Leu Arg Arg Arg Glu
100105110
Glu Lys Gln Ser Asn Ser Thr Ala Cys Gln Asp Leu Tyr Ala Trp Thr
115120125
Asp Gly Ser Ile Ser Gln Phe Arg Asn Trp Tyr Val Asp Glu Pro Ser
130135140
Cys Gly Ser Glu Val Cys Val Val Met Tyr His Gln Pro Ser Ala Pro
145150155160
Ala Gly Ile Gly Gly Pro Tyr Met Phe Gln Trp Asn Asp Asp Arg Cys
165170175
Asn Met Lys Asn Asn Phe Ile Cys Lys Tyr Ser Asp Glu Lys Pro Ala
180185190
Val Pro Ser Arg Glu Ala Glu Gly Glu Glu Thr Glu Leu Thr Thr Pro
195200205
Val Leu Pro Glu Glu Thr Gln Glu Glu Asp Ala Lys Lys Thr Phe Lys
210215220
Glu Ser Arg Glu Ala Ala Leu Asn Leu Ala Tyr Ile Leu Ile Pro Ser
225230235240
Ile Pro Leu Leu Leu Leu Leu Val Val Thr Thr Val Val Cys Trp Val
245250255
Trp Ile Cys Arg Lys Arg Lys Arg Glu Gln Pro Asp Pro Ser Thr Lys
260265270
Lys Gln His Thr Ile Trp Pro Ser Pro His Gln Gly Asn Ser Pro Asp
275280285
Leu Glu Val Tyr Asn Val Ile Arg Lys Gln Ser Glu Ala Asp Leu Ala
290295300
Glu Thr Arg Pro Asp Leu Lys Asn Ile Ser Phe Arg Val Cys Ser Gly
305310315320
Glu Ala Thr Pro Asp Asp Met Ser Cys Asp Tyr Asp Asn Met Ala Val
325330335
Asn Pro Ser Glu Ser Gly Phe Val Thr Leu Val Ser Val Glu Ser Gly
340345350
Phe Val Thr Asn Asp Ile Tyr Glu Phe Ser Pro Asp Gln Met Gly Arg
355360365
Ser Lys Glu Ser Gly Trp Val Glu Asn Glu Ile Tyr Gly Tyr
370375380
<210> 239
<211> 374
<212> PRT
<213> Homo sapiens
<220>
<223> Layilin Isoform 2NP_849156
<400> 239
Met Arg Pro Gly Thr Ala Leu Gln Ala Val Leu Leu Ala Val Leu Leu
151015
Val Gly Leu Arg Ala Ala Thr Gly Arg Leu Leu Ser Gly Gln Pro Val
202530
Cys Arg Gly Gly Thr Gln Arg Pro Cys Tyr Lys Val Ile Tyr Phe His
354045
Asp Thr Ser Arg Arg Leu Asn Phe Glu Glu Ala Lys Glu Ala Cys Arg
505560
Arg Asp Gly Gly Gln Leu Val Ser Ile Glu Ser Glu Asp Glu Gln Lys
65707580
Leu Ile Glu Lys Phe Ile Glu Asn Leu Leu Pro Ser Asp Gly Asp Phe
859095
Trp Ile Gly Leu Arg Arg Arg Glu Glu Lys Gln Ser Asn Ser Thr Ala
100105110
Cys Gln Asp Leu Tyr Ala Trp Thr Asp Gly Ser Ile Ser Gln Phe Arg
115120125
Asn Trp Tyr Val Asp Glu Pro Ser Cys Gly Ser Glu Val Cys Val Val
130135140
Met Tyr His Gln Pro Ser Ala Pro Ala Gly Ile Gly Gly Pro Tyr Met
145150155160
Phe Gln Trp Asn Asp Asp Arg Cys Asn Met Lys Asn Asn Phe Ile Cys
165170175
Lys Tyr Ser Asp Glu Lys Pro Ala Val Pro Ser Arg Glu Ala Glu Gly
180185190
Glu Glu Thr Glu Leu Thr Thr Pro Val Leu Pro Glu Glu Thr Gln Glu
195200205
Glu Asp Ala Lys Lys Thr Phe Lys Glu Ser Arg Glu Ala Ala Leu Asn
210215220
Leu Ala Tyr Ile Leu Ile Pro Ser Ile Pro Leu Leu Leu Leu Leu Val
225230235240
Val Thr Thr Val Val Cys Trp Val Trp Ile Cys Arg Lys Arg Lys Arg
245250255
Glu Gln Pro Asp Pro Ser Thr Lys Lys Gln His Thr Ile Trp Pro Ser
260265270
Pro His Gln Gly Asn Ser Pro Asp Leu Glu Val Tyr Asn Val Ile Arg
275280285
Lys Gln Ser Glu Ala Asp Leu Ala Glu Thr Arg Pro Asp Leu Lys Asn
290295300
Ile Ser Phe Arg Val Cys Ser Gly Glu Ala Thr Pro Asp Asp Met Ser
305310315320
Cys Asp Tyr Asp Asn Met Ala Val Asn Pro Ser Glu Ser Gly Phe Val
325330335
Thr Leu Val Ser Val Glu Ser Gly Phe Val Thr Asn Asp Ile Tyr Glu
340345350
Phe Ser Pro Asp Gln Met Gly Arg Ser Lys Glu Ser Gly Trp Val Glu
355360365
Asn Glu Ile Tyr Gly Tyr
370
<210> 240
<211> 282
<212> PRT
<213> Homo sapiens
<220>
<223> HABP1/C1QBPQ07021
<400> 240
Met Leu Pro Leu Leu Arg Cys Val Pro Arg Val Leu Gly Ser Ser Val
151015
Ala Gly Leu Arg Ala Ala Ala Pro Ala Ser Pro Phe Arg Gln Leu Leu
202530
Gln Pro Ala Pro Arg Leu Cys Thr Arg Pro Phe Gly Leu Leu Ser Val
354045
Arg Ala Gly Ser Glu Arg Arg Pro Gly Leu Leu Arg Pro Arg Gly Pro
505560
Cys Ala Cys Gly Cys Gly Cys Gly Ser Leu His Thr Asp Gly Asp Lys
65707580
Ala Phe Val Asp Phe Leu Ser Asp Glu Ile Lys Glu Glu Arg Lys Ile
859095
Gln Lys His Lys Thr Leu Pro Lys Met Ser Gly Gly Trp Glu Leu Glu
100105110
Leu Asn Gly Thr Glu Ala Lys Leu Val Arg Lys Val Ala Gly Glu Lys
115120125
Ile Thr Val Thr Phe Asn Ile Asn Asn Ser Ile Pro Pro Thr Phe Asp
130135140
Gly Glu Glu Glu Pro Ser Gln Gly Gln Lys Val Glu Glu Gln Glu Pro
145150155160
Glu Leu Thr Ser Thr Pro Asn Phe Val Val Glu Val Ile Lys Asn Asp
165170175
Asp Gly Lys Lys Ala Leu Val Leu Asp Cys His Tyr Pro Glu Asp Glu
180185190
Val Gly Gln Glu Asp Glu Ala Glu Ser Asp Ile Phe Ser Ile Arg Glu
195200205
Val Ser Phe Gln Ser Thr Gly Glu Ser Glu Trp Lys Asp Thr Asn Tyr
210215220
Thr Leu Asn Thr Asp Ser Leu Asp Trp Ala Leu Tyr Asp His Leu Met
225230235240
Asp Phe Leu Ala Asp Arg Gly Val Asp Asn Thr Phe Ala Asp Glu Leu
245250255
Val Glu Leu Ser Thr Ala Leu Glu His Gln Glu Tyr Ile Thr Phe Leu
260265270
Glu Asp Leu Lys Ser Phe Val Lys Ser Gln
275280
<210> 241
<211> 12
<212> PRT
<213> Homo sapiens
<220>
<223> PEP-1
<400> 241
Gly Ala His Trp Gln Phe Asn Ala Leu Thr Val Arg
1510
<210> 242
<211> 724
<212> PRT
<213> Homo sapiens
<220>
<223> human Rhamm protein O75330
<400> 242
Met Ser Phe Pro Lys Ala Pro Leu Lys Arg Phe Asn Asp Pro Ser Gly
151015
Cys Ala Pro Ser Pro Gly Ala Tyr Asp Val Lys Thr Leu Glu Val Leu
202530
Lys Gly Pro Val Ser Phe Gln Lys Ser Gln Arg Phe Lys Gln Gln Lys
354045
Glu Ser Lys Gln Asn Leu Asn Val Asp Lys Asp Thr Thr Leu Pro Ala
505560
Ser Ala Arg Lys Val Lys Ser Ser Glu Ser Lys Glu Ser Gln Lys Asn
65707580
Asp Lys Asp Leu Lys Ile Leu Glu Lys Glu Ile Arg Val Leu Leu Gln
859095
Glu Arg Gly Ala Gln Asp Arg Arg Ile Gln Asp Leu Glu Thr Glu Leu
100105110
Glu Lys Met Glu Ala Arg Leu Asn Ala Ala Leu Arg Glu Lys Thr Ser
115120125
Leu Ser Ala Asn Asn Ala Thr Leu Glu Lys Gln Leu Ile Glu Leu Thr
130135140
Arg Thr Asn Glu Leu Leu Lys Ser Lys Phe Ser Glu Asn Gly Asn Gln
145150155160
Lys Asn Leu Arg Ile Leu Ser Leu Glu Leu Met Lys Leu Arg Asn Lys
165170175
Arg Glu Thr Lys Met Arg Gly Met Met Ala Lys Gln Glu Gly Met Glu
180185190
Met Lys Leu Gln Val Thr Gln Arg Ser Leu Glu Glu Ser Gln Gly Lys
195200205
Ile Ala Gln Leu Glu Gly Lys Leu Val Ser Ile Glu Lys Glu Lys Ile
210215220
Asp Glu Lys Ser Glu Thr Glu Lys Leu Leu Glu Tyr Ile Glu Glu Ile
225230235240
Ser Cys Ala Ser Asp Gln Val Glu Lys Tyr Lys Leu Asp Ile Ala Gln
245250255
Leu Glu Glu Asn Leu Lys Glu Lys Asn Asp Glu Ile Leu Ser Leu Lys
260265270
Gln Ser Leu Glu Glu Asn Ile Val Ile Leu Ser Lys Gln Val Glu Asp
275280285
Leu Asn Val Lys Cys Gln Leu Leu Glu Lys Glu Lys Glu Asp His Val
290295300
Asn Arg Asn Arg Glu His Asn Glu Asn Leu Asn Ala Glu Met Gln Asn
305310315320
Leu Lys Gln Lys Phe Ile Leu Glu Gln Gln Glu Arg Glu Lys Leu Gln
325330335
Gln Lys Glu Leu Gln Ile Asp Ser Leu Leu Gln Gln Glu Lys Glu Leu
340345350
Ser Ser Ser Leu His Gln Lys Leu Cys Ser Phe Gln Glu Glu Met Val
355360365
Lys Glu Lys Asn Leu Phe Glu Glu Glu Leu Lys Gln Thr Leu Asp Glu
370375380
Leu Asp Lys Leu Gln Gln Lys Glu Glu Gln Ala Glu Arg Leu Val Lys
385390395400
Gln Leu Glu Glu Glu Ala Lys Ser Arg Ala Glu Glu Leu Lys Leu Leu
405410415
Glu Glu Lys Leu Lys Gly Lys Glu Ala Glu Leu Glu Lys Ser Ser Ala
420425430
Ala His Thr Gln Ala Thr Leu Leu Leu Gln Glu Lys Tyr Asp Ser Met
435440445
Val Gln Ser Leu Glu Asp Val Thr Ala Gln Phe Glu Ser Tyr Lys Ala
450455460
Leu Thr Ala Ser Glu Ile Glu Asp Leu Lys Leu Glu Asn Ser Ser Leu
465470475480
Gln Glu Lys Ala Ala Lys Ala Gly Lys Asn Ala Glu Asp Val Gln His
485490495
Gln Ile Leu Ala Thr Glu Ser Ser Asn Gln Glu Tyr Val Arg Met Leu
500505510
Leu Asp Leu Gln Thr Lys Ser Ala Leu Lys Glu Thr Glu Ile Lys Glu
515520 525
Ile Thr Val Ser Phe Leu Gln Lys Ile Thr Asp Leu Gln Asn Gln Leu
530535540
Lys Gln Gln Glu Glu Asp Phe Arg Lys Gln Leu Glu Asp Glu Glu Gly
545550555560
Arg Lys Ala Glu Lys Glu Asn Thr Thr Ala Glu Leu Thr Glu Glu Ile
565570575
Asn Lys Trp Arg Leu Leu Tyr Glu Glu Leu Tyr Asn Lys Thr Lys Pro
580585590
Phe Gln Leu Gln Leu Asp Ala Phe Glu Val Glu Lys Gln Ala Leu Leu
595600605
Asn Glu His Gly Ala Ala Gln Glu Gln Leu Asn Lys Ile Arg Asp Ser
610615620
Tyr Ala Lys Leu Leu Gly His Gln Asn Leu Lys Gln Lys Ile Lys His
625630635640
Val Val Lys Leu Lys Asp Glu Asn Ser Gln Leu Lys Ser Glu Val Ser
645650655
Lys Leu Arg Cys Gln Leu Ala Lys Lys Lys Gln Ser Glu Thr Lys Leu
660665670
Gln Glu Glu Leu Asn Lys Val Leu Gly Ile Lys His Phe Asp Pro Ser
675680685
Lys Ala Phe His His Glu Ser Lys Glu Asn Phe Ala Leu Lys Thr Pro
690695700
Leu Lys Glu Gly Asn Thr Asn Cys Tyr Arg Ala Pro Met Glu Cys Gln
705710715720
Glu Ser Trp Lys
<210> 243
<211> 911
<212> PRT
<213> Homo sapiens
<220>
<223> Inter alpha trypsin inhibitor heavy chain 1
P19827
<400> 243
Met Asp Gly Ala Met Gly Pro Arg Gly Leu Leu Leu Cys Met Tyr Leu
151015
Val Ser Leu Leu Ile Leu Gln Ala Met Pro Ala Leu Gly Ser Ala Thr
202530
Gly Arg Ser Lys Ser Ser Glu Lys Arg Gln Ala Val Asp Thr Ala Val
354045
Asp Gly Val Phe Ile Arg Ser Leu Lys Val Asn Cys Lys Val Thr Ser
505560
Arg Phe Ala His Tyr Val Val Thr Ser Gln Val Val Asn Thr Ala Asn
65707580
Glu Ala Arg Glu Val Ala Phe Asp Leu Glu Ile Pro Lys Thr Ala Phe
859095
Ile Ser Asp Phe Ala Val Thr Ala Asp Gly Asn Ala Phe Ile Gly Asp
100105110
Ile Lys Asp Lys Val Thr Ala Trp Lys Gln Tyr Arg Lys Ala Ala Ile
115120125
Ser Gly Glu Asn Ala Gly Leu Val Arg Ala Ser Gly Arg Thr Met Glu
130135140
Gln Phe Thr Ile His Leu Thr Val Asn Pro Gln Ser Lys Val Thr Phe
145150155160
Gln Leu Thr Tyr Glu Glu Val Leu Lys Arg Asn His Met Gln Tyr Glu
165170175
Ile Val Ile Lys Val Lys Pro Lys Gln Leu Val His His Phe Glu Ile
180185190
Asp Val Asp Ile Phe Glu Pro Gln Gly Ile Ser Lys Leu Asp Ala Gln
195200205
Ala Ser Phe Leu Pro Lys Glu Leu Ala Ala Gln Thr Ile Lys Lys Ser
210215220
Phe Ser Gly Lys Lys Gly His Val Leu Phe Arg Pro Thr Val Ser Gln
225230235240
Gln Gln Ser Cys Pro Thr Cys Ser Thr Ser Leu Leu Asn Gly His Phe
245250255
Lys Val Thr Tyr Asp Val Ser Arg Asp Lys Ile Cys Asp Leu Leu Val
260265270
Ala Asn Asn His Phe Ala His Phe Phe Ala Pro Gln Asn Leu Thr Asn
275280285
Met Asn Lys Asn Val Val Phe Val Ile Asp Ile Ser Gly Ser Met Arg
290295300
Gly Gln Lys Val Lys Gln Thr Lys Glu Ala Leu Leu Lys Ile Leu Gly
305310315320
Asp Met Gln Pro Gly Asp Tyr Phe Asp Leu Val Leu Phe Gly Thr Arg
325330335
Val Gln Ser Trp Lys Gly Ser Leu Val Gln Ala Ser Glu Ala Asn Leu
340345350
Gln Ala Ala Gln Asp Phe Val Arg Gly Phe Ser Leu Asp Glu Ala Thr
355360365
Asn Leu Asn Gly Gly Leu Leu Arg Gly Ile Glu Ile Leu Asn Gln Val
370375380
Gln Glu Ser Leu Pro Glu Leu Ser Asn His Ala Ser Ile Leu Ile Met
385390395400
Leu Thr Asp Gly Asp Pro Thr Glu Gly Val Thr Asp Arg Ser Gln Ile
405410415
Leu Lys Asn Val Arg Asn Ala Ile Arg Gly Arg Phe Pro Leu Tyr Asn
420425430
Leu Gly Phe Gly His Asn Val Asp Phe Asn Phe Leu Glu Val Met Ser
435440445
Met Glu Asn Asn Gly Arg Ala Gln Arg Ile Tyr Glu Asp His Asp Ala
450455460
Thr Gln Gln Leu Gln Gly Phe Tyr Ser Gln Val Ala Lys Pro Leu Leu
465470475480
Val Asp Val Asp Leu Gln Tyr Pro Gln Asp Ala Val Leu Ala Leu Thr
485490495
Gln Asn His His Lys Gln Tyr Tyr Glu Gly Ser Glu Ile Val Val Ala
500505510
Gly Arg Ile Ala Asp Asn Lys Gln Ser Ser Phe Lys Ala Asp Val Gln
515520525
Ala His Gly Glu Gly Gln Glu Phe Ser Ile Thr Cys Leu Val Asp Glu
530535540
Glu Glu Met Lys Lys Leu Leu Arg Glu Arg Gly His Met Leu Glu Asn
545550555560
His Val Glu Arg Leu Trp Ala Tyr Leu Thr Ile Gln Glu Leu Leu Ala
565570575
Lys Arg Met Lys Val Asp Arg Glu Glu Arg Ala Asn Leu Ser Ser Gln
580585590
Ala Leu Gln Met Ser Leu Asp Tyr Gly Phe Val Thr Pro Leu Thr Ser
595600605
Met Ser Ile Arg Gly Met Ala Asp Gln Asp Gly Leu Lys Pro Thr Ile
610615620
Asp Lys Pro Ser Glu Asp Ser Pro Pro Leu Glu Met Leu Gly Pro Arg
625630635640
Arg Thr Phe Val Leu Ser Ala Leu Gln Pro Ser Pro Thr His Ser Ser
645650655
Ser Asn Thr Gln Arg Leu Pro Asp Arg Val Thr Gly Val Asp Thr Asp
660665670
Pro His Phe Ile Ile His Val Pro Gln Lys Glu Asp Thr Leu Cys Phe
675680685
Asn Ile Asn Glu Glu Pro Gly Val Ile Leu Ser Leu Val Gln Asp Pro
690695700
Asn Thr Gly Phe Ser Val Asn Gly Gln Leu Ile Gly Asn Lys Ala Arg
705710715720
Ser Pro Gly Gln His Asp Gly Thr Tyr Phe Gly Arg Leu Gly Ile Ala
725730735
Asn Pro Ala Thr Asp Phe Gln Leu Glu Val Thr Pro Gln Asn Ile Thr
740745750
Leu Asn Pro Gly Phe Gly Gly Pro Val Phe Ser Trp Arg Asp Gln Ala
755760765
Val Leu Arg Gln Asp Gly Val Val Val Thr Ile Asn Lys Lys Arg Asn
770775780
Leu Val Val Ser Val Asp Asp Gly Gly Thr Phe Glu Val Val Leu His
785790795800
Arg Val Trp Lys Gly Ser Ser Val His Gln Asp Phe Leu Gly Phe Tyr
805810815
Val Leu Asp Ser His Arg Met Ser Ala Arg Thr His Gly Leu Leu Gly
820825830
Gln Phe Phe His Pro Ile Gly Phe Glu Val Ser Asp Ile His Pro Gly
835840845
Ser Asp Pro Thr Lys Pro Asp Ala Thr Met Val Val Arg Asn Arg Arg
850855860
Leu Thr Val Thr Arg Gly Leu Gln Lys Asp Tyr Ser Lys Asp Pro Trp
865870875880
His Gly Ala Glu Val Ser Cys Trp Phe Ile His Asn Asn Gly Ala Gly
885890895
Leu Ile Asp Gly Ala Tyr Thr Asp Tyr Ile Val Pro Asp Ile Phe
900905910
<210> 244
<211> 946
<212> PRT
<213> Homo sapiens
<220>
<223> Inter alpha trypsin inhibitor heavy chain 2
P19823
<400> 244
Met Lys Arg Leu Thr Cys Phe Phe Ile Cys Phe Phe Leu Ser Glu Val
151015
Ser Gly Phe Glu Ile Pro Ile Asn Gly Leu Ser Glu Phe Val Asp Tyr
202530
Glu Asp Leu Val Glu Leu Ala Pro Gly Lys Phe Gln Leu Val Ala Glu
354045
Asn Arg Arg Tyr Gln Arg Ser Leu Pro Gly Glu Ser Glu Glu Met Met
505560
Glu Glu Val Asp Gln Val Thr Leu Tyr Ser Tyr Lys Val Gln Ser Thr
65707580
Ile Thr Ser Arg Met Ala Thr Thr Met Ile Gln Ser Lys Val Val Asn
859095
Asn Ser Pro Gln Pro Gln Asn Val Val Phe Asp Val Gln Ile Pro Lys
100105110
Gly Ala Phe Ile Ser Asn Phe Ser Met Thr Val Asp Gly Lys Thr Phe
115120125
Arg Ser Ser Ile Lys Glu Lys Thr Val Gly Arg Ala Leu Tyr Ala Gln
130135140
Ala Arg Ala Lys Gly Lys Thr Ala Gly Leu Val Arg Ser Ser Ala Leu
145150155160
Asp Met Glu Asn Phe Arg Thr Glu Val Asn Val Leu Pro Gly Ala Lys
165170175
Val Gln Phe Glu Leu His Tyr Gln Glu Val Lys Trp Arg Lys Leu Gly
180185190
Ser Tyr Glu His Arg Ile Tyr Leu Gln Pro Gly Arg Leu Ala Lys His
195200205
Leu Glu Val Asp Val Trp Val Ile Glu Pro Gln Gly Leu Arg Phe Leu
210215 220
His Val Pro Asp Thr Phe Glu Gly His Phe Asp Gly Val Pro Val Ile
225230235240
Ser Lys Gly Gln Gln Lys Ala His Val Ser Phe Lys Pro Thr Val Ala
245250255
Gln Gln Arg Ile Cys Pro Asn Cys Arg Glu Thr Ala Val Asp Gly Glu
260265270
Leu Val Val Leu Tyr Asp Val Lys Arg Glu Glu Lys Ala Gly Glu Leu
275280285
Glu Val Phe Asn Gly Tyr Phe Val His Phe Phe Ala Pro Asp Asn Leu
290295300
Asp Pro Ile Pro Lys Asn Ile Leu Phe Val Ile Asp Val Ser Gly Ser
305310315320
Met Trp Gly Val Lys Met Lys Gln Thr Val Glu Ala Met Lys Thr Ile
325330335
Leu Asp Asp Leu Arg Ala Glu Asp His Phe Ser Val Ile Asp Phe Asn
340345350
Gln Asn Ile Arg Thr Trp Arg Asn Asp Leu Ile Ser Ala Thr Lys Thr
355360365
Gln Val Ala Asp Ala Lys Arg Tyr Ile Glu Lys Ile Gln Pro Ser Gly
370375380
Gly Thr Asn Ile Asn Glu Ala Leu Leu Arg Ala Ile Phe Ile Leu Asn
385390395400
Glu Ala Asn Asn Leu Gly Leu Leu Asp Pro Asn Ser Val Ser Leu Ile
405410415
Ile Leu Val Ser Asp Gly Asp Pro Thr Val Gly Glu Leu Lys Leu Ser
420425430
Lys Ile Gln Lys Asn Val Lys Glu Asn Ile Gln Asp Asn Ile Ser Leu
435440445
Phe Ser Leu Gly Met Gly Phe Asp Val Asp Tyr Asp Phe Leu Lys Arg
450455460
Leu Ser Asn Glu Asn His Gly Ile Ala Gln Arg Ile Tyr Gly Asn Gln
465470475480
Asp Thr Ser Ser Gln Leu Lys Lys Phe Tyr Asn Gln Val Ser Thr Pro
485490495
Leu Leu Arg Asn Val Gln Phe Asn Tyr Pro His Thr Ser Val Thr Asp
500505510
Val Thr Gln Asn Asn Phe His Asn Tyr Phe Gly Gly Ser Glu Ile Val
515520525
Val Ala Gly Lys Phe Asp Pro Ala Lys Leu Asp Gln Ile Glu Ser Val
530 535540
Ile Thr Ala Thr Ser Ala Asn Thr Gln Leu Val Leu Glu Thr Leu Ala
545550555560
Gln Met Asp Asp Leu Gln Asp Phe Leu Ser Lys Asp Lys His Ala Asp
565570575
Pro Asp Phe Thr Arg Lys Leu Trp Ala Tyr Leu Thr Ile Asn Gln Leu
580585590
Leu Ala Glu Arg Ser Leu Ala Pro Thr Ala Ala Ala Lys Arg Arg Ile
595600605
Thr Arg Ser Ile Leu Gln Met Ser Leu Asp His His Ile Val Thr Pro
610615620
Leu Thr Ser Leu Val Ile Glu Asn Glu Ala Gly Asp Glu Arg Met Leu
625630635640
Ala Asp Ala Pro Pro Gln Asp Pro Ser Cys Cys Ser Gly Ala Leu Tyr
645650655
Tyr Gly Ser Lys Val Val Pro Asp Ser Thr Pro Ser Trp Ala Asn Pro
660665670
Ser Pro Thr Pro Val Ile Ser Met Leu Ala Gln Gly Ser Gln Val Leu
675680685
Glu Ser Thr Pro Pro Pro His Val Met Arg Val Glu Asn Asp Pro His
690695700
Phe Ile Ile Tyr Leu Pro Lys Ser Gln Lys Asn Ile Cys Phe Asn Ile
705710715720
Asp Ser Glu Pro Gly Lys Ile Leu Asn Leu Val Ser Asp Pro Glu Ser
725730735
Gly Ile Val Val Asn Gly Gln Leu Val Gly Ala Lys Lys Pro Asn Asn
740745750
Gly Lys Leu Ser Thr Tyr Phe Gly Lys Leu Gly Phe Tyr Phe Gln Ser
755760765
Glu Asp Ile Lys Ile Glu Ile Ser Thr Glu Thr Ile Thr Leu Ser His
770775780
Gly Ser Ser Thr Phe Ser Leu Ser Trp Ser Asp Thr Ala Gln Val Thr
785790795800
Asn Gln Arg Val Gln Ile Ser Val Lys Lys Glu Lys Val Val Thr Ile
805810815
Thr Leu Asp Lys Glu Met Ser Phe Ser Val Leu Leu His Arg Val Trp
820825830
Lys Lys His Pro Val Asn Val Asp Phe Leu Gly Ile Tyr Ile Pro Pro
835840845
Thr Asn Lys Phe Ser Pro Lys Ala His Gly Leu Ile Gly Gln Phe Met
850855860
Gln Glu Pro Lys Ile His Ile Phe Asn Glu Arg Pro Gly Lys Asp Pro
865870875880
Glu Lys Pro Glu Ala Ser Met Glu Val Lys Gly Gln Lys Leu Ile Ile
885890895
Thr Arg Gly Leu Gln Lys Asp Tyr Arg Thr Asp Leu Val Phe Gly Thr
900905910
Asp Val Thr Cys Trp Phe Val His Asn Ser Gly Lys Gly Phe Ile Asp
915920925
Gly His Tyr Lys Asp Tyr Phe Val Pro Gln Leu Tyr Ser Phe Leu Lys
930935940
Arg Pro
945
<210> 245
<211> 890
<212> PRT
<213> Homo sapiens
<220>
<223> Inter alpha trypsin inhibitor heavy chain 3
Q06033
<400> 245
Met Ala Phe Ala Trp Trp Pro Cys Leu Ile Leu Ala Leu Leu Ser Ser
151015
Leu Ala Ala Ser Gly Phe Pro Arg Ser Pro Phe Arg Leu Leu Gly Lys
202530
Arg Ser Leu Pro Glu Gly Val Ala Asn Gly Ile Glu Val Tyr Ser Thr
354045
Lys Ile Asn Ser Lys Val Thr Ser Arg Phe Ala His Asn Val Val Thr
505560
Met Arg Ala Val Asn Arg Ala Asp Thr Ala Lys Glu Val Ser Phe Asp
65707580
Val Glu Leu Pro Lys Thr Ala Phe Ile Thr Asn Phe Thr Leu Thr Ile
859095
Asp Gly Val Thr Tyr Pro Gly Asn Val Lys Glu Lys Glu Val Ala Lys
100105110
Lys Gln Tyr Glu Lys Ala Val Ser Gln Gly Lys Thr Ala Gly Leu Val
115120125
Lys Ala Ser Gly Arg Lys Leu Glu Lys Phe Thr Val Ser Val Asn Val
130135140
Ala Ala Gly Ser Lys Val Thr Phe Glu Leu Thr Tyr Glu Glu Leu Leu
145150155160
Lys Arg His Lys Gly Lys Tyr Glu Met Tyr Leu Lys Val Gln Pro Lys
165170175
Gln Leu Val Lys His Phe Glu Ile Glu Val Asp Ile Phe Glu Pro Gln
180185190
Gly Ile Ser Met Leu Asp Ala Glu Ala Ser Phe Ile Thr Asn Asp Leu
195200205
Leu Gly Ser Ala Leu Thr Lys Ser Phe Ser Gly Lys Lys Gly His Val
210215220
Ser Phe Lys Pro Ser Leu Asp Gln Gln Arg Ser Cys Pro Thr Cys Thr
225230235240
Asp Ser Leu Leu Asn Gly Asp Phe Thr Ile Thr Tyr Asp Val Asn Arg
245250255
Glu Ser Pro Gly Asn Val Gln Ile Val Asn Gly Tyr Phe Val His Phe
260265270
Phe Ala Pro Gln Gly Leu Pro Val Val Pro Lys Asn Val Ala Phe Val
275280285
Ile Asp Ile Ser Gly Ser Met Ala Gly Arg Lys Leu Glu Gln Thr Lys
290295300
Glu Ala Leu Leu Arg Ile Leu Glu Asp Met Gln Glu Glu Asp Tyr Leu
305310315320
Asn Phe Ile Leu Phe Ser Gly Asp Val Ser Thr Trp Lys Glu His Leu
325330335
Val Gln Ala Thr Pro Glu Asn Leu Gln Glu Ala Arg Thr Phe Val Lys
340345350
Ser Met Glu Asp Lys Gly Met Thr Asn Ile Asn Asp Gly Leu Leu Arg
355360365
Gly Ile Ser Met Leu Asn Lys Ala Arg Glu Glu His Arg Ile Pro Glu
370375380
Arg Ser Thr Ser Ile Val Ile Met Leu Thr Asp Gly Asp Ala Asn Val
385390395400
Gly Glu Ser Arg Pro Glu Lys Ile Gln Glu Asn Val Arg Asn Ala Ile
405410415
Gly Gly Lys Phe Pro Leu Tyr Asn Leu Gly Phe Gly Asn Asn Leu Asn
420425430
Tyr Asn Phe Leu Glu Asn Met Ala Leu Glu Asn His Gly Phe Ala Arg
435440445
Arg Ile Tyr Glu Asp Ser Asp Ala Asp Leu Gln Leu Gln Gly Phe Tyr
450455460
Glu Glu Val Ala Asn Pro Leu Leu Thr Gly Val Glu Met Glu Tyr Pro
465470475480
Glu Asn Ala Ile Leu Asp Leu Thr Gln Asn Thr Tyr Gln His Phe Tyr
485490495
Asp Gly Ser Glu Ile Val Val Ala Gly Arg Leu Val Asp Glu Asp Met
500505510
Asn Ser Phe Lys Ala Asp Val Lys Gly His Gly Ala Thr Asn Asp Leu
515520525
Thr Phe Thr Glu Glu Val Asp Met Lys Glu Met Glu Lys Ala Leu Gln
530535540
Glu Arg Asp Tyr Ile Phe Gly Asn Tyr Ile Glu Arg Leu Trp Ala Tyr
545550555560
Leu Thr Ile Glu Gln Leu Leu Glu Lys Arg Lys Asn Ala His Gly Glu
565570575
Glu Lys Glu Asn Leu Thr Ala Arg Ala Leu Asp Leu Ser Leu Lys Tyr
580585590
His Phe Val Thr Pro Leu Thr Ser Met Val Val Thr Lys Pro Glu Asp
595600605
Asn Glu Asp Glu Arg Ala Ile Ala Asp Lys Pro Gly Glu Asp Ala Glu
610615620
Ala Thr Pro Val Ser Pro Ala Met Ser Tyr Leu Thr Ser Tyr Gln Pro
625630635640
Pro Gln Asn Pro Tyr Tyr Tyr Val Asp Gly Asp Pro His Phe Ile Ile
645650655
Gln Ile Pro Glu Lys Asp Asp Ala Leu Cys Phe Asn Ile Asp Glu Ala
660665670
Pro Gly Thr Val Leu Arg Leu Ile Gln Asp Ala Val Thr Gly Leu Thr
675680685
Val Asn Gly Gln Ile Thr Gly Asp Lys Arg Gly Ser Pro Asp Ser Lys
690695700
Thr Arg Lys Thr Tyr Phe Gly Lys Leu Gly Ile Ala Asn Ala Gln Met
705710715720
Asp Phe Gln Val Glu Val Thr Thr Glu Lys Ile Thr Leu Trp Asn Arg
725730735
Ala Val Pro Ser Thr Phe Ser Trp Leu Asp Thr Val Thr Val Thr Gln
740745750
Asp Gly Leu Ser Met Met Ile Asn Arg Lys Asn Met Val Val Ser Phe
755760765
Gly Asp Gly Val Thr Phe Val Val Val Leu His Gln Val Trp Lys Lys
770775780
His Pro Val His Arg Asp Phe Leu Gly Phe Tyr Val Val Asp Ser His
785790795800
Arg Met Ser Ala Gln Thr His Gly Leu Leu Gly Gln Phe Phe Gln Pro
805810815
Phe Asp Phe Lys Val Ser Asp Ile Arg Pro Gly Ser Asp Pro Thr Lys
820825830
Pro Asp Ala Thr Leu Val Val Lys Asn His Gln Leu Ile Val Thr Arg
835840845
Gly Ser Gln Lys Asp Tyr Arg Lys Asp Ala Ser Ile Gly Thr Lys Val
850855860
Val Cys Trp Phe Val His Asn Asn Gly Glu Gly Leu Ile Asp Gly Val
865870875880
His Thr Asp Tyr Ile Val Pro Asn Leu Phe
885890
<210> 246
<211> 797
<212> PRT
<213> Homo sapiens
<220>
<223> human SPACR protein Q17R60
<400> 246
Met Tyr Leu Glu Thr Arg Arg Ala Ile Phe Val Phe Trp Ile Phe Leu
151015
Gln Val Gln Gly Thr Lys Asp Ile Ser Ile Asn Ile Tyr His Ser Glu
202530
Thr Lys Asp Ile Asp Asn Pro Pro Arg Asn Glu Thr Thr Glu Ser Thr
354045
Glu Lys Met Tyr Lys Met Ser Thr Met Arg Arg Ile Phe Asp Leu Ala
505560
Lys His Arg Thr Lys Arg Ser Ala Phe Phe Pro Thr Gly Val Lys Val
65707580
Cys Pro Gln Glu Ser Met Lys Gln Ile Leu Asp Ser Leu Gln Ala Tyr
859095
Tyr Arg Leu Arg Val Cys Gln Glu Ala Val Trp Glu Ala Tyr Arg Ile
100105110
Phe Leu Asp Arg Ile Pro Asp Thr Gly Glu Tyr Gln Asp Trp Val Ser
115120125
Ile Cys Gln Gln Glu Thr Phe Cys Leu Phe Asp Ile Gly Lys Asn Phe
130135140
Ser Asn Ser Gln Glu His Leu Asp Leu Leu Gln Gln Arg Ile Lys Gln
145150155160
Arg Ser Phe Pro Asp Arg Lys Asp Glu Ile Ser Ala Glu Lys Thr Leu
165170175
Gly Glu Pro Gly Glu Thr Ile Val Ile Ser Thr Asp Val Ala Asn Val
180185190
Ser Leu Gly Pro Phe Pro Leu Thr Pro Asp Asp Thr Leu Leu Asn Glu
195200205
Ile Leu Asp Asn Thr Leu Asn Asp Thr Lys Met Pro Thr Thr Glu Arg
210215220
Glu Thr Glu Phe Ala Val Leu Glu Glu Gln Arg Val Glu Leu Ser Val
225230235240
Ser Leu Val Asn Gln Lys Phe Lys Ala Glu Leu Ala Asp Ser Gln Ser
245250255
Pro Tyr Tyr Gln Glu Leu Ala Gly Lys Ser Gln Leu Gln Met Gln Lys
260265270
Ile Phe Lys Lys Leu Pro Gly Phe Lys Lys Ile His Val Leu Gly Phe
275280285
Arg Pro Lys Lys Glu Lys Asp Gly Ser Ser Ser Thr Glu Met Gln Leu
290295300
Thr Ala Ile Phe Lys Arg His Ser Ala Glu Ala Lys Ser Pro Ala Ser
305310315320
Asp Leu Leu Ser Phe Asp Ser Asn Lys Ile Glu Ser Glu Glu Val Tyr
325330335
His Gly Thr Met Glu Glu Asp Lys Gln Pro Glu Ile Tyr Leu Thr Ala
340345350
Thr Asp Leu Lys Arg Leu Ile Ser Lys Ala Leu Glu Glu Glu Gln Ser
355360365
Leu Asp Val Gly Thr Ile Gln Phe Thr Asp Glu Ile Ala Gly Ser Leu
370375380
Pro Ala Phe Gly Pro Asp Thr Gln Ser Glu Leu Pro Thr Ser Phe Ala
385390395400
Val Ile Thr Glu Asp Ala Thr Leu Ser Pro Glu Leu Pro Pro Val Glu
405410415
Pro Gln Leu Glu Thr Val Asp Gly Ala Glu His Gly Leu Pro Asp Thr
420425430
Ser Trp Ser Pro Pro Ala Met Ala Ser Thr Ser Leu Ser Glu Ala Pro
435440445
Pro Phe Phe Met Ala Ser Ser Ile Phe Ser Leu Thr Asp Gln Gly Thr
450455460
Thr Asp Thr Met Ala Thr Asp Gln Thr Met Leu Val Pro Gly Leu Thr
465470475480
Ile Pro Thr Ser Asp Tyr Ser Ala Ile Ser Gln Leu Ala Leu Gly Ile
485490495
Ser His Pro Pro Ala Ser Ser Asp Asp Ser Arg Ser Ser Ala Gly Gly
500505510
Glu Asp Met Val Arg His Leu Asp Glu Met Asp Leu Ser Asp Thr Pro
515520525
Ala Pro Ser Glu Val Pro Glu Leu Ser Glu Tyr Val Ser Val Pro Asp
530535540
His Phe Leu Glu Asp Thr Thr Pro Val Ser Ala Leu Gln Tyr Ile Thr
545550555560
Thr Ser Ser Met Thr Ile Ala Pro Lys Gly Arg Glu Leu Val Val Phe
565570575
Phe Ser Leu Arg Val Ala Asn Met Ala Phe Ser Asn Asp Leu Phe Asn
580585590
Lys Ser Ser Leu Glu Tyr Arg Ala Leu Glu Gln Gln Phe Thr Gln Leu
595600605
Leu Val Pro Tyr Leu Arg Ser Asn Leu Thr Gly Phe Lys Gln Leu Glu
610615620
Ile Leu Asn Phe Arg Asn Gly Ser Val Ile Val Asn Ser Lys Met Lys
625630635640
Phe Ala Lys Ser Val Pro Tyr Asn Leu Thr Lys Ala Val His Gly Val
645650655
Leu Glu Asp Phe Arg Ser Ala Ala Ala Gln Gln Leu His Leu Glu Ile
660665670
Asp Ser Tyr Ser Leu Asn Ile Glu Pro Ala Asp Gln Ala Asp Pro Cys
675680685
Lys Phe Leu Ala Cys Gly Glu Phe Ala Gln Cys Val Lys Asn Glu Arg
690695700
Thr Glu Glu Ala Glu Cys Arg Cys Lys Pro Gly Tyr Asp Ser Gln Gly
705710715720
Ser Leu Asp Gly Leu Glu Pro Gly Leu Cys Gly Pro Gly Thr Lys Glu
725730735
Cys Glu Val Leu Gln Gly Lys Gly Ala Pro Cys Arg Leu Pro Asp His
740745750
Ser Glu Asn Gln Ala Tyr Lys Thr Ser Val Lys Lys Phe Gln Asn Gln
755760765
Gln Asn Asn Lys Val Ile Ser Lys Arg Asn Ser Glu Leu Leu Thr Val
770775780
Glu Tyr Glu Glu Phe Asn His Gln Asp Trp Glu Gly Asn
785790795
<210> 247
<211> 1241
<212> PRT
<213> Homo sapiens
<220>
<223> human SPACRCAN protein Q9BZV3
<400> 247
Met Ile Met Phe Pro Leu Phe Gly Lys Ile Ser Leu Gly Ile Leu Ile
151015
Phe Val Leu Ile Glu Gly Asp Phe Pro Ser Leu Thr Ala Gln Thr Tyr
202530
Leu Ser Ile Glu Glu Ile Gln Glu Pro Lys Ser Ala Val Ser Phe Leu
354045
Leu Pro Glu Glu Ser Thr Asp Leu Ser Leu Ala Thr Lys Lys Lys Gln
505560
Pro Leu Asp Arg Arg Glu Thr Glu Arg Gln Trp Leu Ile Arg Arg Arg
65707580
Arg Ser Ile Leu Phe Pro Asn Gly Val Lys Ile Cys Pro Asp Glu Ser
859095
Val Ala Glu Ala Val Ala Asn His Val Lys Tyr Phe Lys Val Arg Val
100105110
Cys Gln Glu Ala Val Trp Glu Ala Phe Arg Thr Phe Trp Asp Arg Leu
115120125
Pro Gly Arg Glu Glu Tyr His Tyr Trp Met Asn Leu Cys Glu Asp Gly
130135140
Val Thr Ser Ile Phe Glu Met Gly Thr Asn Phe Ser Glu Ser Val Glu
145150155160
His Arg Ser Leu Ile Met Lys Lys Leu Thr Tyr Ala Lys Glu Thr Val
165170175
Ser Ser Ser Glu Leu Ser Ser Pro Val Pro Val Gly Asp Thr Ser Thr
180185190
Leu Gly Asp Thr Thr Leu Ser Val Pro His Pro Glu Val Asp Ala Tyr
195200205
Glu Gly Ala Ser Glu Ser Ser Leu Glu Arg Pro Glu Glu Ser Ile Ser
210215220
Asn Glu Ile Glu Asn Val Ile Glu Glu Ala Thr Lys Pro Ala Gly Glu
225230235240
Gln Ile Ala Glu Phe Ser Ile His Leu Leu Gly Lys Gln Tyr Arg Glu
245250255
Glu Leu Gln Asp Ser Ser Ser Phe His His Gln His Leu Glu Glu Glu
260265270
Phe Ile Ser Glu Val Glu Asn Ala Phe Thr Gly Leu Pro Gly Tyr Lys
275280285
Glu Ile Arg Val Leu Glu Phe Arg Ser Pro Lys Glu Asn Asp Ser Gly
290295300
Val Asp Val Tyr Tyr Ala Val Thr Phe Asn Gly Glu Ala Ile Ser Asn
305310315320
Thr Thr Trp Asp Leu Ile Ser Leu His Ser Asn Lys Val Glu Asn His
325330335
Gly Leu Val Glu Leu Asp Asp Lys Pro Thr Val Val Tyr Thr Ile Ser
340345350
Asn Phe Arg Asp Tyr Ile Ala Glu Thr Leu Gln Gln Asn Phe Leu Leu
355360365
Gly Asn Ser Ser Leu Asn Pro Asp Pro Asp Ser Leu Gln Leu Ile Asn
370375380
Val Arg Gly Val Leu Arg His Gln Thr Glu Asp Leu Val Trp Asn Thr
385390395400
Gln Ser Ser Ser Leu Gln Ala Thr Pro Ser Ser Ile Leu Asp Asn Thr
405410415
Phe Gln Ala Ala Trp Pro Ser Ala Asp Glu Ser Ile Thr Ser Ser Ile
420425430
Pro Pro Leu Asp Phe Ser Ser Gly Pro Pro Ser Ala Thr Gly Arg Glu
435440445
Leu Trp Ser Glu Ser Pro Leu Gly Asp Leu Val Ser Thr His Lys Leu
450455460
Ala Phe Pro Ser Lys Met Gly Leu Ser Ser Ser Pro Glu Val Leu Glu
465470475480
Val Ser Ser Leu Thr Leu His Ser Val Thr Pro Ala Val Leu Gln Thr
485490495
Gly Leu Pro Val Ala Ser Glu Glu Arg Thr Ser Gly Ser His Leu Val
500505510
Glu Asp Gly Leu Ala Asn Val Glu Glu Ser Glu Asp Phe Leu Ser Ile
515520525
Asp Ser Leu Pro Ser Ser Ser Phe Thr Gln Pro Val Pro Lys Glu Thr
530535540
Ile Pro Ser Met Glu Asp Ser Asp Val Ser Leu Thr Ser Ser Pro Tyr
545550555560
Leu Thr Ser Ser Ile Pro Phe Gly Leu Asp Ser Leu Thr Ser Lys Val
565570575
Lys Asp Gln Leu Lys Val Ser Pro Phe Leu Pro Asp Ala Ser Met Glu
580585590
Lys Glu Leu Ile Phe Asp Gly Gly Leu Gly Ser Gly Ser Gly Gln Lys
595600605
Val Asp Leu Ile Thr Trp Pro Trp Ser Glu Thr Ser Ser Glu Lys Ser
610615620
Ala Glu Pro Leu Ser Lys Pro Trp Leu Glu Asp Asp Asp Ser Leu Leu
625630635640
Pro Ala Glu Ile Glu Asp Lys Lys Leu Val Leu Val Asp Lys Met Asp
645650655
Ser Thr Asp Gln Ile Ser Lys His Ser Lys Tyr Glu His Asp Asp Arg
660665670
Ser Thr His Phe Pro Glu Glu Glu Pro Leu Ser Gly Pro Ala Val Pro
675680685
Ile Phe Ala Asp Thr Ala Ala Glu Ser Ala Ser Leu Thr Leu Pro Lys
690695700
His Ile Ser Glu Val Pro Gly Val Asp Asp Tyr Ser Val Thr Lys Ala
705710715720
Pro Leu Ile Leu Thr Ser Val Ala Ile Ser Ala Ser Thr Asp Lys Ser
725730735
Asp Gln Ala Asp Ala Ile Leu Arg Glu Asp Met Glu Gln Ile Thr Glu
740745750
Ser Ser Asn Tyr Glu Trp Phe Asp Ser Glu Val Ser Met Val Lys Pro
755760765
Asp Met Gln Thr Leu Trp Thr Ile Leu Pro Glu Ser Glu Arg Val Trp
770775780
Thr Arg Thr Ser Ser Leu Glu Lys Leu Ser Arg Asp Ile Leu Ala Ser
785790795800
Thr Pro Gln Ser Ala Asp Arg Leu Trp Leu Ser Val Thr Gln Ser Thr
805810815
Lys Leu Pro Pro Thr Thr Ile Ser Thr Leu Leu Glu Asp Glu Val Ile
820825830
Met Gly Val Gln Asp Ile Ser Leu Glu Leu Asp Arg Ile Gly Thr Asp
835840845
Tyr Tyr Gln Pro Glu Gln Val Gln Glu Gln Asn Gly Lys Val Gly Ser
850855860
Tyr Val Glu Met Ser Thr Ser Val His Ser Thr Glu Met Val Ser Val
865870875880
Ala Trp Pro Thr Glu Gly Gly Asp Asp Leu Ser Tyr Thr Gln Thr Ser
885890895
Gly Ala Leu Val Val Phe Phe Ser Leu Arg Val Thr Asn Met Met Phe
900905910
Ser Glu Asp Leu Phe Asn Lys Asn Ser Leu Glu Tyr Lys Ala Leu Glu
915920925
Gln Arg Phe Leu Glu Leu Leu Val Pro Tyr Leu Gln Ser Asn Leu Thr
930935 940
Gly Phe Gln Asn Leu Glu Ile Leu Asn Phe Arg Asn Gly Ser Ile Val
945950955960
Val Asn Ser Arg Met Lys Phe Ala Asn Ser Val Pro Pro Asn Val Asn
965970975
Asn Ala Val Tyr Met Ile Leu Glu Asp Phe Cys Thr Thr Ala Tyr Asn
980985990
Thr Met Asn Leu Ala Ile Asp Lys Tyr Ser Leu Asp Val Glu Ser Gly
99510001005
Asp Glu Ala Asn Pro Cys Lys Phe Gln Ala Cys Asn Glu Phe Ser Glu
101010151020
Cys Leu Val Asn Pro Trp Ser Gly Glu Ala Lys Cys Arg Cys Phe Pro
1025103010351040
Gly Tyr Leu Ser Val Glu Glu Arg Pro Cys Gln Ser Leu Cys Asp Leu
104510501055
Gln Pro Asp Phe Cys Leu Asn Asp Gly Lys Cys Asp Ile Met Pro Gly
106010651070
His Gly Ala Ile Cys Arg Cys Arg Val Gly Glu Asn Trp Trp Tyr Arg
107510801085
Gly Lys His Cys Glu Glu Phe Val Ser Glu Pro Val Ile Ile Gly Ile
109010951100
Thr Ile Ala Ser Val Val Gly Leu Leu Val Ile Phe Ser Ala Ile Ile
1105111011151120
Tyr Phe Phe Ile Arg Thr Leu Gln Ala His His Asp Arg Ser Glu Arg
112511301135
Glu Ser Pro Phe Ser Gly Ser Ser Arg Gln Pro Asp Ser Leu Ser Ser
114011451150
Ile Glu Asn Ala Val Lys Tyr Asn Pro Val Tyr Glu Ser His Arg Ala
115511601165
Gly Cys Glu Lys Tyr Glu Gly Pro Tyr Pro Gln His Pro Phe Tyr Ser
117011751180
Ser Ala Ser Gly Asp Val Ile Gly Gly Leu Ser Arg Glu Glu Ile Arg
1185119011951200
Gln Met Tyr Glu Ser Ser Glu Leu Ser Arg Glu Glu Ile Gln Glu Arg
120512101215
Met Arg Val Leu Glu Leu Tyr Ala Asn Asp Pro Glu Phe Ala Ala Phe
122012251230
Val Arg Glu Gln Gln Val Glu Glu Val
12351240
<210> 248
<211> 300
<212> PRT
<213> Homo sapiens
<220>
<223> human CD38 protein P28907
<400> 248
Met Ala Asn Cys Glu Phe Ser Pro Val Ser Gly Asp Lys Pro Cys Cys
151015
Arg Leu Ser Arg Arg Ala Gln Leu Cys Leu Gly Val Ser Ile Leu Val
202530
Leu Ile Leu Val Val Val Leu Ala Val Val Val Pro Arg Trp Arg Gln
354045
Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg Phe Pro Glu Thr Val Leu
505560
Ala Arg Cys Val Lys Tyr Thr Glu Ile His Pro Glu Met Arg His Val
65707580
Asp Cys Gln Ser Val Trp Asp Ala Phe Lys Gly Ala Phe Ile Ser Lys
859095
His Pro Cys Asn Ile Thr Glu Glu Asp Tyr Gln Pro Leu Met Lys Leu
100105110
Gly Thr Gln Thr Val Pro Cys Asn Lys Ile Leu Leu Trp Ser Arg Ile
115120125
Lys Asp Leu Ala His Gln Phe Thr Gln Val Gln Arg Asp Met Phe Thr
130135140
Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala Asp Asp Leu Thr Trp Cys
145150155160
Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr Gln Ser Cys Pro Asp Trp
165170175
Arg Lys Asp Cys Ser Asn Asn Pro Val Ser Val Phe Trp Lys Thr Val
180185190
Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp Val Val His Val Met Leu
195200205
Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys Asn Ser Thr Phe Gly Ser
210215220
Val Glu Val His Asn Leu Gln Pro Glu Lys Val Gln Thr Leu Glu Ala
225230235240
Trp Val Ile His Gly Gly Arg Glu Asp Ser Arg Asp Leu Cys Gln Asp
245250255
Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile Ser Lys Arg Asn Ile Gln
260265270
Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp Lys Phe Leu Gln Cys Val
275280285
Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser Glu Ile
290295300
<210> 249
<211> 413
<212> PRT
<213> Homo sapiens
<220>
<223> Intracellular hyaluronan-binding protein 4Q5JVS0
<400> 249
Met Lys Gly Ala Leu Gly Ser Pro Val Ala Ala Ala Gly Ala Ala Met
151015
Gln Glu Ser Phe Gly Cys Val Val Ala Asn Arg Phe His Gln Leu Leu
202530
Asp Asp Glu Ser Asp Pro Phe Asp Ile Leu Arg Glu Ala Glu Arg Arg
354045
Arg Gln Gln Gln Leu Gln Arg Lys Arg Arg Asp Glu Ala Ala Ala Ala
505560
Ala Gly Ala Gly Pro Arg Gly Gly Arg Ser Pro Ala Gly Ala Ser Gly
65707580
His Arg Ala Gly Ala Gly Gly Arg Arg Glu Ser Gln Lys Glu Arg Lys
859095
Ser Leu Pro Ala Pro Val Ala Gln Arg Pro Asp Ser Pro Gly Gly Gly
100105110
Leu Gln Ala Pro Gly Gln Lys Arg Thr Pro Arg Arg Gly Glu Gln Gln
115120125
Gly Trp Asn Asp Ser Arg Gly Pro Glu Gly Met Leu Glu Arg Ala Glu
130135140
Arg Arg Ser Tyr Arg Glu Tyr Arg Pro Tyr Glu Thr Glu Arg Gln Ala
145150155160
Asp Phe Thr Ala Glu Lys Phe Pro Asp Glu Lys Pro Gly Asp Arg Phe
165170175
Asp Arg Asp Arg Pro Leu Arg Gly Arg Gly Gly Pro Arg Gly Gly Met
180185190
Arg Gly Arg Gly Arg Gly Gly Pro Gly Asn Arg Val Phe Asp Ala Phe
195200205
Asp Gln Arg Gly Lys Arg Glu Phe Glu Arg Tyr Gly Gly Asn Asp Lys
210215220
Ile Ala Val Arg Thr Glu Asp Asn Met Gly Gly Cys Gly Val Arg Thr
225230235240
Trp Gly Ser Gly Lys Asp Thr Ser Asp Val Glu Pro Thr Ala Pro Met
245250255
Glu Glu Pro Thr Val Val Glu Glu Ser Gln Gly Thr Pro Glu Glu Glu
260265270
Ser Pro Ala Lys Val Pro Glu Leu Glu Val Glu Glu Glu Thr Gln Val
275280285
Gln Glu Met Thr Leu Asp Glu Trp Lys Asn Leu Gln Glu Gln Thr Arg
290295300
Pro Lys Pro Glu Phe Asn Ile Arg Lys Pro Glu Ser Thr Val Pro Ser
305310315320
Lys Ala Val Val Ile His Lys Ser Lys Tyr Arg Asp Asp Met Val Lys
325330335
Asp Asp Tyr Glu Asp Asp Ser His Val Phe Arg Lys Pro Ala Asn Asp
340345350
Ile Thr Ser Gln Leu Glu Ile Asn Phe Gly Asn Leu Pro Arg Pro Gly
355360365
Arg Gly Ala Arg Gly Gly Thr Arg Gly Gly Arg Gly Arg Ile Arg Arg
370375380
Ala Glu Asn Tyr Gly Pro Arg Ala Glu Val Val Met Gln Asp Val Ala
385390395400
Pro Asn Pro Asp Asp Pro Glu Asp Phe Pro Ala Leu Ser
405410
<210> 250
<211> 378
<212> PRT
<213> Homo sapiens
<220>
<223> human CDC37 protein Q16543
<400> 250
Met Val Asp Tyr Ser Val Trp Asp His Ile Glu Val Ser Asp Asp Glu
151015
Asp Glu Thr His Pro Asn Ile Asp Thr Ala Ser Leu Phe Arg Trp Arg
202530
His Gln Ala Arg Val Glu Arg Met Glu Gln Phe Gln Lys Glu Lys Glu
354045
Glu Leu Asp Arg Gly Cys Arg Glu Cys Lys Arg Lys Val Ala Glu Cys
505560
Gln Arg Lys Leu Lys Glu Leu Glu Val Ala Glu Gly Gly Lys Ala Glu
65707580
Leu Glu Arg Leu Gln Ala Glu Ala Gln Gln Leu Arg Lys Glu Glu Arg
859095
Ser Trp Glu Gln Lys Leu Glu Glu Met Arg Lys Lys Glu Lys Ser Met
100105110
Pro Trp Asn Val Asp Thr Leu Ser Lys Asp Gly Phe Ser Lys Ser Met
115120125
Val Asn Thr Lys Pro Glu Lys Thr Glu Glu Asp Ser Glu Glu Val Arg
130135140
Glu Gln Lys His Lys Thr Phe Val Glu Lys Tyr Glu Lys Gln Ile Lys
145150155160
His Phe Gly Met Leu Arg Arg Trp Asp Asp Ser Gln Lys Tyr Leu Ser
165170175
Asp Asn Val His Leu Val Cys Glu Glu Thr Ala Asn Tyr Leu Val Ile
180185190
Trp Cys Ile Asp Leu Glu Val Glu Glu Lys Cys Ala Leu Met Glu Gln
195200205
Val Ala His Gln Thr Ile Val Met Gln Phe Ile Leu Glu Leu Ala Lys
210215220
Ser Leu Lys Val Asp Pro Arg Ala Cys Phe Arg Gln Phe Phe Thr Lys
225230235240
Ile Lys Thr Ala Asp Arg Gln Tyr Met Glu Gly Phe Asn Asp Glu Leu
245250255
Glu Ala Phe Lys Glu Arg Val Arg Gly Arg Ala Lys Leu Arg Ile Glu
260265270
Lys Ala Met Lys Glu Tyr Glu Glu Glu Glu Arg Lys Lys Arg Leu Gly
275280285
Pro Gly Gly Leu Asp Pro Val Glu Val Tyr Glu Ser Leu Pro Glu Glu
290295300
Leu Gln Lys Cys Phe Asp Val Lys Asp Val Gln Met Leu Gln Asp Ala
305310315320
Ile Ser Lys Met Asp Pro Thr Asp Ala Lys Tyr His Met Gln Arg Cys
325330335
Ile Asp Ser Gly Leu Trp Val Pro Asn Ser Lys Ala Ser Glu Ala Lys
340345350
Glu Gly Glu Glu Ala Gly Pro Gly Asp Pro Leu Leu Glu Ala Val Pro
355360365
Lys Thr Gly Asp Glu Lys Asp Val Ser Val
370375
<210> 251
<211> 560
<212> PRT
<213> Homo sapiens
<220>
<223> Hyaluronan-binding protein 2 PHBPQ14520
<400> 251
Met Phe Ala Arg Met Ser Asp Leu His Val Leu Leu Leu Met Ala Leu
151015
Val Gly Lys Thr Ala Cys Gly Phe Ser Leu Met Ser Leu Leu Glu Ser
202530
Leu Asp Pro Asp Trp Thr Pro Asp Gln Tyr Asp Tyr Ser Tyr Glu Asp
354045
Tyr Asn Gln Glu Glu Asn Thr Ser Ser Thr Leu Thr His Ala Glu Asn
505560
Pro Asp Trp Tyr Tyr Thr Glu Asp Gln Ala Asp Pro Cys Gln Pro Asn
65707580
Pro Cys Glu His Gly Gly Asp Cys Leu Val His Gly Ser Thr Phe Thr
859095
Cys Ser Cys Leu Ala Pro Phe Ser Gly Asn Lys Cys Gln Lys Val Gln
100105110
Asn Thr Cys Lys Asp Asn Pro Cys Gly Arg Gly Gln Cys Leu Ile Thr
115120125
Gln Ser Pro Pro Tyr Tyr Arg Cys Val Cys Lys His Pro Tyr Thr Gly
130135140
Pro Ser Cys Ser Gln Val Val Pro Val Cys Arg Pro Asn Pro Cys Gln
145150155160
Asn Gly Ala Thr Cys Ser Arg His Lys Arg Arg Ser Lys Phe Thr Cys
165170175
Ala Cys Pro Asp Gln Phe Lys Gly Lys Phe Cys Glu Ile Gly Ser Asp
180185190
Asp Cys Tyr Val Gly Asp Gly Tyr Ser Tyr Arg Gly Lys Met Asn Arg
195200205
Thr Val Asn Gln His Ala Cys Leu Tyr Trp Asn Ser His Leu Leu Leu
210215220
Gln Glu Asn Tyr Asn Met Phe Met Glu Asp Ala Glu Thr His Gly Ile
225230235240
Gly Glu His Asn Phe Cys Arg Asn Pro Asp Ala Asp Glu Lys Pro Trp
245250255
Cys Phe Ile Lys Val Thr Asn Asp Lys Val Lys Trp Glu Tyr Cys Asp
260265270
Val Ser Ala Cys Ser Ala Gln Asp Val Ala Tyr Pro Glu Glu Ser Pro
275280285
Thr Glu Pro Ser Thr Lys Leu Pro Gly Phe Asp Ser Cys Gly Lys Thr
290295300
Glu Ile Ala Glu Arg Lys Ile Lys Arg Ile Tyr Gly Gly Phe Lys Ser
305310315320
Thr Ala Gly Lys His Pro Trp Gln Ala Ser Leu Gln Ser Ser Leu Pro
325330335
Leu Thr Ile Ser Met Pro Gln Gly His Phe Cys Gly Gly Ala Leu Ile
340345350
His Pro Cys Trp Val Leu Thr Ala Ala His Cys Thr Asp Ile Lys Thr
355360365
Arg His Leu Lys Val Val Leu Gly Asp Gln Asp Leu Lys Lys Glu Glu
370375380
Phe His Glu Gln Ser Phe Arg Val Glu Lys Ile Phe Lys Tyr Ser His
385390395400
Tyr Asn Glu Arg Asp Glu Ile Pro His Asn Asp Ile Ala Leu Leu Lys
405410415
Leu Lys Pro Val Asp Gly His Cys Ala Leu Glu Ser Lys Tyr Val Lys
420425430
Thr Val Cys Leu Pro Asp Gly Ser Phe Pro Ser Gly Ser Glu Cys His
435440445
Ile Ser Gly Trp Gly Val Thr Glu Thr Gly Lys Gly Ser Arg Gln Leu
450455460
Leu Asp Ala Lys Val Lys Leu Ile Ala Asn Thr Leu Cys Asn Ser Arg
465470475480
Gln Leu Tyr Asp His Met Ile Asp Asp Ser Met Ile Cys Ala Gly Asn
485490495
Leu Gln Lys Pro Gly Gln Asp Thr Cys Gln Gly Asp Ser Gly Gly Pro
500505510
Leu Thr Cys Glu Lys Asp Gly Thr Tyr Tyr Val Tyr Gly Ile Val Ser
515520525
Trp Gly Leu Glu Cys Gly Lys Arg Pro Gly Val Tyr Thr Gln Val Thr
530535540
Lys Phe Leu Asn Trp Ile Lys Ala Thr Ile Lys Ser Glu Ser Gly Phe
545550555560
<210> 252
<211> 275
<212> PRT
<213> Mus musculus
<220>
<223> Mouse TSG-6O08859
<400> 252
Met Val Val Leu Leu Cys Leu Cys Val Leu Leu Trp Glu Glu Ala His
151015
Gly Trp Gly Phe Lys Asn Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Gln Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ala Gly Arg Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly Arg
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Asp Asp Asn Gln Val
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu His Asp Pro Gly Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Glu Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Thr Val Asp Pro Ala Ser Lys Ser Ser Gln Ala
245250255
Lys Asn Thr Ser Thr Thr Gly Asn Lys Lys Phe Leu Pro Gly Arg Phe
260265270
Ser His Leu
275
<210> 253
<211> 276
<212> PRT
<213> Oryctolagus cuniculus
<220>
<223> Rabbit TSG-6 P98065
<400> 253
Met Ile Ile Leu Ile Tyr Leu Phe Val Leu Val Trp Glu Glu Ala Gln
151015
Gly Trp Gly Phe Lys Asn Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Gln Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly Arg
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Ser Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Asp Asp Asn Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asn Phe Asp Leu Glu Tyr Asp Pro Gly Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Glu Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Thr Val Asp Pro Ala Ser Lys Ser Ser Gln Gly
245250255
Lys Asn Thr Ser Thr Val Ser Gly Asn Lys Asn Phe Leu Ala Gly Arg
260265270
Phe Ser His Leu
275
<210> 254
<211> 280
<212> PRT
<213> Bos taurus
<220>
<223> Cow TSG-6Q5W1C4
<400> 254
Met Ile Ile Leu Ile Tyr Leu Phe Val Leu Leu Trp Glu Glu Ala His
151015
Gly Trp Gly Phe Lys Asn Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Gln Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Tyr Glu Gly Gly His
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Asp Asp Asn Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu Asp Asp Pro Ala Cys Leu Ala Asp Tyr
180185190
Val Glu Val Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Glu Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Ala Val Asp Pro Val Ser Lys Ser Ser Gln Gly
245250255
Lys Asn Ala Ser Thr Thr Ser Thr Thr Ser Thr Gly Asn Lys Asn Phe
260265270
Leu Ala Gly Arg Phe Ser His Leu
275280
<210> 255
<211> 2571
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Stabilin-1Q8R4Y4
<400> 255
Met Ala Glu Pro Arg Thr Leu Leu Leu Leu Cys Val Leu Val Leu Cys
151015
Leu Ser Asp Ser Ser Phe Ile Arg Gly Gln Thr Val Arg Ser Lys Arg
202530
Cys Asp Ile His Thr Lys Phe Val Thr His Thr Pro Cys Thr Ala Cys
354045
Ala Ala Ile Arg Arg Gln Leu Cys Pro Trp Gly Trp Ser Arg Asn Phe
505560
Pro Glu Lys Ile Leu Leu Asp Cys Arg Tyr Glu Leu Gln Leu Arg Gly
65707580
Ala Ala Ile Ser Leu Ser Gly Cys Ser Gln Glu Cys Trp Lys Asp Val
859095
Val Gln Lys Ala Cys Cys Pro Gly Tyr Trp Gly Ser Gln Cys Phe Glu
100105110
Cys Pro Gly Gly Pro Ala Thr Pro Cys Ser Gly His Gly Thr Cys Leu
115120125
Asp Gly Ile Glu Gly Asn Gly Thr Cys Val Cys Gln Gly Asn Phe Ser
130135140
Gly Ser Val Cys Gln Glu Cys Arg Asp Pro Asn Arg Phe Gly Pro Asp
145150155160
Cys Gln Ser Val Cys Asn Cys Val His Gly Val Cys Ser His Gly Pro
165170175
Arg Gly Asp Gly Ser Cys Arg Cys Phe Ala Gly Tyr Thr Gly Pro His
180185190
Cys Asp Gln Glu Leu Pro Val Cys Gln Ser Leu Lys Cys Pro Gln Asn
195200205
Ser Gln Cys Ser Ala Glu Ala Pro Thr Cys Lys Cys Leu Pro Gly Tyr
210215220
Thr Gln Gln Asp Asn Val Cys Leu Ala Pro Asp Pro Cys Gln Pro Ser
225230235240
Ala Cys Ser Pro Leu Ala Arg Cys Ser Val Thr Pro Gln Gly Gln Ala
245250255
Gln Cys Gln Cys Pro Glu Asn Tyr His Gly Asp Gly Lys Val Cys Leu
260265270
Pro Arg Asp Pro Cys Leu Thr Asn Phe Gly Gly Cys Pro Ser Asn Ser
275280285
Thr Phe Cys Leu Tyr Arg Gly Pro Gly Lys Ala Thr Cys Met Cys Arg
290295300
Pro Gly Met Thr Ser Ile Asn Asn Asn Ala Ser Glu Gly Cys His Val
305310315320
Ser Cys Lys Pro His Ser Cys Asp Arg Ser Ala Thr Cys Gln Val Thr
325330335
Pro Asp Arg Lys Thr Ser Cys Val Cys Lys Asn Asp Glu Val Gly Asp
340345350
Gly His Ala Cys Tyr Gly His Leu Leu His Glu Val Arg Arg Ala Asn
355360365
Gln Asn Gly Leu Val Phe Leu Arg Leu Arg Ala Ala Ile Ala Met Leu
370375380
Glu Gln Gly Cys Gln Glu Ile Leu Thr Thr Ser Gly Pro Phe Thr Val
385390395400
Leu Val Pro Ser Met Phe Ser Val Ser Ser Val Ser Ser Asn Met Asn
405410415
Ala Thr Leu Ala Gln Gln Leu Cys Arg Gln His Val Ile Ala Gly Glu
420425430
His Met Leu Glu Asn Ala Gly Pro Pro Ser Thr Arg Arg Trp Trp Thr
435440445
Leu Ala Gly Gln Glu Val Thr Ile Thr Phe Lys Asn Met Arg Tyr Ala
450455460
Tyr Lys Tyr Glu Asp Gln Pro Gln Gln Phe Ser Ile His Lys Ala Asn
465470475480
Tyr Ile Ala Ala Asn Gly Val Phe His Thr Val Thr Ala Leu Arg Trp
485490495
Gln Leu Pro Pro Pro Leu Pro Gly Asp Ser Lys Lys Thr Val Gly Gln
500505510
Ile Leu Ala Ser Thr Glu Val Phe Thr Arg Phe Glu Thr Ile Leu Glu
515520525
Asn Cys Gly Leu Pro Ser Ile Leu Asp Gly Pro Gly Pro Phe Thr Val
530535540
Phe Ala Pro Ser Asn Glu Ala Val Asp Ser Leu Arg Asp Gly Arg Leu
545550555560
Ile Tyr Leu Phe Thr Ala Gly Leu Ser Lys Leu Gln Glu Leu Val Arg
565570575
Tyr His Ile Tyr Asn His Gly Gln Leu Thr Val Glu Lys Leu Ile Ser
580585590
Lys Gly Arg Val Leu Thr Met Ala Asn Gln Val Leu Thr Val Asn Ile
595600605
Ser Glu Gly Gly Arg Ile Leu Leu Gly Pro Gly Gly Ile Pro Val Arg
610615620
Arg Val Asp Val Pro Ala Ala Asn Gly Val Ile His Met Leu Glu Gly
625630635640
Ile Leu Leu Pro Pro Thr Ile Leu Pro Ile Leu Pro Lys His Cys Asp
645650655
Glu Glu Gln His Gln Thr Val Leu Gly Ser Cys Val Asp Cys Gln Ala
660665670
Leu Asn Thr Ser Val Cys Pro Pro Asn Ser Val Lys Met Asp Ile Phe
675680685
Pro Lys Glu Cys Val Tyr Ile His Asp Pro Asn Gly Leu Asn Val Leu
690695700
Lys Lys Gly Cys Ala Asp Tyr Cys Asn Gln Thr Ile Thr Lys Arg Gly
705710715720
Cys Cys Lys Gly Phe Phe Gly Pro Asp Cys Thr Gln Cys Pro Gly Gly
725730735
Phe Ser Asn Pro Cys Tyr Gly Lys Gly Asn Cys Ser Asp Gly Val Arg
740745750
Gly Asn Gly Ala Cys Leu Cys Phe Pro Asp Tyr Lys Gly Ile Ala Cys
755760765
His Ile Cys Ser Asp Pro Lys Lys His Gly Glu Gln Cys Gln Glu Asp
770775780
Cys Gly Cys Val His Gly Leu Cys Asp Asn Arg Pro Gly Ser Gly Gly
785790795800
Val Cys Gln Gln Gly Thr Cys Ala Pro Gly Phe Gln Gly Arg Phe Cys
805810815
Asn Glu Ser Met Gly Asn Cys Gly Ser Thr Gly Leu Ala Gln Pro Cys
820825830
His Ser Asp Ala His Cys Val Ile Gln Glu Gly Val Ala Arg Cys Val
835840845
Cys His Asp Gly Phe Glu Gly Asn Gly Phe Ser Cys Lys Arg Ser Asn
850855860
Pro Cys Ser Arg Pro Asp Arg Gly Gly Cys Ser Glu Asn Ala Glu Cys
865870875880
Val Pro Gly Asp Leu Gly Thr His His Cys Ile Cys His Lys Gly Trp
885890895
Ser Gly Asp Gly Arg Ile Cys Val Ala Ile Asp Glu Cys Gly Leu Asp
900905910
Thr Arg Gly Gly Cys His Ala Asp Ala Leu Cys Ser Tyr Val Gly Pro
915920925
Gly Gln Ser Arg Cys Thr Cys Lys Leu Gly Phe Ala Gly Asn Gly Tyr
930935940
Glu Cys Ser Pro Ile Asp Pro Cys Arg Val Gly Asn Gly Gly Cys His
945950955960
Gly Leu Ala Thr Cys Lys Ala Val Gly Gly Gly Gln Arg Val Cys Thr
965970975
Cys Pro Pro His Phe Gly Gly Asp Gly Phe Ser Cys Tyr Gly Asp Ile
980985990
Ile Gln Glu Leu Glu Ala Asn Ala His Phe Ser Ala Phe Ser Gln Trp
99510001005
Phe Lys Asn Ser Ser Ile Thr Leu Pro Ala Asp Ser Arg Val Thr Ala
101010151020
Leu Val Pro Ser Glu Ser Ala Ile Arg Arg Leu Ser Leu Glu Asp Gln
1025103010351040
Ala Phe Trp Leu Gln Pro Lys Met Leu Pro Glu Leu Ala Arg Ala His
104510501055
Phe Leu Gln Gly Ala Phe Ser Glu Glu Glu Leu Ala Arg Leu Asn Gly
106010651070
Gln Gln Val Ala Thr Leu Ser Ala Thr Thr Arg Trp Gln Ile His Asn
107510801085
Ile Ser Gly Lys Val Trp Val Gln Asn Ala Thr Val Asp Val Pro Asp
109010951100
Leu Leu Ala Thr Asn Gly Ile Leu His Ile Val Ser Gln Val Leu Leu
1105111011151120
Pro Pro Arg Gly Asp Met Gln Thr Gly Pro Gly Leu Leu Gln Gln Leu
112511301135
Asp Ser Val Pro Ala Phe Arg Leu Phe Gly Glu Gln Leu Lys His His
114011451150
Lys Leu Val Ala Gln Ile Glu Ala Ala Lys Ala Tyr Thr Ile Phe Val
115511601165
Pro Thr Asn His Ser Leu Glu Thr Gln Gly Asn Asn Ser Val Leu Gly
117011751180
Ile Asp Thr Val Arg His His Val Ile Leu Gly Glu Ala Leu Ser Val
1185119011951200
Glu Val Leu Arg Lys Gly Gly His Arg Asn Ser Leu Leu Gly Pro Ala
120512101215
His Trp Leu Val Phe Tyr Asn His Ser Gly Gln Pro Glu Val Asn His
122012251230
Met Pro Leu Glu Gly Pro Leu Leu Glu Ala Pro Gly Ser Ser Leu Phe
123512401245
Gly Leu Ser Gly Ile Leu Ala Val Gly Ser Ser Arg Cys Leu His Ser
125012551260
His Ala Glu Ala Leu Arg Glu Lys Cys Ile Asn Cys Thr Arg Lys Phe
1265127012751280
Arg Cys Thr Gln Gly Phe Gln Leu Gln Asp Thr Pro Arg Lys Ser Cys
128512901295
Val Tyr Arg Ser Gly Leu Ser Phe Ser Arg Gly Cys Ser Tyr Thr Cys
130013051310
Ala Lys Lys Ile Gln Val Pro Asp Cys Cys Pro Gly Phe Phe Gly Thr
131513201325
Leu Cys Glu Pro Cys Pro Gly Gly Leu Gly Gly Val Cys Ser Gly His
133013351340
Gly Gln Cys Gln Asp Arg Phe Leu Gly Asn Gly Glu Cys Arg Cys Gln
1345135013551360
Glu Gly Phe His Gly Thr Ala Cys Glu Met Cys Glu Leu Gly Arg Tyr
136513701375
Gly Pro Thr Cys Ser Gly Val Cys Asp Cys Asp His Gly Leu Cys Gln
138013851390
Glu Gly Leu Arg Gly Asn Gly Ser Cys Val Cys His Ala Gly Trp Gln
139514001405
Gly Leu Arg Cys Asp Gln Lys Ile Thr Asp His Gln Cys Pro Lys Lys
141014151420
Cys Asp Pro Asn Ala Asn Cys Ile Gln Asp Ser Ala Gly Ile Pro Ala
1425143014351440
Cys Val Cys Ala Ala Gly Tyr Ser Gly Asn Gly Ser Tyr Cys Ser Glu
144514501455
Val Asp Pro Cys Ala Ser Gly His Gly Gly Cys Ser Pro Tyr Ala Asn
146014651470
Cys Thr Lys Val Ala Pro Gly Gln Arg Thr Cys Thr Cys Gln Asp Gly
147514801485
Tyr Thr Gly Asp Gly Glu Leu Cys Gln Glu Ile Asn Ser Cys Leu Val
149014951500
His Asn Gly Gly Cys His Val His Ala Glu Cys Ile Pro Thr Gly Pro
1505151015151520
Gln Gln Val Ser Cys Ser Cys Arg Glu Gly Tyr Ser Gly Asp Gly Ile
152515301535
Gln Thr Cys Lys Leu Leu Asp Pro Cys Ser Gln Asn Asn Gly Gly Cys
154015451550
Ser Pro Tyr Ala Val Cys Lys Ser Thr Gly Asp Gly Gln Arg Thr Cys
155515601565
Ser Cys Asp Ala Thr His Thr Val Gly Asp Gly Ile Thr Cys His Gly
157015751580
Arg Val Gly Leu Glu Leu Leu Arg Asn Lys Tyr Ala Ser Phe Phe Ser
1585159015951600
Leu His Leu Leu Glu Tyr Lys Glu Leu Lys Gly Asp Gly Pro Phe Thr
160516101615
Val Phe Val Pro His Ala Asp Leu Ile Ser Asn Met Ser Gln Asp Glu
162016251630
Leu Ala Arg Ile Arg Ala His Arg Gln Leu Val Phe Arg Tyr His Val
163516401645
Val Gly Cys Arg Lys Leu Trp Ser Gln Glu Met Leu Asp Gln Gly Tyr
165016551660
Ile Thr Thr Leu Ser Gly His Thr Leu Arg Val Ser Glu Arg Glu Gly
1665167016751680
Ser Ile Tyr Leu Asn Asp Phe Ala Arg Val Val Ser Ser Asp Leu Glu
168516901695
Val Val Asn Gly Val Leu His Phe Ile Asp His Val Leu Leu Pro Pro
170017051710
Asp Val Leu His Trp Glu Ser Gly Ala Ile Pro Ile Pro Gln Arg Asn
171517201725
Val Thr Ala Ala Ala Glu Ser Phe Gly Tyr Lys Ile Phe Ser Arg Leu
173017351740
Leu Thr Val Ala Gly Leu Leu Pro Met Leu Gln Asp Ala Ser His Arg
1745175017551760
Pro Phe Thr Met Leu Trp Pro Thr Asp Ser Ala Leu Gln Ala Leu Pro
176517701775
Pro Asp Arg Lys Asn Trp Leu Phe His Glu Asp His Arg Asp Lys Leu
178017851790
Ala Ala Ile Leu Arg Gly His Met Ile Arg Asn Ile Glu Ala Leu Ala
179518001805
Ser Asp Leu Pro Asn Leu Gly Gln Leu Arg Thr Met His Gly Asn Thr
181018151820
Ile Ser Phe Ser Cys Gly Leu Thr Arg Pro Gly Glu Leu Ile Val Gly
1825183018351840
Glu Asp Glu Ala His Ile Val Gln Arg His Leu Thr Phe Glu Gly Gly
184518501855
Leu Ala Tyr Gly Ile Asp Gln Leu Leu Glu Pro Pro Asp Leu Gly Ala
186018651870
Arg Cys Asp Arg Phe Glu Pro Gln Pro Leu Gln Met Lys Thr Cys Ser
187518801885
Ile Cys Gly Leu Glu Pro Pro Cys Pro Arg Gly Ser Arg Glu Gln Gly
189018951900
Ser Pro Glu Thr Cys Trp Arg His Tyr Ser Lys Phe Trp Thr Thr Pro
1905191019151920
Leu His Ser Ile Ser Met Arg Gly Ala Tyr Trp Ile Pro Ser Ser Phe
192519301935
Trp Asn Arg Asn His Met Ser Arg Gly Cys His Arg Asn Cys Val Thr
194019451950
Thr Val Trp Lys Pro Ser Cys Cys Pro Gly His Tyr Gly Ile Asn Cys
195519601965
His Ala Cys Pro Gly Gly Pro Arg Ser Pro Cys Ser Asp His Gly Val
197019751980
Cys Leu Asp Gly Ile Arg Gly Ser Gly Gln Cys Asn Cys His Pro Gly
1985199019952000
Phe Ala Gly Thr Ala Cys Glu Leu Cys Ala Pro Gly Ala Phe Gly Pro
200520102015
Gln Cys Gln Ala Cys Arg Cys Thr Gln His Gly Arg Cys Asp Glu Gly
202020252030
Leu Gly Gly Ser Gly Ser Cys Phe Cys Asp Glu Gly Trp Thr Gly Ala
203520402045
Arg Cys Glu Val Gln Leu Glu Leu Gln Pro Val Cys Thr Pro Pro Cys
205020552060
Ala Pro Gln Ala Val Cys Arg Leu Gly Asn Ser Cys Glu Cys Ser Leu
2065207020752080
Gly Tyr Glu Gly Asp Gly Arg Val Cys Thr Val Ala Asp Leu Cys Gln
208520902095
Lys Gly His Gly Gly Cys Ser Lys His Ala Asn Cys Ser Gln Val Gly
210021052110
Thr Val Val Thr Cys Thr Cys Leu Pro Asp Tyr Glu Gly Asp Gly Trp
211521202125
Ser Cys Arg Ala Arg Asp Pro Cys Leu Asp Gly His Arg Gly Gly Cys
213021352140
Ser Glu His Ala Asp Cys Leu Asn Thr Gly Pro Asn Thr Arg Arg Cys
2145215021552160
Glu Cys His Val Gly Tyr Val Gly Asp Gly Leu Gln Cys Leu Glu Glu
216521702175
Leu Glu Pro Pro Val Asp Arg Cys Leu Gly Gly Ser Ser Pro Cys His
218021852190
Thr Asp Ala Leu Cys Thr Asp Leu His Phe Gln Glu Lys Gln Ala Gly
219522002205
Val Phe His Ile Gln Ala Thr Ser Gly Pro Tyr Gly Leu Thr Phe Ser
221022152220
Glu Ala Lys Glu Ala Cys Glu Gly Gln Gly Ala Val Leu Ala Ser Leu
2225223022352240
Pro Gln Leu Ser Ala Ala Gln Gln Leu Gly Phe His Val Cys Phe Val
224522502255
Gly Trp Leu Ala Asn Gly Ser Ala Ala His Pro Val Val Thr Pro Ala
226022652270
Ala Asp Cys Gly Asn Asn Arg Val Gly Val Val Ser Leu Gly Val Arg
227522802285
Lys Asn Leu Ser Glu Leu Trp Asp Ala Tyr Cys Tyr Arg Val Gln Asp
229022952300
Val Ala Cys Gln Cys Arg Ala Gly Phe Val Gly Asp Gly Ile Ser Thr
2305231023152320
Cys Asn Gly Lys Leu Leu Asp Val Leu Ala Ala Thr Ala Asn Phe Ser
232523302335
Thr Phe Tyr Gly Met Leu Leu Gly Tyr Ala Asn Ala Thr Gln Arg Gly
234023452350
Leu Glu Phe Met Asp Phe Leu Glu Asp Glu Leu Thr Tyr Lys Thr Leu
235523602365
Phe Val Pro Val Asn Lys Gly Phe Val Asp Asn Met Thr Leu Ser Gly
237023752380
Pro Asp Leu Glu Leu His Ala Ser Asn Ala Thr Phe Leu Ser Ile Asn
2385239023952400
Ala Ser Arg Gly Thr Leu Leu Pro Ala His Ser Gly Leu Ser Leu Phe
240524102415
Ile Ser Asp Thr Gly Pro Asp Asn Thr Ser Leu Val Pro Leu Ala Pro
242024252430
Gly Ala Val Val Val Ser His Val Ile Val Trp Asp Ile Met Ala Phe
243524402445
Asn Gly Ile Ile His Ala Leu Ala Ser Pro Leu Leu Met Pro Pro Gln
245024552460
Thr Arg Ala Val Leu Gly Ser Glu Pro Pro Pro Val Ala Leu Ser Leu
2465247024752480
Gly Val Val Val Thr Ser Gly Thr Leu Leu Gly Leu Val Ala Gly Ala
248524902495
Leu Tyr Leu Arg Ala Arg Gly Lys Pro Pro Gly Phe Ser Phe Ser Ala
250025052510
Phe Gln Ala Glu Asp Asn Ala Asp Asp Asp Phe Ser Pro Trp Gln Glu
251525202525
Gly Thr Ser Pro Thr Leu Val Ser Val Pro Asn Pro Val Phe Gly Ser
253025352540
Ser Asp Ile Phe Cys Glu Pro Phe Asp Asp Ser Val Leu Glu Glu Asp
2545255025552560
Phe Pro Asp Thr Gln Arg Val Leu Lys Val Lys
25652570
<210> 256
<211> 2568
<212> PRT
<213> Bos taurus
<220>
<223> Cow Stabilin-1NP_001192499
<400> 256
Met Ala Gly Pro Arg Gly His Leu Leu Leu Cys Phe Leu Ala Leu Cys
151015
Leu Ala Gly Pro Ser Phe Phe Gly Glu Gln Lys Val Arg Ser Lys Arg
202530
Cys Asp Val Lys Thr Lys Phe Val Thr His Ile Pro Cys Thr Pro Cys
354045
Pro Ala Ile Lys Lys Arg Val Cys Pro Leu Gly Trp Ile Arg Ala Phe
505560
Pro Glu Lys Ile Ser Gln Asp Cys Arg Tyr Glu Val Gln Leu Gly Asp
65707580
Ser Leu Leu Ser Met Ser Gly Cys Ser Leu Glu Cys Trp Lys Asp Met
859095
Val Gln Lys Ala Cys Cys Pro Gly Tyr Trp Gly Ser Gln Cys Tyr Glu
100105110
Cys Pro Gly Gly Ala Glu Thr Pro Cys Ser Gly His Gly Thr Cys Leu
115120125
Asp Gly Leu Asp Gly Asn Gly Thr Cys Val Cys Gln Glu Asn Phe Ser
130135140
Gly Ser Ala Cys Gln Glu Cys Arg Asp Pro Asn Arg Phe Gly Pro Asp
145150155160
Cys Gln Ser Val Cys Arg Cys Val His Gly Val Cys Arg His Gly Pro
165170175
Arg Gly Asp Gly Ser Cys Leu Cys Phe Ala Gly Tyr Thr Gly Ala Arg
180185190
Cys Asp Gln Glu Leu Leu Ala Cys Gln Ala Leu Asn Cys Pro Arg Asn
195200 205
Ser Gln Cys Ser Glu Glu Ala Pro Ser Cys Ser Cys Leu Pro Gly Tyr
210215220
Thr Gln Gln Gly His Glu Cys Arg Ala Ser Asp Pro Cys Arg Pro Ser
225230235240
Pro Cys Ser Pro Leu Ala Gln Cys Ser Val Gly Pro Gly Gly Gln Ala
245250255
Gln Cys Arg Cys Pro Glu Asn Tyr His Gly Asp Gly Thr Val Cys Leu
260265270
Pro Gln Asp Pro Cys Thr Thr Asn Asn Gly Gly Cys Pro Ser Asn Ser
275280285
Thr Leu Cys Leu Tyr Arg Lys Pro Gly Gln Ala Ser Cys Leu Cys Lys
290295300
Pro Gly Leu Val Ser Ile Ala His Asp Ser Ser Ala Gly Cys Phe Ala
305310315320
His Cys Ser Ala Phe Ser Cys Asp Arg Ser Ala Thr Cys Gln Val Thr
325330335
Pro Asp Gly Lys Thr Ser Cys Val Cys Lys Glu Gly Glu Val Gly Asp
340345350
Gly Arg Ala Cys Tyr Gly His Leu Leu His Glu Val Gln Lys Ala Ser
355360365
Gln Thr Ser Met Leu Leu Arg Leu Arg Val Thr Phe Ala Met Leu Asp
370375380
Gln Gly Cys Arg Glu Ile Leu Ser Thr Ser Gly Pro Phe Thr Val Leu
385390395400
Ala Pro Leu Val Ser Ser Arg Thr Met Asn Ala Ser Val Ala Gln Gln
405410415
Leu Cys Arg Gln His Ile Ile Ala Gly Gln His Met Leu Glu Glu Ala
420425430
Gly Thr Gln Ala Pro Arg Arg Trp Trp Thr Leu Ala Gly Gln Glu Ile
435440445
Thr Val Ser Phe Ser Arg Phe Arg Lys Tyr Thr Tyr Lys Tyr Gln Asp
450455460
Gln Pro Gln Gln Thr Phe Thr Ile His Lys Ala Asn Tyr Pro Ala Ala
465470475480
Asn Gly Leu Phe His Val Val Thr Ala Leu Arg Leu Gln Pro Pro Pro
485490495
Glu Leu Pro Glu Asp Pro Lys Arg Thr Ile Gly Gln Ile Leu Ala Ser
500505510
Asn Glu Val Phe Ser Arg Phe Glu Thr Ile Leu Glu Asn Cys Gly Leu
515 520525
Pro Ser Phe Leu Asp Gly Pro Gly Pro Phe Thr Val Phe Ala Pro Ser
530535540
Asn Glu Ala Val Asp Gly Leu Arg Asp Gly Arg Leu Val Tyr Leu Phe
545550555560
Thr Ala Gly Leu Ser Lys Leu Gln Glu Leu Val Arg Tyr His Val Tyr
565570575
Asn His Gly Gln Leu Thr Val Glu Lys Leu Leu Ser Lys Gly Arg Val
580585590
Leu Thr Met Ala Asn Gln Ile Leu Ala Val Asn Ile Ser Glu Glu Gly
595600605
Arg Ile Leu Leu Gly Pro Glu Gly Val Pro Leu Arg Arg Val Asp Val
610615620
Leu Ala Ala Asn Gly Val Ile His Met Leu Glu Gly Val Leu Leu Pro
625630635640
Pro Thr Ile Leu Pro Ile Leu Pro Lys Leu Cys Asn Glu Glu Gln His
645650655
Ala Val Val Ala Gly Ser Cys Val Asp Cys Gln Ala Leu Asn Thr Ser
660665670
Thr Cys Pro Pro Asn Ser Val Lys Leu Asp Ile Ser Pro Glu Glu Cys
675680685
Val Tyr Ile His Asp Pro Thr Gly Leu Asn Val Leu Lys Lys Gly Cys
690695700
Ala Tyr Tyr Cys Asn Gln Thr Ile Gln Lys Pro Gly Cys Cys Lys Gly
705710715720
Phe Phe Gly Pro Asp Cys Leu Gln Cys Pro Gly Gly Phe Ser Asn Pro
725730735
Cys Tyr Gly Lys Gly Asn Cys Ser Asp Gly Val Gln Gly Ser Gly Ala
740745750
Cys Leu Cys Phe Pro Asp Tyr Lys Gly Ile Ala Cys His Ile Cys Ser
755760765
Asn Pro Asn Lys His Gly Asp Gln Cys Gln Glu Asp Cys Gly Cys Val
770775780
His Gly Leu Cys Asp Asn Arg Pro Gly Ser Gly Gly Val Cys Gln His
785790795800
Gly Thr Cys Ala Pro Gly Phe Ser Gly Arg Phe Cys Asn Glu Ser Thr
805810815
Val Ser Cys Gly Ser Thr Glu Gln Ala Gln Gln Cys His Pro His Ala
820825830
Arg Cys Val Asn Gln Gly Gly Val Ser Arg Cys Leu Cys Leu Asp Gly
835840845
Phe Glu Gly Asp Gly Phe Ser Cys Thr Pro Ser Asp Pro Cys Ser Arg
850855860
Pro Asp Arg Gly Gly Cys Ser Glu Asn Ala Glu Cys Val Pro Gly Val
865870875880
Arg Gly Ala His His Cys Met Cys His Lys Gly Trp Ser Gly Asp Gly
885890895
Arg Val Cys Val Ala Val Asp Glu Cys Glu Leu Asp Leu Arg Gly Gly
900905910
Cys His Ala Asp Ala Leu Cys Ser Tyr Val Gly Pro Gly Gln Ser Arg
915920925
Cys Thr Cys Lys Leu Gly Phe Ala Gly Asp Gly Tyr Val Cys Ser Pro
930935940
Ile Asp Pro Cys Arg Ala Gly Asn Gly Gly Cys His Asp Leu Ala Thr
945950955960
Cys Arg Ala Val Gly Gly Gly Gln Arg Val Cys Thr Cys Pro Pro Asp
965970975
Tyr Gly Gly Asp Gly Phe Ser Cys Tyr Gly Asp Ile Leu Lys Glu Leu
980985990
Glu Ala Asn Ala His Phe Ser Val Phe Tyr Gln Trp Ile Lys Gly Ala
99510001005
Gly Ile Thr Leu Pro Ala Asp Ser Gln Val Thr Ala Leu Val Pro Ser
101010151020
Glu Ser Ala Ile Arg Arg Leu Ser Thr Glu Asp Gln Ala Phe Trp Leu
1025103010351040
Gln Pro Arg Leu Leu Pro Gln Leu Val Arg Ala His Phe Leu Gln Gly
104510501055
Ala Leu Ser Glu Glu Glu Leu Ala Arg Leu His Gly Gln Asn Val Ser
106010651070
Thr Leu Asn Pro Thr Val Arg Trp Glu Ile His Asn Val Ser Gly Arg
107510801085
Val Trp Val Gln Asn Ala Ser Val Asp Val Ala Asp Leu Leu Ala Thr
109010951100
Asn Gly Val Leu His Val Leu Ser Gln Val Leu Leu Pro Pro Arg Arg
1105111011151120
Asp Val Leu Gly Gly Gln Gly Leu Leu Gln Gln Leu Asp Ser Val Pro
112511301135
Ala Phe His Leu Phe Arg Glu Leu Leu Gln Arg His Arg Leu Val Pro
114011451150
Gln Ile Glu Ala Ala Thr Ala Tyr Thr Ile Phe Val Pro Thr Asn His
115511601165
Ser Leu Glu Ala Gln Ala Asn Ser Ser Ser Leu Asp Ser Asp Val Val
117011751180
Arg His His Val Ile Leu Gly Glu Ala Leu Ser Thr Glu Ala Leu Gly
1185119011951200
Lys Gly Gly His Arg Asn Ser Leu Leu Gly Pro Ala His Trp Leu Val
120512101215
Phe Tyr Asn His Ser Gly Gln Pro Glu Val Asn His Val Pro Leu Glu
122012251230
Gly Pro Val Leu Gln Ala Pro Gly Arg Ser Leu Phe Gly Leu Ser Gly
123512401245
Val Leu Thr Val Gly Ser Ser Arg Cys Leu His Ser His Ala Glu Ala
125012551260
Leu Arg Glu Lys Cys Val Asn Cys Ser Arg Lys Phe Arg Cys Thr Gln
1265127012751280
Gly Tyr Gln Leu Glu Asp Thr Pro Arg Lys Ser Cys Val Tyr Arg Ser
128512901295
Gly Tyr Ser Phe Ser Arg Gly Cys Ser Tyr Thr Cys Ala Lys Lys Ile
130013051310
Gln Val Pro Asp Cys Cys Pro Gly Phe Phe Gly Thr Leu Cys Glu Pro
131513201325
Cys Pro Gly Gly Leu Gly Gly Val Cys Ser Gly His Gly Gln Cys Gln
133013351340
Asp Arg Leu Leu Gly Ser Gly Glu Cys Arg Cys His Glu Gly Phe His
1345135013551360
Gly Thr Ala Cys Glu Met Cys Glu Leu Gly Arg Tyr Gly Pro Asn Cys
136513701375
Thr Gly Val Cys Asp Cys Ala His Gly Leu Cys Gln Glu Gly Leu Arg
138013851390
Gly Asp Gly Ser Cys Val Cys Asn Val Gly Trp Gln Gly Leu Arg Cys
139514001405
Asp Gln Lys Ile Ser Gly Pro Gln Cys Leu Gln Lys Cys Asp Pro Asn
141014151420
Ala Asn Cys Val Gln Asp Ser Ala Ala Ala Pro Val Cys Val Cys Ala
1425143014351440
Ala Gly Tyr Ser Gly Asp Gly Val Ser Cys Ser Ala Val Asp Pro Cys
144514501455
Ala Arg Asp His Gly Gly Cys Ser Pro His Ala Asn Cys Thr Thr Val
146014651470
Ala Pro Gly Gln Arg Thr Cys Thr Cys Leu Asp Gly Tyr Thr Gly Asp
147514801485
Gly Glu Leu Cys Arg Glu Ala Asn Ser Cys Leu Ile Arg His Gly Gly
149014951500
Cys His Met His Ala Glu Cys Ile Pro Thr Gly Pro Gln Gln Val Ser
1505151015151520
Cys Ser Cys Arg Glu Gly Tyr Ser Gly Asp Gly Ile Arg Ala Cys Val
152515301535
Leu Leu Asp Pro Cys Ser Gln Asn Asn Gly Gly Cys Ser Pro Tyr Ala
154015451550
Val Cys Lys Ser Thr Gly Asp Gly Gln Arg Thr Cys Ala Cys Asp Ala
155515601565
Val Arg Thr Val Gly Asp Gly Phe Thr Cys Arg Ala Arg Ile Ser Leu
157015751580
Glu Leu Leu Arg Asp Lys His Ala Ser Phe Phe Ser Leu His Leu Leu
1585159015951600
Glu Tyr Lys Asp Leu Lys Gly Asp Gly Pro Phe Thr Val Phe Val Pro
160516101615
His Ala Asp Leu Leu Thr Asn Met Ser Gln Asp Glu Leu Ala Arg Ile
162016251630
Arg Ala Asn Arg Gln Leu Val Phe Arg Tyr His Val Val Gly Cys Arg
163516401645
Gln Leu Arg Ser Gln Glu Leu Leu Glu Glu Gly Tyr Ala Thr Ala Leu
165016551660
Ser Gly His Pro Leu Arg Phe Ser Glu Arg Glu Gly Asn Ile Tyr Ile
1665167016751680
Asn Asp Phe Ala Arg Val Val Ser Ser Asp Gln Glu Ala Val Asn Gly
168516901695
Val Leu His Phe Ile Asp Arg Val Leu Leu Pro Pro Glu Val Leu His
170017051710
Trp Glu Ala Asp Ala Ala Pro Ala Pro Arg Arg Asn Phe Thr Ala Ala
171517201725
Ala Glu Thr Phe Gly Tyr Lys Ile Phe Ser Gly Leu Val Thr Met Ala
173017351740
Gly Leu Leu Pro Leu Leu Gln Asp Ser Ser His Arg Pro Leu Thr Met
1745175017551760
Leu Trp Pro Thr Asp Ser Ala Leu Gln Ala Leu Pro Pro Asp Arg Gln
176517701775
Val Trp Leu Tyr His Lys Asp His Arg Asp Lys Leu Ala Ala Ile Leu
178017851790
Arg Gly His Val Ile Arg Asn Val Glu Ala Leu Ala Ser Asp Leu Pro
179518001805
Asn Leu Gly Pro Leu Arg Thr Met His Gly Thr Pro Ile Ser Phe Ser
181018151820
Cys Ser His Ala Arg Pro Gly Ala Leu Thr Val Gly Glu Asp Ala Ala
1825183018351840
Arg Ile Val Gln Arg His Leu Pro Phe Glu Gly Gly Leu Ala Tyr Gly
184518501855
Ile Asp Gln Leu Leu Glu Pro Pro Gly Leu Gly Ala Arg Cys Asp Arg
186018651870
Phe Glu Thr Arg Pro Leu Trp Leu Lys Val Cys Ser Ile Cys Gly Leu
187518801885
Glu Pro Pro Cys Pro Pro Gly Ser Gln Glu Gln Gly Ser Pro Glu Ala
189018951900
Cys Trp Arg Tyr Phe Ser Lys Phe Trp Thr Ser Pro Pro Leu His Ser
1905191019151920
Leu Ala Leu Arg Ser Val Trp Thr Arg Pro Ser His Trp Gly His Pro
192519301935
Gln Gly Leu Gly Arg Gly Cys Tyr Arg Asn Cys Val Thr Thr Thr Trp
194019451950
Lys Pro Ser Cys Cys Pro Gly His Tyr Gly Ser Glu Cys Arg Ala Cys
195519601965
Pro Gly Gly Ala Ser Ser Pro Cys Asn Gln Arg Gly Ser Cys Met Asp
197019751980
Gly Met Ser Gly Ser Gly Glu Cys Arg Cys His Thr Arg Phe Ala Gly
1985199019952000
Thr Ala Cys Glu Leu Cys Ala Pro Gly Ala Phe Gly Pro Leu Cys Gln
200520102015
Ala Cys Asn Cys Thr Ser His Gly Arg Cys Asp Glu Gly Leu Gly Gly
202020252030
Ser Gly Ser Cys Phe Cys Asp Glu Gly Trp Thr Gly Pro Arg Cys Glu
203520402045
Val Gln Leu Glu Leu Gln Pro Val Cys Ala Pro Pro Cys Ala Pro Gln
205020552060
Ala Val Cys Arg Ala Gly Asn Ser Cys Glu Cys Ser Leu Gly Tyr Glu
2065207020752080
Gly Asp Gly Arg Thr Cys Thr Val Val Asn Leu Cys Gln Asp Gly Arg
208520902095
Gly Gly Cys Ser Glu His Ala Asn Cys Ser Gln Ala Gly Thr Ala Val
210021052110
Thr Cys Ile Cys Trp Pro Asp Tyr Glu Gly Asp Gly Trp Ser Cys Arg
211521202125
Ala Arg Asn Pro Cys Glu Asp Gly Leu Arg Gly Gly Cys Ser Glu His
213021352140
Ala Asp Cys Leu Asn Thr Gly Pro Asn Thr Arg Arg Cys Val Cys His
2145215021552160
Ala Gly Tyr Val Gly Asp Gly Leu Gln Cys Leu Leu Glu Pro Glu Pro
216521702175
Pro Val Asp Arg Cys Leu Asp Arg Pro Pro Pro Cys His Ala Asp Ala
218021852190
Val Cys Thr Asp Leu His Phe Gln Glu Lys Arg Ala Gly Val Phe His
219522002205
Leu Gln Ala Pro Ser Gly Pro Tyr Gly Leu Asn Phe Ser Glu Ala Glu
221022152220
Ala Ala Cys Gly Ala Gln Gly Ala Val Leu Ala Ser Leu Leu Gln Leu
2225223022352240
Ser Ala Ala Gln Gln Leu Gly Leu His Leu Cys Leu Val Gly Trp Leu
224522502255
Ala Asn Gly Ser Ala Ala His Pro Val Val Phe Pro Ala Ala Asp Cys
226022652270
Gly Asp Gly Gln Val Gly Val Val Ser Leu Gly Ala Arg Glu Asn Leu
227522802285
Ser Glu Arg Trp Asp Ala Tyr Cys Phe Arg Met Arg Asp Val Ala Cys
22902295 2300
Arg Cys Arg Asp Gly Phe Val Gly Asp Gly Thr Ser Val Cys Asn Gly
2305231023152320
Lys Leu Leu Asp Val Leu Ala Thr Thr Ala Asn Phe Ser Ile Phe Tyr
232523302335
Gly Met Leu Leu Gly Tyr Ala Asn Ala Thr Pro Arg Gly Leu Glu Phe
234023452350
Leu Asp Phe Leu Asp Asp Glu Arg Thr Tyr Lys Thr Leu Phe Val Pro
235523602365
Val Asp Glu Ala Phe Thr Asp Asn Thr Thr Leu Ser Gly Pro Asp Leu
237023752380
Glu Leu His Ala Ser Asn Thr Thr Phe Leu Ser Ala Asn Ala Ser Gln
2385239023952400
Gly Ala Leu Leu Pro Ala His Ser Gly Leu Ser Leu Val Ile Gly Asn
240524102415
Leu Gly Pro Gly Asn Ser Ser Arg Ala Pro Glu Val Pro Gly Ala Val
242024252430
Val Val Ser Arg Val Ile Val Trp Asp Ile Leu Ala Phe Asn Gly Ile
243524402445
Ile His Thr Leu Ala Ser Pro Leu Leu Ala Pro Pro Gln Ala Trp Ala
245024552460
Val Val Ala Pro Glu Ala Pro Pro Val Ala Ala Gly Val Gly Ala Val
2465247024752480
Val Ala Ala Gly Ala Val Leu Gly Leu Val Ala Gly Ala Leu Tyr Phe
248524902495
Arg Gly Arg Ser Arg Ser Ala Gly Phe Gly Phe Ser Ala Phe Gln Ala
250025052510
Glu Asp Ala Ala Ala Asp Asp Phe Ser Pro Trp Gln Glu Gly Thr Ser
251525202525
Pro Pro Leu Val Ser Val Pro Asn Pro Val Phe Gly Ser His Glu Ala
253025352540
Phe Cys Glu Pro Phe Asp Asp Ser Val Leu Glu Glu Asp Phe Pro Asp
2545255025552560
Thr Gln Arg Ile Leu Glu Val Lys
2565
<210> 257
<211> 2559
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Stabilin-2Q8R4U0
<400> 257
Met Ala Arg Ser Lys Leu Leu Leu Gly Lys Leu Leu Pro Leu Ile Leu
151015
Ile Phe Leu Gly Leu Leu Val Gln Asn Ala Cys Ser Pro Thr Glu Ala
202530
Pro Glu Leu Thr Lys Arg Cys Asp Lys Lys Ser Thr Leu Thr Ile Lys
354045
Thr Glu Cys Gln Ser Cys Ser Val Asn Ile Ala Val Lys Cys Pro Asp
505560
Gly Tyr Ile Lys Ile Thr Asn Gly Thr Val Gly Val Arg Asp Cys Arg
65707580
Tyr Ser Leu Lys Ile Gln Ser Tyr Val Leu Asp Ile Pro Gly Cys Arg
859095
His Ile Cys Arg Lys Asp Tyr Leu Gln Pro Gln Cys Cys Pro Gly His
100105110
Trp Gly Pro Asp Cys Met Glu Cys Pro Gly Gly Ala Arg Ala Pro Cys
115120125
Gly Gly Arg Gly Val Cys Asp Glu Gly Met Glu Gly Thr Gly Ser Cys
130135140
Ser Cys Arg Ala Gly Phe Arg Gly Thr Ala Cys Glu Asn Cys Ala Ala
145150155160
Glu Asp Val Phe Gly Pro Asn Cys Ser Ala Val Cys Ser Cys Val His
165170175
Gly Val Cys Asn Ser Gly Ile Ser Gly Asp Gly Thr Cys Glu Cys Leu
180185190
Ser Ala Tyr Arg Gly Pro Arg Cys Asp Lys Pro Ile Pro Glu Cys Ala
195200205
Ala Leu Leu Cys Pro Glu Asn Ser Arg Cys Ser Pro Ser Ser Lys Asp
210215220
Glu Thr Lys Leu Gln Cys Lys Cys Leu Pro Ser Tyr Lys Gly Asp Gly
225230235240
Gln Thr Cys Lys Pro Ile Asn Pro Cys Leu Lys Asn Val Cys His Pro
245250255
His Ala Ser Cys Ser Tyr Leu Gly Pro Asn Arg His Ser Cys Val Cys
260265270
Gln Lys Gly Tyr Gln Gly Asp Gly Gln Val Cys Leu Pro Val Asp Pro
275280285
Cys Gln Thr Ser Tyr Gly Asn Cys Pro Thr Lys Ser Thr Val Cys Arg
290295300
Tyr Asp Gly Pro Gly Gln Ser His Cys Glu Cys Lys Glu His Tyr Arg
305310315320
Asn Phe Val Pro Gly Val Gly Cys Ser Met Thr Asp Ile Cys Glu Ser
325330335
Lys Asn Pro Cys His Lys Asn Ala Asn Cys Ser Thr Val Ser Pro Gly
340345350
Gln Thr Gln Cys Thr Cys Gln Lys Gly Tyr Val Gly Asp Gly Leu Asn
355360365
Cys Tyr Gly Asn Ile Met Gln Arg Leu Arg Glu Leu Asn Thr Glu Pro
370375380
Arg Gly Met Trp Gln Gly Gln Leu Thr Ser Phe Ile Ser Ile Leu Asp
385390395400
Arg Thr Tyr Ala Trp Pro Leu Ser Asn Leu Gly Pro Phe Thr Val Leu
405410415
Leu Pro Ser Asp Lys Gly Leu Lys Gly Val Asp Val Lys Glu Leu Leu
420425430
Met Asp Lys Glu Ala Ala Arg Tyr Phe Val Lys Leu His Ile Ile Ala
435440445
Gly Gln Met Ser Thr Glu Gln Met Tyr Asn Leu Asp Thr Phe Tyr Thr
450455460
Leu Thr Gly Lys Ser Gly Glu Ile Ile Asn Lys Asp Lys Asp Asn Gln
465470475480
Leu Lys Leu Lys Leu Tyr Gly Ser Lys Ile Val Gln Ile Ile Gln Gly
485490495
Asn Ile Val Ala Ser Asn Gly Leu Val His Ile Leu Asp Arg Ala Met
500505510
Asp Lys Ile Glu Pro Thr Leu Glu Ser Asn Pro Gln Gln Thr Ile Met
515520525
Thr Met Leu Gln Pro Arg Tyr Gly Lys Phe Arg Ser Leu Leu Glu Lys
530535540
Thr Asn Val Gly Gln Ala Leu Glu Lys Gly Gly Ile Asp Glu Pro Tyr
545550555560
Thr Ile Phe Val Pro Ser Asn Glu Ala Leu Ser Asn Met Thr Ala Gly
565570575
Val Leu Asp Tyr Leu Leu Ser Pro Glu Gly Ser Arg Lys Leu Leu Glu
580585590
Leu Val Arg Tyr His Ile Val Ala Phe Thr Gln Leu Glu Val Ala Thr
595600605
Leu Val Ser Thr Leu His Ile Arg Ser Met Ala Asn Gln Ile Ile Thr
610615620
Phe Asn Ile Ser Ser Lys Gly Gln Ile Leu Ala Asn Asn Val Ala Val
625630635640
Asp Glu Thr Glu Val Ala Ala Lys Asn Gly Arg Ile Tyr Thr Leu Thr
645650655
Gly Val Leu Ile Pro Pro Ser Ile Leu Pro Ile Leu Pro His Arg Cys
660665670
Asn Glu Thr Lys Arg Glu Met Lys Leu Gly Thr Cys Val Arg Cys Phe
675680685
Met Lys Asn Trp Ser Lys Cys Pro Thr Asn Ser Glu Pro Thr Ala Ile
690695700
Phe Thr Asn Lys Cys Phe Tyr Gly Ser Arg Ala Trp Asn Leu Lys Ile
705710715720
Gly Cys Ala Arg Tyr Cys Asp Val Thr Val Glu Ile Pro Arg Cys Cys
725730735
Lys Gly Phe Phe Gly Pro Asp Cys Asn Pro Cys Pro Gly Gly Phe Met
740745750
Asn Pro Cys Ser Gly Asn Gly Gln Cys Ile Asp Gly Leu Gly Gly Asn
755760765
Gly Thr Cys Ile Cys Glu Asp Gly Phe Gln Gly Ser Arg Cys Gln Phe
770775780
Cys Ser Lys Pro Asn Arg Tyr Gly Pro Gln Cys Asn Arg Thr Cys Gln
785790795800
Cys Val His Gly Ile Cys Asp Asn Arg Leu Asp Ser Asp Gly Ser Cys
805810815
Leu Pro Gly Thr Cys Arg Glu Gly Thr Ala Gly Arg Phe Cys Asp Lys
820825830
Gln Thr Ser Ala Cys Gly Pro Tyr Met Gln Phe Cys His Ile His Ala
835840845
Thr Cys Glu Tyr Ser Asn Glu Thr Ala Ser Cys Val Cys Asn Asp Gly
850855860
Tyr Glu Gly Asp Gly Thr Leu Cys Ser Lys Lys Asp Pro Cys Leu Gly
865870875880
Ser Thr Ser Arg Gly Gly Cys Ser Pro Asn Ala Glu Cys Ile Gln Ala
885890895
Ser Thr Gly Thr Tyr Ser Cys Val Cys Gln Arg Gly Trp Thr Gly Asn
900905910
Gly Arg Asp Cys Val Glu Ile Asn Ser Cys Leu Leu Pro Ser Ser Gly
915920925
Gly Cys His Asp Asn Ala Thr Cys Leu Tyr Val Gly Pro Gly Gln Asn
930935940
Glu Cys Glu Cys Lys Lys Gly Phe Arg Gly Asn Gly Ile Asp Cys Glu
945950955960
Pro Ile Ile Ser Cys Leu Glu Gln Ile Glu Lys Cys His Pro Leu Ala
965970975
Thr Cys Gln Tyr Thr Leu Ser Gly Val Trp Ser Cys Val Cys Gln Glu
980985990
Gly Tyr Glu Gly Asn Gly Val Leu Cys Tyr Gly Asn Val Leu Met Glu
99510001005
Leu Ser Phe Leu Ser Glu Ala Ala Val Phe Tyr Gln Trp Ile Asn Asn
101010151020
Ala Ser Leu Gln Ser Met Leu Ser Ala Thr Ser Asn Leu Thr Val Leu
1025103010351040
Val Pro Ser Leu Gln Ala Ile Lys Asp Met Asp Gln Asn Glu Lys Ser
104510501055
Phe Trp Leu Ser Arg Asn Asn Ile Pro Ala Leu Ile Lys Tyr His Thr
106010651070
Leu Leu Gly Thr Tyr Arg Val Ala Asp Leu Gln Thr Leu Pro Ser Ser
107510801085
His Met Leu Ala Thr Ser Leu Gln Gly Ser Phe Leu Arg Leu Asp Lys
109010951100
Ala Asp Gly Asn Ile Thr Ile Glu Gly Ala Ser Phe Val Asp Gly Asp
11051110 11151120
Asn Ala Ala Thr Asn Gly Val Val His Ile Ile Asn Lys Val Leu Ile
112511301135
Pro Gln Arg Gly Leu Thr Gly Ser Leu Pro Ser Leu Leu Thr Arg Leu
114011451150
Glu Gln Met Pro Asp Tyr Ser Ile Phe Arg Gly Tyr Ile Ile His Tyr
115511601165
Asn Leu Ala Ser Ala Ile Glu Ala Ala Asp Ala Tyr Thr Val Phe Val
117011751180
Pro Asn Asn Glu Ala Ile Glu Ser Tyr Ile Arg Glu Lys Lys Ala Thr
1185119011951200
Ser Leu Lys Glu Asp Ile Leu Gln Tyr His Val Val Leu Gly Glu Lys
120512101215
Leu Leu Arg Asn Asp Leu His Asn Gly Met His Arg Glu Thr Met Leu
122012251230
Gly Phe Ser Tyr Leu Leu Ala Phe Phe Leu His Asn Asp Gln Leu Tyr
123512401245
Val Asn Glu Ala Pro Ile Asn Tyr Thr Asn Val Ala Thr Asp Lys Gly
125012551260
Val Ile His Gly Leu Glu Lys Val Leu Glu Ile Lys Lys Asn Arg Cys
1265127012751280
Asp Asn Asn Asp Thr Ile Ile Val Arg Gly Lys Cys Gly Lys Cys Ser
128512901295
Gln Gln Thr Leu Cys Pro Leu Glu Thr Lys Pro Leu Ser Glu Thr Arg
130013051310
Lys Cys Ile Tyr Ser Val Tyr Phe Met Gly Lys Arg Ser Ile Phe Ile
131513201325
Gly Cys Gln Leu Gln Cys Val Arg Thr Ile Ile Thr Ser Ala Cys Cys
133013351340
Ala Gly Phe Phe Gly Pro Gln Cys Gln Ala Cys Pro Gly Lys Gly Gln
1345135013551360
Asn Val Cys Ser Gly Asn Gly Phe Cys Leu Asp Gly Val Asn Gly Thr
136513701375
Gly Thr Cys Glu Cys Glu Gln Gly Phe Asn Gly Thr Ala Cys Glu Thr
138013851390
Cys Thr Glu Gly Lys Tyr Gly Ile His Cys Asp Gln Ala Cys Ser Cys
139514001405
Val His Gly Arg Cys Asn Gln Gly Pro Ser Gly Asp Gly Ser Cys Asp
141014151420
Cys Asp Val Gly Trp Arg Gly Val Lys Cys Asp Ser Glu Ile Thr Thr
1425 143014351440
Asp Asn Cys Asn Gly Thr Cys His Thr Ser Ala Asn Cys Leu Leu Asp
144514501455
Pro Asp Gly Lys Ala Ser Cys Lys Cys Ala Ala Gly Phe Gln Gly Asn
146014651470
Gly Thr Val Cys Thr Ala Ile Asn Ala Cys Glu Ile Ser Asn Gly Gly
147514801485
Cys Ser Ala Lys Ala Asp Cys Lys Arg Thr Ile Pro Gly Ser Arg Val
149014951500
Cys Val Cys Lys Ala Gly Tyr Thr Gly Asp Gly Ile Val Cys Leu Glu
1505151015151520
Ile Asn Pro Cys Leu Glu Asn His Gly Gly Cys Asp Arg His Ala Glu
152515301535
Cys Thr Gln Thr Gly Pro Asn Gln Ala Val Cys Asn Cys Leu Pro Lys
154015451550
Tyr Thr Gly Asp Gly Lys Val Cys Thr Leu Ile Asn Val Cys Leu Thr
155515601565
Asn Asn Gly Gly Cys Ser Pro Phe Ala Phe Cys Asn His Thr Glu Gln
157015751580
Asp Gln Arg Thr Cys Thr Cys Lys Pro Asp Tyr Thr Gly Asp Gly Ile
1585159015951600
Val Cys Arg Gly Ser Ile His Ser Glu Leu Pro Lys Asn Pro Ser Thr
160516101615
Ser Gln Tyr Phe Phe Gln Leu Gln Glu His Ala Val Gln Glu Leu Ala
162016251630
Gly Pro Gly Pro Phe Thr Val Phe Val Pro Ser Ser Asp Ser Phe Asn
163516401645
Ser Glu Ser Lys Leu Lys Val Trp Asp Lys Gln Gly Leu Met Ser Gln
165016551660
Ile Leu Arg Tyr His Val Val Ala Cys Gln Gln Leu Leu Leu Glu Asn
1665167016751680
Leu Lys Val Ile Thr Ser Ala Thr Thr Leu Gln Gly Glu Pro Ile Ser
168516901695
Ile Ser Val Ser Gln Asp Thr Val Leu Ile Asn Lys Lys Ala Lys Val
170017051710
Leu Ser Ser Asp Ile Ile Ser Thr Asn Gly Val Ile His Val Ile Asp
171517201725
Thr Leu Leu Ser Pro Gln Asn Leu Leu Ile Thr Pro Lys Gly Ala Ser
173017351740
Gly Arg Val Leu Leu Asn Leu Thr Thr Val Ala Ala Asn His Gly Tyr
1745175017551760
Thr Lys Phe Ser Lys Leu Ile Gln Asp Ser Gly Leu Leu Lys Val Ile
176517701775
Thr Asp Pro Met His Thr Pro Val Thr Leu Phe Trp Pro Thr Asp Lys
178017851790
Ala Leu Gln Ala Leu Pro Gln Glu Gln Gln Asp Phe Leu Phe Asn Glu
179518001805
Asp Asn Lys Asp Lys Leu Lys Ala Tyr Leu Lys Phe His Val Ile Arg
181018151820
Asp Thr Met Ala Leu Ala Ser Asp Leu Pro Arg Ser Ala Ser Trp Lys
1825183018351840
Thr Leu Gln Gly Ser Glu Leu Ser Val Arg Cys Gly Thr Gly Ser Asp
184518501855
Val Gly Glu Leu Phe Leu Asn Gly Gln Met Cys Arg Ile Ile Gln Arg
186018651870
Arg Leu Leu Phe Asp Gly Gly Val Ala Tyr Gly Ile Asp Cys Leu Leu
187518801885
Met Asp Pro Thr Glu Gly Gly Arg Cys Asp Thr Phe Thr Thr Phe Asn
189018951900
Ile Pro Gly Glu Cys Gly Ser Cys Phe Ser Thr Pro Arg Cys Pro Leu
1905191019151920
Gln Ser Lys Pro Lys Gly Val Arg Lys Lys Cys Ile Tyr Asn Pro Leu
192519301935
Pro Phe Arg Arg Asp Val Glu Gly Cys Gln Asn Leu Cys Thr Leu Val
194019451950
Val His Val Pro Arg Cys Cys Ser Gly Tyr Phe Met Pro Asp Cys Gln
195519601965
Ala Cys Pro Gly Gly Pro Asp Thr Pro Cys Asn Asn Arg Gly Met Cys
197019751980
Tyr Asp Gln Tyr Lys Pro Thr Gly Gln Cys Gln Cys His Thr Gly Phe
1985199019952000
Asn Gly Thr Ala Cys Glu Leu Cys Leu Pro Gly Arg Phe Gly Pro Asp
200520102015
Cys Gln Pro Cys Gly Cys Ser Glu His Gly Gln Cys Asp Glu Gly Ile
202020252030
Thr Gly Ser Gly Gln Cys Leu Cys Glu Ala Gly Trp Thr Gly Arg Phe
203520402045
Cys Asp Ala Pro Thr Val Val Ile Pro Val Cys Ile Pro Ala Cys Ser
205020552060
Met His Ala Thr Cys Met Glu Asn Asn Thr Cys Val Cys Asn Leu Asn
2065207020752080
Tyr Glu Gly Asp Gly Ile Thr Cys Thr Val Val Asp Phe Cys Lys Gln
208520902095
Asn Asn Gly Gly Cys Ala Lys Val Ala Lys Cys Ser Gln Lys Gly Thr
210021052110
Gln Val Ser Cys Ser Cys Gln Lys Gly Tyr Lys Gly Asp Gly His Ser
211521202125
Cys Thr Glu Ile Asp Pro Cys Ala Asn Gly Val Asn Gly Gly Cys His
213021352140
Glu His Ala Thr Cys Arg Met Thr Gly Pro Gly Lys Gln Lys Cys Glu
2145215021552160
Cys Lys Ser His Tyr Val Gly Asp Gly Arg Asp Cys Glu Pro Glu Gln
216521702175
Leu Pro Leu Asp Arg Cys Leu Gln Asp Asn Gly Gln Cys His Pro Asp
218021852190
Ala Asn Cys Val Asp Leu His Phe Gln Asp Thr Thr Val Gly Val Phe
219522002205
His Leu Arg Ser Pro Leu Gly Gln Tyr Lys Leu Thr Phe Asp Lys Ala
221022152220
Lys Glu Ala Cys Ala Lys Glu Ala Ala Ser Ile Ala Thr Tyr Asn Gln
2225223022352240
Leu Ser Tyr Ala Gln Lys Ala Lys Tyr His Leu Cys Ser Ala Gly Trp
224522502255
Leu Glu Ser Gly Arg Val Ala Tyr Pro Thr Ile Tyr Ala Ser Lys Lys
226022652270
Cys Ala Asn Ile Val Gly Ile Val Asp Tyr Gly Thr Arg Thr Asn Lys
227522802285
Ser Glu Met Trp Asp Val Phe Cys Tyr Arg Met Lys Asp Val Asn Cys
229022952300
Thr Cys Lys Ala Gly Tyr Val Gly Asp Gly Phe Ser Cys Asn Gly Asn
2305231023152320
Leu Leu Gln Val Leu Met Ser Phe Pro Ser Leu Thr Asn Phe Leu Thr
232523302335
Glu Val Leu Val Phe Ser Arg Ser Ser Ala Gln Gly Arg Ala Phe Leu
234023452350
Lys His Leu Thr Asp Leu Ser Ile Ser Gly Thr Leu Phe Val Pro Gln
235523602365
Asn Ser Gly Leu Pro Lys Asn Lys Ser Leu Ser Gly Arg Asp Ile Glu
237023752380
His His Leu Thr Asn Val Asn Val Ser Phe Tyr Asp Asp Leu Val Asn
2385239023952400
Gly Thr Val Leu Lys Thr Arg Leu Gly Ser Gln Leu Leu Ile Thr Ser
240524102415
Ser Gln Asp Gln Leu His Gln Glu Ala Arg Phe Val Asp Gly Arg Ala
242024252430
Ile Leu Gln Trp Asp Ile Ile Ala Ser Asn Gly Val Leu His Ile Ile
243524402445
Ser Glu Pro Leu Lys Ala Pro Pro Thr Ala Ala Thr Ala Ala His Ser
245024552460
Gly Leu Gly Thr Gly Ile Phe Cys Ala Val Val Leu Val Thr Gly Ala
2465247024752480
Ile Ala Leu Ala Ala Tyr Ser Tyr Phe Arg Leu Asn Gln Arg Thr Thr
248524902495
Gly Phe Arg Arg Phe Glu Ser Glu Asp Asp Ile Asp Ala Leu Ala Phe
250025052510
Gly Lys Gln Gln Pro Glu Ser Ile Thr Asn Pro Leu Tyr Glu Thr Ser
251525202525
Thr Pro Ala Ala Pro Glu Pro Ser Cys Asp Pro Phe Thr Asp Ser Gly
253025352540
Glu Arg Glu Leu Glu Asn Ser Asp Pro Leu Gly Ala Leu Arg Ser
254525502555
<210> 258
<211> 1431
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat Stabilin-2Q8CFM6
<400> 258
Ser Leu Pro Ser Leu Leu Thr Arg Leu Glu Gln Met Pro Asp Tyr Ser
151015
Ile Phe Arg Gly Tyr Ile Ile His Tyr Asn Leu Ala Ser Ala Ile Glu
202530
Ser Ala Asp Ala Tyr Thr Val Phe Val Pro Asn Asn Glu Ala Ile Glu
354045
Asn Tyr Ile Arg Glu Lys Lys Ala Thr Ser Leu Lys Glu Asp Ile Leu
505560
Arg Tyr His Val Val Leu Gly Glu Lys Leu Leu Lys Asn Asp Leu His
65707580
Asn Gly Met His Arg Glu Thr Met Leu Gly Phe Ser Tyr Leu Leu Ala
859095
Phe Phe Leu Arg Asn Asp Gln Leu Tyr Val Asn Glu Ala Pro Ile Asn
100105110
Tyr Thr Asn Val Ala Thr Asp Lys Gly Val Ile His Gly Leu Glu Lys
115120125
Val Leu Glu Ile Gln Lys Asn Arg Cys Asp Asn Asn Asp Thr Ile Ile
130135140
Val Arg Gly Glu Cys Gly Lys Cys Ser Gln Gln Ala Pro Cys Pro Leu
145150155160
Glu Thr Lys Pro Leu Arg Glu Thr Arg Lys Cys Ile Tyr Ser Ile Tyr
165170175
Phe Met Gly Lys Arg Ser Val Phe Ile Gly Cys Gln Pro Gln Cys Val
180185190
Arg Thr Ile Ile Thr Arg Ala Cys Cys Ala Gly Phe Phe Gly Pro Gln
195200205
Cys Gln Ala Cys Pro Gly Arg Gly Gln Asn Val Cys Ser Gly Asn Gly
210215220
Phe Cys Leu Asp Gly Val Asn Gly Thr Gly Thr Cys Gln Cys Gly Leu
225230235240
Gly Phe Asn Gly Thr Ala Cys Glu Thr Cys Thr Glu Gly Lys Tyr Gly
245250255
Ile His Cys Asp Gln Ala Cys Ser Cys Val His Gly Arg Cys Ser Gln
260265270
Gly Pro Leu Gly Asp Gly Ser Cys Asp Cys Asp Val Gly Trp Arg Gly
275280285
Val Lys Cys Asp Met Glu Ile Thr Thr Asp Asn Cys Asn Gly Thr Cys
290295300
His Thr Ser Ala Asn Cys Leu Leu Asp Pro Asp Gly Lys Ala Ser Cys
305310315320
Lys Cys Ala Ala Gly Phe Arg Gly Asn Gly Thr Val Cys Thr Ala Ile
325330335
Asn Ala Cys Glu Thr Ser Asn Gly Gly Cys Ser Thr Lys Ala Asp Cys
340345350
Lys Arg Thr Thr Pro Gly Asn Arg Val Cys Val Cys Lys Ala Gly Tyr
355360365
Thr Gly Asp Gly Ile Val Cys Leu Glu Ile Asn Pro Cys Leu Glu Asn
370375380
His Gly Gly Cys Asp Arg Asn Ala Glu Cys Thr Gln Thr Gly Pro Asn
385390395400
Gln Ala Val Cys Asn Cys Leu Pro Lys Tyr Thr Gly Asp Gly Lys Val
405410415
Cys Ser Leu Ile Asn Val Cys Leu Thr Asn Asn Gly Gly Cys Ser Pro
420425430
Phe Ala Phe Cys Asn Tyr Thr Glu Gln Asp Gln Arg Ile Cys Thr Cys
435440445
Lys Pro Asp Tyr Thr Gly Asp Gly Ile Val Cys Arg Gly Ser Ile Tyr
450455460
Gly Glu Leu Pro Lys Asn Pro Ser Thr Ser Gln Tyr Phe Phe Gln Leu
465470475480
Gln Glu His Ala Val Arg Glu Leu Ala Gly Pro Gly Pro Phe Thr Val
485490495
Phe Ala Pro Leu Ser Ser Ser Phe Asn His Glu Pro Arg Ile Lys Asp
500505510
Trp Asp Gln Gln Gly Leu Met Ser Gln Val Leu Arg Tyr His Val Val
515520525
Gly Cys Gln Gln Leu Leu Leu Asp Asn Leu Lys Val Thr Thr Ser Ala
530535540
Thr Thr Leu Gln Gly Glu Pro Val Ser Ile Ser Val Ser Gln Asp Thr
545550555560
Val Phe Ile Asn Asn Glu Ala Lys Val Leu Ser Ser Asp Ile Ile Ser
565570575
Thr Asn Gly Val Ile His Val Ile Asp Lys Leu Leu Ser Pro Lys Asn
580585590
Leu Leu Ile Thr Pro Lys Asp Ala Leu Gly Arg Val Leu Gln Asn Leu
595600605
Thr Thr Val Ala Ala Asn His Gly Tyr Thr Lys Phe Ser Lys Leu Ile
610615620
Gln Asp Ser Gly Leu Leu Ser Val Ile Thr Asp Ser Ile His Thr Pro
625630635640
Val Thr Val Phe Trp Pro Thr Asp Lys Ala Leu Glu Ala Leu Pro Pro
645650655
Glu Gln Gln Asp Phe Leu Phe Asn Gln Asp Asn Lys Asp Lys Leu Lys
660665670
Ser Tyr Leu Lys Phe His Val Ile Arg Asp Ser Lys Ala Leu Ala Ser
675680685
Asp Leu Pro Arg Ser Ala Ser Trp Lys Thr Leu Gln Gly Ser Glu Leu
690695700
Ser Val Arg Cys Gly Thr Gly Ser Asp Ile Gly Glu Leu Phe Leu Asn
705710715720
Glu Gln Met Cys Arg Phe Ile His Arg Gly Leu Leu Phe Asp Val Gly
725730735
Val Ala Tyr Gly Ile Asp Cys Leu Leu Met Asn Pro Thr Leu Gly Gly
740745750
Arg Cys Asp Thr Phe Thr Thr Phe Asp Ile Pro Gly Glu Cys Gly Ser
755760765
Cys Ile Phe Thr Pro Lys Cys Pro Leu Lys Ser Lys Pro Lys Gly Val
770775780
Lys Lys Lys Cys Ile Tyr Asn Pro Leu Pro Phe Arg Arg Asn Val Glu
785790795800
Gly Cys Gln Asn Leu Cys Thr Val Val Ile Gln Thr Pro Arg Cys Cys
805810815
His Gly Tyr Phe Met Pro Asp Cys Gln Ala Cys Pro Gly Gly Pro Asp
820825830
Thr Pro Cys Asn Asn Arg Gly Met Cys Arg Asp Leu Tyr Thr Pro Met
835840845
Gly Gln Cys Leu Cys His Thr Gly Phe Asn Gly Thr Ala Cys Glu Leu
850855860
Cys Trp His Gly Arg Phe Gly Pro Asp Cys Gln Pro Arg Ser Cys Ser
865870875880
Glu His Gly Gln Cys Asp Glu Gly Ile Thr Gly Ser Gly Glu Cys Leu
885890895
Cys Glu Thr Gly Trp Thr Ala Ala Ser Cys Asp Thr Pro Thr Ala Val
900905910
Phe Ala Val Cys Thr Pro Ala Cys Ser Val His Ala Thr Cys Thr Glu
915920925
Asn Asn Thr Cys Val Cys Asn Leu Asn Tyr Glu Gly Asp Gly Ile Thr
930935940
Cys Thr Val Val Asp Phe Cys Lys Gln Asn Asn Gly Gly Cys Ala Lys
945950955960
Val Ala Lys Cys Ser Gln Lys Gly Thr Gln Val Ser Cys Ser Cys Lys
965970975
Lys Gly Tyr Lys Gly Asp Gly Tyr Ser Cys Ile Glu Ile Asp Pro Cys
980985990
Ala Asp Gly Val Asn Gly Gly Cys His Glu His Ala Thr Cys Arg Met
99510001005
Thr Gly Pro Gly Lys His Lys Cys Glu Cys Lys Ser His Tyr Val Gly
101010151020
Asp Gly Val Asp Cys Glu Pro Glu Gln Leu Pro Leu Asp Arg Cys Leu
1025103010351040
Gln Asp Asn Gly Gln Cys His Pro Asp Ala Ser Cys Ala Asp Leu Tyr
1045 10501055
Phe Gln Asp Thr Thr Val Gly Val Phe His Leu Arg Ser Pro Leu Gly
106010651070
Gln Tyr Lys Leu Thr Phe Asp Lys Ala Lys Glu Ala Cys Ala Lys Glu
107510801085
Ala Ala Thr Ile Ala Thr Tyr Asn Gln Leu Ser Tyr Ala Gln Lys Ala
109010951100
Lys Tyr His Leu Cys Ser Ala Gly Trp Leu Glu Ser Gly Arg Val Ala
1105111011151120
Tyr Pro Thr Thr Tyr Ala Ser Gln Lys Cys Gly Ala Asn Val Val Gly
112511301135
Ile Val Asp Tyr Gly Ser Arg Ala Asn Lys Ser Glu Met Trp Asp Val
114011451150
Phe Cys Tyr Arg Met Lys Asp Val Asn Cys Thr Cys Lys Ala Gly Tyr
115511601165
Val Gly Asp Gly Phe Ser Cys Ser Gly Asn Leu Leu Gln Val Leu Met
117011751180
Ser Phe Pro Ser Leu Thr Asn Phe Leu Thr Glu Val Leu Ala Phe Ser
1185119011951200
Lys Ser Ser Ala Arg Gly Gln Ala Phe Leu Lys His Leu Thr Asp Leu
120512101215
Ser Ile Arg Gly Thr Leu Phe Val Pro Gln Asn Ser Gly Leu Pro Gly
122012251230
Asn Lys Ser Leu Ser Gly Arg Asp Ile Glu His His Leu Thr Asn Val
123512401245
Asn Val Ser Phe Tyr Asn Asp Leu Val Asn Gly Thr Phe Leu Arg Thr
125012551260
Met Leu Gly Ser Gln Leu Leu Ile Thr Phe Ser Gln Asp Gln Leu His
1265127012751280
Gln Glu Thr Arg Phe Val Asp Gly Arg Ser Ile Leu Gln Trp Asp Ile
128512901295
Ile Ala Ala Asn Gly Ile Leu His Ile Ile Ser Glu Pro Leu Arg Ala
130013051310
Pro Pro Thr Ala Ala Thr Ala Ala His Ser Gly Leu Gly Thr Gly Ile
131513201325
Phe Cys Ala Val Val Leu Val Thr Gly Ala Ile Ala Leu Ala Ala Tyr
133013351340
Ser Tyr Phe Arg Leu Lys Gln Arg Thr Thr Gly Phe Gln Arg Phe Asp
1345135013551360
Gln Lys Arg Thr Leu Met Ser Trp Leu Leu Ala Ser Ser Ser Pro Arg
136513701375
Ile Ser Gln Thr Leu Cys Met Arg Pro Gln Arg Arg His Pro Gln Ser
138013851390
Pro Pro Val Thr Pro Ser Gln Thr Leu Glu Asn Arg Ile Trp Arg Thr
139514001405
Ala Thr Leu Trp Gly His Cys Gly Pro Asp Met Arg Ser Gln Gln Ala
141014151420
Thr Thr Val Thr Val Pro Arg
14251430
<210> 259
<211> 778
<212> PRT
<213> Mus musculus
<220>
<223> Mouse CD44P15379
<400> 259
Met Asp Lys Phe Trp Trp His Thr Ala Trp Gly Leu Cys Leu Leu Gln
151015
Leu Ser Leu Ala His Gln Gln Ile Asp Leu Asn Val Thr Cys Arg Tyr
202530
Ala Gly Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg
354045
Thr Glu Ala Ala Asp Leu Cys Gln Ala Phe Asn Ser Thr Leu Pro Thr
505560
Met Asp Gln Met Lys Leu Ala Leu Ser Lys Gly Phe Glu Thr Cys Arg
65707580
Tyr Gly Phe Ile Glu Gly Asn Val Val Ile Pro Arg Ile His Pro Asn
859095
Ala Ile Cys Ala Ala Asn His Thr Gly Val Tyr Ile Leu Val Thr Ser
100105110
Asn Thr Ser His Tyr Asp Thr Tyr Cys Phe Asn Ala Ser Ala Pro Pro
115120125
Glu Glu Asp Cys Thr Ser Val Thr Asp Leu Pro Asn Ser Phe Asp Gly
130135140
Pro Val Thr Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Ser Lys
145150155160
Lys Gly Glu Tyr Arg Thr His Gln Glu Asp Ile Asp Ala Ser Asn Ile
165170175
Ile Asp Asp Asp Val Ser Ser Gly Ser Thr Ile Glu Lys Ser Thr Pro
180185190
Glu Gly Tyr Ile Leu His Thr Tyr Leu Pro Thr Glu Gln Pro Thr Gly
195200205
Asp Gln Asp Asp Ser Phe Phe Ile Arg Ser Thr Leu Ala Thr Ile Ala
210215220
Ser Thr Val His Ser Lys Ser His Ala Ala Ala Gln Lys Gln Asn Asn
225230235240
Trp Ile Trp Ser Trp Phe Gly Asn Ser Gln Ser Thr Thr Gln Thr Gln
245250255
Glu Pro Thr Thr Ser Ala Thr Thr Ala Leu Met Thr Thr Pro Glu Thr
260265270
Pro Pro Lys Arg Gln Glu Ala Gln Asn Trp Phe Ser Trp Leu Phe Gln
275280285
Pro Ser Glu Ser Lys Ser His Leu His Thr Thr Thr Lys Met Pro Gly
290295300
Thr Glu Ser Asn Thr Asn Pro Thr Gly Trp Glu Pro Asn Glu Glu Asn
305310315320
Glu Asp Glu Thr Asp Thr Tyr Pro Ser Phe Ser Gly Ser Gly Ile Asp
325330335
Asp Asp Glu Asp Phe Ile Ser Ser Thr Ile Ala Thr Thr Pro Arg Val
340345350
Ser Ala Arg Thr Glu Asp Asn Gln Asp Trp Thr Gln Trp Lys Pro Asn
355360365
His Ser Asn Pro Glu Val Leu Leu Gln Thr Thr Thr Arg Met Ala Asp
370375380
Ile Asp Arg Ile Ser Thr Ser Ala His Gly Glu Asn Trp Thr Pro Glu
385390395400
Pro Gln Pro Pro Phe Asn Asn His Glu Tyr Gln Asp Glu Glu Glu Thr
405410415
Pro His Ala Thr Ser Thr Thr Pro Asn Ser Thr Ala Glu Ala Ala Ala
420425430
Thr Gln Gln Glu Thr Trp Phe Gln Asn Gly Trp Gln Gly Lys Asn Pro
435440445
Pro Thr Pro Ser Glu Asp Ser His Val Thr Glu Gly Thr Thr Ala Ser
450455460
Ala His Asn Asn His Pro Ser Gln Arg Ile Thr Thr Gln Ser Gln Glu
465470475480
Asp Val Ser Trp Thr Asp Phe Phe Asp Pro Ile Ser His Pro Met Gly
485490495
Gln Gly His Gln Thr Glu Ser Lys Asp Thr Asp Ser Ser His Ser Thr
500505510
Thr Leu Gln Pro Thr Ala Ala Pro Asn Thr His Leu Val Glu Asp Leu
515520525
Asn Arg Thr Gly Pro Leu Ser Val Thr Thr Pro Gln Ser His Ser Gln
530535540
Asn Phe Ser Thr Leu His Gly Glu Pro Glu Glu Asp Glu Asn Tyr Pro
545550555560
Thr Thr Ser Ile Leu Pro Ser Ser Thr Lys Ser Ser Ala Lys Asp Ala
565570575
Arg Arg Gly Gly Ser Leu Pro Thr Asp Thr Thr Thr Ser Val Glu Gly
580585590
Tyr Thr Phe Gln Tyr Pro Asp Thr Met Glu Asn Gly Thr Leu Phe Pro
595600605
Val Thr Pro Ala Lys Thr Glu Val Phe Gly Glu Thr Glu Val Thr Leu
610615620
Ala Thr Asp Ser Asn Val Asn Val Asp Gly Ser Leu Pro Gly Asp Arg
625630635640
Asp Ser Ser Lys Asp Ser Arg Gly Ser Ser Arg Thr Val Thr His Gly
645650655
Ser Glu Leu Ala Gly His Ser Ser Ala Asn Gln Asp Ser Gly Val Thr
660665670
Thr Thr Ser Gly Pro Met Arg Arg Pro Gln Ile Pro Glu Trp Leu Ile
675680685
Ile Leu Ala Ser Leu Leu Ala Leu Ala Leu Ile Leu Ala Val Cys Ile
690695700
Ala Val Asn Ser Arg Arg Arg Cys Gly Gln Lys Lys Lys Leu Val Ile
705710715720
Asn Gly Gly Asn Gly Thr Val Glu Asp Arg Lys Pro Ser Glu Leu Asn
725730735
Gly Glu Ala Ser Lys Ser Gln Glu Met Val His Leu Val Asn Lys Glu
740745750
Pro Ser Glu Thr Pro Asp Gln Cys Met Thr Ala Asp Glu Thr Arg Asn
755760765
Leu Gln Ser Val Asp Met Lys Ile Gly Val
770775
<210> 260
<211> 503
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat CD44P26051
<400> 260
Met Asp Lys Val Trp Trp His Thr Ala Trp Gly Leu Leu Cys Leu Leu
151015
Gln Leu Ser Leu Ala Gln Gln Gln Ile Asp Leu Asn Ile Thr Cys Arg
202530
Tyr Ala Gly Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser
354045
Arg Thr Glu Ala Ala Asp Leu Cys Glu Ala Phe Asn Thr Thr Leu Pro
505560
Thr Met Ala Gln Met Glu Leu Ala Leu Arg Lys Gly Phe Glu Thr Cys
65707580
Arg Tyr Gly Phe Ile Glu Gly His Val Val Ile Pro Arg Ile His Pro
859095
Asn Ala Ile Cys Ala Ala Asn Asn Thr Gly Val Tyr Ile Leu Leu Ala
100105110
Ser Asn Thr Ser His Tyr Asp Thr Tyr Cys Phe Asn Ala Ser Ala Pro
115120125
Leu Glu Glu Asp Cys Thr Ser Val Thr Asp Leu Pro Asn Ser Phe Asp
130135140
Gly Pro Val Thr Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Ser
145150155160
Lys Lys Gly Glu Tyr Arg Thr His Gln Glu Asp Ile Asp Ala Ser Asn
165170175
Ile Ile Asp Glu Asp Val Ser Ser Gly Ser Thr Ile Glu Lys Ser Thr
180185190
Pro Glu Gly Tyr Ile Leu His Thr Asp Leu Pro Thr Ser Gln Pro Thr
195200205
Gly Asp Arg Asp Asp Ala Phe Phe Ile Gly Ser Thr Leu Ala Thr Ile
210215220
Ala Thr Thr Pro Trp Val Ser Ala His Thr Lys Gln Asn Gln Glu Arg
225230235240
Thr Gln Trp Asn Pro Ile His Ser Asn Pro Glu Val Leu Leu Gln Thr
245250255
Thr Thr Arg Met Thr Asp Ile Asp Arg Asn Ser Thr Ser Ala His Gly
260265270
Glu Asn Trp Thr Gln Glu Pro Gln Pro Pro Phe Asn Asn His Glu Tyr
275280285
Gln Asp Glu Glu Glu Thr Pro His Ala Thr Ser Thr Thr Trp Ala Asp
290295300
Pro Asn Ser Thr Thr Glu Glu Ala Ala Thr Gln Lys Glu Lys Trp Phe
305310315320
Glu Asn Glu Trp Gln Gly Lys Asn Pro Pro Thr Pro Ser Glu Asp Ser
325330335
His Val Thr Glu Gly Thr Thr Ala Ser Ala His Asn Asn His Pro Ser
340345350
Gln Arg Met Thr Thr Gln Ser Gln Glu Asp Val Ser Trp Thr Asp Phe
355360365
Phe Asp Pro Ile Ser His Pro Met Gly Gln Gly His Gln Thr Glu Ser
370375380
Lys Gly His Ser Ser Gly Asn Gln Asp Ser Gly Val Thr Thr Thr Ser
385390395400
Gly Pro Ala Arg Arg Pro Gln Ile Pro Glu Trp Leu Ile Ile Leu Ala
405410415
Ser Leu Leu Ala Leu Ala Leu Ile Leu Ala Val Cys Ile Ala Val Asn
420425430
Ser Arg Arg Arg Cys Gly Gln Lys Lys Lys Leu Val Ile Asn Ser Gly
435440445
Asn Gly Thr Val Glu Asp Arg Lys Pro Ser Glu Leu Asn Gly Glu Ala
450455460
Ser Lys Ser Gln Glu Met Val His Leu Val Asn Lys Glu Pro Thr Glu
465470475480
Thr Pro Asp Gln Phe Met Thr Ala Asp Glu Thr Arg Asn Leu Gln Ser
485490495
Val Asp Met Lys Ile Gly Val
500
<210> 261
<211> 366
<212> PRT
<213> Bos taurus
<220>
<223> Cow CD44 Q29423
<400> 261
Met Asp Thr Phe Trp Trp Arg Ala Ala Trp Gly Leu Cys Leu Val Gln
151015
Leu Ser Leu Ala Gln Ile Asp Leu Asn Ile Thr Cys Arg Tyr Ala Gly
202530
Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Lys Thr Glu
354045
Ala Ala Asp Leu Cys Lys Ala Phe Asn Ser Thr Leu Pro Thr Met Ala
505560
Gln Met Glu Ala Ala Arg Asn Ile Gly Phe Glu Thr Cys Arg Tyr Gly
65707580
Phe Ile Glu Gly His Val Val Ile Pro Arg Ile His Pro Asn Ser Ile
859095
Cys Ala Ala Asn Asn Thr Gly Val Tyr Ile Leu Thr Ser Asn Thr Ser
100105110
Gln Tyr Asp Thr Ile Cys Phe Asn Ala Ser Ala Pro Pro Gly Glu Asp
115120125
Cys Thr Ser Val Thr Asp Leu Pro Asn Ala Phe Glu Gly Pro Ile Thr
130135140
Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Thr Lys Lys Gly Glu
145150155160
Tyr Arg Thr Asn Pro Glu Asp Ile Asn Pro Ser Val Val Ser Pro Ser
165170175
Ser Pro Pro Asp Asp Glu Met Ser Ser Gly Ser Pro Ser Glu Arg Ser
180185190
Thr Ser Gly Gly Tyr Ser Ile Phe His Thr His Leu Pro Thr Val His
195200205
Pro Ser Arg Pro Arg Arg Pro Trp Ser Gln Arg Ala Glu Asn Thr Ser
210215220
Asp Thr Arg Asp Tyr Gly Ser Ser His Asp Pro Ser Gly Arg Ser Tyr
225230235240
Thr Thr His Ala Ser Glu Ser Ala Gly His Ser Ser Gly Ser Glu Glu
245250255
His Gly Ala Asn Thr Thr Ser Gly Pro Met Arg Lys Pro Gln Ile Pro
260265270
Glu Trp Leu Ile Ile Leu Ala Ser Leu Leu Ala Leu Ala Leu Ile Leu
275280285
Ala Val Cys Ile Ala Val Asn Ser Arg Arg Arg Cys Gly Gln Lys Lys
290295300
Lys Leu Val Ile Asn Asn Gly Asn Gly Thr Met Glu Glu Arg Lys Pro
305310315320
Ser Gly Leu Asn Gly Glu Ala Ser Lys Ser Gln Glu Met Val His Leu
325330335
Val Asn Lys Gly Ser Ser Glu Thr Pro Asp Gln Phe Met Thr Ala Asp
340345350
Glu Thr Arg Asn Leu Gln Asn Val Asp Met Lys Ile Gly Val
355360365
<210> 262
<211> 351
<212> PRT
<213> Canis lupus familiaris
<220>
<223> Dog CD44Q28284
<400> 262
Leu Ala Trp Gly Leu Cys Leu Leu Arg Leu Ser Leu Ala Gln Ile Asp
151015
Leu Asn Ile Thr Cys Arg Tyr Ala Gly Val Phe His Val Glu Lys Asn
202530
Gly Arg Tyr Ser Ile Ser Arg Thr Ala Ala Ala Asp Leu Cys Lys Ala
354045
Phe Asn Ser Thr Leu Pro Thr Met Ala Gln Met Glu Arg Ala Leu Ser
505560
Val Gly Phe Glu Thr Cys Arg Tyr Gly Phe Ile Glu Gly His Val Val
65707580
Ile Pro Arg Ile Gln Pro Asn Ala Ile Cys Ala Ala Asn His Thr Gly
859095
Val Tyr Ile Leu Ile Ser Asn Thr Ser Gln Tyr Asp Thr Tyr Cys Phe
100105110
Asn Ala Ser Ala Pro Pro Glu Glu Asp Cys Thr Ser Val Thr His Leu
115120125
Pro Asn Ala Phe Asp Gly Pro Ile Thr Ile Thr Ile Val Asn Arg Asp
130135140
Gly Thr Arg Tyr Ser Gln Lys Gly Glu Tyr Arg Thr Asn Pro Glu Asp
145150155160
Ile Asn Pro Ser Asn Pro Thr Asp Asp Asp Val Ser Ser Gly Ser Ser
165170175
Ser Glu Arg Ser Thr Ser Ala Gly Tyr Asn Ile Phe His Thr His Leu
180185190
Pro Thr Ala Tyr Pro Thr Glu Asp Gln Asp Ser Ser Arg Val Ser Ser
195200205
Asn Ser Asp His Thr Pro Ile Thr Lys Asp His Asp Ser Ser Val His
210215220
Pro Ser Glu Arg Ser His Thr Thr His Gly Ser Glu Ser Ala Gly His
225230235240
Ser Ser Gly Ser Gln Glu Gly Gly Ala Asn Thr Thr Ser Gly Pro Met
245250255
Arg Lys Pro Gln Ile Pro Glu Trp Leu Ile Ile Leu Ala Ser Leu Leu
260265270
Ala Leu Ala Leu Ile Leu Ala Val Cys Ile Ala Val Asn Ser Arg Arg
275280285
Arg Cys Gly Gln Lys Lys Lys Leu Val Ile Asn Asn Gly Asn Gly Ala
290295300
Val Gly Asp Arg Lys Pro Ser Gly Ile Asn Gly Glu Ala Ser Lys Ser
305310315320
Gln Glu Met Val His Leu Val Asn Lys Glu Pro Ser Glu Thr Pro Asp
325330335
Gln Tyr Thr Thr Ala Asp Glu Thr Arg Asn Leu Gln Asn Val Asp
340345350
<210> 263
<211> 359
<212> PRT
<213> Equus caballus
<220>
<223> Horse CD44 Q05078
<400> 263
Met Asp Lys Phe Trp Trp Arg Ala Ala Trp Gly Leu Cys Leu Val Pro
151015
Leu Ser Leu Ala Gln Ile Asp Leu Asn Ile Thr Cys Arg Tyr Ala Gly
202530
Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg Thr Glu
354045
Ala Ala Asp Leu Cys Lys Ala Phe Asn Ser Thr Leu Pro Thr Met Ala
505560
Gln Met Gln Lys Ala Leu Asn Ile Gly Phe Glu Thr Cys Arg Ile Gly
65707580
Phe Ile Glu Gly His Val Val Ile Pro Pro Ile His Pro Asn Ser Ile
859095
Cys Ala Ala Asn Asn Thr Gly Val Tyr Ile Leu Thr Ser Asn Thr Ser
100105110
Gln Tyr Asp Thr Tyr Cys Phe Asn Ala Ser Ala Pro Pro Glu Glu Asp
115120125
Cys Thr Ser Val Thr Asp Leu Pro Asn Ala Phe Glu Gly Pro Ile Thr
130135140
Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Thr Lys Lys Gly Glu
145150155160
Tyr Arg Thr Asn Pro Glu Asp Ile Asn Pro Ser Thr Pro Ala Asp Asp
165170175
Asp Val Ser Ser Gly Ser Ser Ser Glu Arg Ser Thr Ser Gly Gly Tyr
180185190
Ser Ile Phe His Thr His Leu Pro Thr Thr Arg Pro Thr Gln Asp Gln
195200205
Ser Ser Pro Trp Val Ser Asp Ser Pro Glu Lys Thr Pro Thr Thr Lys
210215220
Asp Arg Ala Ser Gly Gly Arg Ala Gln Thr Thr His Gly Ser Glu Thr
225230235240
Ser Gly His Ser Thr Gly Ser Gln Glu Gly Gly Ala Ser Thr Thr Ser
245250255
Gly Pro Ile Arg Arg Pro Gln Ile Pro Glu Trp Leu Ile Ile Leu Ala
260265270
Ser Leu Leu Ala Leu Ala Leu Ile Leu Ala Val Cys Ile Ala Val Asn
275280285
Ser Arg Arg Arg Cys Gly Gln Lys Lys Lys Leu Val Ile Asn Asn Gly
290295300
Asn Gly Ala Val Asp Asp Arg Lys Ala Ser Gly Leu Asn Gly Glu Ala
305310315320
Ser Arg Ser Gln Glu Met Val His Leu Val Asn Lys Glu Ser Ser Glu
325330335
Thr Gln Asp Gln Phe Met Thr Ala Asp Glu Thr Arg Asn Leu Gln Asn
340345350
Val Asp Met Lys Ile Gly Val
355
<210> 264
<211> 362
<212> PRT
<213> Cricetulus griseus
<220>
<223> Hamster CD44P20944
<400> 264
Met Asp Lys Phe Trp Trp His Ala Ala Trp Gly Leu Cys Leu Leu Pro
151015
Leu Ser Leu Ala His Glu Gln Ile Asp Leu Asn Ile Thr Cys Arg Tyr
202530
Ala Gly Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg
35 4045
Thr Glu Ala Ala Asp Leu Cys Gln Ala Phe Asn Ser Thr Leu Pro Thr
505560
Met Asp Gln Met Val Met Ala Leu Ser Lys Gly Phe Glu Thr Cys Arg
65707580
Tyr Gly Phe Ile Glu Gly His Val Val Ile Pro Arg Ile Gln Pro Asn
859095
Ala Ile Cys Ala Ala Asn His Thr Gly Val Tyr Ile Leu Thr Ser Asn
100105110
Thr Ser His Tyr Asp Thr Tyr Cys Phe Asn Ala Ser Ala Pro Leu Glu
115120125
Glu Asp Cys Thr Ser Val Thr Asp Leu Pro Asn Ser Phe Glu Gly Pro
130135140
Val Thr Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Ser Lys Lys
145150155160
Gly Glu Tyr Arg Thr His Gln Glu Asp Ile Asp Ala Ser Asn Thr Thr
165170175
Asp Asp Asp Val Ser Ser Gly Ser Ser Ser Glu Lys Ser Thr Ser Gly
180185190
Gly Tyr Val Phe His Thr Tyr Leu Pro Thr Ile His Ser Thr Ala Asp
195200205
Gln Asp Asp Pro Tyr Phe Ile Gly Ser Thr Met Ala Thr Arg Asp Gln
210215220
Asp Ser Ser Met Asp Pro Arg Gly Asn Ser Leu Thr Val Thr Asp Gly
225230235240
Ser Lys Leu Thr Glu His Ser Ser Gly Asn Gln Asp Ser Gly Leu Asn
245250255
Ser Thr Ser Arg Pro Gly Gly Lys Pro Arg Val Pro Glu Trp Leu Ile
260265270
Val Leu Ala Ser Leu Leu Ala Leu Ala Leu Ile Leu Ala Val Cys Ile
275280285
Ala Val Asn Ser Arg Arg Arg Cys Gly Gln Lys Lys Lys Leu Val Ile
290295300
Asn Ser Gly Asn Gly Lys Val Glu Asp Arg Lys Pro Ser Glu Leu Asn
305310315320
Gly Glu Ala Ser Lys Ser Gln Glu Met Val His Leu Val Asn Lys Glu
325330335
Pro Ser Glu Thr Pro Asp Gln Phe Met Thr Ala Asp Glu Thr Arg Asn
340345350
Leu Gln Asn Val Asp Met Lys Ile Gly Val
355360
<210> 265
<211> 362
<212> PRT
<213> Papio hamadryas
<220>
<223> Baboon CD44 P14745
<400> 265
Met Asp Lys Phe Trp Trp Arg Ala Ala Trp Gly Leu Cys Leu Val Gln
151015
Leu Ser Leu Ala Gln Ile Asp Leu Asn Ile Thr Cys Arg Phe Glu Gly
202530
Ile Tyr His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg Thr Glu
354045
Ala Ala Asp Leu Cys Lys Ala Phe Asn Ser Thr Leu Pro Thr Met Ala
505560
Gln Met Glu Lys Ala Leu Ser Ile Gly Phe Glu Thr Cys Arg Tyr Gly
65707580
Phe Ile Glu Gly His Val Val Ile Pro Arg Ile His Pro Asn Ser Ile
859095
Cys Ala Ala Asn Asn Thr Gly Val Tyr Ile Leu Thr Ser Asn Thr Ser
100105110
Gln Tyr Asp Thr Tyr Cys Phe Asn Ala Ser Ala Pro Pro Gly Glu Asp
115120125
Cys Thr Ser Val Thr Asp Leu Pro Asn Ala Phe Asp Gly Pro Ile Thr
130135140
Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Val Lys Lys Gly Glu
145150155160
Tyr Arg Thr Asn Pro Glu Asp Ile Asn Pro Ser Ser Pro Thr Asp Asp
165170175
Asp Val Ser Ser Gly Ser Ser Ser Glu Arg Ser Ser Thr Leu Gly Gly
180185190
Tyr Ile Phe Tyr Asn His Phe Ser Thr Ser Pro Pro Ile Pro Asp Glu
195200205
Asp Gly Pro Trp Ile Thr Asp Ser Thr Asp Arg Thr Pro Ala Thr Arg
210215220
Asp Gln Gly Ala Phe Asp Pro Ser Gly Gly Ser His Thr Thr His Gly
225230235240
Ser Glu Ser Ala Gly His Ser His Gly Ser Arg Glu Gly Gly Ala Asn
245250255
Thr Thr Ser Gly Pro Leu Arg Thr Pro Gln Ile Pro Glu Trp Leu Ile
260265270
Ile Leu Ala Ser Leu Leu Ala Leu Ala Leu Ile Leu Ala Val Cys Ile
275280285
Ala Val Asn Ser Arg Arg Arg Cys Gly Gln Lys Lys Lys Leu Val Ile
290295300
Asn Asn Gly Asn Gly Ala Val Glu Asp Arg Lys Ser Ser Gly Leu Asn
305310315320
Gly Glu Ala Ser Lys Ser Gln Glu Met Val His Leu Val Asn Lys Glu
325330335
Ser Ser Glu Thr Pro Asp Gln Phe Met Thr Ala Asp Glu Thr Arg Asn
340345350
Leu Gln Asn Val Asp Met Lys Ile Gly Val
355360
<210> 266
<211> 431
<212> PRT
<213> Mesocricetus auratus
<220>
<223> Golden Hamster CD44 Q60522
<400> 266
Met Asp Lys Phe Trp Trp His Ala Ala Trp Gly Leu Cys Leu Leu Pro
151015
Leu Ser Leu Ala Gln Gln Gln Ile Asp Leu Asn Ile Thr Cys Arg Tyr
202530
Ala Gly Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg
354045
Thr Glu Ala Ala Asp Leu Cys Gln Ala Phe Asn Ser Thr Leu Pro Thr
505560
Met Asp Gln Met Val Met Ala Leu Ser Lys Gly Phe Glu Thr Cys Arg
65707580
Tyr Gly Phe Ile Glu Gly His Val Val Ile Pro Arg Ile Gln Pro Asn
859095
Ala Ile Cys Ala Ala Asn His Thr Gly Val Tyr Ile Leu Thr Ser Asn
100105110
Thr Ser His Tyr Asp Thr Tyr Cys Phe Asn Ala Ser Ala Pro Leu Glu
115120125
Glu Asp Cys Thr Ser Val Thr Asp Leu Pro Asn Ser Phe Glu Gly Pro
130135140
Val Thr Ile Thr Ile Val Asn Arg Asp Gly Thr Arg Tyr Ser Lys Lys
145150155160
Gly Glu Tyr Arg Thr His Gln Glu Asp Ile Asp Ala Ser Asn Thr Thr
165170175
Asp Asp Asp Val Ser Ser Gly Ser Ser Ser Glu Lys Ser Thr Ser Gly
180185190
Gly Tyr Val Phe His Thr Tyr Leu Pro Thr Ile His Ser Thr Ala Asp
195200205
Gln Asp Asp Pro Tyr Phe Ile Gly Ser Thr Met Ala Thr Thr Arg Ser
210215220
Gly Gly Lys Asp Gly Arg Arg Gly Gly Gly Leu Pro Lys Asp Ala Thr
225230235240
Thr Ser Leu Glu Gly Tyr Thr Thr His Tyr Pro Glu Thr Met Glu Asn
245250255
Gly Thr Leu Thr Pro Val Thr Pro Ala Lys Thr Gly Val Phe Gly Glu
260265270
Thr Glu Val Thr Val Ala Glu Asp Ser Asn Phe Asn Val Asp Gly Ser
275280285
Leu Pro Gly Asp Gln Asp Ser Ser Met Asp Pro Arg Gly Asn Ser Leu
290295300
Thr Val Thr Asp Gly Ser Lys Leu Thr Gly His Ser Ser Gly Asn Gln
305310315320
Asp Ser Gly Ala Asn Thr Thr Ser Arg Pro Gly Arg Lys Pro Gln Ile
325330335
Pro Glu Trp Leu Ile Val Leu Ala Ser Leu Leu Ala Leu Ala Leu Ile
340345350
Leu Ala Val Cys Ile Ala Val Asn Ser Arg Arg Arg Cys Gly Gln Lys
355360365
Lys Lys Leu Val Ile Asn Ser Gly Asn Gly Lys Val Glu Asp Arg Lys
370375380
Pro Ser Glu Leu Asn Gly Glu Ala Ser Lys Ser Gln Glu Met Val His
385390395400
Leu Val Asn Lys Glu Pro Ser Glu Thr Pro Asp Gln Phe Met Thr Ala
405410415
Asp Glu Thr Arg Asn Leu Gln Asn Val Asp Met Lys Ile Gly Val
420425430
<210> 267
<211> 318
<212> PRT
<213> Mus musculus
<220>
<223> Mouse LYVE-1Q8BHC0
<400> 267
Met Leu Gln His Thr Ser Leu Val Leu Leu Leu Ala Ser Ile Trp Thr
151015
Thr Arg His Pro Val Gln Gly Ala Asp Leu Val Gln Asp Leu Ser Ile
202530
Ser Thr Cys Arg Ile Met Gly Val Ala Leu Val Gly Arg Asn Lys Asn
354045
Pro Gln Met Asn Phe Thr Glu Ala Asn Glu Ala Cys Lys Met Leu Gly
505560
Leu Thr Leu Ala Ser Arg Asp Gln Val Glu Ser Ala Gln Lys Ser Gly
65707580
Phe Glu Thr Cys Ser Tyr Gly Trp Val Gly Glu Gln Phe Ser Val Ile
859095
Pro Arg Ile Phe Ser Asn Pro Arg Cys Gly Lys Asn Gly Lys Gly Val
100105110
Leu Ile Trp Asn Ala Pro Ser Ser Gln Lys Phe Lys Ala Tyr Cys His
115120125
Asn Ser Ser Asp Thr Trp Val Asn Ser Cys Ile Pro Glu Ile Val Thr
130135140
Thr Phe Tyr Pro Val Leu Asp Thr Gln Thr Pro Ala Thr Glu Phe Ser
145150155160
Val Ser Ser Ser Ala Tyr Leu Ala Ser Ser Pro Asp Ser Thr Thr Pro
165170175
Val Ser Ala Thr Thr Arg Ala Pro Pro Leu Thr Ser Met Ala Arg Lys
180185190
Thr Lys Lys Ile Cys Ile Thr Glu Val Tyr Thr Glu Pro Ile Thr Met
195200205
Ala Thr Glu Thr Glu Ala Phe Val Ala Ser Gly Ala Ala Phe Lys Asn
210215220
Glu Ala Ala Gly Phe Gly Gly Val Pro Thr Ala Leu Leu Val Leu Ala
225230235240
Leu Leu Phe Phe Gly Ala Ala Ala Val Leu Ala Val Cys Tyr Val Lys
245250255
Arg Tyr Val Lys Ala Phe Pro Phe Thr Thr Lys Asn Gln Gln Lys Glu
260265270
Met Ile Glu Thr Lys Val Val Lys Glu Glu Lys Ala Asp Asp Val Asn
275280285
Ala Asn Glu Glu Ser Lys Lys Thr Ile Lys Asn Pro Glu Glu Ala Lys
290295300
Ser Pro Pro Lys Thr Thr Val Arg Cys Leu Glu Ala Glu Val
305310315
<210> 268
<211> 322
<212> PRT
<213> Bos taurus
<220>
<223> Cow LYVE-1 Q6UC88
<400> 268
Met Ala Lys Phe Phe Ser Leu Gly Leu Leu Leu Ala Ser Ile Trp Thr
151015
Thr Arg Leu Leu Val Gln Gly Ser Leu Arg Ser Glu Glu Ile Ser Ile
202530
Leu Gly Pro Cys Arg Ile Met Gly Val Thr Leu Val Thr Lys Lys Thr
354045
Gln Pro Leu Leu Asn Phe Thr Glu Ala Gln Glu Ala Cys Arg Leu Val
505560
Gly Leu Thr Leu Ala Ser Gln Asp Gln Val Glu Glu Ala Arg Lys Phe
65707580
Gly Phe Glu Thr Cys Ser Tyr Gly Trp Val Lys Asn Gln Phe Val Val
859095
Ile Pro Arg Ile Ile Ser Asn Pro Lys Cys Gly Lys Ser Gly Val Gly
100105110
Val Val Ile Trp Arg Ser Ser Leu Ser Ser Arg His Arg Ser Tyr Cys
115120125
His Asn Ser Ser Asp Ile Trp Ile Asn Ser Cys Leu Pro Glu Ile Ile
130135140
Thr Thr Asp Asp Pro Leu Phe Asn Thr Glu Thr Ala Thr Tyr Thr Thr
145150155160
Lys Leu Met Val Ser Asp Ser Thr His Ser Glu Leu Ser Thr Asp Gly
165170175
Pro Asp Tyr Val Thr Thr Thr Val Ala Pro Pro Leu Ala Ser Thr Ser
180185190
Thr Pro Arg Lys Arg Lys Leu Ile Cys Ile Thr Glu Ala Phe Met Asp
195200205
Thr Ser Ala Val Ala Thr Glu Arg Glu Ser Asp Ile Gln Asn Arg Pro
210215220
Ala Phe Lys Asn Glu Ala Val Gly Phe Gly Gly Val Pro Thr Ala Leu
225230235240
Leu Val Leu Ala Leu Leu Phe Phe Ala Ala Ala Ala Gly Leu Ala Val
245250255
Cys Tyr Val Lys Arg Tyr Val Lys Ala Phe Pro Phe Thr Asn Lys Asn
260265270
Gln Gln Lys Glu Met Ile Glu Thr Lys Val Val Lys Glu Glu Lys Ala
275280285
Asp Asp Ser Asn Pro Asn Glu Glu Ser Lys Lys Met Asn Lys Thr Pro
290295300
Glu Glu Pro Lys Ser Pro Pro Lys Thr Thr Val Arg Cys Leu Glu Ala
305310315320
Glu Val
<210> 269
<211> 180
<212> PRT
<213> Bos taurus
<220>
<223> Cow HAPLN1 A8E4P9
<400> 269
Met Lys Ser Leu Leu Leu Leu Val Leu Ile Ser Phe Cys Trp Ala Asp
151015
His His Ser Asp Asn Tyr Thr Val Asp His Asp Arg Val Ile His Ile
202530
Gln Ala Glu Asn Gly Pro Arg Leu Leu Val Glu Ala Glu Gln Ala Lys
354045
Val Phe Ser Arg Arg Gly Gly Asn Val Thr Leu Pro Cys Lys Phe Tyr
505560
Arg Asp Pro Thr Ala Phe Gly Ser Gly Thr His Lys Ile Arg Ile Lys
65707580
Trp Thr Lys Leu Thr Ser Asp Tyr Leu Lys Glu Val Asp Val Phe Val
859095
Ser Met Gly Tyr His Lys Lys Thr Tyr Gly Gly Tyr His Gly Arg Val
100105110
Phe Leu Lys Gly Gly Ser Asp Asn Asp Ala Ser Leu Val Ile Thr Asp
115120125
Leu Thr Leu Glu Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile Glu Gly
130135140
Leu Glu Asp Asp Thr Ala Val Val Ala Leu Asp Leu Gln Gly Lys Tyr
145150155160
Gly Val Lys Leu Gly Met Ile Ile Asn His Cys Phe Phe Phe Met Thr
165170175
Ser Asn Val Gln
180
<210> 270
<211> 356
<212> PRT
<213> Mus musculus
<220>
<223> MOUSE HAPLN1 Q9QUP5
<400> 270
Met Arg Ser Leu Leu Leu Leu Val Leu Ile Ser Val Cys Trp Ala Asp
151015
His His Leu Ser Asp Ser Tyr Thr Pro Pro Asp Gln Asp Arg Val Ile
202530
His Ile Gln Ala Glu Asn Gly Pro Arg Leu Leu Val Glu Ala Glu Gln
354045
Ala Lys Val Phe Ser His Arg Gly Gly Asn Val Thr Leu Pro Cys Lys
505560
Phe Tyr Arg Asp Pro Thr Ala Phe Gly Ser Gly Ile His Lys Ile Arg
65707580
Ile Lys Trp Thr Lys Leu Thr Ser Asp Tyr Leu Arg Glu Val Asp Val
859095
Phe Val Ser Met Gly Tyr His Lys Lys Thr Tyr Gly Gly Tyr Gln Gly
100105110
Arg Val Phe Leu Lys Gly Gly Ser Asp Asn Asp Ala Ser Leu Val Ile
115120125
Thr Asp Leu Thr Leu Glu Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile
130135140
Glu Gly Leu Glu Asp Asp Thr Ala Val Val Ala Leu Glu Leu Gln Gly
145150155160
Val Val Phe Pro Tyr Phe Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe
165170175
His Glu Ala Arg Gln Ala Cys Leu Asp Gln Asp Ala Val Ile Ala Ser
180185190
Phe Asp Gln Leu Tyr Asp Ala Trp Arg Gly Gly Leu Asp Trp Cys Asn
195200205
Ala Gly Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro
210215220
Arg Glu Pro Cys Gly Gly Gln Asn Thr Val Pro Gly Val Arg Asn Tyr
225230235240
Gly Phe Trp Asp Lys Asp Lys Ser Arg Tyr Asp Val Phe Cys Phe Thr
245250255
Ser Asn Phe Asn Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu
260265270
Thr Tyr Asp Glu Ala Val Gln Ala Cys Leu Asn Asp Gly Ala Gln Ile
275280285
Ala Lys Val Gly Gln Ile Phe Ala Ala Trp Lys Leu Leu Gly Tyr Asp
290295300
Arg Cys Asp Ala Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile
305310315320
Ser Arg Pro Arg Arg Arg Cys Ser Pro Thr Glu Ala Ala Val Arg Phe
325330335
Val Gly Phe Pro Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe
340345350
Arg Ala Tyr Asn
355
<210> 271
<211> 354
<212> PRT
<213> Rattus norvegicus
<220>
<223> RAT HAPLN1 P03994
<400> 271
Met Arg Ser Leu Leu Phe Leu Val Leu Ile Ser Val Cys Arg Ala Asp
151015
His Leu Ser Asp Ser Tyr Thr Pro Asp Gln Asp Arg Val Ile His Ile
202530
Gln Ala Glu Asn Gly Pro Arg Leu Leu Val Glu Ala Glu Gln Ala Lys
354045
Val Phe Ser His Arg Gly Gly Asn Val Thr Leu Pro Cys Lys Phe Tyr
505560
Arg Asp Pro Thr Ala Phe Gly Ser Gly Ile His Lys Ile Arg Ile Lys
65707580
Trp Thr Lys Leu Thr Ser Asp Tyr Leu Arg Glu Val Asp Val Phe Val
859095
Ser Met Gly Tyr His Lys Lys Thr Tyr Gly Gly Tyr Gln Gly Arg Val
100105110
Phe Leu Lys Gly Gly Ser Asp Asn Asp Ala Ser Leu Ile Ile Thr Asp
115120125
Leu Thr Leu Glu Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile Glu Gly
130135140
Leu Glu Asp Asp Thr Ala Val Val Ala Leu Glu Leu Gln Gly Val Val
145150155160
Phe Pro Tyr Phe Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe His Glu
165170175
Ala Arg Gln Ala Cys Leu Asp Gln Asp Ala Val Ile Ala Ser Phe Asp
180185190
Gln Leu Tyr Asp Ala Trp Arg Gly Gly Leu Asp Trp Cys Asn Ala Gly
195200205
Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro Arg Glu
210215220
Pro Cys Gly Gly Gln Asn Thr Val Pro Gly Val Arg Asn Tyr Gly Phe
225230235240
Trp Asp Lys Asp Lys Ser Arg Tyr Asp Val Phe Cys Phe Thr Ser Asn
245250255
Phe Asn Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu Thr Tyr
260265270
Asp Glu Ala Val Gln Ala Cys Leu Asn Asp Gly Ala Gln Ile Ala Lys
275280285
Val Gly Gln Ile Phe Ala Ala Trp Lys Leu Leu Gly Tyr Asp Arg Cys
290295300
Asp Ala Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ser Arg
305310315320
Pro Arg Arg Arg Cys Ser Pro Thr Glu Ala Ala Val Arg Phe Val Gly
325330335
Phe Pro Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe Arg Ala
340345350
Tyr Asn
<210> 272
<211> 355
<212> PRT
<213> Gallus gallus
<220>
<223> CHICKEN HAPLN1 P07354
<400> 272
Met Thr Ser Leu Leu Phe Leu Val Leu Ile Ser Val Cys Trp Ala Glu
151015
Pro His Pro Asp Asn Ser Ser Leu Glu His Glu Arg Ile Ile His Ile
202530
Gln Glu Glu Asn Gly Pro Arg Leu Leu Val Val Ala Glu Gln Ala Lys
354045
Ile Phe Ser Gln Arg Gly Gly Asn Val Thr Leu Pro Cys Lys Phe Tyr
505560
His Glu His Thr Ser Thr Ala Gly Ser Gly Thr His Lys Ile Arg Val
65707580
Lys Trp Thr Lys Leu Thr Ser Asp Tyr Leu Lys Glu Val Asp Val Phe
859095
Val Ala Met Gly His His Arg Lys Ser Tyr Gly Lys Tyr Gln Gly Arg
100105 110
Val Phe Leu Arg Glu Ser Ser Glu Asn Asp Ala Ser Leu Ile Ile Thr
115120125
Asn Ile Met Leu Glu Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile Glu
130135140
Gly Leu Glu Asp Asp Thr Ala Val Val Ala Leu Asn Leu Glu Gly Val
145150155160
Val Phe Pro Tyr Ser Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe His
165170175
Glu Ala Gln Gln Ala Cys Leu Asp Gln Asp Ser Ile Ile Ala Ser Phe
180185190
Asp Gln Leu Tyr Glu Ala Trp Arg Ser Gly Leu Asp Trp Cys Asn Ala
195200205
Gly Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro Arg
210215220
Glu Pro Cys Gly Gly Lys Asn Thr Val Pro Gly Val Arg Asn Tyr Gly
225230235240
Phe Trp Asp Lys Glu Arg Ser Arg Tyr Asp Val Phe Cys Phe Thr Ser
245250255
Asn Phe Asn Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu Thr
260265270
Tyr Asp Glu Ala Val Gln Ala Cys Leu Lys Asp Gly Ala Gln Ile Ala
275280285
Lys Val Gly Gln Ile Phe Ala Ala Trp Lys Leu Leu Gly Tyr Asp Arg
290295300
Cys Asp Ala Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ser
305310315320
Arg Pro Arg Lys Arg Cys Ser Pro Asn Glu Ala Ala Val Arg Phe Val
325330335
Gly Phe Pro Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe Arg
340345350
Ala Tyr Asn
355
<210> 273
<211> 354
<212> PRT
<213> Bos taurus
<220>
<223> COW HAPLN1 P55252
<400> 273
Met Lys Ser Leu Leu Leu Leu Val Leu Ile Ser Phe Cys Trp Ala Asp
151015
His His Ser Asp Asn Tyr Thr Val Asp His Asp Arg Val Ile His Ile
202530
Gln Ala Glu Asn Gly Pro Arg Leu Leu Val Glu Ala Glu Gln Ala Lys
354045
Val Phe Ser Arg Arg Gly Gly Asn Val Thr Leu Pro Cys Lys Phe Tyr
505560
Arg Asp Pro Thr Ala Phe Gly Ser Gly Thr His Lys Ile Arg Ile Lys
65707580
Trp Thr Lys Leu Thr Ser Asp Tyr Leu Lys Glu Val Asp Val Phe Val
85 9095
Ser Met Gly Tyr His Lys Lys Thr Tyr Gly Gly Tyr His Gly Arg Val
100105110
Phe Leu Lys Gly Gly Ser Asp Asn Asp Ala Ser Leu Val Ile Thr Asp
115120125
Leu Thr Leu Glu Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile Glu Gly
130135140
Leu Glu Asp Asp Thr Ala Val Val Ala Leu Asp Leu Gln Gly Val Val
145150155160
Phe Pro Tyr Phe Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe His Glu
165170175
Ala Gln Gln Ala Cys Leu Asp Gln Asp Ala Val Ile Ala Ser Phe Asp
180185190
Gln Leu Tyr Asp Ala Trp Arg Ser Gly Leu Asp Trp Cys Asn Ala Gly
195200205
Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro Arg Glu
210215220
Pro Cys Gly Gly Gln Asn Thr Val Pro Gly Val Arg Asn Tyr Gly Phe
225230235240
Trp Asp Lys Asp Lys Ser Arg Tyr Asp Val Phe Cys Phe Thr Ser Asn
245250255
Phe Asn Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu Thr Tyr
260265270
Asp Glu Ala Val Gln Ala Cys Leu Asn Asp Gly Ala Gln Ile Ala Lys
275280285
Val Gly Gln Ile Phe Ala Ala Trp Lys Leu Leu Gly Tyr Asp Arg Cys
290295300
Asp Ala Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ser Arg
305310315320
Pro Arg Arg Arg Cys Ser Pro Ser Glu Ala Ala Val Arg Phe Val Gly
325330335
Phe Pro Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe Arg Ala
340345350
Tyr Asn
<210> 274
<211> 354
<212> PRT
<213> Equus caballus
<220>
<223> HORSE HAPLN1 28381
<400> 274
Met Lys Ser Leu Leu Leu Leu Val Leu Ile Ser Ile Cys Gly Ala Asp
151015
His Arg Ser Asp Asn Tyr Thr Leu Asp His Asp Arg Val Ile His Ile
202530
Gln Ala Glu Asn Gly Pro Arg Leu Leu Val Glu Ala Glu Gln Ala Lys
354045
Val Phe Ser His Arg Gly Gly Asn Val Thr Leu Pro Cys Lys Phe Leu
505560
Arg Asp Pro Thr Ala Phe Gly Ser Gly Thr His Lys Ile Arg Ile Lys
65707580
Trp Thr Lys Leu Thr Ser Asp Tyr Leu Lys Glu Val Asp Val Phe Val
859095
Ser Met Gly Tyr His Lys Lys Thr Tyr Gly Gly Tyr Gln Gly Arg Val
100105110
Phe Leu Lys Gly Gly Ser Asp Asn Asp Ala Ser Leu Val Ile Thr Asp
115120125
Leu Thr Leu Asp Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile Glu Gly
130135140
Leu Glu Asp Asp Thr Ala Val Val Ala Leu Asp Leu Gln Gly Val Val
145150155160
Phe Pro Tyr Phe Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe His Glu
165170175
Ala Gln Gln Ala Cys Leu Asp Gln Asp Ala Val Ile Ala Ser Phe Asp
180185190
Gln Leu Tyr Asp Ala Trp Arg Gly Gly Leu Asp Trp Cys Asn Ala Gly
195200205
Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro Arg Glu
210215220
Pro Cys Gly Gly Gln Asn Thr Val Pro Gly Val Arg Asn Tyr Gly Phe
225230235240
Trp Asp Lys Glu Lys Ser Arg Tyr Asp Val Phe Cys Phe Thr Ser Asn
245250255
Phe Asn Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu Thr Tyr
260265270
Asp Glu Ala Val Gln Ala Cys Leu Lys Asp Gly Ala Gln Ile Ala Lys
275280285
Val Gly Gln Ile Phe Ala Ala Trp Lys Leu Leu Gly Tyr Asp Arg Cys
290295300
Asp Ala Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ser Arg
305310315320
Pro Arg Arg Arg Cys Ser Pro Thr Glu Ala Ala Val Arg Phe Val Gly
325330335
Phe Pro Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe Arg Ala
340345350
Tyr Asn
<210> 275
<211> 354
<212> PRT
<213> Sus scrofa
<220>
<223> PIG HAPLN1 P10859
<400> 275
Met Lys Ser Leu Leu Leu Leu Val Leu Ile Ser Val Cys Trp Ala Asp
151015
His Leu Ser Asn Asn Tyr Thr Leu Asp His Asp Arg Val Ile His Ile
202530
Gln Ala Glu Asn Gly Pro Arg Leu Leu Val Glu Ala Glu Gln Ala Lys
354045
Val Phe Ser His Arg Gly Gly Asn Val Thr Leu Pro Cys Lys Phe Phe
505560
Arg Asp Pro Thr Ala Phe Gly Ser Gly Thr His Lys Ile Arg Ile Lys
65707580
Trp Thr Lys Leu Thr Ser Asp Tyr Leu Lys Glu Val Asp Val Phe Val
859095
Ser Met Gly Tyr His Lys Lys Thr Tyr Gly Gly Tyr His Gly Arg Val
100105110
Phe Leu Lys Gly Gly Ser Asp Asn Asp Ala Ser Leu Val Ile Thr Asp
115120125
Leu Thr Leu Glu Asp Tyr Gly Arg Tyr Lys Cys Glu Val Ile Glu Gly
130135140
Leu Glu Asp Asp Thr Ala Val Val Ala Leu Asp Leu Glu Gly Val Val
145150155160
Phe Pro Tyr Phe Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe His Glu
165170175
Ala Gln Gln Ala Cys Leu Asp Gln Asp Ala Val Ile Ala Ser Phe Asp
180185190
Gln Leu Tyr Asp Ala Trp Arg Gly Gly Leu Asp Trp Cys Asn Ala Gly
195200205
Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro Arg Glu
210215220
Pro Cys Gly Gly Gln Asn Thr Val Pro Gly Val Arg Asn Tyr Gly Phe
225230235240
Trp Asp Lys Asp Lys Ser Arg Tyr Asp Val Phe Cys Phe Thr Ser Asn
245250255
Phe Asn Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu Thr Tyr
260265270
Asp Glu Ala Val Gln Ala Cys Leu Asn Asp Gly Ala Gln Ile Ala Lys
275280285
Val Gly Gln Ile Phe Ala Ala Trp Lys Leu Leu Gly Tyr Asp Arg Cys
290295300
Asp Ala Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ser Arg
305310315320
Pro Arg Arg Arg Cys Arg Pro Asn Glu Ala Ala Val Arg Phe Val Gly
325330335
Phe Pro Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe Arg Ala
340345350
Tyr Asn
<210> 276
<211> 341
<212> PRT
<213> Mus musculus
<220>
<223> Mouse HAPLN2 Q9ESM3
<400> 276
Met Pro Ser Arg Ile Pro Leu Pro Ala Phe Cys Cys Phe Leu Leu Pro
151015
Trp Ala Phe Thr Ser Phe His Lys Ala Leu Gly Asn Pro Ala Pro His
202530
Pro Gly Pro His Tyr Leu Leu Pro Pro Ile His Glu Val Ile His Ser
354045
Arg Arg Gly Ala Thr Ala Thr Leu Pro Cys Val Leu Gly Thr Ser Pro
505560
Pro Ser Tyr Lys Val Arg Trp Ser Lys Val Glu Pro Gly Glu Leu Arg
65707580
Glu Thr Leu Ile Leu Ile Thr Asn Gly Leu His Ala Arg Asp Tyr Gly
859095
Leu Leu Gly Gly Arg Ala Ser Leu Arg Arg Gly His Arg Leu Asp Ala
100105110
Ser Leu Ile Ile Lys Asn Val Arg Leu Glu Asp Glu Gly Arg Tyr Arg
115120125
Cys Glu Leu Ile Asn Gly Ile Glu Asp Glu Ser Val Ala Leu Thr Leu
130135140
Arg Leu Glu Gly Val Val Phe Pro Tyr Gln Pro Ser Arg Gly Arg Tyr
145150155160
Gln Phe Asn Tyr Phe Glu Ala Lys Arg Ala Cys Glu Glu Gln Asp Gly
165170175
Arg Leu Ala Thr Tyr Gly Gln Leu Tyr Gln Ala Trp Thr Glu Gly Leu
180185190
Asp Trp Cys Asn Ala Gly Trp Leu Leu Glu Gly Ser Val Arg Tyr Pro
195200205
Val Leu Thr Ala Arg Ala Pro Cys Gly Gly His Gly Arg Pro Gly Ile
210215220
Arg Ser Tyr Gly Pro Arg Asp Arg Ser Arg Asp Arg Tyr Asp Ala Phe
225230235240
Cys Phe Thr Ser Ala Leu Ala Gly Gln Val Phe Phe Val Pro Gly Arg
245250255
Leu Thr Leu Ser Glu Ala His Ala Ala Cys Arg Arg Arg Gly Ala Val
260265270
Val Ala Lys Val Gly His Leu Tyr Ala Ala Trp Lys Phe Ser Gly Leu
275280285
Asp Gln Cys Asp Gly Gly Trp Leu Ala Asp Gly Ser Val Arg Phe Pro
290295300
Ile Thr Thr Pro Arg Pro Arg Cys Gly Gly Leu Pro Asp Pro Gly Val
305310315320
Arg Ser Phe Gly Phe Pro Arg Pro Gln Gln Ala Ser Tyr Gly Thr Tyr
325330335
Cys Tyr Ala Glu Lys
340
<210> 277
<211> 341
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat HAPLN2 Q9ESM2
<400> 277
Met Pro Ser Trp Ile Pro Leu Pro Ala Phe Cys Cys Leu Leu Leu Pro
151015
Trp Ala Phe Thr Val Phe His Lys Thr Leu Gly Asn Pro Ala Pro His
202530
Pro Gly Pro His Tyr Leu Leu Pro Pro Ile His Glu Val Ile His Ser
354045
Arg Arg Gly Ala Thr Ala Thr Leu Pro Cys Val Leu Gly Thr Ser Pro
505560
Pro Ser Tyr Lys Val Arg Trp Ser Lys Val Glu Pro Gly Glu Leu Arg
65707580
Glu Thr Leu Ile Leu Ile Thr Asn Gly Leu His Ala Arg Asp Tyr Gly
859095
Leu Leu Gly Gly Arg Ala Ser Leu Arg Arg Gly His Arg Leu Asp Ala
100105110
Ser Leu Ile Ile Lys Asn Val Arg Leu Glu Asp Glu Gly Arg Tyr Arg
115120125
Cys Glu Leu Ile Asn Gly Ile Glu Asp Glu Ser Val Ala Leu Thr Leu
130135140
Arg Leu Glu Gly Val Val Phe Pro Tyr Gln Pro Ser Arg Gly Arg Tyr
145150155160
Gln Phe Asn Tyr Phe Glu Ala Lys Arg Ala Cys Glu Glu Gln Asp Gly
165170175
Arg Leu Ala Thr Tyr Ser Gln Leu Tyr Gln Ala Trp Thr Glu Gly Leu
180185190
Asp Trp Cys Asn Ala Gly Trp Leu Leu Glu Gly Ser Val Arg Tyr Pro
195200205
Val Leu Asn Ala Arg Ala Pro Cys Gly Gly His Gly Arg Pro Gly Ile
210215220
Arg Ser Tyr Gly Pro Arg Asp Arg Ser Arg Asp Arg Tyr Asp Ala Phe
225230235240
Cys Phe Thr Ser Ala Leu Ala Gly Gln Val Phe Phe Val Pro Gly Arg
245250255
Leu Thr Leu Ser Glu Ala His Ala Val Cys Arg Arg Arg Gly Ala Val
260265270
Val Ala Lys Val Gly His Leu Tyr Ala Ala Trp Lys Phe Ser Gly Leu
275280285
Asp Arg Cys Asp Gly Gly Trp Leu Ala Asp Gly Ser Val Arg Phe Pro
290295300
Ile Thr Thr Pro Arg Pro Arg Cys Gly Gly Leu Pro Asp Pro Gly Val
305310315320
Arg Ser Phe Gly Phe Pro Arg Pro Gln Gln Ala Ala Tyr Gly Thr Tyr
325330335
Cys Tyr Ala Glu Lys
340
<210> 278
<211> 340
<212> PRT
<213> Bos taurus
<220>
<223> Cow HAPLN2 NP_001069152
<400> 278
Met Gln Gly Arg Ile Ser Leu Pro Thr Leu Cys His Phe Leu Leu Pro
151015
Trp Ala Phe Thr Thr Phe His Arg Ala Leu Gly Ser Gln Ala Pro His
202530
Pro Gly Pro His Tyr Leu Leu Pro Pro Ile His Glu Val Ile His Ser
354045
Arg Arg Gly Ala Thr Thr Thr Leu Pro Cys Val Leu Gly Ala Pro Pro
505560
Pro Ser Tyr Lys Val Arg Trp Ser Lys Val Glu Pro Gly Glu Leu Arg
65707580
Glu Thr Pro Ile Leu Ile Thr Asn Gly Leu His Ala Arg Gly Tyr Gly
859095
Pro Leu Gly Gly Arg Ala Arg Met Arg Arg Gly His Arg Leu Asp Ala
100105110
Ser Leu Val Ile Ala Gly Val Arg Leu Glu Asp Glu Gly Arg Tyr Arg
115120125
Cys Glu Leu Ile Asn Gly Ile Glu Asp Glu Ser Val Ala Met Thr Leu
130135140
Arg Leu Glu Gly Val Val Phe Pro Tyr Gln Pro Ser Arg Gly Arg Tyr
145150155160
Gln Phe Asn Tyr Tyr Glu Ala Lys Gln Ala Cys Glu Glu Gln Asp Gly
165170175
Arg Leu Ala Thr Tyr Ala Gln Leu Tyr Gln Ala Trp Thr Glu Gly Leu
180185190
Asp Trp Cys Asn Ala Gly Trp Leu Leu Glu Gly Ser Val Arg Tyr Pro
195200205
Val Leu Thr Ala Arg Ala Pro Cys Gly Gly Arg Gly Arg Pro Gly Ile
210215220
Arg Ser Tyr Gly Pro Arg Asp Arg Lys Arg Asp Arg Tyr Asp Ala Phe
225230235240
Cys Phe Thr Ser Ala Leu Ser Gly His Val Phe Phe Val Pro Gly Arg
245250255
Leu Ser Leu Ser Glu Ala His Ala Ala Cys Arg Arg Arg Gly Ala Met
260265270
Val Ala Lys Val Gly His Leu Tyr Ala Ala Trp Lys Phe Ser Gly Leu
275280285
Asp Gln Cys Asp Gly Gly Trp Leu Ala Asp Gly Ser Val Arg Phe Pro
290295300
Ile Thr Thr Pro Arg Pro Arg Cys Gly Gly Leu Pro Asp Pro Gly Val
305310315320
Arg Ser Phe Gly Phe Pro Arg Pro Gln Gln Ala Asp Tyr Gly Thr Tyr
325330335
Cys Tyr Ser Glu
340
<210> 279
<211> 359
<212> PRT
<213> Mus musculus
<220>
<223> Mouse HAPLN3 Q80WM5
<400> 279
Met Ser Leu Leu Phe Leu Val Leu Leu Ser Pro Phe Pro Cys Val Leu
151015
Gly Leu Pro Phe Tyr Asn Gly Phe Tyr Tyr Ser Asn Asp Leu Ser Gly
202530
Arg Thr Leu Gly Asn Gly Tyr Gly Glu Gly Leu Phe Asn Gly Val Lys
354045
Leu Val Val Glu Thr Thr Glu Glu Ser Leu Phe Ser His Gln Gly Ala
505560
Ser Val Thr Leu Pro Cys His Tyr His Tyr Glu Pro Ala Leu Ala Ser
65707580
Pro Arg His Val Arg Val Lys Trp Trp Lys Leu Ser Glu Asn Gly Ala
859095
Pro Glu Gln Asp Val Leu Val Val Ile Gly Gln Arg His Arg Ser Phe
100105110
Gly Asp Tyr Gln Gly Arg Val Gln Leu Arg Gln Asp Lys Gln Gln Glu
115120125
Val Ser Leu Glu Leu Arg Asp Leu Arg Leu Glu Asp Ser Gly Arg Tyr
130135140
Arg Cys Glu Val Ile Asp Gly Leu Glu Asp Glu Ser Gly Leu Val Glu
145150155160
Leu Glu Leu Arg Gly Val Val Phe Pro Tyr Gln Ser Arg Glu Gly Arg
165170175
Tyr Gln Leu Asn Phe His Glu Ala Gln Gln Ala Cys Gln Glu Gln Gly
180185190
Ala Met Val Ala Thr Phe Glu Gln Leu Phe Arg Ala Trp Glu Glu Gly
195200205
Leu Asp Trp Cys Asn Ala Gly Trp Leu Gln Asp Ala Ser Val Gln Tyr
210215220
Pro Ile Val Leu Pro Arg Gln Pro Cys Gly Gly Leu Gly Leu Ala Pro
225230235240
Gly Val Arg Ser Tyr Gly Gln Arg His His Arg Leu His Arg Tyr Asp
245250255
Val Phe Cys Phe Ala Ala Ala Leu Lys Gly Arg Val Tyr Tyr Leu Glu
260265270
Asn Pro Lys Lys Leu Thr Leu Leu Glu Ala Arg Glu Ala Cys Gln Glu
275280285
Asp Gly Ala Gln Ile Ser Thr Val Gly Gln Leu Phe Ala Ala Trp Lys
290295300
Phe Arg Gly Leu Asp Arg Cys Asp Ala Gly Trp Leu Ala Asp Gly Ser
305310315320
Ala Arg Tyr Pro Ile Val His Pro Arg Leu Asn Cys Gly Pro Pro Glu
325330335
Pro Gly Val Arg Thr Phe Gly Phe Pro Asp Pro His Thr Arg Tyr Gly
340345350
Val Tyr Cys Tyr Val Gln His
355
<210> 280
<211> 359
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat HAPLN3 NP_001008559
<400> 280
Met Gly Leu Leu Phe Leu Val Leu Leu Ser Pro Leu Ser Cys Val Leu
151015
Gly Leu Pro Phe Tyr Asn Gly Phe Tyr Tyr Ser Asn Gly Leu His Gly
202530
Arg Thr Leu Gly Asn Gly Tyr Gly Glu Gly Leu Phe Asn Gly Val Lys
354045
Leu Val Val Glu Thr Thr Glu Glu Ser Leu Phe Ser His Gln Gly Ala
505560
Ser Val Thr Leu Pro Cys His Tyr His Tyr Glu Pro Ala Leu Ala Ser
65707580
Pro Arg His Val Arg Ile Lys Trp Trp Lys Leu Ser Glu Asn Gly Thr
859095
Pro Glu Gln Asp Val Leu Val Ala Ile Gly Gln Arg His Arg Ser Phe
100105110
Gly Asp Tyr Gln Gly Arg Val Gln Leu Arg Gln Asp Lys Glu Gln Glu
115120125
Val Ser Leu Glu Leu Arg Asp Leu Arg Leu Glu Asp Ser Gly Arg Tyr
130135140
Arg Cys Glu Val Ile Asp Gly Leu Glu Asp Glu Ser Gly Leu Val Glu
145150155160
Leu Glu Leu Arg Gly Val Val Phe Pro Tyr Gln Pro Arg Glu Gly Arg
165170175
Tyr Gln Leu Asn Phe His Glu Ala Gln Gln Val Cys Gln Glu Gln Asp
180185190
Ala Val Val Ala Thr Phe Glu Gln Leu Phe Arg Ala Trp Glu Glu Gly
195200205
Leu Asp Trp Cys Asn Ala Gly Trp Leu Gln Asp Ala Ser Val Gln Tyr
210215220
Pro Ile Val Leu Pro Arg Gln Pro Cys Gly Gly Leu Gly Leu Ala Pro
225230235240
Gly Val Arg Ser Tyr Gly Gln Arg His His Arg Leu His Arg Tyr Asp
245250255
Val Phe Cys Phe Ala Ala Ala Leu Lys Gly Arg Val Tyr Tyr Leu Glu
260265270
Asn Pro Glu Lys Leu Thr Leu Leu Glu Ala Arg Glu Ala Cys Gln Glu
275280285
Asp Gly Ala Gln Ile Ser Thr Val Gly Gln Leu Phe Ala Ala Trp Lys
290295300
Phe Arg Gly Leu Asp Arg Cys Asp Ala Gly Trp Leu Ala Asp Gly Ser
305310315320
Ala Arg Tyr Pro Ile Ile His Pro Arg Pro Asn Cys Gly Pro Pro Glu
325330335
Pro Gly Val Arg Thr Phe Gly Phe Pro Asp Pro Asn Thr Arg Tyr Gly
340345350
Val Tyr Cys Tyr His Gln His
355
<210> 281
<211> 360
<212> PRT
<213> Bos taurus
<220>
<223> Cow HAPLN3 NP_001092451.1
<400> 281
Met Gly Leu Arg Leu Pro Ile Leu Leu Leu Leu Leu Cys Cys Val Ser
151015
Gly Leu Pro Phe Tyr Asn Gly Phe Tyr Tyr Ser Asn Arg Pro Asn Gly
202530
Arg Asn Leu Gly Asn Ser Tyr Ser Glu Gly Ile Phe Asn Gly Val Lys
354045
Leu Val Val Glu Thr Pro Glu Glu Thr Leu Phe Ser His Arg Gly Ala
505560
Asn Val Thr Leu Pro Cys Arg Tyr His Tyr Glu Pro Ala Leu Ala Ser
65707580
Pro Arg Pro Val Arg Ile Lys Trp Trp Lys Leu Ser Glu Asn Gly Val
859095
Pro Glu Gln Asp Val Leu Val Ala Ile Gly Leu Arg Gln Arg Thr Phe
100105110
Gly Asp Tyr Arg Gly Arg Val Arg Leu Arg Gln Asp Arg Ala Arg Glu
115120125
Val Ser Leu Glu Ile Arg Asp Leu Arg Leu Glu Asp Tyr Gly Arg Tyr
130135140
Arg Cys Glu Val Ile Asp Gly Leu Glu Asp Glu Ser Gly Leu Val Glu
145150155160
Leu Glu Leu Arg Gly Val Val Phe Pro Tyr Gln His Pro Gln Gly Arg
165170175
Tyr Lys Phe Asn Phe His Glu Ala Gln Gln Ala Cys Glu Glu Gln Asp
180185190
Ala Val Val Ala Ser Phe Glu Gln Leu Phe Arg Ala Trp Glu Glu Gly
195200205
Leu Asp Trp Cys Asn Ala Gly Trp Leu Gln Asp Ala Ser Val Gln Tyr
210215220
Pro Val Thr Gln Ala Arg Arg Pro Cys Gly Gly Leu Gly Leu Ala Pro
225230235240
Gly Val Arg Ser Tyr Gly Pro Arg His Arg Arg Leu His Arg Tyr Asp
245250255
Val Phe Cys Phe Ala Val Ala Leu Arg Gly Gln Val Tyr Tyr Leu Glu
260265270
His Pro Glu Lys Leu Thr Leu Ala Glu Ala Arg Glu Ala Cys Gln Glu
275280285
Asp Gly Ala Gln Ile Ala Lys Val Gly Gln Leu Phe Ala Ala Trp Lys
290295300
Phe Arg Gly Leu Asp Arg Cys Asp Ala Gly Trp Leu Ala Asp Gly Ser
305310315320
Ala Arg Tyr Pro Val Ala His Pro Arg Ser Asn Cys Gly Ala Leu Glu
325330335
Pro Gly Val Arg Ser Phe Gly Phe Pro Asp Pro His Ser Arg Gln Tyr
340345350
Gly Val Tyr Cys Tyr Arg Pro Arg
355360
<210> 282
<211> 402
<212> PRT
<213> Mus musculus
<220>
<223> Mouse HAPLN4 Q80WM4
<400> 282
Met Val Cys Ala Arg Ala Ala Leu Gly Pro Gly Ala Leu Trp Ala Ala
151015
Ala Trp Gly Val Leu Leu Leu Thr Ala Pro Ala Gly Ala Gln Arg Gly
202530
Arg Lys Lys Val Val His Val Leu Glu Gly Glu Ser Gly Ser Val Val
354045
Val Gln Thr Ala Pro Gly Gln Val Val Ser His Arg Gly Gly Thr Ile
505560
Val Leu Pro Cys Arg Tyr His Tyr Glu Ala Ala Ala His Gly His Asp
65707580
Gly Val Arg Leu Lys Trp Thr Lys Val Val Asp Pro Leu Ala Phe Thr
859095
Asp Val Phe Val Ala Leu Gly Pro Gln His Arg Ala Phe Gly Ser Tyr
100105110
Arg Gly Arg Ala Glu Leu Gln Gly Asp Gly Pro Gly Asp Ala Ser Leu
115120125
Val Leu Arg Asn Val Thr Leu Gln Asp Tyr Gly Arg Tyr Glu Cys Glu
130135140
Val Thr Asn Glu Leu Glu Asp Asp Ala Gly Met Val Lys Leu Asp Leu
145150155160
Glu Gly Val Val Phe Pro Tyr His Pro Arg Gly Gly Arg Tyr Lys Leu
165170175
Thr Phe Ala Glu Ala Gln Arg Ala Cys Ala Glu Gln Asp Gly Ile Leu
180185190
Ala Ser Ala Glu Gln Leu His Ala Ala Trp Arg Asp Gly Leu Asp Trp
195200205
Cys Asn Ala Gly Trp Leu Arg Asp Gly Ser Val Gln Tyr Pro Val Asn
210215220
Arg Pro Arg Glu Pro Cys Gly Gly Leu Gly Gly Thr Gly Ser Ala Gly
225230235240
Gly Gly Gly Asp Ala Asn Gly Gly Leu Arg Asn Tyr Gly Tyr Arg His
245250255
Asn Ala Glu Glu Arg Tyr Asp Ala Phe Cys Phe Thr Ser Asn Leu Pro
260265270
Gly Arg Val Phe Phe Leu Lys Pro Leu Arg Pro Val Pro Phe Ser Gly
275280285
Ala Ala Arg Ala Cys Ala Ala Arg Gly Ala Ala Val Ala Lys Val Gly
290295300
Gln Leu Phe Ala Ala Trp Lys Leu Gln Leu Leu Asp Arg Cys Thr Ala
305310315320
Gly Trp Leu Ala Asp Gly Ser Ala Arg Tyr Pro Ile Val Asn Pro Arg
325330335
Ala Arg Cys Gly Gly Arg Arg Pro Gly Val Arg Ser Leu Gly Phe Pro
340345350
Asp Ala Thr Arg Arg Leu Phe Gly Val Tyr Cys Tyr Arg Ala Pro Gly
355360365
Ala Pro Asp Pro Ala Pro Gly Gly Trp Gly Trp Gly Trp Ala Gly Gly
370375380
Gly Gly Trp Ala Gly Gly Ala Arg Asp Pro Ala Ala Trp Thr Pro Leu
385390395400
His Val
<210> 283
<211> 421
<212> PRT
<213> Bos taurus
<220>
<223> Cow HAPLN4 KIAA1926 DAA28318
<400> 283
Met Arg Glu Arg Ser Pro Ser Ala Trp Gly Pro Leu Gly Glu Gly Arg
151015
Thr Gly Arg Met Val Cys Ala Arg Ala Ala Leu Gly Pro Gly Ala Leu
202530
Trp Ala Ala Ala Trp Gly Val Leu Leu Leu Thr Ala Ala Ala Glu Ala
354045
Gln Arg Gly Arg Lys Lys Val Val His Val Leu Glu Gly Glu Ser Gly
505560
Ser Val Val Val Gln Thr Ala Pro Gly Gln Val Val Ser His Arg Gly
65707580
Gly Thr Ile Val Leu Pro Cys Arg Tyr His Tyr Glu Ala Ala Thr His
859095
Gly His Asp Gly Val Arg Leu Lys Trp Thr Lys Val Val Asp Pro Leu
100105110
Ala Phe Ala Asp Val Phe Val Ala Leu Gly Pro Gln His Arg Ala Phe
115120125
Gly Ser Tyr Arg Gly Arg Ala Glu Leu Gln Gly Asp Gly Pro Gly Asp
130135140
Ala Ser Leu Val Leu Arg Asn Val Thr Leu Gln Asp Tyr Gly Arg Tyr
145150155160
Glu Cys Glu Val Thr Asn Glu Leu Glu Asp Asp Thr Gly Met Val Lys
165170175
Leu Asp Leu Glu Gly Val Val Phe Pro Tyr His Pro Arg Gly Gly Arg
180185190
Tyr Lys Leu Thr Phe Ala Glu Ala Gln Arg Ala Cys Ala Glu Gln Asp
195200205
Gly Ile Leu Ala Ser Ala Glu Gln Leu His Ala Ala Trp Arg Asp Gly
210215220
Leu Asp Trp Cys Asn Ala Gly Trp Leu Arg Asp Gly Ser Val Gln Tyr
225230235240
Pro Val Ser Gln Pro Arg Glu Pro Cys Gly Gly Leu Gly Gly Ala Gly
245250255
Ser Ala Gly Ala Gly Gly Gly Ala Ser Gly Gly Val Arg Asn Tyr Gly
260265270
Tyr Arg His Asn Ala Glu Glu Arg Tyr Asp Ala Phe Cys Phe Thr Ser
275280285
Asn Leu Pro Gly Arg Val Phe Phe Leu Lys Pro Leu Arg Pro Val Pro
290295300
Phe Ser Gly Ala Ala Arg Ala Cys Ala Ala Arg Gly Ala Ala Val Ala
305310315320
Lys Val Gly Gln Leu Phe Ala Ala Trp Lys Leu Gln Leu Leu Asp Arg
325330335
Cys Thr Ala Gly Trp Leu Ala Asp Gly Ser Ala Arg Tyr Pro Ile Val
340345350
Asn Pro Arg Ala Arg Cys Gly Gly Arg Arg Pro Gly Val Arg Ser Leu
355360 365
Gly Phe Pro Asp Ala Ser Arg Arg Leu Phe Gly Val Tyr Cys Tyr Arg
370375380
Ala Pro Gly Ala Pro Asp Pro Ala Pro Gly Gly Trp Gly Trp Gly Trp
385390395400
Ala Gly Gly Gly Gly Trp Ala Gly Gly Ser Arg Asp Pro Ala Ala Trp
405410415
Thr Pro Leu Arg Val
420
<210> 284
<211> 400
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat HAPLN4 NP_001101868
<400> 284
Met Ala Cys Ala Pro Gly Ala Leu Gly His Arg Ala Leu Trp Ala Val
151015
Ala Trp Gly Leu Leu Leu Leu Val Pro Val Leu Ala Gly Ala Gln Arg
202530
Gly Arg Lys Lys Val Val His Val Leu Glu Gly Glu Ser Gly Ser Val
354045
Val Val Gln Thr Ala Pro Gly Gln Val Val Ser His Arg Gly Gly Thr
505560
Ile Val Leu Pro Cys Arg Tyr His Tyr Glu Ala Ala Ala His Gly His
65707580
Asp Gly Val Arg Leu Lys Trp Thr Lys Val Val Asp Pro Leu Ala Phe
859095
Ala Asp Val Phe Val Ala Leu Gly Pro Gln His Arg Ala Phe Gly Pro
100105110
Tyr Arg Gly Arg Ala Glu Leu Gln Asn Asp Gly Pro Gly Asp Ala Ser
115120125
Leu Val Leu Arg Asn Val Thr Leu Gln Asp Tyr Gly Arg Tyr Glu Cys
130135140
Glu Val Thr Asn Glu Leu Glu Asp Asp Ala Gly Met Val Lys Leu Asp
145150155160
Leu Glu Gly Val Val Phe Pro Tyr His Pro Arg Gly Gly Arg Tyr Lys
165170175
Met Thr Phe Ala Glu Ala Gln Arg Ala Cys Ala Glu Gln Asp Gly Ile
180185190
Leu Ala Ser Ala Glu Gln Leu His Thr Ala Trp Arg Asp Gly Leu Asp
195200205
Trp Cys Asn Ala Gly Trp Leu Arg Asp Gly Ser Val Gln Tyr Pro Val
210215220
Ser Gln Ala Arg Glu Ala Cys Gly Gly Ser Gly Ser Pro Gly Ala Gly
225230235240
Gly Gly Thr Asn Gly Gly Val Arg Asn Tyr Gly Tyr Arg His Asn Ala
245250255
Glu Glu Arg Tyr Asp Ala Phe Cys Phe Thr Ser Asn Leu Pro Gly Arg
260265270
Val Phe Phe Leu Lys Pro Leu Arg Pro Val Ala Leu Ala Gly Ala Val
275280285
Arg Ala Cys Ala Ala Arg Gly Ala Thr Val Ala Lys Val Gly Gln Leu
290295300
Phe Ala Ala Trp Lys Leu Gln Leu Leu Asp Arg Cys Thr Ala Gly Trp
305310315320
Leu Ala Asp Gly Ser Ala Arg Tyr Pro Ile Val Asn Pro Arg Thr Arg
325330335
Cys Gly Gly Pro Arg Pro Gly Val Arg Ser Leu Gly Phe Pro Asp Ala
340345350
Ser Arg Arg Leu Phe Gly Val Tyr Cys Tyr Arg Ala Pro Gly Ala Pro
355360365
Asp Pro Ala Pro Gly Gly Trp Gly Trp Gly Trp Ala Gly Gly Gly Gly
370375380
Trp Ala Gly Gly Ser Arg Asp Pro Ala Ala Trp Thr Pro Leu Arg Val
385390395400
<210> 285
<211> 537
<212> PRT
<213> Sus scrofa
<220>
<223> Pig Aggrecan Q29011
<220>
<221> VARIANT
<222> 45, 49, 146
<223> Xaa = any amino acid
<400> 285
Ala Ile Ser Val Glu Val Ser Glu Pro Asp Asn Ser Leu Ser Val Ser
151015
Ile Pro Gln Pro Ser Pro Leu Arg Val Leu Leu Gly Gly Ser Leu Thr
202530
Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val Xaa Thr Ala Pro
354045
Xaa Thr Ala Pro Leu Ala Pro Arg Ile Lys Trp Ser Arg Val Ser Lys
505560
Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly Gln Val Arg Val
65707580
Asn Ser Ala Tyr Gln Asp Arg Val Thr Leu Pro Asn Tyr Pro Ala Ile
859095
Pro Ser Asp Ala Thr Leu Glu Ile Gln Asn Leu Arg Ser Asn Asp Ser
100105110
Gly Ile Tyr Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Glu Ala
115120125
Thr Leu Glu Val Val Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile
130135140
Ser Xaa Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
145150155160
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
165170175
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
180185190
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
195200205
Asp Glu Phe Pro Gly Val Ile Thr Tyr Gly Ile Arg Asp Thr Asn Glu
210215220
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe
225230235 240
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu
245250255
Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu
260265270
Ala Trp Arg Gly Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
275280285
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
290295300
Asn Leu Leu Gly Val Arg Thr Val Tyr Leu His Ala Asn Gln Thr Gly
305310315320
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
325330335
Asp Phe Val Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Glu
340345350
Asp Ile Thr Ile Gln Thr Val Thr Trp Pro Asp Val Glu Leu Pro Leu
355360365
Pro Arg Asn Ile Thr Glu Gly Glu Ala Arg Gly Thr Val Ile Leu Thr
370375380
Val Lys Pro Val Phe Glu Phe Ser Pro Thr Ala Pro Glu Pro Glu Glu
385390395400
Pro Phe Thr Phe Ala Pro Gly Thr Gly Ala Thr Ala Phe Pro Glu Ala
405410415
Glu Asn Arg Thr Gly Glu Ala Thr Arg Pro Trp Ala Phe Pro Glu Glu
420425430
Ser Thr Pro Gly Leu Gly Ala Pro Thr Ala Phe Thr Ser Glu Asp Leu
435440445
Val Val Gln Val Thr Ser Ala Ala Thr Glu Glu Gly Thr Glu Gly Pro
450455460
Ser Ala Thr Glu Ala Pro Ser Thr Ser Glu Glu Pro Phe Pro Ser Glu
465470475480
Lys Pro Phe Pro Ser Glu Glu Pro Phe Pro Ser Glu Glu Pro Phe Pro
485490495
Ser Glu Lys Pro Ser Ala Ser Glu Glu Pro Phe Pro Ser Glu Gln Pro
500505510
Ser Thr Leu Ser Ala Pro Val Pro Ser Arg Thr Glu Leu Pro Gly Ser
515520525
Gly Glu Val Ser Gly Ala Pro Glu Val
530535
<210> 286
<211> 2109
<212> PRT
<213> Gallus gallus
<220>
<223> CHICKEN AGGRECAN P07898
<400> 286
Met Thr Thr Leu Leu Leu Val Phe Val Cys Leu Gln Ala Ile Thr Thr
151015
Ala Ala Ser Ala Glu Leu Ser Asp Ser Ser Asp Gly Leu Glu Val Lys
202530
Ile Pro Glu Gln Ser Pro Leu Arg Val Val Leu Gly Ser Ser Leu Asn
354045
Ile Pro Cys Tyr Phe Asn Ile Pro Glu Glu Glu Asp Thr Asn Ala Leu
505560
Leu Thr Pro Arg Ile Lys Trp Ser Lys Leu Ser Asn Gly Thr Glu Ile
65707580
Val Leu Leu Val Ala Thr Gly Gly Lys Ile Arg Leu Asn Ala Glu Tyr
859095
Arg Glu Val Ile Ser Leu Pro Asn Tyr Pro Ala Ile Pro Thr Asp Ala
100105110
Thr Leu Glu Ile Lys Ala Leu Arg Ser Asn His Thr Gly Ile Tyr Arg
115120125
Cys Glu Val Met Tyr Gly Ile Glu Asp Arg Gln Asp Thr Ile Glu Val
130135140
Leu Val Lys Gly Val Val Phe His Tyr Arg Ala Ile Ser Thr Arg Tyr
145150155160
Thr Leu Asn Phe Glu Arg Ala Lys Gln Ala Cys Ile Gln Asn Ser Ala
165170175
Val Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr Glu Asp Gly Tyr
180185190
Glu Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr Val Arg Tyr Pro
195200205
Ile His Leu Pro Arg Glu Arg Cys Tyr Gly Asp Lys Asp Glu Phe Pro
210215220
Gly Val Arg Thr Tyr Gly Val Arg Glu Thr Asp Glu Thr Tyr Asp Val
225230235240
Tyr Cys Tyr Ala Glu Gln Met Gln Gly Lys Val Phe Tyr Ala Thr Ser
245250255
Pro Glu Lys Phe Thr Phe Gln Glu Ala Phe Asp Lys Cys His Ser Leu
260265270
Gly Ala Arg Leu Ala Thr Thr Gly Glu Leu Tyr Leu Ala Trp Lys Asp
275280285
Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp Arg Ser Val Arg
290295300
Tyr Pro Ile Ser Arg Ala Arg Pro Asn Cys Gly Gly Asn Leu Val Gly
305310315320
Val Arg Thr Val Tyr Leu Asn Pro Ala Asn Gln Thr Gly Tyr Pro His
325330335
Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Ser Gly Asp Asp Phe Glu
340345350
Ala Leu Val Pro Gly Leu Phe Thr Asp Glu Val Gly Thr Glu Leu Gly
355360365
Ser Ala Phe Thr Ile Gln Thr Val Thr Gln Thr Glu Val Glu Leu Pro
370375380
Leu Pro Arg Asn Val Thr Glu Glu Glu Ala Arg Gly Ser Ile Ala Thr
385390395400
Leu Glu Pro Met Glu Ile Thr Ala Thr Ala Thr Glu Leu Tyr Glu Ala
405410415
Phe Thr Val Leu Pro Asp Leu Phe Ala Thr Ser Val Thr Val Glu Thr
420425430
Ala Ser Pro Arg Glu Glu Asn Val Thr Arg Glu Glu Ile Thr Gly Ile
435440445
Trp Ala Val Pro Glu Glu Val Thr Thr Ser Val Ser Gly Thr Ala Phe
450455460
Thr Thr Gly Met Ala Glu Val Ser Ser Val Glu Glu Ala Ile Ala Val
465470475480
Thr Ala Thr Pro Gly Leu Glu Ser Ala Ser Pro Phe Thr Ile Glu Asp
485490495
His Leu Val Gln Val Thr Ala Ala Pro Asp Val Ala Leu Leu Pro Arg
500505510
Gln Pro Ile Ser Pro Thr Gly Val Val Phe His Tyr Arg Ala Ala Thr
515520525
Ser Arg Tyr Ala Phe Ser Phe Ile Gln Ala Gln Gln Ala Cys Leu Glu
530535540
Asn Asn Ala Val Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr Glu
545550555560
Ala Gly Phe Asp Gln Cys Asp Ala Gly Trp Leu Arg Asp Gln Thr Val
565570575
Arg Tyr Pro Ile Val Asn Pro Arg Ser Asn Cys Val Gly Asp Lys Glu
580585590
Ser Ser Pro Gly Val Arg Ser Tyr Gly Met Arg Pro Ala Ser Glu Thr
595600605
Tyr Asp Val Tyr Cys Tyr Ile Asp Arg Leu Lys Gly Glu Val Phe Phe
610615620
Ala Thr Gln Pro Glu Gln Phe Thr Phe Gln Glu Ala Gln Leu Tyr Cys
625630635640
Glu Ser Gln Asn Ala Thr Leu Ala Ser Ala Gly Gln Leu His Ala Ala
645650655
Trp Lys Gln Gly Leu Asp Arg Cys Tyr Pro Gly Trp Leu Ala Asp Gly
660665670
Ser Leu Arg Tyr Pro Ile Val Ser Pro Arg Pro Ala Cys Gly Gly Asp
675680685
Ala Pro Gly Val Arg Thr Ile Tyr Gln His His Asn Gln Thr Gly Phe
690695700
Pro Asp Pro Leu Ser Arg His His Ala Phe Cys Phe Arg Ala Leu Pro
705710715720
Ser Val Val Glu Glu Gly Val Thr Ser Leu Phe Glu Glu Glu Val Met
725730735
Val Thr Gln Leu Ile Pro Gly Val Glu Gly Ile Pro Ser Gly Glu Glu
740745750
Thr Thr Val Glu Thr Glu Leu Ser Ser Glu Pro Glu Asn Gln Thr Ala
755760765
Gln Gly Thr Glu Val Phe Pro Thr Asp Val Ser Leu Leu Ser Ala Arg
770775780
Pro Ser Ala Phe Pro Pro Ala Thr Val Ile Pro Glu Glu Thr Ser Thr
785790795800
Asn Ala Ser Ile Pro Glu Val Ser Gly Glu Phe Pro Glu Ser Gly Glu
805810815
His Pro Thr Ser Gly Glu Pro Ser Ala Ser Gly Ala Pro Asp Thr Ser
820825830
Gly Glu Pro Thr Ser Val Gly Phe Glu Leu Ser Gly Glu Gln Ser Gly
835840845
Ile Gly Glu Ser Gly Leu Pro Ser Val Asp Leu Gln Ser Ser Gly Phe
850855860
Val Pro Gly Glu Ser Gly Leu Pro Ser Gly Asp Val Ser Gly Leu Pro
865870875880
Ser Gly Ile Val Asp Ile Ser Gly Leu Pro Ser Ala Glu Glu Glu Val
885890895
Thr Val Ser Val Ser Arg Ile Pro Glu Val Ser Gly Met Pro Ser Gly
900905910
Ala Glu Ser Ser Gly Leu His Ser Gly Phe Ser Gly Glu Ile Ser Gly
915920925
Thr Glu Leu Ile Ser Gly Leu Pro Ser Gly Glu Glu Ser Gly Leu Ala
930935940
Ser Gly Phe Pro Thr Ile Ser Leu Val Asp Ser Thr Leu Val Glu Val
945950955960
Val Thr Ala Ala Pro Gly Arg Gln Glu Glu Gly Lys Gly Ser Ile Gly
965970975
Val Ser Gly Glu Glu Glu Leu Ser Gly Phe Pro Ser Ala Glu Trp Asp
980985990
Ser Ser Gly Ala Arg Gly Leu Pro Ser Gly Ala Glu Thr Ser Gly Glu
99510001005
Gln Ser Gly Val Pro Glu Leu Ser Gly Glu His Ser Gly Val Pro Gly
101010151020
Leu Ser Gly Glu Ala Phe Glu Val Pro Glu Leu Ser Gly Glu His Ser
1025103010351040
Gly Val Thr Glu Leu Ser Gly Glu His Ser Gly Leu Pro Glu Leu Ser
104510501055
Gly Glu Pro Phe Gly Val Pro Glu Leu Ser Gly Phe Pro Ser Gly Leu
106010651070
Asp Ile Ser Gly Glu Pro Ser Gly Ala Pro Glu Val Ser Gly Pro Val
107510801085
Asp Val Ser Gly Leu Thr Ser Gly Val Asp Gly Ser Gly Glu Val Ser
109010951100
Gly Val Thr Phe Ile Ser Thr Ser Leu Gln Glu Val Thr Thr Pro Ser
1105111011151120
Val Ala Glu Ala Glu Ala Lys Glu Ile Leu Glu Ile Ser Gly Leu Pro
112511301135
Ser Gly Glu Thr Ser Gly Met Val Ser Gly Ser Leu Asp Val Ser Gly
114011451150
Gln Pro Ser Gly His Ile Gly Phe Gly Gly Ser Ala Ser Gly Val Leu
115511601165
Glu Met Ser Gly Phe Pro Gly Gly Ala Val Glu Ser Ser Gly Glu Ala
117011751180
Ser Gly Val Glu Val Thr Ser Gly Leu Ala Ser Gly Glu Glu Ser Gly
1185119011951200
Leu Thr Ser Gly Phe Pro Thr Val Ser Leu Val Asp Thr Thr Leu Val
120512101215
Glu Val Val Thr Gln Thr Ser Val Ala Gln Glu Val Gly Glu Gly Pro
122012251230
Ser Gly Met Ile Glu Ile Ser Gly Phe Leu Ser Gly Asp Arg Gly Val
123512401245
Ser Gly Glu Gly Ser Gly Ala Val Gln Ser Ser Gly Leu Pro Ser Gly
125012551260
Thr Gly Asp Phe Ser Gly Glu Pro Ser Gly Ile Pro Tyr Phe Ser Gly
1265127012751280
Asp Ile Ser Gly Ala Thr Asp Leu Ser Gly Gln Pro Ser Ala Val Thr
128512901295
Asp Ile Ser Gly Glu Asp Ser Gly Leu Pro Glu Val Thr Leu Val Thr
130013051310
Ser Asp Leu Val Glu Val Val Thr Arg Pro Thr Val Ser Gln Glu Leu
131513201325
Gly Gly Glu Thr Ala Val Thr Phe Pro Tyr Val Phe Gly Pro Ser Gly
133013351340
Glu Gly Ser Ala Ser Gly Asp Leu Ser Gly Gly Ala Ser Ala Glu Gly
1345135013551360
Gly Ile Glu Thr Ser Thr Ala Tyr Glu Ile Ser Gly Glu Ser Ser Ala
136513701375
Phe Pro Glu Thr Ser Ile Glu Thr Ser Thr Asp Gln Glu Ile Ser Gly
138013851390
Glu Ala Ser Ala Tyr Pro Glu Ile Ser Val Glu Thr Ser Thr His Leu
139514001405
Glu Thr Ser Gly Glu Thr Ser Ala Tyr Pro Glu Ile Ser Thr Glu Thr
141014151420
Ser Thr Ile Gln Glu Val Ser Gly Glu Thr Ser Ala Phe Pro Glu Ile
1425143014351440
Ser Thr Glu Thr Ser Thr Ile Gln Glu Ile Ser Gly Glu Thr Ser Ala
144514501455
Phe Pro Glu Ile Arg Ile Glu Thr Ser Thr Phe Gln Glu Ile Ser Gly
146014651470
Glu Thr Ser Ala Phe Pro Glu Ile Arg Ile Glu Thr Ser Thr Ser Gln
147514801485
Glu Ala Arg Gly Glu Thr Ser Ala Phe Pro Glu Ile Thr Ile Glu Ala
149014951500
Ser Thr Val His Glu Thr Ser Gly Glu Thr Ser Ala Phe Pro Glu Ile
1505151015151520
Ser Ile Glu Thr Ser Thr Val His Glu Thr Ser Gly Glu Thr Ser Ala
152515301535
Phe Pro Glu Ile Ser Ile Glu Thr Ser Thr Val His Glu Ile Ser Gly
154015451550
Glu Ser Ser Ala Phe Pro Glu Ile Arg Ile Glu Thr Ser Thr Ser Gln
155515601565
Glu Ala Arg Gly Glu Thr Ser Ala Phe Pro Glu Ile Thr Ile Glu Ala
157015751580
Ser Thr Ile Gln Glu Ile Ser Gly Glu Thr Ser Ala Phe Pro Glu Ile
1585159015951600
Ser Ile Glu Thr Ser Thr Val Arg Glu Ile Ser Gly Glu Thr Ser Ala
160516101615
Phe Pro Glu Ile Arg Ile Glu Thr Ser Thr Ser Gln Glu Ala Arg Gly
162016251630
Glu Thr Ser Ala Leu Pro Glu Ile Thr Ile Glu Thr Ser Thr Val His
163516401645
Glu Thr Ser Gly Glu Ala Ser Ala Phe Pro Glu Ile Ser Ile Glu Thr
165016551660
Ser Thr Arg Gln Glu Ala Arg Ser Glu Ala Ser Ala Tyr Pro Glu Val
1665167016751680
Ser Ile Glu Ala Ser Thr Thr Gln Glu Val Ser Gly Glu Ser Ser Ala
168516901695
Phe Pro Glu Ile Ser Val Glu Thr Ser Thr Ser Gln Glu Ala Arg Gly
170017051710
Glu Thr Ser Ala Phe Pro Glu Ile Gly Ile Glu Thr Ser Thr Ala His
171517201725
Glu Gly Ser Gly Glu Thr Pro Gly Leu Pro Ala Val Ser Thr Asp Thr
173017351740
Ala Ala Thr Ser Leu Ala Ser Gly Glu Pro Ser Gly Ala Pro Glu Lys
1745175017551760
Glu Thr Pro Asp Thr Thr Ser His Leu Ile Thr Gly Val Ser Gly Glu
176517701775
Thr Ser Val Pro Asp Ala Val Ile Ser Thr Ser Ala Pro Asp Val Glu
178017851790
Leu Ala Gln Glu Pro Arg Asn Thr Glu Glu Thr Gln Leu Glu Ile Glu
179518001805
Pro Ser Thr Pro Ala Ala Ser Gly Gln Glu Thr Glu Thr Ala Ala Val
181018151820
Leu Asp Asn Pro His Leu Pro Ala Thr Ala Thr Ala Ala Leu His Pro
1825183018351840
Ala Ser Gln Glu Ala Val Asp Ala Leu Gly Pro Thr Thr Glu Asp Thr
184518501855
Asp Glu Cys His Ser Ser Pro Cys Leu Asn Gly Ala Thr Cys Val Asp
186018651870
Gly Ile Asp Ser Phe Lys Cys Leu Cys Leu Pro Ser Tyr Gly Gly Asp
187518801885
Leu Cys Glu Ile Asp Leu Ala Asn Cys Glu Glu Gly Trp Ile Lys Phe
189018951900
Gln Gly His Cys Tyr Arg His Phe Glu Glu Arg Glu Thr Trp Met Asp
1905191019151920
Ala Glu Ser Arg Cys Arg Glu His Gln Ala His Leu Ser Ser Ile Ile
192519301935
Thr Pro Glu Glu Gln Glu Phe Val Asn Ser His Ala Gln Asp Tyr Gln
194019451950
Trp Ile Gly Leu Ser Asp Arg Ala Val Glu Asn Asp Phe Arg Trp Ser
195519601965
Asp Gly His Ser Leu Gln Phe Glu Asn Trp Arg Pro Asn Gln Pro Asp
197019751980
Asn Phe Phe Phe Ala Gly Glu Asp Cys Val Val Met Ile Trp His Glu
1985199019952000
Gln Gly Glu Trp Asn Asp Val Pro Cys Asn Tyr His Leu Pro Phe Thr
200520102015
Cys Lys Lys Gly Thr Val Ala Cys Gly Asp Pro Pro Val Val Glu Asn
202020252030
Ala Arg Thr Phe Gly Arg Lys Lys Asp Arg Tyr Glu Ile Asn Ser Leu
203520402045
Val Arg Tyr Gln Cys Asp His Gly Tyr Ile Gln Arg His Val Pro Thr
205020552060
Ile Arg Cys Gln Pro Asn Gly His Trp Glu Glu Pro Arg Ile Ser Cys
2065207020752080
Thr Asn Pro Ser Ser Tyr Gln Arg Arg Leu Tyr Lys Arg Ser Pro Arg
208520902095
Ser Arg Leu Arg Pro Gly Val Val His Arg Pro Thr His
21002105
<210> 287
<211> 2132
<212> PRT
<213> Mus musculus
<220>
<223> MOUSE AGGRECAN Q61282
<400> 287
Met Thr Thr Leu Leu Leu Val Phe Val Thr Leu Arg Val Ile Ala Ala
151015
Val Ile Ser Glu Glu Val Pro Asp His Asp Asn Ser Leu Ser Val Ser
202530
Ile Pro Gln Pro Ser Pro Leu Lys Val Leu Leu Gly Ser Ser Leu Thr
354045
Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val Thr Thr Ala Pro
505560
Ser Thr Ala Pro Leu Thr Pro Arg Ile Lys Trp Ser Arg Val Ser Lys
65707580
Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly Gln Val Arg Val
859095
Asn Ser Ile Tyr Gln Asp Lys Val Ser Leu Pro Asn Tyr Pro Ala Ile
100105110
Pro Ser Asp Ala Thr Leu Glu Ile Gln Asn Leu Arg Ser Asn Asp Ser
115120125
Gly Ile Tyr Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Glu Ala
130135140
Thr Leu Glu Val Ile Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile
145150155160
Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
165170175
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
180185190
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
195200205
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
210215220
Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu
225230235240
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe
245250255
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu
260265270
Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu
275280285
Ala Trp Gln Gly Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
290295300
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
305310315320
Asn Leu Leu Gly Val Arg Thr Val Tyr Leu His Ala Asn Gln Thr Gly
325330335
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
340345350
Asp Phe Val Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Asp
355360365
Asp Ile Thr Ile Gln Thr Val Thr Trp Pro Asp Leu Glu Leu Pro Leu
370375380
Pro Arg Asn Val Thr Glu Gly Glu Ala Leu Gly Ser Val Ile Leu Thr
385390395400
Ala Lys Pro Ile Phe Asp Leu Ser Pro Thr Ile Ser Glu Pro Gly Glu
405410415
Ala Leu Thr Leu Ala Pro Glu Val Gly Ser Thr Ala Phe Pro Glu Ala
420425430
Glu Glu Arg Thr Gly Glu Ala Thr Arg Pro Trp Gly Phe Pro Ala Glu
435440445
Val Thr Arg Gly Pro Asp Ser Ala Thr Ala Phe Ala Ser Glu Asp Leu
450455460
Val Val Arg Val Thr Ile Ser Pro Gly Ala Ala Glu Val Pro Gly Gln
465470475480
Pro Arg Leu Pro Gly Gly Val Val Phe His Tyr Arg Pro Gly Ser Thr
485490495
Arg Tyr Ser Leu Thr Phe Glu Glu Ala Gln Gln Ala Cys Met His Thr
500505510
Gly Ala Val Ile Ala Ser Pro Glu Gln Leu Gln Ala Ala Tyr Glu Ala
515520525
Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Gln Asp Gln Thr Val Arg
530535540
Tyr Pro Ile Val Ser Pro Arg Thr Pro Cys Val Gly Asp Lys Asp Ser
545550555560
Ser Pro Gly Val Arg Thr Tyr Gly Val Arg Pro Ser Ser Glu Thr Tyr
565570575
Asp Val Tyr Cys Tyr Val Asp Lys Leu Glu Gly Glu Val Phe Phe Ala
580585590
Thr Arg Leu Glu Gln Phe Thr Phe Gln Glu Ala Arg Ala Phe Cys Ala
595600605
Ala Gln Asn Ala Thr Leu Ala Ser Thr Gly Gln Leu Tyr Ala Ala Trp
610615620
Ser Gln Gly Leu Asp Lys Cys Tyr Ala Gly Trp Leu Ala Asp Gly Thr
625630635640
Leu Arg Tyr Pro Ile Ile Thr Pro Arg Pro Ala Cys Gly Gly Asp Lys
645650655
Pro Gly Val Arg Thr Val Tyr Leu Tyr Pro Asn Gln Thr Gly Leu Pro
660665670
Asp Pro Leu Ser Lys His His Ala Phe Cys Phe Arg Gly Val Ser Val
675680685
Ala Pro Ser Pro Gly Glu Glu Gly Gly Ser Thr Pro Thr Ser Pro Ser
690695700
Asp Ile Glu Asp Trp Ile Val Thr Gln Val Gly Pro Gly Val Asp Ala
705710715720
Val Pro Leu Glu Pro Lys Thr Thr Glu Val Pro Tyr Phe Thr Thr Glu
725730735
Pro Arg Lys Gln Thr Glu Trp Glu Pro Ala Tyr Thr Pro Val Gly Thr
740745750
Ser Pro Gln Pro Gly Ile Pro Pro Thr Trp Leu Pro Thr Leu Pro Ala
755760765
Ala Glu Glu His Thr Glu Ser Pro Ser Ala Ser Glu Glu Pro Ser Ala
770775780
Ser Ala Val Pro Ser Thr Ser Glu Glu Pro Tyr Thr Ser Ser Phe Ala
785790795800
Val Pro Ser Met Thr Glu Leu Pro Gly Ser Gly Glu Ala Ser Gly Ala
805810815
Pro Asp Leu Ser Gly Asp Phe Thr Gly Ser Gly Asp Ala Ser Gly Arg
820825830
Leu Asp Ser Ser Gly Gln Pro Ser Gly Gly Ile Glu Ser Gly Leu Pro
835840845
Ser Gly Asp Leu Asp Ser Ser Gly Leu Ser Pro Thr Val Ser Ser Gly
850855860
Leu Pro Val Glu Ser Gly Ser Ala Ser Gly Asp Gly Glu Val Pro Trp
865870875880
Ser His Thr Pro Thr Val Gly Arg Leu Pro Ser Gly Gly Glu Ser Pro
885890895
Glu Gly Ser Ala Ser Ala Ser Gly Thr Gly Asp Leu Ser Gly Leu Pro
900905910
Ser Gly Gly Glu Ile Thr Glu Thr Ser Thr Ser Gly Ala Glu Glu Thr
915920925
Ser Gly Leu Pro Ser Gly Gly Asp Gly Leu Glu Thr Ser Thr Ser Gly
930935940
Val Asp Asp Val Ser Gly Ile Pro Thr Gly Arg Glu Gly Leu Glu Thr
945950955960
Ser Ala Ser Gly Val Glu Asp Leu Ser Gly Leu Pro Ser Gly Glu Glu
965970975
Gly Ser Glu Thr Ser Thr Ser Gly Ile Glu Asp Ile Ser Val Leu Pro
980985990
Thr Gly Gly Glu Ser Leu Glu Thr Ser Ala Ser Gly Val Gly Asp Leu
99510001005
Ser Gly Leu Pro Ser Gly Gly Glu Ser Leu Glu Thr Ser Ala Ser Gly
101010151020
Ala Glu Asp Val Thr Gln Leu Pro Thr Glu Arg Gly Gly Leu Glu Thr
1025103010351040
Ser Ala Ser Gly Val Glu Asp Ile Thr Val Leu Pro Thr Gly Arg Glu
104510501055
Ser Leu Glu Thr Ser Ala Ser Gly Val Glu Asp Val Ser Gly Leu Pro
106010651070
Ser Gly Arg Glu Gly Leu Glu Thr Ser Ala Ser Gly Ile Glu Asp Ile
107510801085
Ser Val Phe Pro Thr Glu Ala Glu Gly Leu Asp Thr Ser Ala Ser Gly
109010951100
Gly Tyr Val Ser Gly Ile Pro Ser Gly Gly Asp Gly Thr Glu Thr Ser
1105111011151120
Ala Ser Gly Val Glu Asp Val Ser Gly Leu Pro Ser Gly Gly Glu Gly
112511301135
Leu Glu Thr Ser Ala Ser Gly Val Glu Asp Leu Gly Pro Ser Thr Arg
114011451150
Asp Ser Leu Glu Thr Ser Ala Ser Gly Val Asp Val Thr Gly Phe Pro
115511601165
Ser Gly Arg Gly Asp Pro Glu Thr Ser Val Ser Gly Val Gly Asp Asp
117011751180
Phe Ser Gly Leu Pro Ser Gly Lys Glu Gly Leu Glu Thr Ser Ala Ser
1185119011951200
Gly Ala Glu Asp Leu Ser Gly Leu Pro Ser Gly Lys Glu Asp Leu Val
120512101215
Gly Ser Ala Ser Gly Ala Leu Asp Phe Gly Lys Leu Pro Pro Gly Thr
122012251230
Leu Gly Ser Gly Gln Thr Pro Glu Val Asn Gly Phe Pro Ser Gly Phe
123512401245
Ser Gly Glu Tyr Ser Gly Ala Asp Ile Gly Ser Gly Pro Ser Ser Gly
125012551260
Leu Pro Asp Phe Ser Gly Leu Pro Ser Gly Phe Pro Thr Val Ser Leu
1265127012751280
Val Asp Ser Thr Leu Val Glu Val Ile Thr Ala Thr Thr Ser Ser Glu
128512901295
Leu Glu Gly Arg Gly Thr Ile Gly Ile Ser Gly Ser Gly Glu Val Ser
130013051310
Gly Leu Pro Leu Gly Glu Leu Asp Ser Ser Ala Asp Ile Ser Gly Leu
131513201325
Pro Ser Gly Thr Glu Leu Ser Gly Gln Ala Ser Gly Ser Pro Asp Ser
133013351340
Ser Gly Glu Thr Ser Gly Phe Phe Asp Val Ser Gly Gln Pro Phe Gly
1345135013551360
Ser Ser Gly Val Ser Glu Glu Thr Ser Gly Ile Pro Glu Ile Ser Gly
136513701375
Gln Pro Ser Gly Thr Pro Asp Thr Thr Ala Thr Ser Gly Val Thr Glu
138013851390
Leu Asn Glu Leu Ser Ser Gly Gln Pro Asp Val Ser Gly Asp Gly Ser
139514001405
Gly Ile Leu Phe Gly Ser Gly Gln Ser Ser Gly Ile Thr Ser Val Ser
141014151420
Gly Glu Thr Ser Gly Ile Ser Asp Leu Ser Gly Gln Pro Ser Gly Phe
142514301435 1440
Pro Val Phe Ser Gly Thr Ala Thr Arg Thr Pro Asp Leu Ala Ser Gly
144514501455
Thr Ile Ser Gly Ser Gly Glu Ser Ser Gly Ile Thr Phe Val Asp Thr
146014651470
Ser Phe Val Glu Val Thr Pro Thr Thr Phe Arg Glu Glu Glu Gly Leu
147514801485
Gly Ser Val Glu Leu Ser Gly Phe Pro Ser Gly Glu Thr Glu Leu Ser
149014951500
Gly Thr Ser Gly Thr Val Asp Val Ser Glu Gln Ser Ser Gly Ala Ile
1505151015151520
Asp Ser Ser Gly Leu Thr Ser Pro Thr Pro Glu Phe Ser Gly Leu Pro
152515301535
Ser Gly Val Ala Glu Val Ser Gly Glu Phe Ser Gly Val Glu Thr Gly
154015451550
Ser Ser Leu Pro Ser Gly Ala Phe Asp Gly Ser Gly Leu Val Ser Gly
155515601565
Phe Pro Thr Val Ser Leu Val Asp Arg Thr Leu Val Glu Ser Ile Thr
157015751580
Gln Ala Pro Thr Ala Gln Glu Ala Gly Glu Gly Pro Ser Gly Ile Leu
1585159015951600
Glu Phe Ser Gly Ala His Ser Gly Thr Pro Asp Ile Ser Gly Glu Leu
160516101615
Ser Gly Ser Leu Asp Leu Ser Thr Leu Gln Ser Gly Gln Met Glu Thr
162016251630
Ser Thr Glu Thr Pro Ser Ser Pro Tyr Phe Ser Gly Asp Phe Ser Ser
163516401645
Thr Thr Asp Val Ser Gly Glu Ser Ile Ala Ala Thr Thr Gly Ser Gly
165016551660
Glu Ser Ser Gly Leu Pro Glu Val Thr Leu Asn Thr Ser Glu Leu Val
1665167016751680
Glu Gly Val Thr Glu Pro Thr Val Ser Gln Glu Leu Gly His Gly Pro
168516901695
Ser Met Thr Tyr Thr Pro Arg Leu Phe Glu Ala Ser Gly Asp Ala Ser
170017051710
Ala Ser Gly Asp Leu Gly Gly Ala Val Thr Asn Phe Pro Gly Ser Gly
171517201725
Ile Glu Ala Ser Val Pro Glu Ala Ser Ser Asp Leu Ser Ala Tyr Pro
173017351740
Glu Ala Gly Val Gly Val Ser Ala Ala Pro Glu Ala Ser Ser Lys Leu
17451750 17551760
Ser Glu Phe Pro Asp Leu His Gly Ile Thr Ser Ala Phe His Glu Thr
176517701775
Asp Leu Glu Met Thr Thr Pro Ser Thr Glu Val Asn Ser Asn Pro Trp
178017851790
Thr Phe Gln Glu Gly Thr Arg Glu Gly Ser Ala Ala Pro Glu Val Ser
179518001805
Gly Glu Ser Ser Thr Thr Ser Asp Ile Asp Thr Gly Thr Ser Gly Val
181018151820
Pro Ser Ala Thr Pro Met Ala Ser Gly Asp Arg Thr Glu Ile Ser Gly
1825183018351840
Glu Trp Ser Asp His Thr Ser Glu Val Asn Val Ala Ile Ser Ser Thr
184518501855
Ile Thr Glu Ser Glu Trp Ala Gln Pro Thr Arg Tyr Pro Thr Glu Thr
186018651870
Leu Gln Glu Ile Glu Ser Pro Asn Pro Ser Tyr Ser Gly Glu Glu Thr
187518801885
Gln Thr Ala Glu Thr Thr Met Ser Leu Thr Asp Ala Pro Thr Leu Ser
189018951900
Ser Ser Glu Gly Ser Gly Glu Thr Glu Ser Thr Val Ala Asp Gln Glu
1905191019151920
Gln Cys Glu Glu Gly Trp Thr Lys Phe Gln Gly His Cys Tyr Arg His
192519301935
Phe His Asp Arg Glu Thr Trp Val Asp Ala Glu Arg Arg Cys Arg Glu
194019451950
Gln Gln Ser His Leu Ser Ser Ile Val Thr Pro Glu Glu Gln Glu Phe
195519601965
Val Asn Lys Asn Ala Gln Asp Tyr Gln Trp Ile Gly Leu Asn Asp Arg
197019751980
Thr Ile Glu Gly Asp Phe Arg Trp Ser Asp Gly His Ser Leu Gln Phe
1985199019952000
Glu Lys Trp Arg Pro Asn Gln Pro Asp Asn Phe Phe Ala Thr Gly Glu
200520102015
Asp Cys Val Val Met Ile Trp His Glu Arg Gly Glu Trp Asn Asp Val
202020252030
Pro Cys Asn Tyr Gln Leu Pro Phe Thr Cys Lys Lys Gly Thr Val Ala
203520402045
Cys Gly Asp Pro Pro Val Val Glu His Ala Arg Thr Leu Gly Gln Lys
205020552060
Lys Asp Arg Tyr Glu Ile Ser Ser Leu Val Arg Tyr Gln Cys Thr Glu
2065 207020752080
Gly Phe Val Gln Arg His Val Pro Thr Ile Arg Cys Gln Pro Ser Gly
208520902095
His Trp Glu Glu Pro Arg Ile Thr Cys Thr Asp Pro Asn Thr Tyr Lys
210021052110
His Arg Leu Gln Lys Arg Ser Met Arg Pro Thr Arg Arg Ser Arg Pro
211521202125
Ser Met Ala His
2130
<210> 288
<211> 2364
<212> PRT
<213> Bos taurus
<220>
<223> COW AGGRECAN P13608
<400> 288
Met Thr Thr Leu Leu Leu Val Phe Val Thr Leu Arg Val Ile Thr Ala
151015
Ala Ile Ser Val Glu Val Ser Glu Pro Asp Asn Ser Leu Ser Val Ser
202530
Ile Pro Glu Pro Ser Pro Leu Arg Val Leu Leu Gly Ser Ser Leu Thr
354045
Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val Thr Thr Ala Pro
505560
Ser Thr Ala Pro Leu Ala Pro Arg Ile Lys Trp Ser Arg Ile Ser Lys
65707580
Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly Arg Val Arg Val
859095
Asn Ser Ala Tyr Gln Asp Lys Val Thr Leu Pro Asn Tyr Pro Ala Ile
100105110
Pro Ser Asp Ala Thr Leu Glu Ile Gln Asn Met Arg Ser Asn Asp Ser
115120125
Gly Ile Leu Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Gln Ala
130135140
Thr Leu Glu Val Val Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile
145150155160
Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
165170175
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
180185190
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
195200205
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
210215220
Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu
225230235240
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe
245250255
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu
260265270
Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu
275280285
Ala Trp Gln Gly Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
290295300
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
305310315320
Asn Leu Leu Gly Val Arg Thr Val Tyr Leu His Ala Asn Gln Thr Gly
325330335
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
340345350
Asp Phe Val Asp Ile Pro Glu Ser Phe Phe Gly Val Gly Gly Glu Glu
355360365
Asp Ile Thr Ile Gln Thr Val Thr Trp Pro Asp Val Glu Leu Pro Leu
370375380
Pro Arg Asn Ile Thr Glu Gly Glu Ala Arg Gly Ser Val Ile Leu Thr
385390395400
Ala Lys Pro Asp Phe Glu Val Ser Pro Thr Ala Pro Glu Pro Glu Glu
405410415
Pro Phe Thr Phe Val Pro Glu Val Arg Ala Thr Ala Phe Pro Glu Val
420425430
Glu Asn Arg Thr Glu Glu Ala Thr Arg Pro Trp Ala Phe Pro Arg Glu
435440445
Ser Thr Pro Gly Leu Gly Ala Pro Thr Ala Phe Thr Ser Glu Asp Leu
450455460
Val Val Gln Val Thr Leu Ala Pro Gly Ala Ala Glu Val Pro Gly Gln
465470475480
Pro Arg Leu Pro Gly Gly Val Val Phe His Tyr Arg Pro Gly Ser Ser
485490495
Arg Tyr Ser Leu Thr Phe Glu Glu Ala Lys Gln Ala Cys Leu Arg Thr
500505510
Gly Ala Ile Ile Ala Ser Pro Glu Gln Leu Gln Ala Ala Tyr Glu Ala
515520525
Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Gln Asp Gln Thr Val Arg
530535540
Tyr Pro Ile Val Ser Pro Arg Thr Pro Cys Val Gly Asp Lys Asp Ser
545550555560
Ser Pro Gly Val Arg Thr Tyr Gly Val Arg Pro Pro Ser Glu Thr Tyr
565570575
Asp Val Tyr Cys Tyr Val Asp Arg Leu Glu Gly Glu Val Phe Phe Ala
580585590
Thr Arg Leu Glu Gln Phe Thr Phe Trp Glu Ala Gln Glu Phe Cys Glu
595600605
Ser Gln Asn Ala Thr Leu Ala Thr Thr Gly Gln Leu Tyr Ala Ala Trp
610615620
Ser Arg Gly Leu Asp Lys Cys Tyr Ala Gly Trp Leu Ala Asp Gly Ser
625630635640
Leu Arg Tyr Pro Ile Val Thr Pro Arg Pro Ala Cys Gly Gly Asp Lys
645650655
Pro Gly Val Arg Thr Val Tyr Leu Tyr Pro Asn Gln Thr Gly Leu Leu
660665670
Asp Pro Leu Ser Arg His His Ala Phe Cys Phe Arg Gly Val Ser Ala
675680685
Ala Pro Ser Pro Glu Glu Glu Glu Gly Ser Ala Pro Thr Ala Gly Pro
690695700
Asp Val Glu Glu Trp Met Val Thr Gln Val Gly Pro Gly Val Ala Ala
705710715720
Val Pro Ile Gly Glu Glu Thr Thr Ala Ile Pro Gly Phe Thr Val Glu
725730735
Pro Glu Asn Lys Thr Glu Trp Glu Leu Ala Tyr Thr Pro Ala Gly Thr
740745750
Leu Pro Leu Pro Gly Ile Pro Pro Thr Trp Pro Pro Thr Gly Glu Ala
755760765
Thr Glu Glu His Thr Glu Gly Pro Ser Ala Thr Glu Val Pro Ser Ala
770775780
Ser Glu Lys Pro Phe Pro Ser Glu Glu Pro Phe Pro Pro Glu Glu Pro
785790795800
Phe Pro Ser Glu Lys Pro Phe Pro Pro Glu Glu Leu Phe Pro Ser Glu
805810815
Lys Pro Phe Pro Ser Glu Lys Pro Phe Pro Ser Glu Glu Pro Phe Pro
820825830
Ser Glu Lys Pro Phe Pro Pro Glu Glu Leu Phe Pro Ser Glu Lys Pro
835840845
Ile Pro Ser Glu Glu Pro Phe Pro Ser Glu Glu Pro Phe Pro Ser Glu
850855860
Lys Pro Phe Pro Pro Glu Glu Pro Phe Pro Ser Glu Lys Pro Ile Pro
865870875880
Ser Glu Glu Pro Phe Pro Ser Glu Lys Pro Phe Pro Ser Glu Glu Pro
885890895
Phe Pro Ser Glu Glu Pro Ser Thr Leu Ser Ala Pro Val Pro Ser Arg
900905910
Thr Glu Leu Pro Ser Ser Gly Glu Val Ser Gly Val Pro Glu Ile Ser
915920925
Gly Asp Phe Thr Gly Ser Gly Glu Ile Ser Gly His Leu Asp Phe Ser
930935940
Gly Gln Pro Ser Gly Glu Ser Ala Ser Gly Leu Pro Ser Glu Asp Leu
945950955960
Asp Ser Ser Gly Leu Thr Ser Thr Val Gly Ser Gly Leu Pro Val Glu
965970975
Ser Gly Leu Pro Ser Gly Glu Glu Glu Arg Ile Thr Trp Thr Ser Ala
980985990
Pro Lys Val Asp Arg Leu Pro Ser Gly Gly Glu Gly Pro Glu Val Ser
99510001005
Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly Gly Glu Val His Leu
101010151020
Glu Ile Ser Ala Ser Gly Val Glu Asp Ile Ser Gly Leu Pro Ser Gly
1025103010351040
Gly Glu Val His Leu Glu Ile Ser Ala Ser Gly Val Glu Asp Leu Ser
104510501055
Arg Ile Pro Ser Gly Glu Gly Pro Glu Ile Ser Ala Ser Gly Val Glu
106010651070
Asp Ile Ser Gly Leu Pro Ser Gly Glu Glu Gly His Leu Glu Ile Ser
107510801085
Ala Ser Gly Val Glu Asp Leu Ser Gly Ile Pro Ser Gly Glu Gly Pro
109010951100
Glu Val Ser Ala Ser Gly Val Glu Asp Leu Ile Gly Leu Pro Ser Gly
1105111011151120
Glu Gly Pro Glu Val Ser Ala Ser Gly Val Glu Asp Leu Ser Arg Leu
112511301135
Pro Ser Gly Glu Gly Pro Glu Val Ser Ala Ser Gly Val Glu Asp Leu
114011451150
Ser Gly Leu Pro Ser Gly Glu Gly Pro Glu Val Ser Val Ser Gly Val
115511601165
Glu Asp Leu Ser Arg Leu Pro Ser Gly Glu Gly Pro Glu Val Ser Ala
117011751180
Ser Gly Val Glu Asp Leu Ser Arg Leu Pro Ser Gly Glu Gly Pro Glu
1185119011951200
Ile Ser Val Ser Gly Val Glu Asp Ile Ser Ile Leu Pro Ser Gly Glu
120512101215
Gly Pro Glu Val Ser Ala Ser Gly Val Glu Asp Leu Ser Val Leu Pro
122012251230
Ser Gly Glu Gly His Leu Glu Ile Ser Thr Ser Gly Val Glu Asp Leu
123512401245
Ser Val Leu Pro Ser Gly Glu Gly His Leu Glu Thr Ser Ser Gly Val
125012551260
Glu Asp Ile Ser Arg Leu Pro Ser Gly Glu Gly Pro Glu Val Ser Ala
1265127012751280
Ser Gly Val Glu Asp Leu Ser Val Leu Pro Ser Gly Glu Asp His Leu
128512901295
Glu Ile Ser Ala Ser Gly Val Glu Asp Leu Gly Val Leu Pro Ser Gly
130013051310
Glu Asp His Leu Glu Ile Ser Ala Ser Gly Val Glu Asp Ile Ser Arg
131513201325
Leu Pro Ser Gly Glu Gly Pro Glu Val Ser Ala Ser Gly Val Glu Asp
133013351340
Leu Ser Val Leu Pro Ser Gly Glu Gly His Leu Glu Ile Ser Ala Ser
1345135013551360
Gly Val Glu Asp Leu Ser Arg Leu Pro Ser Gly Gly Glu Asp His Leu
136513701375
Glu Thr Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu Pro Ser Gly
138013851390
Arg Glu Gly Leu Glu Ile Ser Ala Ser Gly Ala Gly Asp Leu Ser Gly
139514001405
Leu Thr Ser Gly Lys Glu Asp Leu Thr Gly Ser Ala Ser Gly Ala Leu
141014151420
Asp Leu Gly Arg Ile Pro Ser Val Thr Leu Gly Ser Gly Gln Ala Pro
1425143014351440
Glu Ala Ser Gly Leu Pro Ser Gly Phe Ser Gly Glu Tyr Ser Gly Val
144514501455
Asp Leu Glu Ser Gly Pro Ser Ser Gly Leu Pro Asp Phe Ser Gly Leu
146014651470
Pro Ser Gly Phe Pro Thr Val Ser Leu Val Asp Thr Thr Leu Val Glu
147514801485
Val Val Thr Ala Thr Thr Ala Gly Glu Leu Glu Gly Arg Gly Thr Ile
149014951500
Asp Ile Ser Gly Ala Gly Glu Thr Ser Gly Leu Pro Phe Ser Glu Leu
1505151015151520
Asp Ile Ser Gly Gly Ala Ser Gly Leu Ser Ser Gly Ala Glu Leu Ser
152515301535
Gly Gln Ala Ser Gly Ser Pro Asp Ile Ser Gly Glu Thr Ser Gly Leu
154015451550
Phe Gly Val Ser Gly Gln Pro Ser Gly Phe Pro Asp Ile Ser Gly Glu
155515601565
Thr Ser Gly Leu Leu Glu Val Ser Gly Gln Pro Ser Gly Phe Tyr Gly
157015751580
Glu Ile Ser Gly Val Thr Glu Leu Ser Gly Leu Ala Ser Gly Gln Pro
1585159015951600
Glu Ile Ser Gly Glu Ala Ser Gly Ile Leu Ser Gly Leu Gly Pro Pro
160516101615
Phe Gly Ile Thr Asp Leu Ser Gly Glu Ala Pro Gly Ile Pro Asp Leu
162016251630
Ser Gly Gln Pro Ser Gly Leu Pro Glu Phe Ser Gly Thr Ala Ser Gly
163516401645
Ile Pro Asp Leu Val Ser Ser Ala Val Ser Gly Ser Gly Glu Ser Ser
165016551660
Gly Ile Thr Phe Val Asp Thr Ser Leu Val Glu Val Thr Pro Thr Thr
1665167016751680
Phe Lys Glu Glu Glu Gly Leu Gly Ser Val Glu Leu Ser Gly Leu Pro
168516901695
Ser Gly Glu Leu Gly Val Ser Gly Thr Ser Gly Leu Ala Asp Val Ser
170017051710
Gly Leu Ser Ser Gly Ala Ile Asp Ser Ser Gly Phe Thr Ser Gln Pro
171517201725
Pro Glu Phe Ser Gly Leu Pro Ser Gly Val Thr Glu Val Ser Gly Glu
173017351740
Ala Ser Gly Ala Glu Ser Gly Ser Ser Leu Pro Ser Gly Ala Tyr Asp
1745175017551760
Ser Ser Gly Leu Pro Ser Gly Phe Pro Thr Val Ser Phe Val Asp Arg
176517701775
Thr Leu Val Glu Ser Val Thr Gln Ala Pro Thr Ala Gln Glu Ala Gly
178017851790
Glu Gly Pro Ser Gly Ile Leu Glu Leu Ser Gly Ala Pro Ser Gly Ala
179518001805
Pro Asp Met Ser Gly Asp His Leu Gly Ser Leu Asp Gln Ser Gly Leu
181018151820
Gln Ser Gly Leu Val Glu Pro Ser Gly Glu Pro Ala Ser Thr Pro Tyr
1825183018351840
Phe Ser Gly Asp Phe Ser Gly Thr Thr Asp Val Ser Gly Glu Ser Ser
184518501855
Ala Ala Thr Ser Thr Ser Gly Glu Ala Ser Gly Leu Pro Glu Val Thr
186018651870
Leu Ile Thr Ser Glu Leu Val Glu Gly Val Thr Glu Pro Thr Val Ser
187518801885
Gln Glu Leu Gly Gln Arg Pro Pro Val Thr Tyr Thr Pro Gln Leu Phe
189018951900
Glu Ser Ser Gly Glu Ala Ser Ala Ser Gly Asp Val Pro Arg Phe Pro
1905191019151920
Gly Ser Gly Val Glu Val Ser Ser Val Pro Glu Ser Ser Gly Glu Thr
192519301935
Ser Ala Tyr Pro Glu Ala Glu Val Gly Ala Ser Ala Ala Pro Glu Ala
194019451950
Ser Gly Gly Ala Ser Gly Ser Pro Asn Leu Ser Glu Thr Thr Ser Thr
195519601965
Phe His Glu Ala Asp Leu Glu Gly Thr Ser Gly Leu Gly Val Ser Gly
197019751980
Ser Pro Ser Ala Phe Pro Glu Gly Pro Thr Glu Gly Leu Ala Thr Pro
1985199019952000
Glu Val Ser Gly Glu Ser Thr Thr Ala Phe Asp Val Ser Val Glu Ala
200520102015
Ser Gly Ser Pro Ser Ala Thr Pro Leu Ala Ser Gly Asp Arg Thr Asp
202020252030
Thr Ser Gly Asp Leu Ser Gly His Thr Ser Gly Leu Asp Ile Val Ile
203520402045
Ser Thr Thr Ile Pro Glu Ser Glu Trp Thr Gln Gln Thr Gln Arg Pro
205020552060
Ala Glu Ala Arg Leu Glu Ile Glu Ser Ser Ser Pro Val His Ser Gly
2065207020752080
Glu Glu Ser Gln Thr Ala Asp Thr Ala Thr Ser Pro Thr Asp Ala Ser
208520902095
Ile Pro Ala Ser Ala Gly Gly Thr Asp Asp Ser Glu Ala Thr Thr Thr
210021052110
Asp Ile Asp Glu Cys Leu Ser Ser Pro Cys Leu Asn Gly Ala Thr Cys
211521202125
Val Asp Ala Ile Asp Ser Phe Thr Cys Leu Cys Leu Pro Ser Tyr Gln
213021352140
Gly Asp Val Cys Glu Ile Gln Lys Leu Cys Glu Glu Gly Trp Thr Lys
2145215021552160
Phe Gln Gly His Cys Tyr Arg His Phe Pro Asp Arg Ala Thr Trp Val
216521702175
Asp Ala Glu Ser Gln Cys Arg Lys Gln Gln Ser His Leu Ser Ser Ile
218021852190
Val Thr Pro Glu Glu Gln Glu Phe Val Asn Asn Asn Ala Gln Asp Tyr
219522002205
Gln Trp Ile Gly Leu Asn Asp Lys Thr Ile Glu Gly Asp Phe Arg Trp
221022152220
Ser Asp Gly His Ser Leu Gln Phe Glu Asn Trp Arg Pro Asn Gln Pro
2225223022352240
Asp Asn Phe Phe Ala Thr Gly Glu Asp Cys Val Val Met Ile Trp His
224522502255
Glu Lys Gly Glu Trp Asn Asp Val Pro Cys Asn Tyr Gln Leu Pro Phe
226022652270
Thr Cys Lys Lys Gly Thr Val Ala Cys Gly Glu Pro Pro Val Val Glu
227522802285
His Ala Arg Ile Phe Gly Gln Lys Lys Asp Arg Tyr Glu Ile Asn Ala
229022952300
Leu Val Arg Tyr Gln Cys Thr Glu Gly Phe Ile Gln Gly His Val Pro
2305231023152320
Thr Ile Arg Cys Gln Pro Ser Gly His Trp Glu Glu Pro Arg Ile Thr
232523302335
Cys Thr Asp Pro Ala Thr Tyr Lys Arg Arg Leu Gln Lys Arg Ser Ser
234023452350
Arg Pro Leu Arg Arg Ser His Pro Ser Thr Ala His
23552360
<210> 289
<211> 2333
<212> PRT
<213> Canis familiaris
<220>
<223> DOG AGGRECAN Q28343
<400> 289
Met Thr Thr Leu Leu Trp Val Phe Val Thr Leu Arg Val Ile Thr Ala
151015
Ala Ser Ser Glu Glu Thr Ser Asp His Asp Asn Ser Leu Ser Val Ser
202530
Ile Pro Glu Pro Ser Pro Met Arg Val Leu Leu Gly Ser Ser Leu Thr
354045
Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val Thr Thr Ala Pro
505560
Ser Thr Ala Pro Leu Ala Pro Arg Ile Lys Trp Ser Arg Ile Thr Lys
65707580
Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly Gln Val Arg Ile
859095
Asn Ser Ala Tyr Gln Asp Lys Val Ser Leu Pro Asn Tyr Pro Ala Ile
100105110
Pro Ser Asp Ala Thr Leu Glu Ile Gln Asn Leu Arg Ser Asn Asp Ser
115120125
Gly Ile Tyr Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Glu Ala
130135140
Thr Leu Glu Val Val Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile
145150155160
Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
165170175
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
180185190
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
195200205
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
210215220
Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu
225230235240
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Leu
245250255
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu
260265270
Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu
275280285
Ala Trp Gln Gly Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
290295300
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
305310315320
Asn Leu Leu Gly Val Arg Thr Val Tyr Leu His Ala Asn Gln Thr Gly
325330335
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
340345350
Asp Phe Val Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Glu
355360365
Asp Ile Thr Ile Gln Thr Val Thr Trp Pro Asp Val Glu Leu Pro Leu
370375380
Pro Arg Asn Ile Thr Glu Gly Glu Ala Arg Gly Asn Val Ile Leu Thr
385390395400
Val Lys Pro Ile Phe Asp Leu Ser Pro Thr Ala Pro Glu Pro Glu Glu
405410415
Pro Phe Thr Phe Val Pro Glu Pro Glu Lys Pro Phe Thr Phe Ala Thr
420425430
Asp Val Gly Val Thr Ala Phe Pro Glu Ala Glu Asn Arg Thr Gly Glu
435440445
Ala Thr Arg Pro Trp Gly Val Pro Glu Glu Ser Thr Pro Gly Pro Ala
450455460
Phe Thr Ala Phe Thr Ser Glu Asp His Val Val Gln Val Thr Ala Val
465470475480
Pro Gly Ala Ala Glu Val Pro Gly Gln Pro Arg Leu Pro Gly Gly Val
485490495
Val Phe His Tyr Arg Pro Gly Ser Ala Arg Tyr Ser Leu Thr Phe Glu
500505510
Glu Ala Gln Gln Ala Cys Leu Arg Thr Gly Ala Val Ile Ala Ser Pro
515520525
Glu Gln Leu Gln Ala Ala Tyr Glu Ala Gly Tyr Glu Gln Cys Asp Ala
530535540
Gly Trp Leu Gln Asp Gln Thr Val Arg Tyr Pro Ile Val Ser Pro Arg
545550555560
Thr Pro Cys Val Gly Asp Lys Asp Ser Ser Pro Gly Val Arg Thr Tyr
565570575
Gly Val Arg Pro Pro Ser Glu Thr Tyr Asp Val Tyr Cys Tyr Val Asp
580585590
Lys Leu Glu Gly Glu Val Phe Phe Ile Thr Arg Leu Glu Gln Phe Thr
595600605
Phe Gln Glu Ala Leu Ala Phe Cys Glu Ser His Asn Ala Thr Leu Ala
610615620
Ser Thr Gly Gln Leu Tyr Ala Ala Trp Arg Gln Gly Leu Asp Lys Cys
625630635640
Tyr Ala Gly Trp Leu Ser Asp Gly Ser Leu Arg Tyr Pro Ile Val Thr
645650655
Pro Arg Pro Ser Cys Gly Gly Asp Lys Pro Gly Val Arg Thr Val Tyr
660665670
Leu Tyr Pro Asn Gln Thr Gly Leu Pro Asp Pro Leu Ser Arg His His
675680685
Val Phe Cys Phe Arg Gly Val Ser Gly Val Pro Ser Pro Gly Glu Glu
690695700
Glu Gly Gly Thr Pro Thr Pro Ser Val Val Glu Asp Trp Ile Pro Thr
705710715720
Gln Val Gly Pro Val Val Pro Ser Val Pro Met Gly Glu Glu Thr Thr
725730735
Ala Ile Leu Asp Phe Thr Ile Glu Pro Glu Asn Gln Thr Glu Trp Glu
740745750
Pro Ala Tyr Ser Pro Ala Gly Thr Ser Pro Leu Pro Gly Ile Pro Pro
755760765
Thr Trp Pro Pro Thr Ser Thr Ala Thr Glu Glu Ser Thr Glu Gly Pro
770775780
Ser Gly Thr Glu Val Pro Ser Val Ser Glu Glu Pro Ser Pro Ser Glu
785790795800
Glu Pro Phe Pro Trp Glu Glu Leu Ser Thr Leu Ser Pro Pro Gly Pro
805810815
Ser Gly Thr Glu Leu Pro Gly Ser Gly Glu Ala Ser Gly Val Pro Glu
820825830
Val Ser Gly Asp Phe Thr Gly Ser Gly Glu Val Ser Gly His Pro Asp
835840845
Ser Ser Gly Gln Leu Ser Gly Glu Ser Ala Ser Gly Leu Pro Ser Glu
850855860
Asp Leu Asp Ser Ser Gly Leu Thr Ser Ala Val Gly Ser Gly Leu Ala
865870875880
Ser Gly Asp Glu Asp Arg Ile Thr Leu Ser Ser Ile Pro Lys Val Glu
885890895
Gly Glu Gly Leu Glu Thr Ser Ala Ser Gly Val Glu Asp Leu Ser Gly
900905910
Leu Pro Ser Gly Arg Glu Gly Leu Glu Thr Ser Thr Ser Gly Val Gly
915920925
Asp Leu Ser Gly Leu Pro Ser Gly Glu Gly Leu Glu Val Ser Ala Ser
930935940
Gly Val Glu Asp Leu Ser Gly Leu Pro Ser Gly Glu Gly Pro Glu Thr
945950955960
Ser Thr Ser Gly Val Gly Asp Leu Ser Arg Leu Pro Ser Gly Glu Gly
965970975
Pro Glu Val Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu Pro Ser
980985990
Gly Arg Glu Gly Leu Glu Thr Ser Thr Ser Gly Val Glu Asp Leu Ser
99510001005
Gly Leu Pro Ser Gly Glu Gly Pro Glu Ala Ser Thr Ser Gly Val Gly
101010151020
Asp Leu Ser Arg Leu Pro Ser Gly Glu Gly Pro Glu Val Ser Ala Ser
1025103010351040
Gly Val Glu Asp Leu Ser Gly Leu Pro Ser Gly Glu Gly Leu Glu Ala
104510501055
Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu Pro Ser Gly Glu Gly
106010651070
Pro Glu Ala Ser Ala Ser Gly Val Gly Asp Leu Ser Arg Leu Pro Ser
107510801085
Gly Glu Gly Pro Glu Val Ser Ala Ser Gly Val Glu Asp Leu Ser Gly
109010951100
Leu Ser Ser Gly Glu Ser Pro Glu Ala Ser Ala Ser Gly Val Gly Asp
1105111011151120
Leu Ser Gly Leu Pro Ser Gly Arg Glu Gly Leu Glu Thr Ser Ala Ser
112511301135
Gly Val Gly Asp Leu Ser Gly Leu Pro Ser Gly Glu Gly Gln Glu Ala
114011451150
Ser Ala Ser Gly Val Glu Asp Leu Ser Arg Leu Pro Ser Gly Glu Gly
115511601165
Pro Glu Ala Ser Ala Ser Gly Val Gly Glu Leu Ser Gly Leu Pro Ser
117011751180
Gly Arg Glu Gly Leu Glu Thr Ser Ala Ser Gly Val Gly Asp Leu Ser
1185119011951200
Gly Leu Pro Ser Gly Glu Gly Pro Glu Ala Phe Ala Ser Gly Val Glu
120512101215
Asp Leu Ser Ile Leu Pro Ser Gly Glu Gly Pro Glu Ala Ser Ala Ser
122012251230
Gly Val Gly Asp Leu Ser Gly Leu Pro Ser Gly Arg Glu Gly Leu Glu
123512401245
Thr Ser Thr Ser Gly Val Gly Asp Leu Ser Gly Leu Pro Ser Gly Arg
125012551260
Glu Gly Leu Glu Thr Ser Thr Ser Gly Val Gly Asp Leu Ser Gly Leu
1265127012751280
Pro Ser Gly Glu Gly Pro Glu Ala Ser Ala Ser Gly Ile Gly Asp Ile
128512901295
Ser Gly Leu Pro Ser Gly Arg Glu Gly Leu Glu Thr Ser Ser Ser Gly
130013051310
Val Glu Asp His Pro Glu Thr Ser Ala Ser Gly Val Glu Asp Leu Ser
131513201325
Gly Leu Pro Ser Gly Val Glu Gly His Pro Glu Thr Ser Ala Ser Gly
133013351340
Val Glu Asp Leu Ser Asp Leu Ser Ser Gly Gly Glu Gly Leu Glu Thr
1345135013551360
Ser Ala Ser Gly Ala Glu Asp Leu Ser Gly Phe Pro Ser Gly Lys Glu
136513701375
Asp Leu Ile Gly Ser Ala Ser Gly Ala Leu Asp Phe Gly Arg Ile Pro
138013851390
Ser Gly Thr Leu Gly Ser Gly Gln Ala Pro Glu Ala Ser Ser Leu Pro
139514001405
Ser Gly Phe Ser Gly Glu Tyr Ser Gly Val Asp Phe Gly Ser Gly Pro
141014151420
Ile Ser Gly Leu Pro Asp Phe Ser Gly Leu Pro Ser Gly Phe Pro Thr
1425143014351440
Ile Ser Leu Val Asp Thr Thr Leu Val Glu Val Ile Thr Thr Thr Ser
144514501455
Ala Ser Glu Leu Glu Gly Arg Gly Thr Ile Gly Ile Ser Gly Ala Gly
146014651470
Glu Thr Ser Gly Leu Pro Val Ser Glu Leu Asp Ile Ser Gly Ala Val
147514801485
Ser Gly Leu Pro Ser Gly Ala Glu Leu Ser Gly Gln Ala Ser Gly Ser
149014951500
Pro Asp Met Ser Gly Glu Thr Ser Gly Phe Phe Gly Val Ser Gly Gln
1505151015151520
Pro Ser Gly Phe Pro Asp Ile Ser Gly Gly Thr Ser Gly Leu Phe Glu
152515301535
Val Ser Gly Gln Pro Ser Gly Phe Ser Gly Glu Thr Ser Gly Val Thr
154015451550
Glu Leu Ser Gly Leu Tyr Ser Gly Gln Pro Asp Val Ser Gly Glu Ala
155515601565
Ser Gly Val Pro Ser Gly Ser Gly Gln Pro Phe Gly Met Thr Asp Leu
157015751580
Ser Gly Glu Thr Ser Gly Val Pro Asp Ile Ser Gly Gln Pro Ser Gly
1585159015951600
Leu Pro Glu Phe Ser Gly Thr Thr Ser Gly Ile Pro Asp Leu Val Ser
160516101615
Ser Thr Met Ser Gly Ser Gly Glu Ser Ser Gly Ile Thr Phe Val Asp
162016251630
Thr Ser Leu Val Glu Val Thr Pro Thr Thr Phe Lys Glu Lys Lys Arg
163516401645
Leu Gly Ser Val Glu Leu Ser Gly Leu Pro Ser Gly Glu Val Asp Leu
165016551660
Ser Gly Ala Ser Gly Thr Met Asp Ile Ser Gly Gln Ser Ser Gly Ala
1665167016751680
Thr Asp Ser Ser Gly Leu Thr Ser His Leu Pro Lys Phe Ser Gly Leu
168516901695
Pro Ser Gly Ala Ala Glu Val Ser Gly Glu Ser Ser Gly Ala Glu Val
170017051710
Gly Ser Ser Leu Pro Ser Gly Thr Tyr Glu Gly Ser Gly Asn Phe His
171517201725
Pro Ala Phe Pro Thr Val Phe Leu Val Asp Arg Thr Leu Val Glu Ser
173017351740
Val Thr Gln Ala Pro Thr Ala Gln Glu Ala Gly Glu Gly Pro Ser Gly
1745175017551760
Ile Leu Glu Leu Ser Gly Ala His Ser Gly Ala Pro Asp Val Ser Gly
176517701775
Asp His Ser Gly Ser Leu Asp Leu Ser Gly Met Gln Ser Gly Leu Val
178017851790
Glu Pro Ser Gly Glu Pro Ser Ser Thr Pro Tyr Phe Ser Gly Asp Phe
179518001805
Ser Gly Thr Met Asp Val Thr Gly Glu Pro Ser Thr Ala Met Ser Ala
181018151820
Ser Gly Glu Ala Ser Gly Leu Leu Glu Val Thr Leu Ile Thr Ser Glu
1825183018351840
Phe Val Glu Gly Val Thr Glu Pro Thr Val Ser Gln Glu Leu Ala Gln
184518501855
Arg Pro Pro Val Thr His Thr Pro Gln Leu Phe Glu Ser Ser Gly Glu
186018651870
Ala Ser Ala Ser Gly Glu Ile Ser Gly Ala Thr Pro Ala Phe Pro Gly
187518801885
Ser Gly Leu Glu Ala Ser Ser Val Pro Glu Ser Ser Ser Glu Thr Ser
189018951900
Asp Phe Pro Glu Arg Ala Val Gly Val Ser Ala Ala Pro Glu Ala Ser
1905191019151920
Gly Gly Ala Ser Gly Ala Pro Asp Val Ser Glu Ala Thr Ser Thr Phe
192519301935
Pro Glu Ala Asp Val Glu Gly Ala Ser Gly Leu Gly Val Ser Gly Gly
194019451950
Thr Ser Ala Phe Pro Glu Ala Pro Arg Glu Gly Ser Ala Thr Pro Glu
195519601965
Val Gln Glu Glu Pro Thr Thr Ser Tyr Asp Val Gly Arg Glu Ala Leu
197019751980
Gly Trp Pro Ser Ala Thr Pro Thr Ala Ser Gly Asp Arg Ile Glu Val
1985199019952000
Ser Gly Asp Leu Ser Gly His Thr Ser Gly Leu Asp Val Val Ile Ser
200520102015
Thr Ser Val Pro Glu Ser Glu Trp Ile Gln Gln Thr Gln Arg Pro Ala
202020252030
Glu Ala His Leu Glu Ile Glu Ala Ser Ser Pro Leu His Ser Gly Glu
203520402045
Glu Thr Gln Thr Ala Glu Thr Ala Thr Ser Pro Thr Asp Asp Ala Ser
205020552060
Ile Pro Thr Ser Pro Ser Gly Thr Asp Glu Ser Ala Pro Ala Ile Pro
2065207020752080
Asp Ile Asp Glu Cys Leu Ser Ser Pro Cys Leu Asn Gly Ala Thr Cys
208520902095
Val Asp Ala Ile Asp Ser Phe Thr Cys Leu Cys Leu Pro Ser Tyr Arg
210021052110
Gly Asp Leu Cys Glu Ile Asp Gln Glu Leu Cys Glu Glu Gly Trp Thr
211521202125
Lys Phe Gln Gly His Cys Tyr Arg Tyr Phe Pro Asp Arg Glu Ser Trp
213021352140
Val Asp Ala Glu Ser Arg Cys Arg Ala Gln Gln Ser His Leu Ser Ser
2145215021552160
Ile Val Thr Pro Glu Glu Gln Glu Phe Val Asn Asn Asn Ala Gln Asp
216521702175
Tyr Gln Trp Ile Gly Leu Asn Asp Arg Thr Ile Glu Gly Asp Phe Arg
218021852190
Trp Ser Asp Gly His Ser Leu Gln Phe Glu Asn Trp Arg Pro Asn Gln
219522002205
Pro Asp Asn Phe Phe Val Ser Gly Glu Asp Cys Val Val Met Ile Trp
221022152220
His Glu Lys Gly Glu Trp Asn Asp Val Pro Cys Asn Tyr Tyr Leu Pro
2225223022352240
Phe Thr Cys Lys Lys Gly Thr Val Ala Cys Gly Asp Pro Pro Val Val
224522502255
Glu His Ala Arg Thr Phe Gly Gln Lys Lys Asp Arg Tyr Glu Ile Asn
226022652270
Ser Leu Val Arg Tyr Gln Cys Thr Glu Gly Phe Val Gln Arg His Val
227522802285
Pro Thr Ile Arg Cys Gln Pro Ser Gly His Trp Glu Lys Pro Arg Ile
229022952300
Thr Cys Thr Asp Pro Ser Thr Tyr Lys Arg Arg Leu Gln Lys Arg Ser
2305231023152320
Ser Arg Ala Pro Arg Arg Ser Arg Pro Ser Thr Ala His
23252330
<210> 290
<211> 2124
<212> PRT
<213> Rattus norvegicus
<220>
<223> RAT AGGRECAN P07897
<400> 290
Met Thr Thr Leu Leu Leu Val Phe Val Thr Leu Arg Val Ile Ala Ala
151015
Val Ile Ser Glu Glu Val Pro Asp His Asp Asn Ser Leu Ser Val Ser
202530
Ile Pro Gln Pro Ser Pro Leu Lys Ala Leu Leu Gly Thr Ser Leu Thr
354045
Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val Thr Thr Ala Pro
505560
Ser Thr Ala Pro Leu Thr Pro Arg Ile Lys Trp Ser Arg Val Ser Lys
65707580
Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly Gln Val Arg Val
859095
Asn Ser Ile Tyr Gln Asp Lys Val Ser Leu Pro Asn Tyr Pro Ala Ile
100105110
Pro Ser Asp Ala Thr Leu Glu Ile Gln Asn Leu Arg Ser Asn Asp Ser
115120125
Gly Ile Tyr Arg Cys Glu Val Met His Gly Ile Glu Asp Ser Glu Ala
130135140
Thr Leu Glu Val Ile Val Lys Gly Ile Val Phe His Tyr Arg Ala Ile
145150155160
Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
165170175
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
180185190
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
195200205
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
210215220
Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu
225230235240
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe
245250255
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Asn Glu
260265270
Cys Arg Thr Val Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu
275280285
Ala Trp Gln Gly Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
290295300
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
305310315320
Asn Leu Leu Gly Val Arg Thr Val Tyr Leu His Ala Asn Gln Thr Gly
325330335
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
340345350
Asp Phe Val Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Glu
355360365
Asp Ile Thr Ile Gln Thr Val Thr Trp Pro Asp Leu Glu Leu Pro Leu
370375 380
Pro Arg Asn Ile Thr Glu Gly Glu Ala Arg Gly Asn Val Ile Leu Thr
385390395400
Ala Lys Pro Ile Phe Asp Met Ser Pro Thr Val Ser Glu Pro Gly Glu
405410415
Ala Leu Thr Leu Ala Pro Glu Val Gly Thr Thr Val Phe Pro Glu Ala
420425430
Gly Glu Arg Thr Glu Lys Thr Thr Arg Pro Trp Gly Phe Pro Glu Glu
435440445
Ala Thr Arg Gly Pro Asp Ser Ala Thr Ala Phe Ala Ser Glu Asp Leu
450455460
Val Val Arg Val Thr Ile Ser Pro Gly Ala Val Glu Val Pro Gly Gln
465470475480
Pro Arg Leu Pro Gly Gly Val Val Phe His Tyr Arg Pro Gly Ser Thr
485490495
Arg Tyr Ser Leu Thr Phe Glu Glu Ala Gln Gln Ala Cys Ile Arg Thr
500505510
Gly Ala Ala Ile Ala Ser Pro Glu Gln Leu Gln Ala Ala Tyr Glu Ala
515520525
Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Gln Asp Gln Thr Val Arg
530535540
Tyr Pro Ile Val Ser Pro Arg Thr Pro Cys Val Gly Asp Lys Asp Ser
545550555560
Ser Pro Gly Val Arg Thr Tyr Gly Val Arg Pro Ser Ser Glu Thr Tyr
565570575
Asp Val Tyr Cys Tyr Val Asp Lys Leu Glu Gly Glu Val Phe Phe Ala
580585590
Thr Gln Met Glu Gln Phe Thr Phe Gln Glu Ala Gln Ala Phe Cys Ala
595600605
Ala Gln Asn Ala Thr Leu Ala Ser Thr Gly Gln Leu Tyr Ala Ala Trp
610615620
Ser Gln Gly Leu Asp Lys Cys Tyr Ala Gly Trp Leu Ala Asp Gly Thr
625630635640
Leu Arg Tyr Pro Ile Val Asn Pro Arg Pro Ala Cys Gly Gly Asp Lys
645650655
Pro Gly Val Arg Thr Val Tyr Leu Tyr Pro Asn Gln Thr Gly Leu Pro
660665670
Asp Pro Leu Ser Lys His His Ala Phe Cys Phe Arg Gly Val Ser Val
675680685
Val Pro Ser Pro Gly Gly Thr Pro Thr Ser Pro Ser Asp Ile Glu Asp
690 695700
Trp Ile Val Thr Arg Val Glu Pro Gly Val Asp Ala Val Pro Leu Glu
705710715720
Pro Glu Thr Thr Glu Val Pro Tyr Phe Thr Thr Glu Pro Glu Lys Gln
725730735
Thr Glu Trp Glu Pro Ala Tyr Thr Pro Val Gly Thr Ser Pro Leu Pro
740745750
Gly Ile Pro Pro Thr Trp Leu Pro Thr Val Pro Ala Ala Glu Glu His
755760765
Thr Glu Ser Pro Ser Ala Ser Gln Glu Pro Ser Ala Ser Gln Val Pro
770775780
Ser Thr Ser Glu Glu Pro Tyr Thr Pro Ser Leu Ala Val Pro Ser Gly
785790795800
Thr Glu Leu Pro Ser Ser Gly Asp Thr Ser Gly Ala Pro Asp Leu Ser
805810815
Gly Asp Phe Thr Gly Ser Thr Asp Thr Ser Gly Arg Leu Asp Ser Ser
820825830
Gly Glu Pro Ser Gly Gly Ser Glu Ser Gly Leu Pro Ser Gly Asp Leu
835840845
Asp Ser Ser Gly Leu Gly Pro Thr Val Ser Ser Gly Leu Pro Val Glu
850855860
Ser Gly Ser Ala Ser Gly Asp Gly Glu Ile Pro Trp Ser Ser Thr Pro
865870875880
Thr Val Asp Arg Leu Pro Ser Gly Gly Glu Ser Leu Glu Gly Ser Ala
885890895
Ser Ala Ser Gly Thr Gly Asp Leu Ser Gly Leu Pro Ser Gly Gly Glu
900905910
Ile Thr Glu Thr Ser Ala Ser Gly Thr Glu Glu Ile Ser Gly Leu Pro
915920925
Ser Gly Gly Asp Asp Leu Glu Thr Ser Thr Ser Gly Ile Asp Gly Ala
930935940
Ser Val Leu Pro Thr Gly Arg Gly Gly Leu Glu Thr Ser Ala Ser Gly
945950955960
Val Glu Asp Leu Ser Gly Leu Pro Ser Gly Glu Glu Gly Ser Glu Thr
965970975
Ser Thr Ser Gly Ile Glu Asp Ile Ser Val Leu Pro Thr Gly Glu Ser
980985990
Pro Glu Thr Ser Ala Ser Gly Val Gly Asp Leu Ser Gly Leu Pro Ser
99510001005
Gly Gly Glu Ser Leu Glu Thr Ser Ala Ser Gly Val Glu Asp Val Thr
101010151020
Gln Leu Pro Thr Glu Arg Gly Gly Leu Glu Thr Ser Ala Ser Gly Ile
1025103010351040
Glu Asp Ile Thr Val Leu Pro Thr Gly Arg Glu Asn Leu Glu Thr Ser
104510501055
Ala Ser Gly Val Glu Asp Val Ser Gly Leu Pro Ser Gly Lys Glu Gly
106010651070
Leu Glu Thr Ser Ala Ser Gly Ile Glu Asp Ile Ser Val Phe Pro Thr
107510801085
Glu Ala Glu Gly Leu Glu Thr Ser Ala Ser Gly Gly Tyr Val Ser Gly
109010951100
Ile Pro Ser Gly Glu Asp Gly Thr Glu Thr Ser Thr Ser Gly Val Glu
1105111011151120
Gly Val Ser Gly Leu Pro Ser Gly Gly Glu Gly Leu Glu Thr Ser Ala
112511301135
Ser Gly Val Glu Asp Leu Gly Leu Pro Thr Arg Asp Ser Leu Glu Thr
114011451150
Ser Ala Ser Gly Val Asp Val Thr Gly Tyr Pro Ser Gly Arg Glu Asp
115511601165
Thr Glu Thr Ser Val Pro Gly Val Gly Asp Asp Leu Ser Gly Leu Pro
117011751180
Ser Gly Gln Glu Gly Leu Glu Thr Ser Ala Ser Gly Ala Glu Asp Leu
1185119011951200
Gly Gly Leu Pro Ser Gly Lys Glu Asp Leu Val Gly Ser Ala Ser Gly
120512101215
Ala Leu Asp Phe Gly Lys Leu Pro Ser Gly Thr Leu Gly Ser Gly Gln
122012251230
Thr Pro Glu Ala Ser Gly Leu Pro Ser Gly Phe Ser Gly Glu Tyr Ser
123512401245
Gly Val Asp Ile Gly Ser Gly Pro Ser Ser Gly Leu Pro Asp Phe Ser
125012551260
Gly Leu Pro Ser Gly Phe Pro Thr Val Ser Leu Val Asp Ser Thr Leu
1265127012751280
Val Glu Val Ile Thr Ala Thr Thr Ala Ser Glu Leu Glu Gly Arg Gly
128512901295
Thr Ile Ser Val Ser Gly Ser Gly Glu Glu Ser Gly Pro Pro Leu Ser
130013051310
Glu Leu Asp Ser Ser Ala Asp Ile Ser Gly Leu Pro Ser Gly Thr Glu
131513201325
Leu Ser Gly Gln Thr Ser Gly Ser Leu Asp Val Ser Gly Glu Thr Ser
133013351340
Gly Phe Phe Asp Val Ser Gly Gln Pro Phe Gly Ser Ser Gly Thr Gly
1345135013551360
Glu Gly Thr Ser Gly Ile Pro Glu Val Ser Gly Gln Ala Val Arg Ser
136513701375
Pro Asp Thr Thr Glu Ile Ser Glu Leu Ser Gly Leu Ser Ser Gly Gln
138013851390
Pro Asp Val Ser Gly Glu Gly Ser Gly Ile Leu Phe Gly Ser Gly Gln
139514001405
Ser Ser Gly Ile Thr Ser Val Ser Gly Glu Thr Ser Gly Ile Ser Asp
141014151420
Leu Ser Gly Gln Pro Ser Gly Phe Pro Val Leu Ser Gly Thr Thr Pro
1425143014351440
Gly Thr Pro Asp Leu Ala Ser Gly Ala Met Ser Gly Ser Gly Asp Ser
144514501455
Ser Gly Ile Thr Phe Val Asp Thr Ser Leu Ile Glu Val Thr Pro Thr
146014651470
Thr Phe Arg Glu Glu Glu Gly Leu Gly Ser Val Glu Leu Ser Gly Leu
147514801485
Pro Ser Gly Glu Thr Asp Leu Ser Gly Thr Ser Gly Met Val Asp Val
149014951500
Ser Gly Gln Ser Ser Gly Ala Ile Asp Ser Ser Gly Leu Ile Ser Pro
1505151015151520
Thr Pro Glu Phe Ser Gly Leu Pro Ser Gly Val Ala Glu Val Ser Gly
152515301535
Glu Val Ser Gly Val Glu Thr Gly Ser Ser Leu Ser Ser Gly Ala Phe
154015451550
Asp Gly Ser Gly Leu Val Ser Gly Phe Pro Thr Val Ser Leu Val Asp
155515601565
Arg Thr Leu Val Glu Ser Ile Thr Leu Ala Pro Thr Ala Gln Glu Ala
157015751580
Gly Glu Gly Pro Ser Ser Ile Leu Glu Phe Ser Gly Ala His Ser Gly
1585159015951600
Thr Pro Asp Ile Ser Gly Asp Leu Ser Gly Ser Leu Asp Gln Ser Thr
160516101615
Trp Gln Pro Gly Trp Thr Glu Ala Ser Thr Glu Pro Pro Ser Ser Pro
162016251630
Tyr Phe Ser Gly Asp Phe Ser Ser Thr Thr Asp Ala Ser Gly Glu Ser
163516401645
Ile Thr Ala Pro Thr Gly Ser Gly Glu Thr Ser Gly Leu Pro Glu Val
165016551660
Thr Leu Ile Thr Ser Glu Leu Val Glu Gly Val Thr Glu Pro Thr Val
1665167016751680
Ser Gln Glu Leu Gly His Gly Pro Ser Met Thr Tyr Thr Pro Arg Leu
168516901695
Phe Glu Ala Ser Gly Glu Ala Ser Ala Ser Gly Asp Leu Gly Gly Pro
170017051710
Val Thr Ile Phe Pro Gly Ser Gly Val Glu Ala Ser Val Pro Glu Gly
171517201725
Ser Ser Asp Pro Ser Ala Tyr Pro Glu Ala Gly Val Gly Val Ser Ala
173017351740
Ala Pro Glu Ala Ser Ser Gln Leu Ser Glu Phe Pro Asp Leu His Gly
1745175017551760
Ile Thr Ser Ala Ser Arg Glu Thr Asp Leu Glu Met Thr Thr Pro Gly
176517701775
Thr Glu Val Ser Ser Asn Pro Trp Thr Phe Gln Glu Gly Thr Arg Glu
178017851790
Gly Ser Ala Ala Pro Glu Val Ser Gly Glu Ser Ser Thr Thr Ser Asp
179518001805
Ile Asp Ala Gly Thr Ser Gly Val Pro Phe Ala Thr Pro Met Thr Ser
181018151820
Gly Asp Arg Thr Glu Ile Ser Gly Glu Trp Ser Asp His Thr Ser Glu
1825183018351840
Val Asn Val Thr Val Ser Thr Thr Val Pro Glu Ser Arg Trp Ala Gln
184518501855
Ser Thr Gln His Pro Thr Glu Thr Leu Gln Glu Ile Gly Ser Pro Asn
186018651870
Pro Ser Tyr Ser Gly Glu Glu Thr Gln Thr Ala Glu Thr Ala Lys Ser
187518801885
Leu Thr Asp Thr Pro Thr Leu Ala Ser Pro Glu Gly Ser Gly Glu Thr
189018951900
Glu Ser Thr Ala Ala Asp Gln Glu Gln Cys Glu Glu Gly Trp Thr Lys
1905191019151920
Phe Gln Gly His Cys Tyr Arg His Phe Pro Asp Arg Glu Thr Trp Val
192519301935
Asp Ala Glu Arg Arg Cys Arg Glu Gln Gln Ser His Leu Ser Ser Ile
194019451950
Val Thr Pro Glu Glu Gln Glu Phe Val Asn Lys Asn Ala Gln Asp Tyr
195519601965
Gln Trp Ile Gly Leu Asn Asp Arg Thr Ile Glu Gly Asp Phe Arg Trp
197019751980
Ser Asp Gly His Ser Leu Gln Phe Glu Lys Trp Arg Pro Asn Gln Pro
1985199019952000
Asp Asn Phe Phe Ala Thr Gly Glu Asp Cys Val Val Met Ile Trp His
200520102015
Glu Arg Gly Glu Trp Asn Asp Val Pro Cys Asn Tyr Gln Leu Pro Phe
202020252030
Thr Cys Lys Lys Gly Thr Val Ala Cys Gly Glu Pro Pro Ala Val Glu
203520402045
His Ala Arg Thr Leu Gly Gln Lys Lys Asp Arg Tyr Glu Ile Ser Ser
205020552060
Leu Val Arg Tyr Gln Cys Thr Glu Gly Phe Val Gln Arg His Val Pro
2065207020752080
Thr Ile Arg Cys Gln Pro Ser Ala Asp Trp Glu Glu Pro Arg Ile Thr
208520902095
Cys Thr Asp Pro Asn Thr Tyr Lys His Arg Leu Gln Lys Arg Thr Met
210021052110
Arg Pro Thr Arg Arg Ser Arg Pro Ser Met Ala His
21152120
<210> 291
<211> 394
<212> PRT
<213> Oryctolagus cuniculus
<220>
<223> RABBIT AGGRECAN Q28670
<220>
<221> VARIANT
<222> 289
<223> Xaa = any amino acid
<400> 291
Ser Thr Ala Pro Leu Thr Pro Arg Ile Lys Trp Ser Arg Ile Ser Lys
151015
Asp Lys Glu Val Val Leu Leu Val Ala Asn Glu Gly Arg Val Arg Ile
202530
Asn Ser Ala Tyr Gln Asp Lys Val Ser Leu Pro Asn Tyr Pro Ala Ile
354045
Pro Ser Asp Ala Thr Leu Glu Ile Gln Ser Leu Arg Ser Asn Asp Ser
505560
Gly Ile Tyr Arg Cys Glu Val Met His Gly Leu Glu Asp Ser Glu Ala
65707580
Thr Leu Glu Val Val Val Lys Gly Val Val Phe His Tyr Arg Ala Ile
859095
Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln Arg Ala Cys Leu
100105110
Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu Gln Ala Ala Tyr
115120125
Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr
130135140
Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys Tyr Gly Asp Lys
145150155160
Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg Asp Thr Asn Glu
165170175
Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu Gly Glu Val Phe
180185190
Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala Ala Ser Glu
195 200205
Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln Leu Tyr Leu
210215220
Ala Trp Gln Ala Gly Met Asp Met Cys Ser Ala Gly Trp Leu Ala Asp
225230235240
Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn Cys Gly Gly
245250255
Asn Leu Leu Gly Val Arg Thr Val Tyr Val His Ala Asn Gln Thr Gly
260265270
Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr Thr Gly Glu
275280285
Xaa Phe Met Asp Ile Pro Glu Asn Phe Phe Gly Val Gly Gly Glu Glu
290295300
Asp Ile Thr Val Gln Thr Val Thr Trp Pro Asp Val Glu Leu Pro Val
305310315320
Pro Arg Asn Ile Thr Glu Gly Glu Ala Arg Gly Ser Val Val Leu Thr
325330335
Ala Lys Pro Val Leu Asp Val Ser Pro Thr Ala Pro Gln Pro Glu Glu
340345350
Thr Phe Ala Pro Gly Leu Gly Ala Thr Ala Phe Pro Gly Val Glu Asn
355360365
Gly Thr Glu Glu Ala Thr Arg Pro Arg Gly Phe Ala Asp Glu Ala Ala
370375380
Leu Gly Pro Ser Ser Ala Thr Ala Phe Thr
385390
<210> 292
<211> 883
<212> PRT
<213> Rattus norvegicus
<220>
<223> RAT BREVICAN P55068
<400> 292
Met Ile Pro Leu Leu Leu Ser Leu Leu Ala Ala Leu Val Leu Thr Gln
151015
Ala Pro Ala Ala Leu Ala Asp Asp Leu Lys Glu Asp Ser Ser Glu Asp
202530
Arg Ala Phe Arg Val Arg Ile Gly Ala Ala Gln Leu Arg Gly Val Leu
354045
Gly Gly Ala Leu Ala Ile Pro Cys His Val His His Leu Arg Pro Pro
505560
Pro Ser Arg Arg Ala Ala Pro Gly Phe Pro Arg Val Lys Trp Thr Phe
65707580
Leu Ser Gly Asp Arg Glu Val Glu Val Leu Val Ala Arg Gly Leu Arg
859095
Val Lys Val Asn Glu Ala Tyr Arg Phe Arg Val Ala Leu Pro Ala Tyr
100105110
Pro Ala Ser Leu Thr Asp Val Ser Leu Val Leu Ser Glu Leu Arg Pro
115120125
Asn Asp Ser Gly Val Tyr Arg Cys Glu Val Gln His Gly Ile Asp Asp
130135140
Ser Ser Asp Ala Val Glu Val Lys Val Lys Gly Val Val Phe Leu Tyr
145150155160
Arg Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe Ala Gly Ala Gln Glu
165170175
Ala Cys Ala Arg Ile Gly Ala Arg Ile Ala Thr Pro Glu Gln Leu Tyr
180185190
Ala Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Ser
195200205
Asp Gln Thr Val Arg Tyr Pro Ile Gln Asn Pro Arg Glu Ala Cys Tyr
210215220
Gly Asp Met Asp Gly Tyr Pro Gly Val Arg Asn Tyr Gly Val Val Gly
225230235240
Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Asp Leu Asn Gly
245250255
Glu Leu Phe Leu Gly Ala Pro Pro Gly Lys Leu Thr Trp Glu Glu Ala
260265270
Arg Asp Tyr Cys Leu Glu Arg Gly Ala Gln Ile Ala Ser Thr Gly Gln
275280285
Leu Tyr Ala Ala Trp Asn Gly Gly Leu Asp Arg Cys Ser Pro Gly Trp
290295300
Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ile Thr Pro Ser Gln Arg
305310315320
Cys Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro Asn
325330335
Gln Thr Gly Phe Pro Ser Lys Gln Asn Arg Phe Asn Val Tyr Cys Phe
340345350
Arg Asp Ser Ala His Pro Ser Ala Phe Ser Glu Ala Ser Ser Pro Ala
355360365
Ser Asp Gly Leu Glu Ala Ile Val Thr Val Thr Glu Lys Leu Glu Glu
370375380
Leu Gln Leu Pro Gln Glu Ala Val Glu Ser Glu Ser Arg Gly Ala Ile
385390395400
Tyr Ser Ile Pro Ile Thr Glu Asp Gly Gly Gly Gly Ser Ser Thr Pro
405410415
Glu Asp Pro Ala Glu Ala Pro Arg Thr Pro Leu Glu Ser Glu Thr Gln
420425430
Ser Val Ala Pro Pro Thr Gly Ser Ser Glu Glu Glu Gly Glu Ala Leu
435440445
Glu Glu Glu Glu Arg Phe Lys Asp Thr Glu Thr Pro Lys Glu Glu Lys
450455460
Glu Gln Glu Asn Leu Trp Val Trp Pro Thr Glu Leu Ser Ser Pro Leu
465470475480
Pro Thr Gly Leu Glu Thr Glu His Ser Leu Ser Gln Val Ser Pro Pro
485490495
Ala Gln Ala Val Leu Gln Val Gly Ala Ser Pro Ser Pro Arg Pro Pro
500505510
Arg Val His Gly Pro Thr Val Glu Thr Leu Gln Pro Pro Gly Glu Gly
515520525
Ser Leu Thr Ser Thr Pro Asp Gly Ala Arg Glu Val Gly Gly Glu Thr
530535540
Gly Ser Pro Glu Leu Ser Gly Val Pro Arg Glu Arg Glu Glu Ala Gly
545550555560
Ser Ser Ser Leu Glu Asp Gly Pro Ser Leu Leu Pro Glu Thr Trp Ala
565570575
Pro Val Gly Thr Arg Glu Val Glu Thr Pro Ser Glu Glu Lys Ser Gly
580585590
Arg Thr Val Leu Thr Gly Thr Ser Val Gln Ala Gln Pro Val Leu Pro
595600605
Thr Asp Ser Ala Ser Arg Gly Gly Val Ala Val Ala Pro Ser Ser Gly
610615620
Asp Cys Ile Pro Ser Pro Cys His Asn Gly Gly Thr Cys Leu Glu Glu
625630635640
Lys Glu Gly Phe Arg Cys Leu Cys Val Pro Gly Tyr Gly Gly Asp Leu
645650655
Cys Asp Val Gly Leu His Phe Cys Ser Pro Gly Trp Glu Pro Phe Gln
660665670
Gly Ala Cys Tyr Lys His Phe Ser Thr Arg Arg Ser Trp Glu Glu Ala
675680685
Glu Ser Gln Cys Arg Ala Leu Gly Ala His Leu Thr Ser Ile Cys Thr
690695700
Pro Glu Glu Gln Asp Phe Val Asn Asp Arg Tyr Arg Glu Tyr Gln Trp
705710715720
Ile Gly Leu Asn Asp Arg Thr Ile Glu Gly Asp Phe Leu Trp Ser Asp
725730735
Gly Pro Pro Leu Leu Tyr Glu Asn Trp Asn Pro Gly Gln Pro Asp Ser
740745750
Tyr Phe Leu Ser Gly Glu Asn Cys Val Val Met Val Trp His Asp Gln
755760765
Gly Gln Trp Ser Asp Val Pro Cys Asn Tyr His Leu Ser Tyr Thr Cys
770775780
Lys Met Gly Leu Val Ser Cys Gly Pro Pro Pro Gln Leu Pro Leu Ala
785790795800
Gln Ile Phe Gly Arg Pro Arg Leu Arg Tyr Ala Val Asp Thr Val Leu
805810815
Arg Tyr Arg Cys Arg Asp Gly Leu Ala Gln Arg Asn Leu Pro Leu Ile
820825830
Arg Cys Gln Glu Asn Gly Leu Trp Glu Ala Pro Gln Ile Ser Cys Val
835840845
Pro Arg Arg Pro Ala Arg Ala Leu Arg Ser Met Thr Ala Pro Glu Gly
850855860
Pro Arg Gly Gln Leu Pro Arg Gln Arg Lys Ala Leu Leu Thr Pro Pro
865870875880
Ser Ser Leu
<210> 293
<211> 883
<212> PRT
<213> Mus musculus
<220>
<223> MOUSE BREVICAN Q61361
<400> 293
Met Ile Pro Leu Leu Leu Ser Leu Leu Ala Ala Leu Val Leu Thr Gln
151015
Ala Pro Ala Ala Leu Ala Asp Asp Leu Lys Glu Asp Ser Ser Glu Asp
202530
Arg Ala Phe Arg Val Arg Ile Gly Ala Thr Gln Leu Arg Gly Val Leu
354045
Gly Gly Ala Leu Ala Ile Pro Cys His Val His His Leu Arg Pro Pro
505560
His Ser Arg Arg Ala Ala Pro Gly Phe Pro Arg Val Lys Trp Thr Phe
65707580
Leu Ser Gly Asp Arg Glu Val Glu Val Leu Val Ala Arg Gly Leu Arg
859095
Val Lys Val Asn Glu Ala Tyr Arg Phe Arg Val Ala Leu Pro Ala Tyr
100105110
Pro Ala Ser Leu Thr Asp Val Ser Leu Val Leu Ser Glu Leu Arg Pro
115120125
Asn Asp Ser Gly Val Tyr Arg Cys Glu Val Gln His Gly Ile Asp Asp
130135140
Ser Ser Asp Ala Val Glu Val Lys Val Lys Gly Val Val Phe Leu Tyr
145150155160
Arg Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe Ala Gly Ala Gln Glu
165170175
Ala Cys Ala Arg Ile Gly Ala Arg Ile Ala Thr Pro Glu Gln Leu Tyr
180185190
Ala Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Ser
195200205
Asp Gln Thr Val Arg Tyr Pro Ile Gln Asn Pro Arg Glu Ala Cys Ser
210215220
Gly Asp Met Asp Gly Tyr Pro Gly Val Arg Asn Tyr Gly Val Val Gly
225230235240
Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Asp Leu Asn Gly
245250255
Glu Leu Phe Leu Gly Ala Pro Pro Ser Lys Leu Thr Trp Glu Glu Ala
260265270
Arg Asp Tyr Cys Leu Glu Arg Gly Ala Gln Ile Ala Ser Thr Gly Gln
275280285
Leu Tyr Ala Ala Trp Asn Gly Gly Leu Asp Arg Cys Ser Pro Gly Trp
290295300
Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ile Thr Pro Ser Gln Arg
305310315320
Cys Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro Asn
325330335
Gln Thr Gly Phe Pro Ser Lys Gln Asn Arg Phe Asn Val Tyr Cys Phe
340345350
Arg Asp Ser Ala His Pro Ser Ala Ser Ser Glu Ala Ser Ser Pro Ala
355360365
Ser Asp Gly Leu Glu Ala Ile Val Thr Val Thr Glu Lys Leu Glu Glu
370375380
Leu Gln Leu Pro Gln Glu Ala Met Glu Ser Glu Ser Arg Gly Ala Ile
385390395400
Tyr Ser Ile Pro Ile Ser Glu Asp Gly Gly Gly Gly Ser Ser Thr Pro
405410415
Glu Asp Pro Ala Glu Ala Pro Arg Thr Pro Leu Glu Ser Glu Thr Gln
420425430
Ser Ile Ala Pro Pro Thr Glu Ser Ser Glu Glu Glu Gly Val Ala Leu
435440445
Glu Glu Glu Glu Arg Phe Lys Asp Leu Glu Ala Leu Glu Glu Glu Lys
450455460
Glu Gln Glu Asp Leu Trp Val Trp Pro Arg Glu Leu Ser Ser Pro Leu
465470475480
Pro Thr Gly Ser Glu Thr Glu His Ser Leu Ser Gln Val Ser Pro Pro
485490495
Ala Gln Ala Val Leu Gln Leu Gly Ala Ser Pro Ser Pro Gly Pro Pro
500505510
Arg Val Arg Gly Pro Pro Ala Glu Thr Leu Leu Pro Pro Arg Glu Gly
515520525
Ser Pro Thr Ser Thr Pro Gly Gly Ala Arg Glu Val Gly Gly Glu Thr
530535540
Gly Ser Pro Glu Leu Ser Gly Val Pro Arg Glu Ser Glu Glu Ala Gly
545550555560
Ser Ser Ser Leu Glu Asp Gly Pro Ser Leu Leu Pro Ala Thr Trp Ala
565570575
Pro Val Gly Pro Arg Glu Leu Glu Thr Pro Ser Glu Glu Lys Ser Gly
580585590
Arg Thr Val Leu Ala Gly Thr Ser Val Gln Ala Gln Pro Val Leu Pro
595600605
Thr Asp Ser Ala Ser His Gly Gly Val Ala Val Ala Pro Ser Ser Gly
610615620
Asp Cys Ile Pro Ser Pro Cys His Asn Gly Gly Thr Cys Leu Glu Glu
625630635640
Lys Glu Gly Phe Arg Cys Leu Cys Leu Pro Gly Tyr Gly Gly Asp Leu
645650655
Cys Asp Val Gly Leu His Phe Cys Ser Pro Gly Trp Glu Ala Phe Gln
660665670
Gly Ala Cys Tyr Lys His Phe Ser Thr Arg Arg Ser Trp Glu Glu Ala
675680685
Glu Ser Gln Cys Arg Ala Leu Gly Ala His Leu Thr Ser Ile Cys Thr
690695700
Pro Glu Glu Gln Asp Phe Val Asn Asp Arg Tyr Arg Glu Tyr Gln Trp
705710715720
Ile Gly Leu Asn Asp Arg Thr Ile Glu Gly Asp Phe Leu Trp Ser Asp
725730735
Gly Ala Pro Leu Leu Tyr Glu Asn Trp Asn Pro Gly Gln Pro Asp Ser
740745750
Tyr Phe Leu Ser Gly Glu Asn Cys Val Val Met Val Trp His Asp Gln
755760765
Gly Gln Trp Ser Asp Val Pro Cys Asn Tyr His Leu Ser Tyr Thr Cys
770775780
Lys Met Gly Leu Val Ser Cys Gly Pro Pro Pro Gln Leu Pro Leu Ala
785790795800
Gln Ile Phe Gly Arg Pro Arg Leu Arg Tyr Ala Val Asp Thr Val Leu
805810815
Arg Tyr Arg Cys Arg Asp Gly Leu Ala Gln Arg Asn Leu Pro Leu Ile
820825830
Arg Cys Gln Glu Asn Gly Leu Trp Glu Ala Pro Gln Ile Ser Cys Val
835840845
Pro Arg Arg Pro Gly Arg Ala Leu Arg Ser Met Asp Ala Pro Glu Gly
850855860
Pro Arg Gly Gln Leu Ser Arg His Arg Lys Ala Pro Leu Thr Pro Pro
865870875880
Ser Ser Leu
<210> 294
<211> 912
<212> PRT
<213> Bos taurus
<220>
<223> COW BREVICAN Q28062
<400> 294
Met Ala Pro Leu Phe Leu Pro Leu Leu Ala Thr Leu Val Leu Ala Trp
151015
Ile Pro Val Ala Leu Ala Asp Ala Leu Glu Gly Asp Ser Ser Glu Asp
202530
Arg Ala Phe Arg Val Arg Ile Ala Gly Asp Ala Pro Leu Gln Gly Val
354045
Leu Gly Gly Ala Leu Thr Ile Pro Cys His Val His Tyr Leu Arg Pro
505560
Ser Pro Ser Arg Arg Ala Ala Gln Gly Ser Pro Arg Val Lys Trp Thr
65707580
Phe Leu Ser Gly Gly Arg Glu Ala Glu Val Leu Val Ala Arg Gly Leu
859095
Arg Val Lys Val Ser Glu Ala Tyr Arg Phe Arg Val Ala Leu Pro Ala
100105110
Tyr Pro Ala Ser Leu Thr Asp Val Ser Leu Val Leu Ser Glu Leu Arg
115120125
Pro Asn Asp Ser Gly Ile Tyr Arg Cys Glu Val Gln His Gly Ile Asp
130135140
Asp Ser Ser Asp Ala Val Glu Val Lys Val Lys Gly Val Val Phe Leu
145150155160
Tyr Arg Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe Ala Gly Ala Gln
165170175
Glu Ala Cys Ala Arg Ile Gly Ala Arg Ile Ala Thr Pro Glu Gln Leu
180185190
Tyr Ala Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu
195200205
Ser Asp Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro Arg Glu Ala Cys
210215220
Tyr Gly Asp Met Asp Gly Phe Pro Gly Val Arg Asn Tyr Gly Val Val
225230235240
Asp Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Glu Leu Asn
245250255
Gly Glu Leu Phe Leu Gly Ala Pro Pro Asp Lys Leu Thr Leu Glu Glu
260265270
Ala Arg Thr Tyr Cys Gln Glu Arg Gly Ala Lys Ile Ala Thr Thr Gly
275280285
Gln Leu Tyr Ala Ala Trp Asp Gly Gly Leu Asp Arg Cys Ser Ser Gly
290295300
Trp Leu Ser Asp Gly Ser Val Arg Tyr Pro Ile Val Thr Pro Ser Gln
305310315320
Arg Cys Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro
325330335
Asn Gln Thr Gly Phe Pro Asn Lys His Ser Arg Phe Asn Val Tyr Cys
340345350
Phe Arg Asp Ser Ala Gln Pro Ser Ala Ile Pro Glu Ala Ala Asn Pro
355360365
Ala Ser His Leu Ala Ser Asp Ala Leu Glu Ala Ile Val Thr Val Thr
370375380
Glu Thr Leu Glu Glu Leu Lys Leu Pro Gln Glu Ala Val Glu Ser Glu
385390395400
Ser Arg Gly Ala Ile Tyr Ser Ile Pro Ile Ile Glu Asp Gly Gly Gly
405410415
Gly Ser Ser Thr Pro Glu Asp Pro Ala Glu Ala Pro Arg Thr Leu Leu
420425430
Glu Phe Glu Thr Gln Ser Ile Val Pro Pro Leu Gly Ser Ser Glu Glu
435440445
Glu Gly Lys Val Leu Glu Gln Glu Glu Lys Tyr Arg Gly Glu Glu Glu
450455460
Lys Glu Glu Glu Glu Glu Glu Glu Glu Val Glu Asp Glu Ala Leu Trp
465470475480
Ala Trp Pro Ser Glu Leu Ser Ser Leu Asp Pro Glu Ala Pro Leu Pro
485490495
Thr Glu Pro Val Pro Glu Glu Ser Leu Thr Gln Ala Ser Pro Pro Val
500505510
Arg Ala Ala Leu Gln Pro Gly Val Ser Pro Pro Pro Tyr Asp Glu Pro
515520525
Glu Ala Pro Arg Pro Pro Arg Val Leu Gly Pro Pro Thr Lys Thr Leu
530535540
Pro Thr Pro Arg Glu Gly Asn Leu Ala Ser Pro Pro Pro Ser Thr Leu
545550555560
Val Gly Ala Arg Glu Ile Glu Glu Glu Thr Gly Gly Pro Glu Leu Ser
565570575
Gly Ala Pro Arg Gly Glu Ser Glu Glu Thr Gly Ser Ser Glu Asp Ala
580585590
Pro Ser Leu Leu Pro Ala Thr Arg Ala Pro Gly Asp Thr Arg Asp Leu
595600605
Glu Thr Pro Ser Glu Glu Asn Ser Arg Arg Thr Val Pro Ala Gly Thr
610615620
Ser Val Arg Ala Gln Pro Val Leu Pro Thr Asp Ser Ala Ser Arg Gly
625630635640
Gly Val Ala Val Ala Pro Ser Ser Gly Asp Cys Val Pro Ser Pro Cys
645650655
His Asn Gly Gly Thr Cys Leu Glu Glu Glu Glu Gly Val Arg Cys Leu
660665670
Cys Leu Pro Gly Tyr Gly Gly Asp Leu Cys Asp Val Gly Leu His Phe
675680685
Cys Ser Pro Gly Trp Asp Ala Phe Gln Gly Ala Cys Tyr Lys His Phe
690695700
Ser Ala Arg Arg Ser Trp Glu Glu Ala Glu Asn Lys Cys Arg Met Tyr
705710715720
Gly Ala His Leu Ala Ser Ile Ser Thr Pro Glu Glu Gln Asp Phe Ile
725730 735
Asn Asn Arg Tyr Arg Glu Tyr Gln Trp Ile Gly Leu Asn Asp Arg Thr
740745750
Ile Glu Gly Asp Phe Leu Trp Ser Asp Gly Val Pro Leu Leu Tyr Glu
755760765
Asn Trp Asn Pro Gly Gln Pro Asp Ser Tyr Phe Leu Ser Gly Glu Asn
770775780
Cys Val Val Met Val Trp His Asp Gln Gly Gln Trp Ser Asp Val Pro
785790795800
Cys Asn Tyr His Leu Ser Tyr Thr Cys Lys Met Gly Leu Val Ser Cys
805810815
Gly Pro Pro Pro Glu Leu Pro Leu Ala Glu Val Phe Gly Arg Pro Arg
820825830
Leu Arg Tyr Glu Val Asp Thr Val Leu Arg Tyr Arg Cys Arg Glu Gly
835840845
Leu Thr Gln Arg Asn Leu Pro Leu Ile Arg Cys Gln Glu Asn Gly Arg
850855860
Trp Gly Leu Pro Gln Ile Ser Cys Val Pro Arg Arg Pro Ala Arg Ala
865870875880
Leu Arg Pro Val Glu Ala Gln Glu Gly Arg Pro Trp Arg Leu Val Gly
885890895
His Trp Lys Ala Arg Leu Asn Pro Ser Pro Asn Pro Ala Pro Gly Pro
900905910
<210> 295
<211> 417
<212> PRT
<213> Felis catus
<220>
<223> CAT BREVICAN P41725
<220>
<221> VARIANT
<222> 367
<223> Xaa = any amino acid
<400> 295
Met Ala Pro Leu Phe Leu Pro Leu Leu Ile Ala Leu Ala Leu Ala Pro
151015
Gly Pro Thr Ala Ser Ala Asp Val Leu Glu Gly Asp Ser Ser Glu Asp
202530
Arg Ala Phe Arg Val Arg Ile Ser Gly Asn Ala Pro Leu Gln Gly Val
354045
Leu Gly Gly Ala Leu Thr Ile Ser Cys His Val His Tyr Leu Arg Pro
505560
Pro Pro Gly Arg Arg Ala Val Leu Gly Ser Pro Arg Val Lys Trp Thr
65707580
Phe Leu Ser Gly Gly Arg Glu Ala Glu Val Leu Val Ala Arg Gly Leu
859095
Arg Val Lys Val Ser Glu Ala Tyr Arg Phe Arg Val Ala Leu Pro Ala
100105110
Tyr Pro Ala Ser Leu Thr Asp Val Ser Leu Ala Leu Ser Glu Leu Arg
115120125
Pro Asn Asp Ser Gly Ile Tyr Arg Cys Glu Val Gln His Gly Ile Asp
130135140
Asp Ser Ser Asp Ala Val Glu Val Lys Val Lys Gly Val Val Phe Leu
145150155160
Tyr Arg Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe Ala Arg Ala Gln
165170175
Glu Ala Cys Ala Arg Ile Gly Ala Arg Ile Ala Thr Pro Glu Gln Leu
180185190
Tyr Ala Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu
195200205
Ser Asp Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro Arg Glu Ala Cys
210215220
Tyr Gly Asp Met Asp Gly Phe Pro Gly Val Arg Asn Tyr Gly Leu Val
225230235240
Asp Pro Asp Asp Leu Tyr Asp Ile Tyr Cys Tyr Ala Glu Asp Leu Asn
245250255
Gly Glu Leu Phe Leu Gly Ala Pro Pro Asp Asn Val Thr Leu Glu Glu
260265270
Ala Thr Ala Tyr Cys Arg Glu Arg Gly Ala Glu Ile Ala Thr Thr Gly
275280285
Gln Leu Tyr Ala Ala Trp Asp Gly Gly Leu Asp Arg Cys Ser Pro Gly
290295300
Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Val Thr Pro Ser Gln
305310315320
Arg Cys Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro
325330335
Asn Gln Thr Gly Phe Pro Asn Lys Tyr Ser Arg Phe Asn Val Tyr Cys
340345350
Phe Arg Asp Ser Gly Gln Pro Ser Thr Thr Pro Glu Ala Ser Xaa Pro
355360365
Ala Ser Asp Gly Leu Glu Ala Ile Val Thr Val Thr Glu Thr Leu Glu
370375380
Glu Leu His Val Pro Arg Glu Ala Val Glu Ser Glu Ser Arg Gly Ala
385390395400
Ile Tyr Ser Val Pro Ile Val Glu Asp Gly Gly Gly Ala Arg Ser Pro
405410415
Pro
<210> 296
<211> 3357
<212> PRT
<213> Mus musculus
<220>
<223> MOUSE VERSICAN Q62059
<400> 296
Met Leu Ile Asn Met Lys Gly Ile Leu Trp Met Cys Ser Thr Leu Leu
151015
Leu Thr His Ala Leu His Gln Ala Lys Met Glu Thr Ser Pro Pro Val
202530
Lys Gly Ser Leu Ser Gly Lys Val Val Leu Pro Cys His Phe Ser Thr
354045
Leu Pro Thr Leu Pro Pro Asn Tyr Asn Thr Ser Glu Phe Leu Arg Ile
505560
Lys Trp Ser Lys Met Glu Val Asp Lys Asn Gly Lys Asp Ile Lys Glu
65707580
Thr Thr Val Leu Val Ala Gln Asn Gly Asn Ile Lys Ile Gly Gln Asp
859095
Tyr Lys Gly Arg Val Ser Val Pro Thr His Pro Asp Asp Val Gly Asp
100105110
Ala Ser Leu Thr Met Val Lys Leu Arg Ala Ser Asp Ala Ala Val Tyr
115120125
Arg Cys Asp Val Met Tyr Gly Ile Glu Asp Thr Gln Asp Thr Met Ser
130135140
Leu Ala Val Asp Gly Val Val Phe His Tyr Arg Ala Ala Thr Ser Arg
145150155160
Tyr Thr Leu Asn Phe Ala Ala Ala Gln Gln Ala Cys Leu Asp Ile Gly
165170175
Ala Val Ile Ala Ser Pro Glu Gln Leu Phe Ala Ala Tyr Glu Asp Gly
180185190
Phe Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp Gln Thr Val Arg Tyr
195200205
Pro Ile Arg Ala Pro Arg Glu Gly Cys Tyr Gly Asp Met Met Gly Lys
210215220
Glu Gly Val Arg Thr Tyr Gly Phe Arg Ser Pro Gln Glu Thr Tyr Asp
225230235240
Val Tyr Cys Tyr Val Asp His Leu Asp Gly Asp Val Phe His Ile Thr
245250255
Ala Pro Ser Lys Phe Thr Phe Glu Glu Ala Glu Ala Glu Cys Thr Ser
260265270
Arg Asp Ala Arg Leu Ala Thr Val Gly Glu Leu Gln Ala Ala Trp Arg
275280285
Asn Gly Phe Asp Gln Cys Asp Tyr Gly Trp Leu Ser Asp Ala Ser Val
290295300
Arg His Pro Val Thr Val Ala Arg Ala Gln Cys Gly Gly Gly Leu Leu
305310315320
Gly Val Arg Thr Leu Tyr Arg Phe Glu Asn Gln Thr Cys Phe Pro Leu
325330335
Pro Asp Ser Arg Phe Asp Ala Tyr Cys Phe Lys Pro Lys Gln Asn Ile
340345350
Ser Glu Ala Thr Thr Ile Glu Met Asn Ile Leu Ala Glu Thr Ser Ser
355360365
Pro Ser Leu Ser Lys Glu Pro His Met Val Pro Asp Arg Ala Thr Pro
370375380
Val Ile Pro Leu Ala Thr Glu Leu Pro Ile Phe Thr Thr His Phe Pro
385390395400
Pro Ala Gly Asn Ile Val Asn Ser Glu Gln Lys Ser Val Val Tyr Ser
405410415
Gln Ala Ile Thr Gly Arg Leu Ala Thr Glu Ser Pro Thr Thr Thr Arg
420425430
Asn Thr Ile Asn Ser Trp Asp Leu Asn Asp Ser Leu Ala Ser Gly Ser
435440445
Gly Pro Leu Gly Met Pro Asp Ile Ser Glu Ile Lys Glu Glu Glu Leu
450455460
Arg Ser Thr Thr Val Ile Ser Gln His Ala Thr Gly Ser Gln Ala Val
465470475480
Ile Thr Glu Asp Thr Gln Thr His Glu Ser Val Ser Gln Ile Glu Gln
485490495
Ile Glu Val Gly Pro Leu Val Thr Ser Met Glu Ile Thr Asn His Ile
500505510
Ser Leu Lys Glu Leu Pro Glu Lys Asn Lys Thr Pro Tyr Glu Ser Thr
515520525
Glu Val Thr Leu Glu His Thr Thr Glu Met Pro Thr Val Ser Ala Ser
530535540
Pro Glu Leu Ala Thr Thr Ser His Tyr Gly Phe Thr Leu Arg Glu Asp
545550555560
Asp Arg Glu Asp Arg Thr Leu Thr Val Arg Ser Asp Gln Ser Thr Arg
565570575
Val Phe Ser Gln Ile Pro Glu Val Ile Thr Val Ser Lys Thr Ser Glu
580585590
Asp Thr Thr Tyr Ser Gln Leu Gly Asp Leu Glu Ser Ile Ser Thr Ser
595600605
Thr Ile Thr Met Leu Gly Thr Asp Arg Ser Leu Ile Asp Lys Glu Lys
610615620
Glu Pro Lys Thr Asn Gly Lys Val Thr Glu Asp Glu Phe Gly Gln Ser
625630635640
Gln Pro Thr Thr Thr Phe Pro Ser Gln His Leu Thr Glu Val Glu Leu
645650655
Leu Pro Tyr Ser Gly Asp Thr Thr Ser Val Glu Gly Ile Ser Thr Val
660665670
Ile Tyr Pro Ser Leu Gln Thr Asp Val Thr Gln Gly Arg Glu Arg Thr
675680685
Glu Thr Pro Arg Pro Glu Leu Lys Lys Asp Pro Tyr Thr Val Asp Glu
690695700
Ile Pro Glu Lys Val Thr Lys Asp Pro Phe Ile Gly Lys Thr Glu Glu
705710715720
Val Phe Ser Gly Met Pro Leu Ser Thr Ser Ser Ser Glu Ser Ser Val
725730735
Glu Arg Thr Glu Ser Val Ser Pro Ala Leu Thr Ile Glu Lys Leu Thr
740745750
Gly Lys Pro Thr Glu Ala Arg Asp Val Glu Glu Met Thr Thr Leu Thr
755760765
Arg Leu Glu Thr Asp Val Thr Lys Ser Asp Lys Asp Val Thr Arg Val
770775780
His Leu Thr His Ser Thr Leu Asn Val Glu Val Val Thr Val Ser Lys
785790795800
Trp Pro Gly Asp Glu Asp Asn Ser Thr Ser Lys Pro Leu Pro Ser Thr
805810815
Glu His Ala Gly Phe Thr Lys Leu Pro Pro Val Pro Leu Ser Thr Ile
820825830
Gly Ile Asn Gly Lys Asp Lys Glu Ile Pro Ser Phe Thr Asp Gly Gly
835840845
Gly Glu Tyr Thr Leu Phe Pro Asp Gly Thr Pro Lys Pro Leu Glu Lys
850855860
Val Ser Glu Glu Asp Leu Ala Ser Gly Glu Leu Thr Val Thr Phe His
865870875880
Thr Ser Thr Ser Ile Gly Ser Ala Glu Lys Ser Ala Ser Gly Glu Pro
885890895
Thr Thr Gly Asp Arg Phe Leu Pro Thr Thr Ser Thr Glu Asp Gln Val
900905910
Ile Asn Ala Thr Ala Glu Gly Ser Ala Leu Gly Glu Asp Thr Glu Ala
915920925
Ser Lys Pro Leu Phe Thr Gly Pro Pro Phe Val His Thr Ser Asp Val
930935940
Glu Glu Leu Ala Phe Val Asn Tyr Ser Ser Thr Gln Glu Pro Thr Thr
945950955960
Tyr Val Asp Ile Ser His Thr Ser Pro Leu Ser Ile Ile Pro Lys Thr
965970975
Glu Trp Ser Val Leu Glu Thr Ser Val Pro Leu Glu Asp Glu Ile Leu
980985990
Gly Lys Ser Asp Gln Asp Ile Leu Glu Gln Thr His Leu Glu Ala Thr
99510001005
Met Ser Pro Gly Ala Leu Arg Thr Thr Gly Val Ser Gln Gly Glu Thr
101010151020
Gln Glu Glu Pro Gln Thr Pro Gly Ser Pro Phe Pro Thr Phe Ser Ser
1025103010351040
Thr Ala Val Met Ala Lys Glu Thr Thr Ala Phe Glu Glu Gly Glu Gly
104510501055
Ser Thr Tyr Thr Pro Ser Glu Gly Arg Leu Met Thr Gly Ser Glu Arg
106010651070
Val Pro Gly Leu Glu Thr Thr Pro Val Gly Thr Ser Tyr Pro Pro Gly
107510801085
Ala Ile Thr Asp Gln Glu Val Glu Met Asp Thr Met Val Thr Leu Met
109010951100
Ser Thr Ile Arg Pro Thr Val Val Ser Ser Thr Glu Ser Glu Val Ile
1105111011151120
Tyr Glu Ala Glu Gly Ser Ser Pro Thr Glu Phe Ala Ser Thr Leu Arg
112511301135
Pro Phe Gln Thr His Val Thr Gln Leu Met Glu Glu Thr Thr Glu Glu
114011451150
Gly Lys Lys Ala Ser Leu Asp Tyr Thr Asp Leu Gly Ser Gly Leu Phe
115511601165
Glu Pro Arg Ala Thr Glu Leu Pro Lys Phe Pro Ser Thr Pro Ser Asp
11701175 1180
Ile Ser Val Phe Thr Ala Ile Asp Ser Leu His Arg Thr Pro Pro Leu
1185119011951200
Ser Pro Ser Ser Ser Phe Thr Glu Glu Gln Arg Val Phe Glu Glu Glu
120512101215
Ser Ser Glu Lys Thr Thr Gly Asp Ile Leu Pro Gly Glu Ser Val Thr
122012251230
Gln His Pro Val Thr Thr Leu Ile Asp Ile Val Ala Met Lys Thr Glu
123512401245
Ser Asp Ile Asp His Met Thr Ser Lys Pro Pro Val Thr Gln Pro Thr
125012551260
Arg Pro Ser Val Val Glu Arg Lys Thr Thr Ser Lys Thr Gln Glu Leu
1265127012751280
Ser Thr Ser Thr Pro Ala Ala Gly Thr Lys Phe His Pro Asp Ile Asn
128512901295
Val Tyr Ile Ile Glu Val Arg Glu Asn Lys Thr Gly Arg Leu Ser Asp
130013051310
Met Ile Val Ser Gly His Pro Ile Asp Ser Glu Ser Lys Glu Glu Glu
131513201325
Pro Cys Ser Glu Glu Thr Asp Pro Leu His Asp Leu Phe Ala Glu Ile
133013351340
Leu Pro Glu Leu Pro Asp Ser Phe Glu Ile Asp Ile Tyr His Ser Glu
1345135013551360
Glu Asp Glu Asp Gly Glu Glu Asp Cys Val Asn Ala Thr Asp Val Thr
136513701375
Thr Thr Pro Ser Val Gln Tyr Ile Asn Gly Lys Gln Leu Val Thr Thr
138013851390
Val Pro Lys Asp Pro Glu Ala Ala Glu Ala Arg Arg Gly Gln Tyr Glu
139514001405
Ser Val Ala Pro Ser Gln Asn Phe Pro Asp Ser Ser Ala Thr Asp Thr
141014151420
His Gln Phe Ile Leu Ala Glu Thr Glu Ser Ser Thr Thr Met Gln Phe
1425143014351440
Lys Lys Ser Lys Glu Gly Thr Glu Leu Leu Glu Ile Thr Trp Lys Pro
144514501455
Glu Thr Tyr Pro Glu Thr Pro Asp His Val Ser Ser Gly Glu Pro Asp
146014651470
Val Phe Pro Thr Leu Ser Ser His Asp Gly Lys Thr Thr Arg Trp Ser
147514801485
Glu Ser Ile Thr Glu Ser Ser Pro Asn Leu Glu Asn Pro Val His Lys
1490 14951500
Gln Pro Lys Pro Val Pro Leu Phe Pro Glu Glu Ser Ser Gly Glu Gly
1505151015151520
Ala Ile Glu Gln Ala Ser Gln Glu Thr Ile Leu Ser Arg Ala Thr Glu
152515301535
Val Ala Leu Gly Lys Glu Thr Asp Gln Ser Pro Thr Leu Ser Thr Ser
154015451550
Ser Ile Leu Ser Ser Ser Val Ser Val Asn Val Leu Glu Glu Glu Pro
155515601565
Leu Thr Leu Thr Gly Ile Ser Gln Thr Asp Glu Ser Met Ser Thr Ile
157015751580
Glu Ser Trp Val Glu Ile Thr Pro Ser Gln Thr Val Lys Phe Ser Glu
1585159015951600
Ser Ser Ser Ala Pro Ile Ile Glu Gly Ser Gly Glu Val Glu Glu Asn
160516101615
Lys Asn Lys Ile Phe Asn Met Val Thr Asp Leu Pro Gln Arg Asp Pro
162016251630
Thr Asp Thr Leu Ser Pro Leu Asp Met Ser Lys Ile Met Ile Thr Asn
163516401645
His His Ile Tyr Ile Pro Ala Thr Ile Ala Pro Leu Asp Ser Lys Leu
165016551660
Pro Ser Pro Asp Ala Arg Pro Thr Thr Val Trp Asn Ser Asn Ser Thr
1665167016751680
Ser Glu Trp Val Ser Asp Lys Ser Phe Glu Gly Arg Lys Lys Lys Glu
168516901695
Asn Glu Asp Glu Glu Gly Ala Val Asn Ala Ala His Gln Gly Glu Val
170017051710
Arg Ala Ala Thr Glu Arg Ser Asp His Leu Leu Leu Thr Pro Glu Leu
171517201725
Glu Ser Ser Asn Val Asp Ala Ser Ser Asp Leu Ala Thr Trp Glu Gly
173017351740
Phe Ile Leu Glu Thr Thr Pro Thr Glu Ser Glu Lys Glu Met Ala Asn
1745175017551760
Ser Thr Pro Val Phe Arg Glu Thr Ile Gly Val Ala Asn Val Glu Ala
176517701775
Gln Pro Phe Glu His Ser Ser Ser Ser His Pro Arg Val Gln Glu Glu
178017851790
Leu Thr Thr Leu Ser Gly Asn Pro Pro Ser Leu Phe Thr Asp Leu Gly
179518001805
Ser Gly Asp Ala Ser Thr Gly Met Glu Leu Ile Thr Ala Ser Leu Phe
181018151820
Thr Leu Asp Leu Glu Ser Glu Thr Lys Val Lys Lys Glu Leu Pro Ser
1825183018351840
Thr Pro Ser Pro Ser Val Glu Ile Ser Ser Ser Phe Glu Pro Thr Gly
184518501855
Leu Thr Pro Ser Thr Val Leu Asp Ile Glu Ile Ala Gly Val Met Ser
186018651870
Gln Thr Ser Gln Lys Thr Leu Ile Ser Glu Ile Ser Gly Lys Pro Thr
187518801885
Ser Gln Ser Gly Val Arg Asp Leu Tyr Thr Gly Phe Pro Met Gly Glu
189018951900
Asp Phe Ser Gly Asp Phe Ser Glu Tyr Pro Thr Val Ser Tyr Pro Thr
1905191019151920
Met Lys Glu Glu Thr Val Gly Met Gly Gly Ser Asp Asp Glu Arg Val
192519301935
Arg Asp Thr Gln Thr Ser Ser Ser Ile Pro Thr Thr Ser Asp Asn Ile
194019451950
Tyr Pro Val Pro Asp Ser Lys Gly Pro Asp Ser Thr Val Ala Ser Thr
195519601965
Thr Ala Phe Pro Trp Glu Glu Val Met Ser Ser Ala Glu Gly Ser Gly
197019751980
Glu Gln Leu Ala Ser Val Arg Ser Ser Val Gly Pro Val Leu Pro Leu
1985199019952000
Ala Val Asp Ile Phe Ser Gly Thr Glu Ser Pro Tyr Phe Asp Glu Glu
200520102015
Phe Glu Glu Val Ala Ala Val Thr Glu Ala Asn Glu Arg Pro Thr Val
202020252030
Leu Pro Thr Ala Ala Ser Gly Asn Thr Val Asp Leu Thr Glu Asn Gly
203520402045
Tyr Ile Glu Val Asn Ser Thr Met Ser Leu Asp Phe Pro Gln Thr Met
205020552060
Glu Pro Ser Lys Leu Trp Ser Lys Pro Glu Val Asn Leu Asp Lys Gln
2065207020752080
Glu Ile Gly Arg Glu Thr Val Thr Lys Glu Lys Ala Gln Gly Gln Lys
208520902095
Thr Phe Glu Ser Leu His Ser Ser Phe Ala Pro Glu Gln Thr Ile Leu
210021052110
Glu Thr Gln Ser Leu Ile Glu Thr Glu Phe Gln Thr Ser Asp Tyr Ser
211521202125
Met Leu Thr Thr Leu Lys Thr Tyr Ile Thr Asn Lys Glu Val Glu Glu
213021352140
Glu Gly Met Ser Ile Ala His Met Ser Thr Pro Gly Pro Gly Ile Lys
2145215021552160
Asp Leu Glu Ser Tyr Thr Thr His Pro Glu Ala Pro Gly Lys Ser His
216521702175
Ser Phe Ser Ala Thr Ala Leu Val Thr Glu Ser Gly Ala Ala Arg Ser
218021852190
Val Leu Met Asp Ser Ser Thr Gln Glu Glu Glu Ser Ile Lys Leu Phe
219522002205
Gln Lys Gly Val Lys Leu Thr Asn Lys Glu Ser Asn Ala Asp Leu Ser
221022152220
Phe Ser Gly Leu Gly Ser Gly Gly Ala Leu Pro Pro Leu Pro Thr Thr
2225223022352240
Ser Val Asn Leu Thr Asp Met Lys Gln Ile Ile Ser Thr Leu Tyr Ala
224522502255
Glu Thr Ser His Met Glu Ser Leu Gly Thr Ser Ile Leu Gly Asp Lys
226022652270
Met Glu Asp His Glu Arg Met Glu Asp Val Ser Ser Asn Glu Val Arg
227522802285
Met Leu Ile Ser Lys Ile Gly Ser Ile Ser Gln Asp Ser Thr Glu Ala
229022952300
Leu Asp Thr Thr Leu Ser His Thr Gly Thr Glu Glu Pro Thr Thr Ser
2305231023152320
Thr Leu Pro Phe Val Lys Leu Met Asp Leu Glu Arg Ser Pro Lys Gln
232523302335
Asp Pro Ser Gly Gly Lys Arg Lys Pro Lys Thr His Arg Pro Gln Thr
234023452350
Met Ser Gly Leu Ile Ser Asn Glu Asn Ser Ser Ala Ser Glu Ala Glu
235523602365
Glu Gly Ala Thr Ser Pro Thr Ala Phe Leu Pro Gln Thr Tyr Ser Val
237023752380
Glu Met Thr Lys His Phe Ala Pro Ser Glu Ser Gln Pro Ser Asp Leu
2385239023952400
Phe Asn Val Asn Ser Gly Glu Gly Ser Gly Glu Val Asp Thr Leu Asp
240524102415
Leu Val Tyr Thr Ser Gly Thr Thr Gln Ala Ser Ser Gln Gly Asp Ser
242024252430
Met Leu Ala Ser His Gly Phe Leu Glu Lys His Pro Glu Val Ser Lys
243524402445
Thr Glu Ala Gly Ala Thr Asp Val Ser Pro Thr Ala Ser Ala Met Phe
245024552460
Leu His His Ser Glu Tyr Lys Ser Ser Leu Tyr Pro Thr Ser Thr Leu
2465247024752480
Pro Ser Thr Glu Pro Tyr Lys Ser Pro Ser Glu Gly Ile Glu Asp Gly
248524902495
Leu Gln Asp Asn Ile Gln Phe Glu Gly Ser Thr Leu Lys Pro Ser Arg
250025052510
Arg Lys Thr Thr Glu Ser Ile Ile Ile Asp Leu Asp Lys Glu Asp Ser
251525202525
Lys Asp Leu Gly Leu Thr Ile Thr Glu Ser Ala Ile Val Lys Ser Leu
253025352540
Pro Glu Leu Thr Ser Asp Lys Asn Ile Ile Ile Asp Ile Asp His Thr
2545255025552560
Lys Pro Val Tyr Glu Tyr Ile Pro Gly Ile Gln Thr Asp Leu Asp Pro
256525702575
Glu Ile Lys Leu Glu Ser His Gly Ser Ser Glu Glu Ser Leu Gln Val
258025852590
Gln Glu Lys Tyr Glu Gly Ala Val Thr Leu Ser Pro Thr Glu Glu Ser
259526002605
Phe Glu Gly Ser Gly Asp Ala Leu Leu Ala Gly Tyr Thr Gln Ala Ile
261026152620
Tyr Asn Glu Ser Val Thr Pro Asn Asp Gly Lys Gln Ala Glu Asp Ile
2625263026352640
Ser Phe Ser Phe Ala Thr Gly Ile Pro Val Ser Ser Thr Glu Thr Glu
264526502655
Leu His Thr Phe Phe Pro Thr Ala Ser Thr Leu His Ile Pro Ser Lys
266026652670
Leu Thr Thr Ala Ser Pro Glu Ile Asp Lys Pro Asn Ile Glu Ala Ile
267526802685
Ser Leu Asp Asp Ile Phe Glu Ser Ser Thr Leu Ser Asp Gly Gln Ala
269026952700
Ile Ala Asp Gln Ser Glu Val Ile Ser Thr Leu Gly His Leu Glu Lys
2705271027152720
Thr Gln Glu Glu Tyr Glu Glu Lys Lys Tyr Gly Gly Pro Ser Phe Gln
272527302735
Pro Glu Phe Phe Ser Gly Val Gly Glu Val Leu Thr Asp Pro Pro Ala
274027452750
Tyr Val Ser Ile Gly Ser Thr Tyr Leu Ile Ala Gln Thr Leu Thr Glu
275527602765
Leu Pro Asn Val Val Arg Pro Ser Asp Ser Thr His Tyr Thr Glu Ala
277027752780
Thr Pro Glu Val Ser Ser Leu Ala Glu Leu Ser Pro Gln Ile Pro Ser
2785279027952800
Ser Pro Phe Pro Val Tyr Val Asp Asn Gly Val Ser Lys Phe Pro Glu
280528102815
Val Pro His Thr Ser Ala Gln Pro Val Ser Thr Val Thr Ser Ser Gln
282028252830
Lys Ser Ile Glu Ser Pro Phe Lys Glu Val His Ala Asn Ile Glu Glu
283528402845
Thr Ile Lys Pro Leu Gly Gly Asn Val His Arg Thr Glu Pro Pro Ser
285028552860
Met Ser Arg Asp Pro Ala Leu Asp Val Ser Glu Asp Glu Ser Lys His
2865287028752880
Lys Leu Leu Glu Glu Leu Glu Thr Ser Pro Thr Lys Pro Glu Thr Ser
288528902895
Gln Asp Phe Pro Asn Lys Ala Lys Asp His Ile Pro Gly Glu Thr Val
290029052910
Gly Met Leu Ala Gly Ile Arg Thr Thr Glu Ser Glu Pro Val Ile Thr
291529202925
Ala Asp Asp Met Glu Leu Gly Gly Ala Thr Gln Gln Pro His Ser Ala
293029352940
Ser Ala Ala Phe Arg Val Glu Thr Gly Met Val Pro Gln Pro Ile Gln
2945295029552960
Gln Glu Pro Glu Arg Pro Thr Phe Pro Ser Leu Glu Ile Asn His Glu
296529702975
Thr His Thr Ser Leu Phe Gly Glu Ser Ile Leu Ala Thr Ser Glu Lys
298029852990
Gln Val Ser Gln Lys Ile Leu Asp Asn Ser Asn Gln Ala Thr Val Ser
299530003005
Ser Thr Leu Asp Leu His Thr Ala His Ala Leu Ser Pro Phe Ser Ile
301030153020
Leu Asp Asn Ser Asn Glu Thr Ala Phe Leu Ile Gly Ile Ser Glu Glu
3025303030353040
Ser Val Glu Gly Thr Ala Val Tyr Leu Pro Gly Pro Asp Leu Cys Lys
304530503055
Thr Asn Pro Cys Leu Asn Gly Gly Thr Cys Tyr Pro Thr Glu Thr Ser
306030653070
Tyr Val Cys Thr Cys Ala Pro Gly Tyr Ser Gly Asp Gln Cys Glu Leu
307530803085
Asp Phe Asp Glu Cys His Ser Asn Pro Cys Arg Asn Gly Ala Thr Cys
309030953100
Val Asp Gly Phe Asn Thr Phe Arg Cys Leu Cys Leu Pro Ser Tyr Val
3105311031153120
Gly Ala Leu Cys Glu Gln Asp Thr Glu Thr Cys Asp Tyr Gly Trp His
312531303135
Lys Phe Gln Gly Gln Cys Tyr Lys Tyr Phe Ala His Arg Arg Thr Trp
314031453150
Asp Ala Ala Glu Arg Glu Cys Arg Leu Gln Gly Ala His Leu Thr Ser
315531603165
Ile Leu Ser His Glu Glu Gln Met Phe Val Asn Arg Val Gly His Asp
317031753180
Tyr Gln Trp Ile Gly Leu Asn Asp Lys Met Phe Glu His Asp Phe Arg
3185319031953200
Trp Thr Asp Gly Ser Ala Leu Gln Tyr Glu Asn Trp Arg Pro Asn Gln
320532103215
Pro Asp Ser Phe Phe Ser Ala Gly Glu Asp Cys Val Val Ile Ile Trp
322032253230
His Glu Asn Gly Gln Trp Asn Asp Val Pro Cys Asn Tyr His Leu Thr
323532403245
Tyr Thr Cys Lys Lys Gly Thr Val Ala Cys Gly Gln Pro Pro Val Val
325032553260
Glu Asn Ala Lys Thr Phe Gly Lys Met Lys Pro Arg Tyr Glu Ile Asn
3265327032753280
Ser Leu Ile Arg Tyr His Cys Lys Asp Gly Phe Ile Gln Arg His Leu
328532903295
Pro Thr Ile Arg Cys Leu Gly Asn Gly Arg Trp Ala Met Pro Lys Ile
330033053310
Thr Cys Met Asn Pro Ser Ala Tyr Gln Arg Thr Tyr Ser Lys Lys Tyr
331533203325
Leu Lys Asn Ser Ser Ser Ala Lys Asp Asn Ser Ile Asn Thr Ser Lys
333033353340
His Glu His Arg Trp Ser Arg Arg Gln Glu Thr Arg Arg
334533503355
<210> 297
<211> 2738
<212> PRT
<213> Rattus norvegicus
<220>
<223> RAT VERSICAN Q9ERB4
<400> 297
Met Leu Ile Asn Met Asn Gly Ile Leu Trp Met Cys Ser Thr Leu Leu
151015
Leu Thr His Ala Leu His Lys Ala Lys Met Glu Glu Asn Pro Pro Val
202530
Lys Gly Ser Leu Ser Gly Lys Val Ile Leu Pro Cys His Phe Ser Thr
354045
Leu Pro Thr Leu Pro Pro Asp Tyr Asn Thr Ser Glu Phe Leu Arg Ile
505560
Lys Trp Ser Lys Ile Glu Val Asp Lys Asn Gly Lys Asp Ile Lys Glu
65707580
Thr Thr Val Leu Val Ala Gln Asp Gly Asn Ile Lys Ile Gly Gln Asp
859095
Tyr Lys Gly Arg Val Ser Val Pro Thr His Pro Asp Asp Val Gly Asp
100105110
Ala Ser Leu Thr Met Val Lys Leu Arg Ala Ser Asp Ala Gly Val Tyr
115120125
Arg Cys Asp Val Met Tyr Gly Ile Glu Asp Thr Gln Asn Thr Met Ser
130135140
Leu Ala Val Asp Gly Val Val Phe His Tyr Arg Ala Ala Thr Ser Arg
145150155160
Tyr Thr Leu Asn Phe Glu Ser Ala Gln Gln Ala Cys Leu Asp Ile Gly
165170175
Ala Val Ile Ala Thr Pro Glu Gln Leu Phe Ala Ala Tyr Glu Asp Gly
180185190
Phe Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp Gln Thr Val Arg Tyr
195200205
Pro Ile Arg Ala Pro Arg Glu Gly Cys Tyr Gly Asp Met Met Gly Lys
210215220
Glu Gly Val Arg Thr Tyr Gly Phe Arg Ser Pro Gln Glu Thr Tyr Asp
225230235240
Val Tyr Cys Tyr Val Asp His Leu Asp Gly Asp Val Phe His Ile Thr
245250255
Ala Pro Ser Lys Phe Thr Phe Glu Glu Ala Glu Ala Glu Cys Ala Asn
260265270
Arg Asp Ala Arg Leu Ala Thr Val Gly Glu Leu His Ala Ala Trp Arg
275280285
Asn Gly Phe Asp Gln Cys Asp Tyr Gly Trp Leu Ser Asp Ala Ser Val
290295300
Arg His Pro Val Thr Val Ala Arg Ala Gln Cys Gly Gly Gly Leu Leu
305310315320
Gly Val Arg Thr Leu Tyr Arg Phe Glu Asn Gln Thr Cys Phe Pro Leu
325330335
Pro Asp Ser Arg Phe Asp Ala Tyr Cys Phe Lys Arg Ser Pro Leu Ser
340345350
Ile Ile Pro Lys Thr Glu Trp Ser Val Ser Glu Thr Ser Val Pro Leu
355360365
Glu Asp Glu Val Leu Gly Lys Ser Asp Gln Asp Thr Leu Glu Gln Thr
370375380
His Leu Glu Ala Thr Met Ser Pro Glu Ala Leu Ser Thr Ile Glu Val
385390395400
Thr Gln Gly Glu Thr Gln Glu Glu Pro Gln Thr Pro Gly Ile Pro Phe
405410415
Pro Ala Leu Ser Ser Thr Ala Val Met Thr Lys Glu Thr Thr Ala Phe
420425430
Glu Glu Glu Gly Glu Gly Ser Thr Tyr Thr Leu Ser Glu Asp Arg Leu
435440445
Met Thr Asp Ser Glu Ile Val Pro Ser Leu Glu Thr Thr Pro Val Gly
450455460
Thr Ser Tyr Pro Gly Gly Ala Met Thr Gln Gln Glu Val Glu Met Asp
465470475480
Thr Met Val Thr Gln Met Ser Ser Ile Arg Pro Thr Val Val Leu Ser
485490495
Thr Glu Pro Glu Val Ser Tyr Glu Ala Glu Gly Ser Ser Pro Met Glu
500505510
Phe Ala Ser Thr Leu Lys Pro Phe Gly Thr Gln Val Thr Gln Leu Val
515520525
Glu Glu Thr Thr Glu Glu Gly Lys Lys Thr Pro Leu Asp Tyr Thr Asp
530535540
Leu Gly Ser Gly Leu Phe Glu Gln Pro Arg Val Thr Glu Leu Pro Asp
545550555560
Phe Ser Met Thr Pro Ser Asp Ile Ser Val Phe Thr Ala Ile Asp Ser
565570575
Leu His Arg Thr Thr Pro Leu Arg Pro Pro Ser Pro Phe Thr Glu Glu
580585590
Pro His Ile Phe Glu Lys Glu Pro Ser Glu Lys Thr Thr Gly Asp Ile
595600605
Ile Leu Pro Arg Glu Ser Val Thr Gln His Pro Leu Thr Thr Leu Met
610615620
Asp Ile Ile Ala Lys Lys Thr Glu Ser Asp Ile Asp His Glu Tyr His
625630635640
Met Thr Ser Lys Pro Pro Val Met Gln Pro Thr Arg Pro Ser Val Val
645650655
Glu Arg Lys Thr Thr Ser Lys Pro Gln Glu Leu Ser Thr Ser Pro Pro
660665670
Pro Ala Gly Thr Lys Phe His Pro Asp Ile Asn Val Tyr Ile Ile Glu
675680685
Val Arg Glu Asn Lys Thr Gly Arg Met Ser Asp Met Val Val Asn Gly
690695700
His Pro Ile Asp Ser Glu Ser Lys Glu Glu Glu Pro Cys Ser Glu Glu
705710715720
Thr Asp Pro Leu His Asp Leu Phe Ala Glu Ile Leu Pro Glu Leu Pro
725730735
Asp Ser Phe Glu Ile Asp Ile Tyr His Ser Glu Glu Asp Glu Asp Gly
740745750
Glu Glu Asp Cys Val Asn Ala Thr Asp Val Thr Thr Thr Pro Ser Val
755760765
Gln Tyr Ile Thr Gly Lys Pro His Val Thr Thr Val Pro Lys Asn Pro
770775780
Glu Ala Ala Glu Ala Arg Arg Gly Leu Tyr Glu Ser Val Ala Pro Ser
785790795800
Gln Asn Phe Ser Asn Thr Ser Ala Thr Asp Thr His Gln Phe Ile Pro
805810815
Ala Glu Thr Glu Leu Ser Thr Thr Met Gln Phe Thr Lys Ser Lys Glu
820825830
Ala Thr Glu Leu Leu Glu Ile Thr Trp Lys Pro Glu Thr Tyr Pro Glu
835840845
Thr Pro Glu His Phe Ser Ser Gly Glu Pro Asp Val Phe Pro Thr Leu
850855860
Pro Ser His Asp Gly Lys Thr Thr Lys Trp Ser Glu Phe Ile Thr Glu
865870875880
Ser Asn Pro Asn Thr Glu Asn Pro Glu His Lys Gln Pro Lys Pro Ile
885890895
Pro Leu Phe Pro Glu Glu Phe Ser Gly Glu Gly Ala Ile Asp Gln Ala
900905910
Ser Gln Gln Thr Ile Phe Ser Arg Ala Thr Glu Val Ala Leu Gly Lys
915920925
Glu Thr Asp Gln Ser Pro Thr Ile Ser Thr Ser Ser Ile Arg Ser Gly
930935940
Ser Val Ser Val His Ala Leu Glu Glu Asp Pro Ile Ala Leu Thr Gly
945950955960
Ile Ser Gln Thr Asp Glu Ser Met Ser Thr Val Glu Ser Trp Val Glu
965970975
Met Thr Pro Ser Gln Thr Val Glu Phe Ser Gly Ser Ser Ser Ala Pro
980985990
Thr Ile Glu Gly Ser Gly Glu Val Glu Glu Tyr Thr Asn Lys Ile Phe
99510001005
Asn Thr Val Thr Asp Leu Pro Gln Arg Glu Pro Thr Asp Thr Leu Ile
101010151020
Pro Leu Asp Met Ser Asn Ile Met Ile Thr Asp His His Ile Tyr Thr
1025103010351040
Pro Ala Thr Thr Ala Pro Leu Asp Ser Gln Leu Pro Ser Thr Asp Ala
104510501055
Arg Pro Thr Gln Phe Gly Ile Gln Thr Thr Thr Ser Glu Trp Val Ser
106010651070
Ser Thr Ser Phe Glu Gly Arg Lys Thr Glu Glu Asp Lys Glu Arg Asp
107510801085
Thr Asn Ala Ala His Thr Gly Glu Val Gln Pro Ala Thr Glu Arg Ser
109010951100
Asp Arg Leu Leu Leu Thr Ser Glu Leu Glu Ser Ser Asn Val Ala Ala
1105111011151120
Ser Ser Pro Leu Asp Thr Trp Glu Gly Phe Val Pro Glu Thr Thr Ser
112511301135
Thr Val Ser Glu Lys Glu Met Ala Asn Thr Thr Pro Val Phe Thr Glu
114011451150
Thr Ser Asp Val Ala Asn Leu Glu Thr Gln Ser Phe Glu His Ser Ser
115511601165
Ser Ser Gln Pro Arg Val Gln Glu Glu Leu Thr Thr Leu Ser Gly Lys
117011751180
Pro Pro Leu Ile Phe Met Asp Leu Gly Ser Gly Asp Ala Ser Thr Asp
1185119011951200
Met Glu Phe Ile Thr Ala Ser Ser Phe Thr Leu Asp Leu Glu Ser Asp
120512101215
Thr Lys Val Lys Lys Glu Leu Pro Ser Thr Leu Ser Pro Ser Val Glu
122012251230
Thr Ser Ser Ser Ser Glu Pro Ile Gly Leu Ala Pro Ser Thr Val Leu
123512401245
Asp Ile Glu Ile Val Glu Val Met Asn Gln Thr Ser Lys Lys Thr Leu
125012551260
Ile Ser Glu Leu Ser Gly Lys Pro Thr Ser Gln Ala Glu Val Arg Asp
1265127012751280
Leu Tyr Pro Gly Leu Gly Glu Asp Phe Ser Gly Asp Ser Ser Glu Tyr
128512901295
Pro Thr Val Ser Ser Thr Thr Met Lys Glu Glu Thr Val Gly Met Gly
130013051310
Gly Ser Glu Asn Glu Arg Val Lys Asp Thr Gln Thr Leu Ser Ser Ile
131513201325
Pro Pro Thr Ser Asp Asn Ile Asn Pro Val Pro Asp Ser Lys Gly Phe
133013351340
Gly Ser Thr Val Ala Ser Thr Thr Ala Phe Pro Trp Glu Glu Phe Met
1345135013551360
Thr Ser Ala Glu Gly Ser Gly Glu Glu Leu Ser Ser Val Arg Ser Ser
136513701375
Val Ser Leu Val Leu Pro Leu Gly Val Asp Ile Leu Pro Thr Thr Glu
138013851390
Ser Pro Tyr Phe Asp Gln Glu Phe Glu Glu Ala Ala Ala Val Thr Glu
139514001405
Ala Gly Lys Gln Ser Ala Leu Pro Ile Ala Val Ser Gly Asn Thr Val
141014151420
Asp Leu Thr Glu Asn Arg Asp Ile Glu Val Asn Ser Thr Met Ser Val
1425143014351440
Asp Leu Pro Gln Thr Met Glu Pro Ala Lys Leu Trp Ser Lys Pro Glu
144514501455
Val Asn Pro Glu Lys Gln Glu Ile Gly Ser Glu Thr Val Thr Gln Asp
146014651470
Lys Ala Gln Gly Gln Lys Ser Phe Glu Ser Leu His Ser Ser Leu Ala
147514801485
Pro Glu Gln Thr Thr Leu Glu Ser Gln Ser Leu Ile Glu Thr Glu Val
149014951500
Gln Thr Ser Tyr Tyr Ser Met Leu Thr Thr Met Lys Thr Tyr Asn Thr
1505151015151520
Asn Glu Glu Val Glu Glu Glu Gly Thr Ser Ile Ala His Met Ser Thr
152515301535
Pro Gly Pro Gly Ile Lys Gly Leu Glu Ser Tyr Pro Thr His Pro Glu
154015451550
Ala Thr Gly Lys Ser Tyr Ser Phe Ser Ala Ser Ala Leu Val Thr Glu
155515601565
Ser Gly Pro Ala Arg Ser Val Val Met Asp Ser Ser Thr Gln Glu Glu
157015751580
Glu Ser Ile Lys Leu Phe Gln Lys Asp Met Ile Leu Thr His Lys Glu
1585159015951600
Ser Asn Ser Asp Leu Ser Phe Ser Gly Leu Gly Ser Gly Glu Ala Leu
160516101615
Pro Pro Leu Pro Thr Thr Ser Val Ser Leu Thr Asp Met Gly Lys Ile
162016251630
Asn Ser Thr Leu Tyr Pro Glu Thr Ser His Met Glu Ser Leu Gly Thr
163516401645
Ser Ile Leu Gly Asp Asn His Glu Arg Met Lys Asn Val Ser Asn Glu
165016551660
Val Arg Thr Leu Ile Ser Glu Thr Gly Ser Ile Ser Gln Asp Ser Thr
1665167016751680
Glu Ala Pro Asn Thr Thr Leu Ser Asp Thr Arg Thr Glu Glu Ser Thr
168516901695
Thr Ser Pro Leu Pro Phe Met Lys Leu Met Asp Thr Glu His Ser Pro
170017051710
Lys Gln Thr Leu Arg Trp Glu Glu Glu Ile Gln Thr His Arg Pro Gln
171517201725
Thr Met Thr Gly Gln Met Thr Asn Asp Asn Ser Ser Val Ser Glu Ala
173017351740
Glu Ala Ala Ala Thr Ser Ala Pro Ala Phe Leu Pro Glu Thr Tyr Ser
1745175017551760
Val Glu Met Thr Lys Ala Phe Ala Thr Ser Pro Ser Gln Thr Ser Asp
176517701775
Leu Phe Asp Ala Asn Ser Gly Glu Gly Ser Gly Glu Val Asp Gly Leu
178017851790
Asp Leu Val Tyr Thr Ser Arg Thr Thr Gln Ala Ser Ser Gln Gly Asp
179518001805
Ser Met Phe Ala Ser His Gly Phe Ile Glu Lys His Pro Glu Val Ser
181018151820
Arg Thr Glu Thr Gly Ala Thr Asp Gly Ser Pro Thr Ala Ser Ala Met
1825183018351840
Phe Leu His Gln Ser Glu Tyr Asn Glu Ser Ser Leu Tyr Pro Thr Ser
184518501855
Thr Leu Pro Ser Thr Val Thr Tyr Glu Ser Pro Ser Glu Gly Ile Ala
186018651870
Asp Gly Leu Gln Asp His Ile Arg Phe Glu Val Ser Thr Leu Lys Pro
187518801885
Ser Arg Arg Lys Ala Thr Glu Ser Val Ile Ile Asp Leu Asp Lys Glu
189018951900
Asp Ser Lys Asp Leu Gly Leu Ala Ile Thr Glu Ser Ala Ile Val Glu
1905191019151920
Ile Leu Pro Glu Leu Thr Ser Asp Arg Asn Ile Ile Ile Asp Ile Asp
192519301935
His Thr Lys Pro Val Tyr Glu Tyr Ile Pro Gly Ile Gln Thr Asp Leu
194019451950
Asp Ser Asp Ile Pro Leu Gly Ser His Gly Ser Ser Glu Glu Ser Leu
195519601965
Glu Val Gln Glu Lys Tyr Glu Ala Thr Ile Asn Leu Ser Pro Thr Glu
197019751980
Glu Ala Phe Asp Gly Ser Gly Asp Ala Leu Pro Ala Gly His Thr Gln
1985199019952000
Ala Ile Tyr Asn Glu Ser Val Thr Pro Ser Asp Gly Lys Gln Pro Glu
200520102015
Asp Ile Ser Phe Ser Phe Ala Thr Gly Ile Pro Val Ser Ser Thr Glu
202020252030
Thr Glu Leu Asn Thr Phe Phe Pro Thr Val Ser Thr Leu His Ile Pro
203520402045
Ser Lys Leu Thr Thr Ala Ser Pro Glu Ile Asp Lys Pro Asn Ile Glu
205020552060
Ala Ile Ser Leu Asp Asp Ile Phe Glu Ser Ser Thr Leu Ser Asp Gly
2065207020752080
Gln Ala Ile Ala Asp Gln Ser Glu Val Ile Ser Thr Leu Gly His Leu
208520902095
Glu Lys Thr Gln Glu Glu Tyr Glu Glu Lys Lys Tyr Gly Gly Pro Ser
210021052110
Phe Gln Pro Glu Phe Phe Ser Gly Val Gly Glu Val Phe Thr Asp Ala
211521202125
Pro Ala Tyr Val Ser Ile Gly Arg Thr Tyr Ser Val Ala Gln Pro Leu
213021352140
Thr Glu Phe Pro Asn Val Val Gly Gln Ser Asp Ser Thr His Tyr Thr
2145215021552160
Glu Ala Thr Ser Ala Val Ser Ser Val Thr Glu Leu Ser Pro Gln Thr
216521702175
Pro Ser Ser Pro Ser Pro Val Tyr Ile Asp Ser Gly Val Ser Glu Phe
218021852190
Thr Glu Val Pro His Lys Ser Ala Gln Pro Ala Pro Thr Ala Ala Ser
219522002205
Ser Gln Lys Leu Ile Glu Gly Ser Phe Lys Lys Val Arg Ala Asn Ile
221022152220
Glu Ala Thr Ile Lys Ser Leu Gly Glu Asn Asp His Gly Thr Glu Ser
2225223022352240
Pro Ser Met Ser Pro Ser Pro Ala Leu Asp Ile Ser Glu Asp Asp Ser
224522502255
Lys Pro Lys Leu Leu Glu Asp Leu Glu Thr Ser Pro Thr Lys Thr Glu
226022652270
Thr Ser Gln Asp Ser Pro Asn Lys Ala Asn Asp Gln Ile Pro Gly Lys
227522802285
Thr Ala Gly Ile Leu Ala Gly Ile Lys Thr Thr Glu Ser Gly Pro Val
229022952300
Val Thr Ala Ala Asp Asp Met Glu Leu Gly Asp Ala Thr Gln Arg Pro
2305231023152320
His Ser Ala Ser Ala Pro Ala Ala Phe Arg Val Glu Thr Ser Met Val
232523302335
Pro Gln Pro Ile Pro Gln Glu Pro Glu Arg Pro Thr Phe Pro Ser Leu
234023452350
Glu Ile Asn His Glu Thr His Thr Ser Leu Phe Glu Glu Ser Ile Leu
235523602365
Ala Thr Ser Glu Lys Gln Val Ser Gln Arg Ile Leu Asp Tyr Ser Asn
237023752380
Gln Ala Thr Val Ser Thr Leu Asp Leu Asn Thr Glu His Ser Ile Pro
2385239023952400
Pro Phe Ser Ile Leu Asp Asn Ser Asn Glu Thr Ala Phe Leu Ile Gly
240524102415
Ile Ser Glu Glu Thr Val Glu Gly Thr Ala Val Tyr Leu Pro Gly Pro
242024252430
Asp Leu Cys Lys Thr Asn Pro Cys Leu Asn Gly Gly Thr Cys Tyr Pro
243524402445
Thr Glu Thr Ser Tyr Val Cys Thr Cys Ala Pro Gly Tyr Ser Gly Asp
245024552460
Gln Cys Glu Leu Asp Phe Asp Glu Cys His Ser Asn Pro Cys Arg Asn
2465247024752480
Gly Ala Thr Cys Val Asp Gly Leu Asn Thr Phe Arg Cys Leu Cys Leu
248524902495
Pro Ser Tyr Val Gly Ala Leu Cys Glu Gln Asp Thr Glu Thr Cys Asp
250025052510
Tyr Gly Trp His Lys Phe Gln Gly Gln Cys Tyr Lys Tyr Phe Ala His
251525202525
Arg Arg Thr Trp Asp Ala Ala Glu Arg Glu Cys Arg Leu Gln Gly Ala
253025352540
His Leu Thr Ser Ile Leu Ser His Glu Glu Gln Met Phe Val Asn Arg
2545255025552560
Val Gly His Asp Tyr Gln Trp Ile Gly Leu Asn Asp Lys Met Phe Glu
256525702575
His Asp Phe Arg Trp Thr Asp Gly Ser Ala Leu Gln Tyr Glu Asn Trp
258025852590
Arg Pro Asn Gln Pro Asp Ser Phe Phe Ser Ala Gly Glu Asp Cys Val
259526002605
Val Ile Ile Trp His Glu Asn Gly Gln Trp Asn Asp Val Pro Cys Asn
261026152620
Tyr His Leu Thr Tyr Thr Cys Lys Lys Gly Thr Val Ala Cys Gly Gln
2625263026352640
Pro Pro Val Val Glu Asn Ala Lys Thr Phe Gly Lys Met Lys Pro Arg
264526502655
Tyr Glu Ile Asn Ser Leu Ile Arg Tyr His Cys Lys Asp Gly Phe Ile
266026652670
Gln Arg His Leu Pro Thr Ile Arg Cys Leu Gly Asn Gly Arg Trp Ala
267526802685
Met Pro Lys Ile Thr Cys Met Asn Pro Ser Ala Tyr Gln Arg Thr Tyr
269026952700
Ser Lys Lys Tyr Leu Lys Asn Ser Ser Ser Val Lys Asp Asn Ser Ile
2705271027152720
Asn Thr Ser Lys His Glu His Arg Trp Ser Arg Arg Trp Gln Glu Thr
272527302735
Arg Arg
<210> 298
<211> 862
<212> PRT
<213> Macaca nemestrina
<220>
<223> PIG-TAILED MACAQUE VERSICAN Q28858
<400> 298
Tyr Pro Ile Arg Ala Pro Arg Val Gly Cys Tyr Gly Asp Met Met Gly
151015
Lys Ala Gly Val Arg Thr Tyr Gly Phe Arg Ser Pro Gln Glu Thr Tyr
202530
Asp Val Tyr Cys Tyr Val Asp His Leu Asp Gly Asp Val Phe His Leu
354045
Thr Ala Pro Ser Lys Phe Thr Phe Glu Glu Ala Ala Lys Glu Cys Glu
505560
Asn Gln Asp Ala Arg Leu Ala Thr Val Gly Glu Leu Gln Ala Ala Trp
65707580
Arg Asn Gly Phe Asp Gln Cys Asp Tyr Gly Trp Leu Ser Asp Ala Ser
859095
Val Arg His Pro Val Thr Val Ala Arg Ala Gln Cys Gly Gly Gly Leu
100105110
Leu Gly Val Arg Thr Leu Tyr Arg Phe Glu Asn Gln Thr Gly Phe Pro
115120125
Pro Pro Asp Ser Arg Phe Asp Ala Tyr Cys Phe Lys Arg Arg Met Ser
130135140
Asp Leu Ser Val Ile Gly His Pro Ile Asp Ser Glu Ser Lys Glu Asp
145150155160
Glu Pro Cys Ser Glu Glu Thr Asp Pro Val His Asp Leu Met Ala Glu
165170175
Ile Leu Pro Glu Phe Pro Asp Ile Ile Glu Ile Asp Leu Tyr His Ser
180185190
Glu Glu Asn Glu Glu Glu Glu Glu Glu Cys Ala Asn Ala Thr Asp Val
195200205
Thr Thr Thr Pro Ser Val Gln Tyr Ile Asn Gly Lys His Leu Val Thr
210215220
Thr Val Pro Lys Asp Pro Glu Ala Ala Ser Gly Thr Ile Ser Thr Asn
225230235240
Phe Pro Gln Thr Met Glu Pro Ala Lys Leu Trp Ser Arg Gln Glu Val
245250255
Asn Pro Glu Arg Gln Glu Ile Glu Ser Glu Thr Thr Ser Glu Glu Gln
260265270
Ile Gln Glu Glu Lys Ser Phe Glu Ser Pro Gln Asn Ser Pro Ala Thr
275280285
Glu Gln Thr Ile Phe Asp Ser Gln Thr Phe Thr Glu Thr Glu Leu Lys
290295300
Thr Thr Gly Tyr Ser Val Leu Thr Thr Lys Lys Thr Tyr Ser Asp Asp
305310315320
Lys Glu Met Glu Glu Glu Gly Thr Ser Leu Ala Asn Met Ser Thr Pro
325330335
Val Pro Asp Ala Asn Gly Val Glu Ser Phe Thr Thr Leu Pro Glu Ala
340345350
Thr Glu Lys Ser His Phe Phe Leu Ala Thr Ala Leu Val Thr Glu Ser
355360365
Ile Pro Ala Glu His Val Val Thr Asp Ser Pro Ile Lys Glu Glu Glu
370375380
Ser Thr Lys His Phe Pro Lys Gly Met Arg Pro Thr Ile Gln Glu Leu
385390395400
Asp Thr Glu Leu Leu Phe Ser Gly Leu Gly Ser Gly Glu Glu Val Leu
405410415
Pro Thr Leu Pro Thr Lys Ser Val Asn Phe Thr Glu Val Glu Gln Ile
420425430
Arg Asn Thr Phe Tyr Pro His Thr Ser Gln Val Glu Ser Thr Ser Ser
435440445
Asp Lys Leu Glu Asp Phe Asn Arg Met Glu Asn Val Ala Lys Glu Val
450455460
Gly Pro Leu Gly Ser Gln Thr Asp Ile Phe Glu Gly Asn Glu Ser Val
465470475480
Thr Ser Thr Thr Leu Ile Glu Ile Leu Ser Asp Pro Gly Ala Glu Gly
485490495
Pro Thr Val Ala Pro Leu Pro Phe Phe Ala Asn Ile Gly His Pro Gln
500505510
Asn Gln Thr Leu Arg Trp Ala Glu Glu Ile Gln Thr Ser Lys Leu Glu
515520525
Pro Ser Glu Glu Asp Gly Lys Pro Glu Leu Leu Glu Glu Thr Glu Ala
530535540
Ser Pro Thr Glu Phe Ile Ala Val Glu Gly Thr Glu Ile Leu Gln Asp
545550555560
Phe Gln Asn Lys Thr Asp Gly Gln Val Ser Gly Glu Ala Ile Lys Met
565570575
Phe Pro Thr Ile Lys Thr Pro Glu Ala Gly Thr Val Ile Thr Thr Ala
580585590
Asn Glu Ile Lys Leu Glu Gly Ala Thr Gln Trp Pro His Ser Thr Ser
595600605
Ala Ser Ala Thr Tyr Gly Ile Glu Ala Gly Val Met Pro Trp Leu Ser
610615620
Pro Gln Thr Ser Glu Arg Pro Thr Leu Ser Ser Ser Pro Glu Ile Asn
625630635640
Pro Glu Thr Gln Ala Ala Leu Ile Arg Gly Gln Asp Ser Thr Val Ala
645650655
Ala Ser Glu Gln Gln Val Thr Ala Arg Ile Leu Asp Thr Asn Asp Gln
660665670
Ala Thr Val Ser Pro Val Glu Phe Asn Thr Glu Val Ala Thr Pro Pro
675680685
Phe Ser Leu Leu Glu Thr Ser Asn Glu Thr Asp Phe Leu Ile Gly Ile
690695700
Asn Glu Glu Ser Val Glu Gly Thr Ala Ile Tyr Leu Pro Gly Pro Asp
705710715720
Arg Cys Lys Met Asn Pro Cys Leu Asn Gly Gly Thr Cys Tyr Pro Thr
725730735
Glu Thr Ser Tyr Val Cys Thr Cys Val Pro Gly Tyr Ser Gly Asp Gln
740745750
Cys Glu Leu Asp Phe Asp Glu Cys His Ser Asn Pro Cys Arg Asn Gly
755760765
Ala Thr Cys Ala Asp Gly Phe Asn Thr Phe Arg Cys Leu Cys Leu Pro
770775780
Ser Tyr Val Gly Ala Leu Cys Glu Gln Asp Ile Glu Thr Cys Asp Tyr
785790795800
Gly Trp His Lys Phe Gln Gly Gln Cys Tyr Lys Tyr Phe Ala His Arg
805810815
Arg Thr Trp Asp Ala Ala Glu Arg Glu Cys Arg Leu Gln Gly Ala His
820825830
Leu Thr Ser Ile Leu Ser His Glu Glu Gln Met Phe Val Asn Arg Val
835840845
Gly His Asp Tyr Gln Trp Ile Gly Leu Asn Asp Lys Met Phe
850855860
<210> 299
<211> 3381
<212> PRT
<213> Bos taurus
<220>
<223> COW VERSICAN P81282
<400> 299
Met Leu Ile Asn Ile Lys Ser Ile Leu Trp Met Cys Ser Thr Leu Ile
151015
Ala Ala His Ala Leu Gln Lys Val Asn Met Glu Lys Ser Pro Pro Val
202530
Lys Gly Ser Leu Ser Gly Lys Val Asn Leu Pro Cys His Phe Ser Thr
354045
Met Pro Thr Leu Pro Pro Ser Tyr Asn Thr Thr Ser Glu Phe Leu Arg
505560
Ile Lys Trp Ser Lys Ile Glu Leu Asp Lys Thr Gly Lys Asp Leu Lys
65707580
Glu Thr Thr Val Leu Val Ala Gln Asn Gly Asn Ile Lys Ile Gly Gln
859095
Asp Tyr Lys Gly Arg Val Ser Val Pro Thr His Pro Glu Asp Val Gly
100105110
Asp Ala Ser Leu Thr Met Val Lys Leu Leu Ala Ser Asp Ala Gly Arg
115120125
Tyr Arg Cys Asp Val Met Tyr Gly Ile Glu Asp Thr Gln Asp Thr Val
130135140
Ser Leu Thr Val Glu Gly Val Val Phe His Tyr Arg Ala Ala Thr Ser
145150155160
Arg Tyr Thr Leu Asn Phe Glu Met Ala Gln Lys Ala Cys Val Asp Ile
165170175
Gly Ala Val Ile Ala Thr Pro Glu Gln Leu His Ala Ala Tyr Glu Asp
180185190
Gly Phe Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp Gln Thr Val Arg
195200205
Tyr Pro Ile Arg Val Pro Arg Glu Gly Cys Tyr Gly Asp Met Met Gly
210215220
Lys Glu Gly Val Arg Thr Tyr Gly Phe Arg Ala Pro His Glu Thr Tyr
225230235240
Asp Val Tyr Cys Tyr Val Asp His Leu Asp Gly Asp Val Phe His Ile
245250255
Thr Ala Pro Asn Lys Phe Thr Phe Glu Glu Ala Gly Glu Glu Cys Lys
260265270
Thr Gln Asp Ala Arg Leu Ala Thr Val Gly Glu Leu Gln Ala Ala Trp
275280285
Arg Asn Gly Phe Asp Arg Cys Asp Tyr Gly Trp Leu Leu Asp Ala Ser
290295300
Val Arg His Pro Val Thr Val Ala Arg Ala Gln Cys Gly Gly Gly Leu
305310315320
Leu Gly Val Arg Thr Leu Tyr Arg Phe Glu Asn Gln Thr Gly Phe Pro
325330335
Thr Pro Asp Ser Arg Phe Asp Ala Tyr Cys Phe Lys Pro Lys Gln Asn
340345350
Ile Ser Glu Ala Thr Thr Ile Glu Leu Asn Met Leu Ala Glu Thr Val
355360365
Ser Pro Thr Leu Leu Glu Glu Leu Gln Val Gly Leu Asp Arg Met Thr
370375380
Pro Ile Val Pro Leu Ile Thr Glu Leu Pro Val Ile Thr Thr Lys Val
385390395400
Pro Pro Ile Gly Asn Ile Val Asn Phe Glu Gln Lys Ser Thr Val Gln
405410415
Pro Leu Thr Ser Thr His Arg Ser Ala Thr Glu Ser Leu Pro Pro Asp
420425430
Gly Ser Met Lys Lys Pro Trp Asp Met Asp Tyr Tyr Ser Pro Ser Ala
435440445
Ser Gly Pro Leu Gly Glu Pro Asp Val Ser Glu Ile Lys Glu Glu Val
450455460
Pro Gln Ser Thr Thr Val Val Ser His His Ala Pro Asp Ser Trp Asp
465470475480
Gly Val Lys Glu Asp Leu Gln Ile Lys Asp Ser Val Thr Gln Ile Glu
485490495
Gln Ile Glu Val Gly Pro Leu Val Thr Ser Met Glu Ile Ser Lys His
500505510
Ile Pro Ser Lys Glu Phe Thr Val Thr Val Thr Pro Phe Val Ser Thr
515520525
Thr Met Thr Leu Glu Ser Lys Thr Glu Lys Lys Ala Ile Ser Thr Val
530535540
Ser Glu Ser Val Thr Thr Ser His Tyr Gly Phe Thr Leu Arg Glu Gly
545550555560
Asp Gly Glu Asp Arg Ile Ser Thr Val Arg Ser Gly Gln Ser Thr Ser
565570575
Ile Phe Ser Gln Ile Pro Glu Val Ile Thr Val Ser Lys Thr Ser Glu
580585590
Asp Thr Thr Arg Gly Gln Leu Glu Asp Val Glu Ser Val Ser Ala Ser
595600605
Thr Ile Val Ser Pro Asp Ser Asp Gly Ser Pro Met Asp His Arg Gln
610615620
Glu Lys Gln Thr His Gly Arg Ile Thr Glu Gly Phe Leu Gly Gln Tyr
625630635640
Val Ser Thr Thr Pro Phe Pro Ser Gln His His Thr Glu Val Glu Leu
645650655
Phe Pro Tyr Ser Gly Asp Lys Arg Leu Val Glu Gly Thr Ser Thr Val
660665670
Ile Ser Pro Thr Pro Arg Thr Gly Arg Glu Arg Thr Glu Thr Leu Arg
675680685
Pro Ala Met Arg Thr Val Thr Tyr Thr Asn Asp Glu Ile Gln Glu Lys
690695700
Ile Thr Lys Asp Ser Ser Ile Glu Lys Ile Glu Glu Glu Gly Phe Ser
705710715720
Gly Met Lys Phe Pro Thr Ala Ser Pro Glu Gln Ile His His Thr Lys
725730735
Tyr Ser Val Gly Met Thr Lys Ser Phe Glu Ser Pro Ala Leu Met Thr
740745750
Thr Thr Lys Pro Gly Val Thr Pro Thr Glu Ala Thr Asp Val Glu Glu
755760765
Asp Phe Thr Thr Pro Ser Gly Leu Glu Thr Asp Gly Tyr Gln Asp Thr
770775780
Thr Glu Tyr Glu Glu Gly Ile Thr Thr Val His Leu Ile Gln Ser Thr
785790795800
Leu Asn Val Glu Val Val Thr Val Ser Lys Trp Ser Leu Asp Glu Asp
805810815
Asn Thr Thr Ser Lys Pro Leu Gly Ser Thr Glu His Val Gly Ser Pro
820825830
Lys Leu Pro Pro Ala Leu Ile Thr Thr Thr Gly Val Ser Gly Lys Asp
835840845
Lys Glu Met Pro Ser Leu Thr Glu Asp Gly Arg Asp Glu Phe Thr Arg
850855860
Ile Pro Gly Ser Thr Gln Arg Pro Leu Glu Glu Phe Thr Glu Glu Asp
865870875880
Thr Thr Asp His Glu Lys Phe Thr Val Arg Phe Gln Pro Thr Thr Ser
885890895
Ile Ala Thr Thr Glu Lys Ser Thr Leu Arg Asp Ser Ile Thr Glu Glu
900905910
Arg Val Pro Pro Phe Thr Ser Thr Glu Val Arg Val Thr His Ala Thr
915920925
Ile Glu Gly Ser Ala Leu Asp Glu Gly Glu Asp Val Asp Val Ser Lys
930935940
Pro Leu Ser Thr Val Pro Gln Phe Ala His Pro Ser Asp Val Glu Gly
945950955960
Ser Thr Phe Val Asn Tyr Ser Ser Thr Gln Glu Pro Thr Thr Tyr Val
965970975
Asp Thr Ser His Thr Ile Pro Leu Pro Val Ile Pro Lys Thr Glu Trp
980985990
Gly Val Leu Val Pro Ser Ile Pro Ser Glu Gly Glu Val Leu Gly Glu
99510001005
Pro Ser Gln Asp Ile Arg Val Ile Asn Gln Thr His Phe Glu Ala Ser
101010151020
Met Tyr Pro Glu Thr Val Arg Thr Thr Thr Glu Ile Thr Gln Glu Ala
1025103010351040
Thr Arg Glu Asp Phe Leu Trp Lys Glu Gln Thr Pro Glu Lys Pro Val
104510501055
Ser Pro Pro Ser Ser Thr Thr Asp Thr Ala Lys Glu Thr Thr Pro Pro
106010651070
Leu Asp Glu Gln Glu Ser Asp Gly Ser Ala Tyr Thr Val Phe Glu Asp
107510801085
Arg Ser Val Met Gly Ser Asp Arg Val Ser Val Leu Val Thr Thr Pro
109010951100
Ile Gly Lys Phe Glu Gln His Thr Ser Phe Pro Pro Gly Ala Val Thr
1105111011151120
Lys Ala Lys Thr Asp Glu Val Val Thr Leu Thr Pro Thr Thr Gly Ser
112511301135
Lys Val Thr Phe Ser Pro Trp Pro Lys Gln Lys Tyr Glu Thr Glu Gly
114011451150
Thr Ser Pro Arg Gly Phe Val Ser Pro Phe Ser Ile Gly Val Thr Gln
115511601165
Leu Ile Glu Glu Thr Thr Thr Glu Lys Arg Glu Lys Thr Ser Leu Asp
117011751180
Tyr Ile Asp Leu Gly Ser Gly Leu Phe Glu Lys Pro Lys Ala Thr Glu
1185119011951200
Leu Pro Glu Phe Ser Thr Val Lys Ala Thr Val Pro Ser Asp Thr Ala
120512101215
Ala Phe Ser Ser Ala Asp Arg Leu His Thr Pro Ser Ala Ser Thr Glu
122012251230
Lys Pro Pro Leu Ile Asp Arg Glu Pro Asp Glu Glu Thr Thr Ser Asp
123512401245
Met Val Ile Ile Gly Glu Ser Thr Ser Arg Val Pro Pro Thr Thr Leu
125012551260
Glu Asp Ile Val Ala Lys Lys Thr Glu Thr Asp Ile Asp Arg Glu Tyr
1265127012751280
Phe Thr Thr Ser Ser Thr Ser Thr Thr Gln Pro Thr Arg Pro Pro Thr
128512901295
Val Glu Gly Lys Glu Ala Phe Gly Pro Gln Ala Phe Ser Thr Pro Glu
130013051310
Pro Pro Ala Gly Thr Lys Phe His Pro Asp Ile Asn Val Tyr Ile Ile
131513201325
Glu Val Arg Glu Asn Lys Thr Gly Arg Met Ser Asp Phe Ser Val Ser
133013351340
Gly His Pro Ile Asp Ser Glu Ser Lys Glu Asp Glu Pro Cys Ser Glu
1345135013551360
Glu Thr Asp Pro Glu His Asp Leu Ile Ala Glu Ile Leu Pro Glu Leu
136513701375
Leu Gly Met Leu His Ser Glu Glu Asp Glu Glu Asp Glu Glu Cys Ala
138013851390
Asn Ala Thr Asp Val Thr Thr Thr Pro Ser Val Gln Tyr Ile Asn Gly
139514001405
Lys His Val Val Thr Thr Val Pro Lys Asp Pro Glu Ala Ala Glu Ala
14101415 1420
Arg Arg Gly Gln Phe Glu Ser Val Ala Pro Ser Gln Asn Phe Ser Asp
1425143014351440
Ser Ser Glu Ser Asp Ser His Gln Phe Ile Ile Thr His Ala Gly Leu
144514501455
Pro Thr Ala Met Gln Pro Asn Glu Ser Lys Glu Thr Thr Glu Ser Leu
146014651470
Glu Ile Thr Trp Arg Pro Glu Ile Tyr Pro Glu Thr Ala Glu Pro Phe
147514801485
Ser Ser Gly Glu Pro Asp Ile Phe Pro Thr Ala Ser Ile His Glu Gly
149014951500
Glu Ala Thr Glu Gly Pro Asp Ser Ile Thr Glu Lys Asn Pro Glu Leu
1505151015151520
Asp His Leu Val His Glu His Ala Glu Ser Val Pro Leu Phe Pro Glu
152515301535
Glu Ser Ser Gly Asp Ala Ala Ile Asp Gln Glu Ser Gln Lys Ile Ile
154015451550
Phe Ser Gly Ala Thr Glu Gly Thr Phe Gly Glu Glu Ala Glu Lys Ser
155515601565
Ser Thr Thr His Thr Pro Ser Met Val Ala Ser Ser Val Ser Ala Pro
157015751580
Val Ser Glu Asp Ala Ser Phe Ile Leu Thr Gly Thr Pro Gln Ser Asp
1585159015951600
Glu Pro Leu Ser Thr Val Glu Ser Trp Val Glu Ile Thr Pro Arg His
160516101615
Thr Val Glu Phe Ser Gly Ser Pro Ser Ile Pro Ile Pro Glu Gly Ser
162016251630
Gly Glu Ala Glu Glu Asp Lys Asp Lys Ile Phe Ala Met Ile Thr Asp
163516401645
Leu Ser Gln Arg Asn Thr Thr Asp Pro Arg Val Thr Ser Asp Thr Ser
165016551660
Lys Ile Met Ile Thr Glu Ser Leu Val Asp Val Pro Thr Thr Thr Ile
1665167016751680
Tyr Ser Ile Ser Glu Gln Val Ser Ala Val Val Pro Thr Lys Phe Val
168516901695
Arg Glu Thr Asp Thr Tyr Glu Trp Val Phe Ser Pro Pro Leu Glu Glu
170017051710
Thr Thr Arg Lys Glu Glu Glu Lys Gly Thr Thr Gly Thr Ala Ser Thr
171517201725
Val Glu Val His Ser Pro Thr Gln Arg Leu Asp Gln Phe Val Ser Pro
1730 17351740
Ser Glu Leu Glu Ser Ser Ser Glu Thr Pro Pro Asp Asp Ser Ala Ala
1745175017551760
Ala Thr Arg Lys Ser Phe Thr Ser Gln Met Thr Pro Thr Gln Ser Glu
176517701775
Arg Glu Thr Thr Ser Ser Thr Val Val Phe Lys Glu Thr Glu Val Leu
178017851790
Asp Asn Leu Ala Ala Gln Thr Thr Asp Pro Ser Leu Ser Ser Gln Pro
179518001805
Gly Val Leu Glu Val Ser Pro Thr Val Pro Gly Ser Pro Val Ser Leu
181018151820
Phe Met Glu Gln Gly Ser Gly Glu Ala Ala Val Asp Pro Glu Thr Thr
1825183018351840
Thr Val Ser Ser Leu Ser Leu Asn Ile Glu Pro Glu Ile Leu Ala Lys
184518501855
Glu Glu Ala Ala Gly Ala Trp Ser Pro Asn Val Glu Thr Val Phe Pro
186018651870
Phe Glu Pro Thr Glu Gln Val Leu Ser Thr Ala Val Asp Arg Glu Val
187518801885
Ala Glu Thr Ile Ser Gln Thr Ser Lys Glu Asn Leu Val Ser Glu Ile
189018951900
Ser Gly Glu Pro Thr His Arg Ala Glu Ile Lys Gly Phe Ser Thr Asp
1905191019151920
Phe Pro Leu Glu Glu Asp Phe Ser Gly Asp Phe Arg Glu Tyr Ser Thr
192519301935
Val Ser Tyr Pro Ile Thr Lys Glu Glu Ile Val Met Met Glu Gly Ser
194019451950
Gly Asp Ala Ala Phe Lys Asp Thr Gln Met Leu Pro Ser Val Thr Pro
195519601965
Thr Ser Asp Leu Ser Asn His Thr Ala Asp Ser Glu Glu Pro Gly Ser
197019751980
Thr Leu Val Ser Thr Ser Ala Phe Pro Trp Glu Glu Phe Thr Ala Ser
1985199019952000
Ala Glu Gly Ser Gly Glu Pro Leu Leu Ser Val Ser Ser Ser Val Asp
200520102015
Gln Val Phe Pro Ser Ala Ala Gly Lys Ala Ser Gly Thr Asp Ser Pro
202020252030
Phe Ile Asp Gln Arg Leu Gly Glu Glu Gly Ala Ile Asn Glu Thr Asp
203520402045
Gln Arg Ser Thr Ile Leu Pro Thr Ala Glu Ala Glu Ser Thr Lys Ala
205020552060
Ser Thr Glu Glu Gly Glu Val Lys Glu Asn His Thr Val Ser Met Asp
2065207020752080
Phe Pro Pro Thr Val Glu Pro Asp Glu Leu Trp Pro Arg Gln Glu Val
208520902095
Asn Pro Val Arg Gln Gly Asn Gly Ser Glu Ile Val Ser Glu Glu Lys
210021052110
Thr Gln Glu Gln Glu Ser Phe Glu Pro Leu Gln Ser Ser Val Ala Pro
211521202125
Glu Gln Thr Thr Phe Asp Ser Gln Thr Phe Pro Glu Pro Gly Leu Gln
213021352140
Thr Thr Gly Tyr Phe Thr Leu Thr Thr Lys Lys Thr Tyr Ser Thr Asp
2145215021552160
Glu Arg Met Glu Glu Glu Val Ile Ser Leu Ala Asp Val Ser Thr Pro
216521702175
Thr Leu Asp Ser Lys Gly Leu Val Leu Tyr Thr Thr Leu Pro Glu Val
218021852190
Thr Glu Lys Ser His Phe Phe Leu Ala Thr Ala Ser Val Thr Glu Ser
219522002205
Val Pro Ala Glu Ser Val Ile Ala Gly Ser Thr Ile Lys Glu Glu Glu
221022152220
Ser Ile Lys Pro Phe Pro Lys Val Thr Ser Pro Ile Ile Lys Glu Ser
2225223022352240
Asp Thr Asp Leu Ile Phe Ser Gly Leu Gly Ser Gly Glu Glu Val Leu
224522502255
Pro Thr Leu Gly Ser Val Asn Phe Thr Glu Ile Glu Gln Val Leu Ser
226022652270
Thr Leu Tyr Pro Leu Thr Ser Gln Val Gln Ser Leu Glu Ala Ser Ile
227522802285
Leu Asn Asp Thr Ser Gly Asp Tyr Glu Gly Met Glu Asn Val Ala Asn
229022952300
Glu Met Arg Pro Leu Ile Ser Lys Thr Asp Ser Ile Phe Glu Asp Gly
2305231023152320
Glu Thr Ala Ser Ser Thr Thr Leu Pro Glu Ile Leu Ser Asp Ala Arg
232523302335
Thr Glu Gly Pro Phe Thr Ala Pro Leu Thr Phe Ser Thr Gly Pro Gly
234023452350
Gln Pro Gln Asn Gln Thr His Arg Arg Ala Glu Glu Ile Gln Thr Ser
235523602365
Arg Pro Gln Pro Leu Thr Asp Gln Val Ser Ser Glu Asn Ser Val Thr
237023752380
Ala Glu Thr Lys Glu Thr Ala Thr Pro Ala Thr Asp Phe Leu Ala Arg
2385239023952400
Thr Tyr Asp Leu Glu Met Ala Lys Gly Phe Val Thr Pro Thr Pro Lys
240524102415
Pro Ser Asp Leu Phe Tyr Glu His Ser Gly Glu Gly Ser Gly Glu Leu
242024252430
Asp Ala Val Gly Ala Glu Val His Ala Ser Gly Met Thr Gln Ala Thr
243524402445
Arg Gln Gly Ser Thr Thr Phe Val Ser Asp Arg Ser Leu Glu Lys His
245024552460
Pro Lys Val Pro Ser Val Glu Ala Val Thr Val Asn Gly Phe Pro Thr
2465247024752480
Val Ser Met Val Leu Pro Leu His Pro Glu Gln Arg Glu Gly Ser Pro
248524902495
Glu Ala Thr Gly Thr Pro Ala Ser Thr Ala Ser Tyr Glu Lys Ala Thr
250025052510
Glu Gly Ala Ala Asp Ser Phe Gln Asp His Phe Trp Gly Phe Lys Asp
251525202525
Ser Thr Leu Lys Pro Asp Lys Arg Lys Ala Thr Glu Ser Ile Ile Ile
253025352540
Asp Leu Asp Lys Glu Asp Lys Asp Leu Ile Leu Thr Met Thr Glu Ser
2545255025552560
Thr Ile Leu Glu Ile Ile Pro Glu Leu Thr Ser Asp Lys Asn Thr Val
256525702575
Ile Asp Ile Asp His Thr Lys Pro Ile Tyr Glu Asp Ile Leu Gly Met
258025852590
Gln Thr Asp Leu Asp Pro Glu Val Pro Ser Gly Pro Pro Asp Ser Ser
259526002605
Glu Glu Ser Thr Gln Val Gln Glu Lys Tyr Glu Ala Ala Val Asn Leu
261026152620
Ser Ser Thr Glu Glu Asn Phe Glu Ala Ser Gly Asp Ile Leu Leu Ala
2625263026352640
Asn Tyr Thr Gln Ala Thr Pro Glu Ser Lys Ala Pro Glu Asp Arg Asn
264526502655
Pro Leu Asp His Thr Asp Phe Ile Phe Thr Thr Gly Ile Pro Ile Leu
266026652670
Ser Ser Glu Thr Glu Leu Asp Val Leu Leu Pro Thr Ala Thr Ser Leu
267526802685
Pro Ile Pro Ser Lys Ser Ala Thr Val Asn Pro Glu Ser Lys Thr Glu
269026952700
Ala Lys Thr Leu Glu Asp Ile Phe Glu Ser Ser Thr Leu Ser Asp Gly
2705271027152720
Gln Ala Ile Ala Asp Gln Ser Glu Val Ile Ser Thr Leu Gly Tyr Leu
272527302735
Glu Arg Thr Gln Asn Glu Asp Glu Ala Lys Lys Tyr Val Ser Pro Ser
274027452750
Phe Gln Pro Glu Phe Ser Ser Gly Ala Glu Glu Ala Leu Thr Asp Pro
275527602765
Thr Pro Tyr Val Ser Ile Gly Thr Thr Tyr Leu Thr Ala Gln Ser Leu
277027752780
Thr Glu Ala Pro Asp Val Met Glu Gly Ala Arg Leu Pro Asp Ser Ile
2785279027952800
Asp Thr Ser Thr Val Ser Ala Phe Ser Glu Leu Leu Ser Gln Thr Pro
280528102815
Ser Phe Pro Pro Leu Ser Ile His Leu Gly Ser Gly Asp Ser Glu His
282028252830
Ser Glu Asp Leu Gln Pro Ser Ala Leu Pro Ser Thr Asp Ala Ser Thr
283528402845
Pro Pro Val Ser Ser Gly Glu Leu Ala Asn Ile Glu Ala Thr Phe Lys
285028552860
Pro Ser Ser Glu Glu Asp Phe Tyr Ile Thr Glu Pro Pro Ser Leu Pro
2865287028752880
Pro Asp Thr Glu Pro Ser Glu Asp Glu Ser Lys Pro Lys Leu Leu Glu
288528902895
Pro Thr Glu Ala Ser Ala Thr Glu Leu Ile Ala Gln Glu Glu Ile Glu
290029052910
Ile Phe Gln Asn Ser Asp Asn Thr Thr Ser Val Gln Val Ser Gly Glu
291529202925
Ala Val Lys Val Phe Pro Ser Ile Glu Thr Pro Glu Ala Glu Ala Ile
293029352940
Val Thr Ala Ala Ser Glu Thr Lys Leu Glu Gly Ala Thr Leu Arg Pro
2945295029552960
His Ser Thr Ser Ala Ser Val Ile His Gly Val Glu Ala Gly Val Val
296529702975
Pro Gln Pro Ser Pro Gln Thr Ser Glu Arg Pro Thr Ile Leu Ser Pro
298029852990
Leu Glu Ile Ser Pro Glu Thr Gln Ala Ala Leu Ile Arg Gly Glu Asp
299530003005
Ser Thr Val Ala Ala Pro Lys Gln Gln Val Pro Thr Arg Met Leu Asp
301030153020
Ser Asn Lys Gln Ala Thr Leu Ser Thr Thr Glu Leu Asn Thr Glu Leu
3025303030353040
Ala Thr Pro Ser Phe Pro Leu Leu Glu Thr Ser Asn Glu Thr Ser Phe
304530503055
Leu Ile Gly Ile Asn Glu Glu Ser Val Glu Gly Thr Ala Val Tyr Leu
306030653070
Pro Gly Pro Asp Arg Cys Lys Met Asn Pro Cys Leu Asn Gly Gly Thr
307530803085
Cys Tyr Pro Thr Glu Thr Ser Tyr Val Cys Thr Cys Val Pro Gly Tyr
309030953100
Ser Gly Asp Arg Cys Glu Leu Asp Phe Asp Glu Cys His Ser Asn Pro
3105311031153120
Cys Arg Asn Gly Ala Thr Cys Ile Asp Gly Phe Asn Thr Phe Arg Cys
312531303135
Leu Cys Leu Pro Ser Tyr Val Gly Ala Leu Cys Glu Gln Asp Thr Glu
314031453150
Thr Cys Asp Tyr Gly Trp His Lys Phe Gln Gly Gln Cys Tyr Lys Tyr
315531603165
Phe Ala His Arg Arg Thr Trp Asp Ala Ala Glu Arg Glu Cys Arg Leu
317031753180
Gln Gly Ala His Leu Thr Ser Ile Leu Ser His Glu Glu Gln Met Phe
3185319031953200
Val Asn Arg Val Gly His Asp Tyr Gln Trp Ile Gly Leu Asn Asp Lys
320532103215
Met Phe Glu His Asp Phe Arg Trp Thr Asp Gly Ser Thr Leu Gln Tyr
322032253230
Glu Asn Trp Arg Pro Asn Gln Pro Asp Ser Phe Phe Ser Thr Gly Glu
323532403245
Asp Cys Val Val Ile Ile Trp His Glu Asn Gly Gln Trp Asn Asp Val
325032553260
Pro Cys Asn Tyr His Leu Thr Tyr Thr Cys Lys Lys Gly Thr Val Ala
3265327032753280
Cys Gly Gln Pro Pro Val Val Glu Asn Ala Lys Thr Phe Gly Lys Met
328532903295
Lys Pro Arg Tyr Glu Ile Asn Ser Leu Ile Arg Tyr His Cys Lys Asp
330033053310
Gly Phe Ile Gln Arg His Leu Pro Thr Ile Arg Cys Leu Gly Asn Gly
331533203325
Arg Trp Ala Met Pro Lys Ile Thr Cys Leu Asn Pro Ser Ala Tyr Gln
333033353340
Arg Thr Tyr Ser Lys Lys Tyr Phe Lys Asn Ser Ser Ser Ala Lys Asp
3345335033553360
Asn Ser Ile Asn Thr Ser Lys His Asp His Arg Trp Ser Arg Arg Trp
336533703375
Gln Glu Ser Arg Arg
3380
<210> 300
<211> 3562
<212> PRT
<213> Gallus gallus
<220>
<223> CHICKEN VERSICAN Q90953
<400> 300
Met Leu Leu Asn Ile Lys Ser Ile Ile Trp Met Cys Ser Thr Leu Ala
151015
Ile Thr Tyr Met Leu Pro Lys Val Lys Ala Glu Lys Lys Thr Leu Val
202530
Lys Gly Ser Leu Ser Gly Thr Ser Val Leu Pro Cys Phe Phe Ser Thr
354045
Thr Pro Thr Ile Ala Ser Ser Tyr Ala Ala Glu Tyr Leu Arg Ile Lys
505560
Trp Ser Lys Val Glu Leu Asp Lys Ser Gly Lys Asp Ala Lys Glu Thr
65707580
Thr Val Leu Val Ala Gln Asn Gly Asn Ile Lys Ile Gly Gln Asn Tyr
859095
Lys Asp Arg Val Ser Val Pro Thr His Ser Glu Glu Thr Gly Asp Ala
100105110
Ser Leu Thr Phe Ser Arg Leu Arg Ala Ser Asp Ala Gly Val Tyr Arg
115120125
Cys Asp Val Met Tyr Gly Val Glu Asp Thr Gln Gly Ile Val Ser Leu
130135140
Ala Val Asp Gly Val Val Phe His Tyr Arg Ala Ala Thr Ser Arg Tyr
145150155160
Thr Leu Asn Phe Thr Gln Ala Gln Gln Thr Cys Leu Asp Asn Gly Ala
165170175
Val Ile Ala Ser Pro Glu Gln Leu Lys Ala Ala Tyr Glu Asp Gly Phe
180185190
Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp Gln Thr Val Arg Tyr Pro
195200205
Ile Arg His Pro Arg Ile Gly Cys Phe Gly Asp Lys Met Gly Lys Lys
210215220
Gly Val Arg Thr Tyr Gly Arg Arg Phe Pro Asn Glu Thr Tyr Asp Val
225230235240
Tyr Cys Tyr Val Glu His Met Gln Asp Glu Val Val His Val Ser Val
245250255
Pro Glu Lys Leu Thr Phe Glu Glu Ala Lys Glu Leu Cys Arg Lys Arg
260265270
Asp Gly Val Leu Ala Ser Val Gly Asn Met Tyr Val Ala Trp Arg Asn
275280285
Gly Phe Asp Gln Cys Asp Tyr Gly Trp Leu Ala Asp Gly Ser Val Arg
290295300
Tyr Pro Ala Ser Val Ala Arg Pro Gln Cys Gly Gly Gly Leu Leu Gly
305310315320
Val Arg Thr Leu Tyr Arg Tyr Glu Asn Gln Thr Gly Phe Pro Tyr Pro
325330335
Asp Ser Lys Phe Asp Ala Tyr Cys Tyr Glu Arg Lys Lys Ile Val Ser
340345350
Glu Pro Thr Thr Val Lys Leu Val Thr Thr Leu Lys Thr Asp Ser Val
355360365
Glu Leu Ser Ser Ala Lys Val Thr Leu Lys Pro Ser Val Phe Glu Ser
370375380
Ser Val Thr Glu Val Ala Val Thr Lys Thr Lys Val Pro Ala Trp Glu
385390395400
Glu Ala Thr Leu Glu Thr Glu Asp Thr Lys Met Thr Thr Glu Val Ala
405410415
Glu Glu Lys Arg Glu Met Glu Val Leu Met Glu Asn Ile Lys Leu Thr
420425430
Thr Leu Leu Pro Gln Thr Val Thr Asp Gly Glu Ile Ser Pro Tyr Asp
435440445
Thr Leu Gly Arg Thr Glu Tyr Asp Val Ser Pro Arg Leu Thr Glu Ser
450455460
Thr Ser Ala Ala Leu Glu Val Glu His Thr Tyr Ser Glu Ala Glu Leu
465470475480
Ser Glu Glu Gln Gly Arg Ser Glu Ser Thr Glu Asp Ala Phe Leu Thr
485490495
Ser Val Val Phe Gln Asp Ser Thr Ala Val Ala Lys Ser Ser Thr Gly
500505510
Ser Trp Glu Asp Ile Glu Thr Gly Asp Thr Gln Lys His Asp Gly Asp
515520525
Asn Gln Thr Glu Gln Ile Glu Val Gly Pro Val Met Thr Ala Thr Asp
530535540
Ser Leu Val Pro Ala Ser Gln Arg Glu Leu Pro Arg Thr Gly Ser Ser
545550555560
Val Ser Leu Thr Lys Glu Asn Leu Tyr Leu Gly Ser His Ser Thr Lys
565570575
Glu Pro Thr Lys Lys Ser Met Glu Ala Lys Ser Asp Lys Lys Leu Thr
580585590
Thr Val Val Ile Pro Lys Ala Leu Phe Thr Asp Gln Tyr Asp Leu Thr
595600605
Thr Gly Gly Glu Gly Arg Glu Ser Met Tyr Thr Val Met Pro Asp Arg
610615620
Val Ser Gly Val Ala Leu Val Ser Ile Pro Glu Ser Asp Val Pro Ala
625630635640
Val Ser Glu Thr Leu Met Asp Glu Leu Ala Val Thr Thr Gly Gln Ser
645650655
Ser Thr Ala Asp Glu Ser Thr Pro Phe Ile Lys Phe Ser Ser Ser Ala
660665670
Thr Glu Leu Asp Asn Glu Ala Ser Ala Glu Gly Ser Arg Glu Asp Leu
675680685
Lys Asp Val His Leu Thr Thr Ser Ser Gly Ile Pro Val Ser Phe Thr
690695700
Leu Phe Thr Ala Asn Glu Thr Gly Ser Glu Val Thr Ala Leu Ser Glu
705710715720
Ser Thr Ser Ala Pro Gln Lys Phe Glu Glu Gly Ile Thr Ser Val Leu
725730735
His Ser Ser Gln Gln Thr Glu Gly Ser Ala Ile Leu Glu Lys Gln Glu
740745750
Lys Thr Lys Glu Pro Glu Met Ser Thr Ile Asp Ala Lys Val Leu Tyr
755760765
Ile Thr Thr Val Val Pro Ala Ser Val Thr Ala Gly Ser Glu Gly Arg
770775780
Phe Gly Ser Glu Lys Phe Thr His Thr Pro Pro Val Ser Gly Met Trp
785790795800
Leu Gln Thr Asp Lys Asp Gln Val Tyr Met Thr Glu Glu Thr Ser His
805810815
Thr Lys Arg Ile Glu Leu Asp Thr Glu Asp Asp Ile Ser Gly Met Glu
820825830
Pro Thr Ser Ser Pro Gly Gln Ile Ile Glu Tyr Thr Lys His Leu Gly
835840845
Ala Pro Val Ser Ala Val Thr Asp Glu Thr Lys Thr Ser Met Glu Thr
850855860
Ala Glu Thr Glu Ser Asp Glu Glu Val Val Ser Ala Asp Phe Asp Gln
865870875880
Thr Lys Gly Thr Thr Glu Val Phe His Thr Ser Ser Ser Leu Asp Leu
885890895
Glu Lys Phe Thr Leu Ser Lys Ile Pro Glu Asp Glu Ser Ser Ala Thr
900905910
Val Lys Ser Phe Ser Ser Ser Ser Gly Thr Val Leu Pro Thr Ala Val
915920925
Ala Thr Val Leu Glu Val Thr Asp His Glu Ala Asp Glu Thr Ser Gly
930935940
Tyr Val Leu Asn Met Thr Phe Ser Thr Pro Glu Gly Glu Gln Arg Lys
945950955960
Ala Thr Glu Lys Ser Pro Ala Thr Ser Ala Glu Asp Glu Val Ser Thr
965970975
Gly Thr Glu Ile Ser Lys Tyr Thr Met Thr Glu Gly Gly Gln Ile Ser
980985990
Ser Val Thr Ser Ala Glu Lys Glu Ser Val Ala Ala Leu Gln Glu Arg
99510001005
Glu Glu Gln Pro Ser Val Gly Leu Pro Glu Thr Lys Glu Pro Phe Lys
101010151020
Phe Thr Asp Val Thr Glu Ile Glu Thr Thr Val Pro Gln Arg Glu Gly
1025103010351040
Asp Thr Ser Leu Val Pro Val Thr Val Gly Ser Glu Asp Ile Gly Glu
104510501055
Met Gln Val Thr Asp His Thr Ser Phe Asp Ser Ile Ile His Thr Glu
106010651070
Ala Thr Val Thr Ser Thr Lys Ala Ser Glu Val Phe Pro Lys Glu Leu
107510801085
Ser Thr Lys Asp Gln Asp Arg Glu Leu Gly Thr Ala Met Gly Ser Thr
109010951100
Leu Pro Val Thr Ser Val Gln Met His Glu Gln Lys Thr Thr Ala Gly
1105111011151120
Phe Glu Ser Pro Gln Thr Thr Thr Gln Glu Lys His Asp Glu Met Gly
112511301135
Ser Ala Tyr Asp Glu Met Tyr Pro Ala Thr Glu Leu Ser Val Pro Ala
114011451150
Leu Met Leu Thr Glu Tyr Gly Gln Val Ser Gly Pro Val Glu Thr Ser
115511601165
Thr Arg Ser Leu His Leu Thr Gly Thr Pro Lys Ala Glu Thr Ala Thr
117011751180
Asp Gln Glu Glu Lys Ile Thr Glu Ala Val Pro Val Thr Phe Gly Thr
1185119011951200
Gln Ala Lys Val Tyr Glu Ser Lys Gly Thr Thr Thr Arg Glu Glu Asp
120512101215
Arg Asp Val Gly Ser Trp Asn Ser Val Leu Pro Pro His Thr Met Leu
122012251230
Ser Ser Pro Ser Thr Ala Gly Ser Ile Ser Leu Leu Thr Leu Gly Ala
123512401245
Ser Pro Ser Gln Thr Pro Glu Gly Ser Gly Ile Ser Glu Glu Leu Glu
125012551260
Glu Val Lys Thr Val Pro Phe Ser Ser Arg Ala Thr Asp Lys Thr Thr
1265127012751280
Val Ile Ser Asp Leu Thr Thr Ser Ser Ile Ser Ala Val Asp Lys Ile
128512901295
Gln Pro Thr Ser Ala Ser Lys Pro Phe Val Ser Ser Lys Ser Pro Arg
130013051310
Ile Ile Pro Glu Glu Asp Glu Glu Val Thr Ser Ser Asp Ile Ile Val
131513201325
Ile Asp Glu Ser Ile Ser Pro Ser Lys Ala Ser Ala Glu Asp Asp Leu
133013351340
Thr Gly Lys Met Val Glu Pro Glu Ile Asp Lys Glu Tyr Phe Thr Ser
1345135013551360
Ser Thr Ala Thr Ala Val Ala Arg Pro Thr Ala Pro Pro Thr Val Met
136513701375
Glu Ala Thr Glu Ala Leu Gln Pro Gln Glu Val Ser Pro Thr Ser His
138013851390
Pro Asp Ser Gly Thr Asp Ile Arg Leu Tyr Val Ile Gln Ile Thr Gly
139514001405
Asn Asp Thr Asp His Pro Val Asn Glu Phe Leu Asp Leu Phe Ser Arg
141014151420
His Ile Leu Pro His Ala Val Asp Glu Thr His Thr Asp Ala Glu Ser
1425143014351440
Ala Gln Thr Glu Pro Cys Thr Ser Asp Ser Val Gln Asp Ser Ser Glu
144514501455
Tyr Ile Ile Leu Asp Pro Phe Phe Pro Asn Phe Met Asp Phe Glu Glu
146014651470
Glu Glu Glu Asp Cys Glu Asn Thr Thr Asp Val Thr Thr Pro Pro Ala
147514801485
Leu Gln Phe Ile Asn Gly Lys Gln Gln Val Thr Ser Ala Pro Lys Ser
149014951500
Thr Lys Ala Glu Glu Ala Arg Ser Asp Gln Ile Glu Ser Val Ala His
1505151015151520
Ser Lys Asn Val Thr Phe Ser Gln Ile Asn Glu Thr Asn Thr Phe Ile
152515301535
Ile Ser Glu Thr Glu Ala Ser Gly Thr Met Gln Pro Ser Lys Ala Gly
154015451550
Glu Val Met Gly Ala Phe Glu Val Thr Gln Pro Thr Ala Asp Val Ala
155515601565
Met Leu Glu Pro Val Tyr Ser Gly Glu Ser Glu Val Thr Thr Thr Asp
157015751580
Lys Tyr Leu Glu Ile Thr Ser Val Tyr Glu Gln Ser Pro Lys Lys Asn
1585159015951600
Lys Glu Thr Val Met Trp His Gly Thr Glu Glu Ser Ser Thr Lys Asp
160516101615
Thr Lys Asn Leu Leu Leu Ile Thr Asn Glu Ser Ser Gly Asp Gly Ser
162016251630
Thr Glu Ser Asp Leu Ser Arg Ser Val Phe Thr Glu Ile Leu Thr Met
163516401645
Ser Ser His Glu Asp Ser Glu Lys Ile Ser His Thr Thr Ser Val Pro
165016551660
Thr Ile Leu Ser Val Glu Arg Ser Ala Val Thr Ala Ala Pro Ser Ala
1665167016751680
Asp Ser Asp Thr Ala Thr Val Gly Ile Asp Val Lys Asp Leu Ile Pro
168516901695
Lys Gly Gly Thr Ala Thr Pro Gly Asn Tyr Tyr Lys Ser Thr Ile Lys
170017051710
Leu Asp Ala Glu Phe Pro Phe Glu Ser Asn Pro Glu Ala Thr Ser His
171517201725
Thr Thr Lys Pro Asp Met Thr Ala Ser Ser Phe Ile Val Leu Glu Gly
173017351740
Ser Gly Asp Val Glu Glu Asn Ser Thr Leu Ala Ser Ala Met Thr Thr
1745175017551760
Glu Thr Ala Val Ala Glu Thr Leu Ser Val Gln Asp Thr Ser Leu Gly
176517701775
Ser Gly Thr Val Leu Pro Thr Glu Ile Ser Val Thr Ile Ser Glu Ile
178017851790
Thr Pro Ala Leu Pro Gly Gly Thr Arg Ile Leu Tyr Ser Thr Phe Asp
179518001805
Gln Ser Ser Glu Ala Thr Val Ser Thr Asn Phe Val Ser Glu Leu Ile
181018151820
Met Glu Gln Val Val Gly Ser Ser Val Ala Thr Glu Lys Lys Val Glu
1825183018351840
Asp Glu Lys Glu Val Gln Thr Thr Val Tyr Ser Ser Gln Glu Ile Ser
184518501855
Thr Thr Asp Ala Lys Gly Lys Ser Glu Leu Asp Glu Phe Gly Ser Thr
186018651870
Thr Asn Glu Val Arg Thr Val Ser Gln Glu Pro Thr Pro Leu Arg Glu
187518801885
Ile Val Pro Ile Thr Gly Thr Met His Ser Glu Ile Lys Lys Val Thr
189018951900
Ala Thr Pro Phe Leu Arg Glu Lys Leu Phe Ile Asn Glu Gly Ser Ala
1905191019151920
Glu Glu Pro Ala Asp Leu Phe Ala Gly Ser Pro Thr Arg Lys Val Val
192519301935
Ser Thr Asp Ser Pro Phe Thr Asp Ser Gly Ser Gly Asp Ile Asp Val
194019451950
Ile Thr Glu Ser Ala Thr Leu Thr Ser Val Pro Ser Arg Ser Val Ile
195519601965
Glu Thr Gln Thr Val Lys His Glu Gly Asn Ile Asn Val Ile Ser Val
197019751980
Ser Leu Lys Asn Thr Thr Thr Glu Tyr Glu Glu His Ile Gly Thr Gly
1985199019952000
Gly Pro Val Thr Ser Val Ser Ser Thr Gly Ser Asp Gly Leu Thr Glu
200520102015
Glu Ser Glu Val Ala Ile Glu Met Ser Glu Asn Val Phe Ser Thr Glu
202020252030
Asn Gln Gly Glu Pro Thr Gln Glu Ala Val Pro Thr Tyr Thr Ala Pro
203520402045
Ser Asp Ile Lys Ser Arg Leu Gly Ser Arg Arg Glu Val Thr Ser His
205020552060
Val Thr Pro Val Ile Arg Thr Lys Asp Leu Glu Thr Ala Glu Val Thr
2065207020752080
Ser Ser Pro Glu Ser Val Val Asn Asn Ser Thr Leu Asp Thr Met Val
208520902095
Thr His Gly Thr Ile Arg Ala Val Ala Glu Ser Thr Glu Ser Lys Lys
210021052110
Gly Lys Gly Ser Phe Ser Ala Val Ser Leu Gly Lys Ile Leu Met Ile
211521202125
Glu His Gly Ser Gly Glu Glu Leu Lys Val Asp Ser Ser Thr Thr Lys
213021352140
Leu Met Ser Asn Gly Pro Thr Glu Lys Leu Leu Gly Ser His Phe Ser
2145215021552160
Phe Phe Asp Gln Gly Ser Gly Glu Ala Glu Thr Leu Thr Glu Ser Phe
216521702175
Thr Lys Ala Ser Val Ser Pro Thr Gly Lys Pro Glu Pro Gln Glu Gln
218021852190
Tyr Gly Arg Lys Thr Val Ser Met Pro Ser Ala Val Val His Ala Tyr
219522002205
Thr Ala Glu Pro Asn Glu Leu Val Thr Ser Thr Glu His Asp Ile Thr
221022152220
Ser Leu Gln Thr Val Thr Asp Thr Glu Met Glu Glu Lys Ala Ala Asn
2225223022352240
Glu Leu Thr Val Thr Ser Phe Ala Thr Asn Leu Pro Leu Ser Glu Asp
224522502255
Val His Ser Trp Glu Asp Arg Pro Arg Glu Ile Leu Pro Lys Ala Ile
226022652270
Glu Ser Ser Gly Glu Ala Thr Glu Asp Pro Phe Phe Ile Ser Thr Gln
227522802285
Ala Asn His Glu His Val Glu Phe Leu Ser Val Pro Thr Ile Arg Pro
229022952300
His Ser Glu Glu Asn Lys Val Glu Ala Glu Ser Asp Glu Lys Ile Leu
2305231023152320
Leu Pro Phe Asn Asn Asp Arg Val Thr Glu Ser Ala Val Ile Glu Arg
232523302335
Lys Tyr Leu Ser Ser Pro Phe Thr Asp Thr Glu Gln Glu Glu Glu Leu
234023452350
Val Gln Asn Ile Phe Pro Thr Glu Asp Ile Pro Arg Leu Phe Leu Thr
235523602365
Pro Lys Glu Glu Lys Pro Thr Asn Asn Glu Leu Ile Ser Asp Pro Leu
237023752380
Phe Ser Gly Gln Gly Ser Gly Asp Glu Phe Thr Val Ile Pro Ser Val
2385239023952400
Glu Ser Leu Ala Val Lys Glu Thr Thr Asn Thr Leu Ser Pro Trp Pro
240524102415
Phe His Pro Ala Ser Val Gly Pro Lys Leu Ser Thr Asp Lys Thr Gln
242024252430
Val Phe Glu Ser Gly Ser Thr Asp Ser Asn Ala Glu Ile Asn Glu Glu
243524402445
Ile Thr Thr Thr Ala Ala Glu Leu Thr Glu Thr Ala Tyr Ser Met Ala
245024552460
Thr Ser Ser Pro Ala Leu Glu Glu Glu Ser Ser Ser His Ser Asn Ser
2465247024752480
Lys Asp Lys Asp Ile Thr His Tyr Phe Leu Val Ile Glu Asp Pro Tyr
248524902495
Asn Lys Glu Met Asp His Arg Arg Gly Glu Asn Gly Thr Ser Arg Pro
250025052510
Leu Pro Thr Pro Gly Asp Val Ser Leu Glu Glu Ser Ser His Met Leu
251525202525
Thr Thr Asp Asp Val Thr Pro Val Ser Val Ile Leu Ser Glu Thr Pro
253025352540
Tyr Leu Glu Met Gly Lys Ser Leu Ala Thr Ser Ala Thr Lys Met Pro
2545255025552560
Ser Arg Val Leu Pro Glu Ser Ser Gly Glu Gly Ser Gly Trp Asp Gly
256525702575
Val Ser Asp Ser Phe Ala Pro Asp Thr Leu Thr His Ser Thr Ala Pro
258025852590
Ser Val Met Glu Val Glu Leu Thr Ala Ser Ser His Ile Pro Gly Val
259526002605
Tyr Ser Glu Val Met Thr Thr His Val Pro Gly Asp Gly Ser Gln Thr
261026152620
Val Ile Thr Gly Leu Ala Ser Leu Phe Thr Glu Glu Lys Glu Ile Val
2625263026352640
Ala Asn Arg Thr Ala Ala Asp Pro Lys Thr Gly Thr Ser Glu Glu Leu
264526502655
Thr Ser Asp Thr Gly Met Ser Leu Asp Ile Ile Pro Val Val Asp Asp
266026652670
Arg Arg His Val Thr Leu Asn Val Ser Val Tyr Gly Asp Ile Thr Leu
267526802685
Ile Glu Glu Arg Leu Gln Ile Pro Ser Glu Lys Thr Thr Ile Ile Asp
269026952700
Met Asp His Ser Lys Ser Met Pro Glu Asp Ile Ile Ser Val Gln Thr
2705271027152720
Met Pro Asn Leu Val Ile Arg Ser Thr Gln Val Ser Asp Asp Asn Met
272527302735
Lys Ala Glu Glu Asp Lys Tyr Asp Ser Ile Leu Asn Phe Ser Thr Val
274027452750
Glu Glu Asn Ser Phe Gly Ser Gly Asp Asn Leu Ser Leu Thr Thr Ser
275527602765
Ile Gln Pro Ser Ser Glu Ser Val Thr Ala Gly His Gly Pro Lys Leu
277027752780
Val Asp Lys Asp Leu Gly Ser Gly Tyr Ala Met Gln Phe Ala Thr Glu
2785279027952800
Thr Leu Thr Thr Thr Val Leu Asn Glu Leu Gly Ile Phe Leu Pro Thr
280528102815
Val Pro Ser Leu Val Ser Pro His Met Pro His Glu Ser Lys Glu Ser
282028252830
Glu Phe Glu Ala Lys His Ile Gly Arg Thr Ser Thr Thr Asp Asp Val
283528402845
Tyr Glu Pro Tyr Thr Ser Ala Asn Asn Gln Val Ile Thr Asp Gln Ser
285028552860
Lys Thr Met Ser Ile Ser Gly Phe Ser Gly Met Gly Gln Glu Glu Ser
2865287028752880
Gly Asp Lys Lys Pro Met Ile Pro Ser Leu Thr Pro Asp Leu Thr Met
288528902895
Glu Thr Glu Lys Ala Leu Thr Thr Asp Thr Phe Asp Val Ser Met Val
290029052910
Thr Thr Gln Ser Met Ser Gln His Ala Thr Val Ser Ser Ser Ser Ser
291529202925
Glu Glu Lys His Ser Thr Val Tyr Met Gln Thr Lys Ser Ala Ser Thr
293029352940
Glu Tyr Glu Glu Thr Asp Ser Val Ser Leu Asn Ser Val Ser Gln Asn
2945295029552960
Pro Lys Ser Ser Val Thr Val Trp Leu Val Asn Gly Val Ser Lys Tyr
296529702975
Pro Glu Val Ile Ile Pro Ser Thr Ser Ser Ala Lys Asp Ser Asp Gln
298029852990
Ser Asp His Ser Ser Asp Gly Thr Phe Lys Glu Val Ser Ser Asp Met
299530003005
Ala Ala Thr Tyr Lys Pro Pro Thr Thr Asp Leu Asp Thr Thr Val Ser
301030153020
Ser Leu Leu Val Phe Ser Pro Glu Pro Glu Ser Glu Ser Ile Ser Thr
3025303030353040
Glu Ser Thr Pro His Phe Asn Lys Phe Val Thr Glu Arg Ser Glu Glu
304530503055
Thr Glu Ser Ser Val Asn Asp Leu Ile Ile Glu Glu Asn Ala Thr Val
306030653070
Ser Gly Asp Ser Pro Ser Ile His Asp Tyr Pro Thr Ala Phe Trp Asn
307530803085
Phe Gly Glu Arg Thr Ser Thr Asp Val Pro Lys Leu Ser Thr Ile Glu
309030953100
Val Glu Phe Ser Ser Glu Arg Val Lys Asn Pro Ser Gln Glu Ser Asp
3105311031153120
Arg Ser Thr Glu Arg Glu Arg Pro Arg Leu Ser Ser Ala Pro Val Ser
312531303135
Asp Ser Pro Asn Ser Ile Glu Val Gly Val Phe Lys Pro Asp Gln Glu
314031453150
Ala Val Thr Met Leu Thr Ser Ser Leu Glu Pro Leu Asp Arg Ser Leu
315531603165
Glu Thr Gln Ser Ala Leu Leu Gly Pro Leu Leu Gly Gln Gln Glu Ile
317031753180
Thr Thr Ile Ser Ser Asn Ile Ala Thr Asn Asn Thr Ala Pro Gly Asn
3185319031953200
Asn Pro Tyr Ser Asn Glu Gln Ser Thr Ile Ser Ser Glu Leu Leu Asn
320532103215
Thr Ile Glu Leu Val Thr Ser Ser Phe Ser Leu Pro Glu Val Thr Asn
322032253230
Gly Ser Asp Phe Leu Ile Gly Thr Ser Val Gly Ser Val Glu Gly Thr
323532403245
Ala Val Gln Ile Pro Gly Gln Asp Pro Cys Lys Ser Asn Pro Cys Leu
325032553260
Asn Gly Gly Thr Cys Tyr Pro Arg Gly Ser Phe Tyr Ile Cys Thr Cys
3265327032753280
Leu Pro Gly Phe Asn Gly Glu Gln Cys Glu Leu Asp Ile Asp Glu Cys
328532903295
Gln Ser Asn Pro Cys Arg Asn Gly Ala Thr Cys Ile Asp Gly Leu Asn
330033053310
Thr Phe Thr Cys Leu Cys Leu Pro Ser Tyr Ile Gly Ala Leu Cys Glu
331533203325
Gln Asp Thr Glu Thr Cys Asp Tyr Gly Trp His Lys Phe Gln Gly Gln
333033353340
Cys Tyr Lys Tyr Phe Ala His Arg Arg Thr Trp Asp Thr Ala Glu Arg
3345335033553360
Glu Cys Arg Leu Gln Gly Ala His Leu Thr Ser Ile Leu Ser His Glu
336533703375
Glu Gln Val Phe Val Asn Arg Ile Gly His Asp Tyr Gln Trp Ile Gly
338033853390
Leu Asn Asp Lys Met Phe Glu Arg Asp Phe Arg Trp Thr Asp Gly Ser
339534003405
Pro Leu Gln Tyr Glu Asn Trp Arg Pro Asn Gln Pro Asp Ser Phe Phe
341034153420
Ser Ala Gly Glu Asp Cys Val Val Ile Ile Trp His Glu Asn Gly Gln
3425343034353440
Trp Asn Asp Val Pro Cys Asn Tyr His Leu Thr Tyr Thr Cys Lys Lys
344534503455
Gly Thr Val Ala Cys Gly Gln Pro Pro Val Val Glu Asn Ala Lys Thr
346034653470
Phe Gly Lys Met Lys Pro Arg Tyr Glu Ile Asn Ser Leu Ile Arg Tyr
347534803485
His Cys Lys Asp Gly Phe Ile Gln Arg His Ile Pro Thr Ile Arg Cys
349034953500
Gln Gly Asn Gly Arg Trp Asp Met Pro Lys Ile Thr Cys Met Asn Pro
3505351035153520
Ser Thr Tyr Gln Arg Thr Tyr Ser Lys Lys Tyr Tyr Tyr Lys His Ser
352535303535
Ser Ser Gly Lys Gly Thr Ser Leu Asn Ser Ser Lys His Tyr His Arg
354035453550
Trp Ile Arg Thr Trp Gln Asp Ser Arg Arg
35553560
<210> 301
<211> 1268
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Neurocan P55066
<400> 301
Met Gly Ala Gly Ser Val Trp Ala Ser Gly Leu Leu Leu Leu Trp Leu
151015
Leu Leu Leu Val Ala Gly Asp Gln Asp Thr Gln Asp Thr Thr Ala Thr
202530
Glu Lys Gly Leu Arg Met Leu Lys Ser Gly Ser Gly Pro Val Arg Ala
354045
Ala Leu Ala Glu Leu Val Ala Leu Pro Cys Phe Phe Thr Leu Gln Pro
505560
Arg Leu Ser Ser Leu Arg Asp Ile Pro Arg Ile Lys Trp Thr Lys Val
65707580
Gln Thr Ala Ser Gly Gln Arg Gln Asp Leu Pro Ile Leu Val Ala Lys
859095
Asp Asn Val Val Arg Val Ala Lys Gly Trp Gln Gly Arg Val Ser Leu
100105110
Pro Ala Tyr Pro Arg His Arg Ala Asn Ala Thr Leu Leu Leu Gly Pro
115120125
Leu Arg Ala Ser Asp Ser Gly Leu Tyr Arg Cys Gln Val Val Lys Gly
130135140
Ile Glu Asp Glu Gln Asp Leu Val Thr Leu Glu Val Thr Gly Val Val
145150155160
Phe His Tyr Arg Ala Ala Arg Asp Arg Tyr Ala Leu Thr Phe Ala Glu
165170175
Ala Gln Glu Ala Cys Arg Leu Ser Ser Ala Thr Ile Ala Ala Pro Arg
180185190
His Leu Gln Ala Ala Phe Glu Asp Gly Phe Asp Asn Cys Asp Ala Gly
195200205
Trp Leu Ser Asp Arg Thr Val Arg Tyr Pro Ile Thr Gln Ser Arg Pro
210215220
Gly Cys Tyr Gly Asp Arg Ser Ser Leu Pro Gly Val Arg Ser Tyr Gly
225230235240
Arg Arg Asp Pro Gln Glu Leu Tyr Asp Val Tyr Cys Phe Ala Arg Glu
245250255
Leu Gly Gly Glu Val Phe Tyr Val Gly Pro Ala Arg Arg Leu Thr Leu
260265270
Ala Gly Ala Arg Ala Gln Cys Gln Arg Gln Gly Ala Ala Leu Ala Ser
275280285
Val Gly Gln Leu His Leu Ala Trp His Glu Gly Leu Asp Gln Cys Asp
290295300
Pro Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Gln Thr Pro
305310315320
Arg Arg Arg Cys Gly Gly Pro Ala Pro Gly Val Arg Thr Val Tyr Arg
325330335
Phe Ala Asn Arg Thr Gly Phe Pro Ala Pro Gly Ala Arg Phe Asp Ala
340345350
Tyr Cys Phe Arg Ala His His His Thr Ala Gln His Gly Asp Ser Glu
355360365
Ile Pro Ser Ser Gly Asp Glu Gly Glu Ile Val Ser Ala Glu Gly Pro
370375380
Pro Gly Arg Glu Leu Lys Pro Ser Leu Gly Glu Gln Glu Val Ile Ala
385390395400
Pro Asp Phe Gln Glu Pro Leu Met Ser Ser Gly Glu Gly Glu Pro Pro
405410415
Asp Leu Thr Trp Thr Gln Ala Pro Glu Glu Thr Leu Gly Ser Thr Pro
420425430
Gly Gly Pro Thr Leu Ala Ser Trp Pro Ser Ser Glu Lys Trp Leu Phe
435440445
Thr Gly Ala Pro Ser Ser Met Gly Val Ser Ser Pro Ser Asp Met Gly
450455460
Val Asp Met Glu Ala Thr Thr Pro Leu Gly Thr Gln Val Ala Pro Thr
465470475480
Pro Thr Met Arg Arg Gly Arg Phe Lys Gly Leu Asn Gly Arg His Phe
485490495
Gln Gln Gln Gly Pro Glu Asp Gln Leu Pro Glu Val Ala Glu Pro Ser
500505510
Ala Gln Pro Pro Thr Leu Gly Ala Thr Ala Asn His Met Arg Pro Ser
515520525
Ala Ala Thr Glu Ala Ser Glu Ser Asp Gln Ser His Ser Pro Trp Ala
530535540
Ile Leu Thr Asn Glu Val Asp Glu Pro Gly Ala Gly Ser Leu Gly Ser
545550555560
Arg Ser Leu Pro Glu Ser Leu Met Trp Ser Pro Ser Leu Ile Ser Pro
565570575
Ser Val Pro Ser Thr Glu Ser Thr Pro Ser Pro Lys Pro Gly Ala Ala
580585590
Glu Ala Pro Ser Val Lys Ser Ala Ile Pro His Leu Pro Arg Leu Pro
595600605
Ser Glu Pro Pro Ala Pro Ser Pro Gly Pro Ser Glu Ala Leu Ser Ala
610615620
Val Ser Leu Gln Ala Ser Ser Ala Asp Gly Ser Pro Asp Phe Pro Ile
625630635640
Val Ala Met Leu Arg Ala Pro Lys Leu Trp Leu Leu Pro Arg Ser Thr
645650655
Leu Val Pro Asn Met Thr Pro Val Pro Leu Ser Pro Ala Ser Pro Leu
660665670
Pro Ser Trp Val Pro Glu Glu Gln Ala Val Arg Pro Val Ser Leu Gly
675680685
Ala Glu Asp Leu Glu Thr Pro Phe Gln Thr Thr Ile Ala Ala Pro Val
690695700
Glu Ala Ser His Arg Ser Pro Asp Ala Asp Ser Ile Glu Ile Glu Gly
705710715720
Thr Ser Ser Met Arg Ala Thr Lys His Pro Ile Ser Gly Pro Trp Ala
725730735
Ser Leu Asp Ser Ser Asn Val Thr Met Asn Pro Val Pro Ser Asp Ala
740745750
Gly Ile Leu Gly Thr Glu Ser Gly Val Leu Asp Leu Pro Gly Ser Pro
755760765
Thr Ser Gly Gly Gln Ala Thr Val Glu Lys Val Leu Ala Thr Trp Leu
770775780
Pro Leu Pro Gly Gln Gly Leu Asp Pro Gly Ser Gln Ser Thr Pro Met
785790795800
Glu Ala His Gly Val Ala Val Ser Met Glu Pro Thr Val Ala Leu Glu
805810815
Gly Gly Ala Thr Glu Gly Pro Met Glu Ala Thr Arg Glu Val Val Pro
820825830
Ser Thr Ala Asp Ala Thr Trp Glu Ser Glu Ser Arg Ser Ala Ile Ser
835840845
Ser Thr His Ile Ala Val Thr Met Ala Arg Ala Gln Gly Met Pro Thr
850855860
Leu Thr Ser Thr Ser Ser Glu Gly His Pro Glu Pro Lys Gly Gln Met
865870875880
Val Ala Gln Glu Ser Leu Glu Pro Leu Asn Thr Leu Pro Ser His Pro
885890895
Trp Ser Ser Leu Val Val Pro Met Asp Glu Val Ala Ser Val Ser Ser
900905910
Gly Glu Pro Thr Gly Leu Trp Asp Ile Pro Ser Thr Leu Ile Pro Val
915920925
Ser Leu Gly Leu Asp Glu Ser Val Leu Asn Val Val Ala Glu Ser Pro
930935940
Ser Val Glu Gly Phe Trp Glu Glu Val Ala Ser Gly Gln Glu Asp Pro
945950955960
Thr Asp Pro Cys Glu Asn Asn Pro Cys Leu His Gly Gly Thr Cys His
965970975
Thr Asn Gly Thr Val Tyr Gly Cys Ser Cys Asp Gln Gly Tyr Ala Gly
980985990
Glu Asn Cys Glu Ile Asp Ile Asp Asp Cys Leu Cys Ser Pro Cys Glu
99510001005
Asn Gly Gly Thr Cys Ile Asp Glu Val Asn Gly Phe Ile Cys Leu Cys
101010151020
Leu Pro Ser Tyr Gly Gly Ser Leu Cys Glu Lys Asp Thr Glu Gly Cys
1025103010351040
Asp Arg Gly Trp His Lys Phe Gln Gly His Cys Tyr Arg Tyr Phe Ala
104510501055
His Arg Arg Ala Trp Glu Asp Ala Glu Arg Asp Cys Arg Arg Arg Ala
106010651070
Gly His Leu Thr Ser Val His Ser Pro Glu Glu His Lys Phe Ile Asn
107510801085
Ser Phe Gly His Glu Asn Ser Trp Ile Gly Leu Asn Asp Arg Thr Val
109010951100
Glu Arg Asp Phe Gln Trp Thr Asp Asn Thr Gly Leu Gln Tyr Glu Asn
1105111011151120
Trp Arg Glu Lys Gln Pro Asp Asn Phe Phe Ala Gly Gly Glu Asp Cys
112511301135
Val Val Met Val Ala His Glu Ser Gly Arg Trp Asn Asp Val Pro Cys
114011451150
Asn Tyr Asn Leu Pro Tyr Val Cys Lys Lys Gly Thr Val Leu Cys Gly
115511601165
Pro Pro Pro Ala Val Glu Asn Ala Ser Leu Val Gly Val Arg Lys Ile
117011751180
Lys Tyr Asn Val His Ala Thr Val Arg Tyr Gln Cys Asp Glu Gly Phe
1185119011951200
Ser Gln His Arg Val Ala Thr Ile Arg Cys Arg Asn Asn Gly Lys Trp
120512101215
Asp Arg Pro Gln Ile Met Cys Ile Lys Pro Arg Arg Ser His Arg Met
122012251230
Arg Arg His His His His Pro His Arg His His Lys Pro Arg Lys Glu
123512401245
His Arg Lys His Lys Arg His Pro Ala Glu Asp Trp Glu Lys Asp Glu
125012551260
Gly Asp Phe Cys
1265
<210> 302
<211> 1257
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat Neurocan P55067
<400> 302
Met Gly Ala Glu Ser Val Trp Ala Ser Gly Leu Leu Val Leu Trp Leu
151015
Leu Leu Leu Val Ser Gly Asp Gln Asp Thr Gln Asp Thr Thr Thr Thr
202530
Glu Lys Gly Leu His Met Leu Lys Ser Gly Ser Gly Pro Ile Gln Ala
354045
Ala Leu Ala Glu Leu Val Ala Leu Pro Cys Phe Phe Thr Leu Gln Pro
505560
Arg Gln Ser Pro Leu Gly Asp Ile Pro Arg Ile Lys Trp Thr Lys Val
65707580
Gln Thr Ala Ser Gly Gln Arg Gln Asp Leu Pro Ile Leu Val Ala Lys
859095
Asp Asn Val Val Arg Val Ala Lys Gly Trp Gln Gly Arg Val Ser Leu
100105110
Pro Ala Tyr Pro Arg His Arg Ala Asn Ala Thr Leu Leu Leu Gly Pro
115120125
Leu Arg Ala Ser Asp Ser Gly Leu Tyr Arg Cys Gln Val Val Lys Gly
130135140
Ile Glu Asp Glu Gln Asp Leu Val Thr Leu Glu Val Thr Gly Val Val
145150155160
Phe His Tyr Arg Ala Ala Arg Asp Arg Tyr Ala Leu Thr Phe Ala Glu
165170175
Ala Gln Glu Ala Cys His Leu Ser Ser Ala Thr Ile Ala Ala Pro Arg
180185190
His Leu Gln Ala Ala Phe Glu Asp Gly Phe Asp Asn Cys Asp Ala Gly
195200205
Trp Leu Ser Asp Arg Thr Val Arg Tyr Pro Ile Thr Gln Ser Arg Pro
210215220
Gly Cys Tyr Gly Asp Arg Ser Ser Leu Pro Gly Val Arg Ser Tyr Gly
225230235240
Arg Arg Asp Pro Gln Glu Leu Tyr Asp Val Tyr Cys Phe Ala Arg Glu
245250255
Leu Gly Gly Glu Val Phe Tyr Val Gly Pro Ala Arg Arg Leu Thr Leu
260265270
Ala Gly Ala Arg Ala Leu Cys Gln Arg Gln Gly Ala Ala Leu Ala Ser
275280285
Val Gly Gln Leu His Leu Ala Trp His Glu Gly Leu Asp Gln Cys Asp
290295300
Pro Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Gln Thr Pro
305310315320
Arg Arg Arg Cys Gly Gly Ser Ala Pro Gly Val Arg Thr Val Tyr Arg
325330335
Phe Ala Asn Arg Thr Gly Phe Pro Ala Pro Gly Ala Arg Phe Asp Ala
340345350
Tyr Cys Phe Arg Ala His His His Thr Pro Gln Arg Gly Asp Ser Glu
355360365
Ile Pro Ser Ser Gly Asp Glu Gly Glu Ile Val Ser Ala Glu Gly Pro
370375380
Pro Ala Pro Glu Leu Lys Pro Arg Leu Gly Glu Gln Glu Val Ile Thr
385390395400
Pro Asp Phe Gln Glu Pro Leu Val Ser Ser Gly Glu Asp Glu Pro Leu
405410415
Asp Leu Thr Arg Thr Gln Ala Ser Gln Glu Thr Leu Ala Ser Thr Pro
420425430
Gly Gly Pro Thr Leu Ala Ser Trp Leu Leu Thr Gly Val Thr Ser Ser
435440445
Thr Gly Val Pro Ser Pro Ser Ser Leu Gly Val Asp Met Glu Glu Thr
450455460
Thr Pro Ser Gly Thr Gln Val Ala Pro Thr Pro Thr Met Arg Arg Gly
465470475480
Arg Phe Lys Gly Leu Asn Gly Arg His Phe Gln Gln Gln Gly Pro Glu
485490495
Asp Gln Leu Leu Glu Ala Ala Glu Ala Ser Ala Gln Pro Pro Thr Leu
500505510
Glu Val Thr Ala Asp His Met Gly Pro Ser Ala Ala Thr Glu Ala Leu
515520525
Glu Ser Asp Gln Ser His Ser Pro Trp Ala Ile Leu Thr Asn Glu Val
530535540
Asp Val Pro Gly Ala Gly Ser Leu Gly Ser Arg Ser Leu Pro Glu Ser
545550555560
Arg Lys Trp Ser Pro Ser Leu Ile Ser Pro Ser Thr Val Pro Ser Thr
565570575
Asp Ser Thr Pro Gly Leu Lys Pro Gly Ala Asp Glu Ala Pro Gly Val
580585590
Lys Ser Ala Ile His His Pro Pro Trp Leu Pro Ser Glu Pro Ala Val
595600605
Pro Ser Ser Ile Pro Ser Glu Ala Leu Ser Ala Val Ser Leu Gln Ala
610615620
Ser Pro Gly Asp Gly Ser Pro Asp Phe Pro Ile Val Ala Met Leu Arg
625630635640
Ala Pro Lys Leu Trp Leu Leu Pro His Ser Thr Leu Val Pro Asn Val
645650655
Ser Pro Ile Pro Leu Ser Pro Ala Ser Pro Leu Pro Ser Ser Val Pro
660665670
Glu Glu Gln Ala Val Arg Pro Val Ser Phe Gly Ala Glu Asp Pro Glu
675680685
Thr Pro Phe Gln Thr Thr Met Ala Ala Pro Gly Glu Ala Ser His Gly
690695700
Ser Pro Glu Ala Asp Ser Ile Glu Ile Glu Gly Ile Ser Ser Met Gln
705710715720
Ala Thr Lys His Pro Ile Ser Gly Pro Trp Ala Ser Leu Asp Ser Ser
725730735
Asn Val Thr Val Asn Pro Val Pro Ser Asp Ala Gly Ile Leu Gly Thr
740745750
Glu Ser Gly Val Leu Asp Leu Pro Gly Ser Pro Thr Ser Asp Gly Gln
755760765
Ala Thr Val Asp Met Val Leu Ala Thr Trp Leu Pro Leu Pro Gly His
770775780
Gly Leu Asp Thr Gly Ser Gln Ser Thr Pro Met Glu Ala His Gly Val
785790795800
Thr Met Ser Val Glu Pro Thr Val Ala Leu Glu Gly Gly Ala Thr Lys
805810815
Asp Pro Met Glu Ala Thr Met Asp Val Val Pro Ser Thr Val Asp Ala
820825830
Thr Ser Gly Ser Glu Pro Lys Ser Ser Ile Ser Ser Thr His Val Val
835840845
Val Thr Ala Ala Gly Asp Gln Gly Thr Pro Thr Leu Thr Pro Thr Ser
850855860
Ser Glu Gly Gln Val Val Ala Gln Glu Ser Leu Gly Thr Leu Thr Ser
865870875880
Leu Pro Ser His Pro Trp Ser Ser Leu Ala Ser Ser Met Asp Glu Val
885890895
Ala Ser Val Ser Ser Gly Glu Pro Thr Arg Leu Trp Asp Ile Pro Ser
900905910
Thr Leu Ile Pro Val Ser Leu Gly Leu Asp Glu Ser Asp Leu Lys Val
915920925
Val Ala Glu Ser Pro Gly Leu Glu Gly Phe Trp Glu Glu Val Ala Ser
930935940
Gly Gln Glu Asp Pro Thr Asp Pro Cys Glu Asn Asn Pro Cys Leu His
945950955960
Gly Gly Thr Cys Arg Thr Asn Gly Thr Met Tyr Gly Cys Ser Cys Asp
965970975
Gln Gly Tyr Ala Gly Glu Asn Cys Glu Ile Asp Ile Asp Asp Cys Leu
980985990
Cys Ser Pro Cys Glu Asn Gly Gly Thr Cys Ile Asp Glu Val Asn Gly
99510001005
Phe Ile Cys Leu Cys Leu Pro Ser Tyr Gly Gly Asn Leu Cys Glu Lys
101010151020
Asp Thr Glu Gly Cys Asp Arg Gly Trp His Lys Phe Gln Gly His Cys
1025103010351040
Tyr Arg Tyr Phe Ala His Arg Arg Ala Trp Glu Asp Ala Glu Arg Asp
104510501055
Cys Arg Arg Arg Ala Gly His Leu Thr Ser Val His Ser Pro Glu Glu
106010651070
His Lys Phe Ile Asn Ser Phe Gly His Glu Asn Ser Trp Ile Gly Leu
107510801085
Asn Asp Arg Thr Val Glu Arg Asp Phe Gln Trp Thr Asp Asn Thr Gly
109010951100
Leu Gln Tyr Glu Asn Trp Arg Glu Lys Gln Pro Asp Asn Phe Phe Ala
1105111011151120
Gly Gly Glu Asp Cys Val Val Met Val Ala His Glu Asn Gly Arg Trp
112511301135
Asn Asp Val Pro Cys Asn Tyr Asn Leu Pro Tyr Val Cys Lys Lys Gly
114011451150
Thr Val Leu Cys Gly Pro Pro Pro Ala Val Glu Asn Ala Ser Leu Val
115511601165
Gly Val Arg Lys Val Lys Tyr Asn Val His Ala Thr Val Arg Tyr Gln
117011751180
Cys Asp Glu Gly Phe Ser Gln His His Val Ala Thr Ile Arg Cys Arg
1185119011951200
Ser Asn Gly Lys Trp Asp Arg Pro Gln Ile Val Cys Thr Lys Pro Arg
120512101215
Arg Ser His Arg Met Arg Arg His His His His Pro His Arg His His
122012251230
Lys Pro Arg Lys Glu His Arg Lys His Lys Arg His Pro Ala Glu Asp
123512401245
Trp Glu Lys Asp Glu Gly Asp Phe Cys
12501255
<210> 303
<211> 1321
<212> PRT
<213> Pan troglodytes
<220>
<223> Chimpanzee Neurocan Q51S41
<400> 303
Met Gly Thr Pro Phe Val Trp Ala Leu Gly Leu Leu Met Leu Gln Met
151015
Leu Leu Phe Val Ala Gly Glu Gln Gly Thr Gln Asp Ile Ala Asp Ala
202530
Ser Glu Arg Gly Leu His Met Gln Lys Leu Gly Ser Gly Ser Val Gln
354045
Ala Ala Leu Ala Glu Leu Val Ala Leu Pro Cys Leu Phe Thr Leu Gln
505560
Pro Gln Pro Ser Ala Ala Arg Asp Ala Pro Arg Ile Lys Trp Thr Lys
65707580
Val Arg Thr Ala Ser Gly Gln Arg Gln Asp Leu Pro Ile Leu Val Ala
859095
Lys Asp Asn Val Val Lys Val Ala Lys Ser Trp Gln Gly Arg Val Ser
100105110
Leu Pro Ser Tyr Pro Arg Arg Arg Ala Asn Ala Thr Leu Leu Leu Gly
115120125
Pro Leu Arg Ala Ser Asp Ser Gly Leu Tyr Arg Cys Gln Val Val Arg
130135140
Gly Ile Glu Asp Glu Gln Asp Leu Val Pro Leu Glu Val Thr Gly Val
145 150155160
Val Phe His Tyr Arg Ser Ala Arg Asp Arg Tyr Ala Leu Thr Phe Ala
165170175
Glu Ala Gln Glu Ala Cys Arg Leu Ser Ser Ala Ile Ile Ala Ala Pro
180185190
Arg His Leu Gln Ala Ala Phe Glu Asp Gly Phe Asp Asn Cys Asp Ala
195200205
Gly Trp Leu Ser Asp Arg Thr Val Arg Tyr Pro Ile Thr Gln Ser Arg
210215220
Pro Gly Cys Tyr Gly Asp Arg Ser Ser Leu Pro Gly Val Arg Ser Tyr
225230235240
Gly Arg Arg Asn Pro Gln Glu Leu Tyr Asp Val Tyr Cys Phe Ala Arg
245250255
Glu Leu Gly Gly Glu Val Phe Tyr Val Gly Pro Ala Arg Arg Leu Thr
260265270
Leu Ala Gly Ala Arg Ala Gln Cys Arg Arg Gln Gly Ala Ala Leu Ala
275280285
Ser Val Gly Gln Leu His Leu Ala Trp His Glu Gly Leu Asp Gln Cys
290295300
Asp Pro Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Gln Thr
305310315320
Pro Arg Arg Arg Cys Gly Gly Pro Ala Pro Gly Val Arg Thr Val Tyr
325330335
Arg Phe Ala Asn Arg Thr Gly Phe Pro Ser Pro Ala Glu Arg Phe Asp
340345350
Ala Tyr Cys Phe Arg Ala His His Pro Thr Ser Gln His Gly Asp Leu
355360365
Glu Thr Pro Ser Ser Gly Asp Glu Gly Glu Ile Leu Ser Ala Glu Gly
370375380
Pro Pro Val Arg Glu Leu Glu Pro Thr Leu Glu Glu Glu Glu Val Val
385390395400
Thr Pro Asp Phe Gln Glu Pro Leu Val Ser Ser Gly Glu Glu Glu Pro
405410415
Leu Ile Leu Glu Glu Lys Gln Glu Ser Gln Gln Thr Leu Ser Pro Thr
420425430
Pro Gly Asp Pro Met Leu Ala Ser Trp Pro Thr Gly Glu Val Trp Leu
435440445
Ser Thr Val Ala Pro Ser Pro Ser Asp Met Gly Ala Gly Thr Ala Ala
450455460
Ser Ser His Thr Glu Val Ala Pro Thr Asp Pro Met Pro Arg Arg Arg
465470475480
Gly Arg Phe Lys Gly Leu Asn Gly Arg Tyr Phe Gln Gln Gln Glu Pro
485490495
Glu Pro Gly Leu Gln Gly Gly Met Glu Ala Ser Ala Gln Pro Pro Thr
500505510
Ser Glu Ala Ala Gly Asn Gln Met Glu Pro Pro Leu Ala Met Ala Val
515520525
Thr Glu Met Leu Gly Ser Gly Gln Ser Arg Ser Pro Trp Ala Asp Leu
530535540
Thr Asn Glu Val Asp Met Pro Gly Ala Gly Ser Ala Gly Gly Lys Ser
545550555560
Ser Pro Glu Pro Trp Leu Trp Pro Pro Thr Met Val Pro Pro Ser Ile
565570575
Ser Gly His Ser Arg Ala Pro Val Leu Glu Leu Glu Lys Ala Glu Gly
580585590
Pro Ser Ala Arg Pro Ala Thr Pro Asp Leu Phe Trp Ser Pro Leu Glu
595600605
Ala Thr Val Ser Ala Pro Ser Pro Ala Pro Trp Glu Ala Phe Pro Val
610615620
Ala Thr Ser Pro Asp Leu Pro Met Met Ala Met Leu Arg Gly Pro Lys
625630635640
Glu Trp Met Leu Pro His Pro Thr Pro Ile Ser Thr Glu Ala Asn Arg
645650655
Val Glu Ala His Gly Glu Ala Thr Thr Thr Pro Pro Pro Ser Pro Ala
660665670
Ala Glu Thr Lys Val Tyr Ser Leu Pro Leu Ser Leu Thr Pro Thr Gly
675680685
Gln Gly Gly Glu Ala Met Pro Thr Thr Pro Glu Ser Pro Gly Ala Asp
690695700
Phe Arg Glu Thr Gly Glu Thr Ser Pro Ala Gln Val Asn Lys Ala Glu
705710715720
His Ser Ser Ser Ser Pro Trp Pro Ser Val Asn Arg Asn Val Ala Val
725730735
Gly Phe Val Pro Thr Glu Thr Ala Thr Glu Pro Thr Gly Leu Arg Gly
740745750
Ile Ser Gly Ser Glu Ser Gly Val Leu Asp Thr Ala Glu Ser Pro Thr
755760765
Ser Gly Leu Gln Ala Thr Val Asp Glu Val Gln Asp Pro Trp Pro Ser
770775780
Val Tyr Ser Lys Gly Leu Gly Ala Ser Ser Pro Ser Ala Pro Leu Gly
785790795800
Ser Pro Gly Val Phe Leu Val Pro Lys Val Thr Pro Ser Leu Glu Pro
805810815
Trp Val Ala Thr Asp Glu Gly Pro Thr Val Asn Pro Met Asp Ser Thr
820825830
Val Thr Leu Ala Pro Ser Asp Ala Ser Gly Ile Trp Glu Pro Gly Ser
835840845
Gln Val Phe Glu Glu Ala Glu Ser Thr Thr Leu Ser Pro Gln Val Ala
850855860
Leu Asp Thr Ser Ile Val Thr Pro Leu Thr Thr Leu Glu Gln Gly Asp
865870875880
Lys Val Gly Val Pro Ala Met Ser Thr Leu Gly Ser Ser Ser Ser Gln
885890895
Pro His Pro Glu Pro Glu Asp Gln Val Glu Thr Gln Gly Thr Ser Gly
900905910
Ala Ser Val Pro Pro His Gln Ser Ser Pro Leu Gly Lys Pro Ala Val
915920925
Pro Pro Gly Thr Pro Thr Ala Ala Ser Val Gly Glu Ser Ala Ser Val
930935940
Ser Ser Gly Glu Pro Thr Val Pro Trp Asp Pro Ser Ser Thr Leu Leu
945950955960
Pro Val Thr Leu Gly Ile Glu Asp Phe Glu Leu Glu Val Leu Ala Gly
965970975
Ser Pro Gly Val Glu Ser Phe Trp Glu Glu Val Ala Ser Gly Glu Glu
980985990
Pro Ala Leu Pro Gly Thr Pro Met Lys Ala Gly Ala Glu Glu Val His
99510001005
Ser Asp Pro Cys Glu Asn Asn Pro Cys Leu His Gly Gly Thr Cys Asn
101010151020
Ala Asn Gly Thr Met Tyr Gly Cys Ser Cys Asp Gln Gly Phe Ala Gly
1025103010351040
Glu Asn Cys Glu Ile Asp Ile Asp Asp Cys Leu Cys Ser Pro Cys Glu
104510501055
Asn Gly Gly Thr Cys Ile Asp Glu Val Asn Gly Phe Val Cys Leu Cys
106010651070
Leu Pro Ser Tyr Gly Gly Ser Phe Cys Glu Lys Asp Thr Glu Gly Cys
107510801085
Asp Arg Gly Trp His Lys Phe Gln Gly His Cys Tyr Arg Tyr Phe Ala
109010951100
His Arg Arg Ala Trp Glu Asp Ala Glu Arg Asp Cys Arg Arg Arg Ser
1105111011151120
Gly His Leu Thr Ser Val His Ser Ser Glu Glu His Ser Phe Ile Asn
112511301135
Ser Phe Gly His Glu Asn Thr Trp Ile Gly Leu Asn Asp Arg Ile Val
114011451150
Glu Arg Asp Phe Gln Trp Thr Asp Asn Thr Gly Leu Gln Phe Glu Asn
115511601165
Trp Arg Glu Asn Gln Pro Asp Asn Phe Phe Ala Gly Gly Glu Asp Cys
117011751180
Val Val Met Val Ala His Glu Ser Gly Arg Trp Asn Asp Val Pro Cys
1185119011951200
Asn Tyr Asn Leu Pro Tyr Val Cys Lys Lys Gly Thr Val Leu Cys Gly
120512101215
Pro Pro Pro Ala Val Glu Asn Ala Ser Leu Ile Gly Ala Arg Lys Ala
122012251230
Lys Tyr Asn Val His Ala Thr Val Arg Tyr Gln Cys Asn Glu Gly Phe
123512401245
Ala Gln His His Val Ala Thr Ile Arg Cys Arg Ser Asn Gly Lys Trp
125012551260
Asp Arg Pro Gln Ile Val Cys Thr Lys Pro Arg Arg Ser His Arg Met
1265127012751280
Arg Arg His His His His His Gln His His His Gln His His His His
128512901295
Lys Ser Arg Lys Glu Arg Arg Lys His Lys Lys His Pro Thr Glu Asp
130013051310
Trp Glu Lys Asp Glu Gly Asn Phe Cys
13151320
<210> 304
<211> 381
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Layilin Q8C351
<400> 304
Met Gln Pro Gly Ala Ala Leu Gln Ala Met Leu Leu Ala Val Leu Leu
151015
Ala Lys Pro Arg Asp Ser Lys Gly Arg Leu Leu Ser Ala Ser Asp Leu
202530
Asp Pro Arg Gly Gly Gln Leu Val Cys Arg Gly Gly Thr Arg Arg Pro
354045
Cys Tyr Lys Val Ile Tyr Phe His Asp Ala Phe Gln Arg Leu Asn Phe
50 5560
Glu Glu Ala Lys Glu Thr Cys Met Glu Asp Gly Gly Gln Leu Val Ser
65707580
Ile Glu Thr Glu Asp Glu Gln Arg Leu Ile Glu Lys Phe Ile Glu Asn
859095
Leu Leu Ala Ser Asp Gly Asp Phe Trp Ile Gly Leu Lys Arg Leu Glu
100105110
Glu Lys Gln Ser Asn Asn Thr Ala Cys Gln Asp Leu Tyr Ala Trp Thr
115120125
Asp Gly Ser Thr Ser Gln Phe Arg Asn Trp Tyr Val Asp Glu Pro Ser
130135140
Cys Gly Ser Glu Val Cys Val Val Met Tyr His Gln Pro Ser Ala Pro
145150155160
Pro Gly Ile Gly Gly Ser Tyr Met Phe Gln Trp Asn Asp Asp Arg Cys
165170175
Asn Met Lys Asn Asn Phe Ile Cys Lys Tyr His Asp Asp Lys Pro Ser
180185190
Thr Thr Pro Ser Ile Trp Pro Gly Gly Glu Ala Thr Glu Pro Ala Thr
195200205
Pro Leu Leu Pro Glu Glu Thr Gln Lys Glu Asp Thr Lys Glu Thr Phe
210215220
Lys Glu Arg Arg Glu Ala Ala Leu Asn Leu Ala Tyr Ile Leu Ile Pro
225230235240
Ser Ile Pro Leu Phe Leu Leu Leu Val Val Thr Ser Ala Val Cys Trp
245250255
Val Trp Ile Cys Arg Arg Lys Arg Glu Gln Thr Asp Pro Ser Thr Lys
260265270
Glu Gln His Thr Ile Trp Pro Thr Pro Arg Gln Glu Asn Ser Pro Asn
275280285
Leu Asp Val Tyr Asn Val Ile Arg Lys Gln Ser Glu Ala Asp Leu Ala
290295300
Glu Pro Arg Pro Asp Leu Lys Asn Ile Ser Phe Arg Val Cys Ser Gly
305310315320
Glu Ala Met Pro Asp Asp Met Ser Cys Asp Tyr Glu Asn Ile Ala Val
325330335
Asn Pro Ser Glu Ser Gly Phe Val Thr Leu Ala Ser Met Glu Ser Gly
340345350
Phe Val Thr Asn Asp Ile Tyr Glu Phe Ser Pro Asp Arg Met Gly Arg
355360365
Ser Lys Glu Ser Gly Trp Val Glu Asn Glu Ile Tyr Tyr
370375380
<210> 305
<211> 374
<212> PRT
<213> Cricetulus griseus
<220>
<223> Chinese Hamster Layilin Q9Z209
<400> 305
Met Gln Pro Gly Pro Ala Leu Gln Ala Val Leu Leu Ala Val Leu Leu
151015
Ser Glu Pro Arg Ser Ser Lys Gly Arg Leu Leu Ser Gly Gln Leu Val
202530
Cys Arg Gly Gly Thr Arg Arg Pro Cys Tyr Lys Val Ile Tyr Phe His
354045
Asp Ala Phe Gln Arg Leu Asn Phe Glu Glu Ala Lys Glu Ala Cys Arg
505560
Arg Asp Gly Gly Gln Leu Val Ser Ile Glu Thr Glu Asp Glu Gln Arg
65707580
Leu Ile Glu Lys Phe Ile Glu Asn Leu Leu Ala Ser Asp Gly Asp Phe
859095
Trp Ile Gly Leu Arg Arg Leu Glu Val Lys Gln Val Asn Asn Thr Ala
100105110
Cys Gln Asp Leu Tyr Ala Trp Thr Asp Gly Ser Thr Ser Gln Phe Arg
115120125
Asn Trp Tyr Val Asp Glu Pro Ser Cys Gly Ser Glu Val Cys Val Val
130135140
Met Tyr His Gln Pro Ser Ala Pro Pro Gly Ile Gly Gly Ser Tyr Met
145150155160
Phe Gln Trp Asn Asp Asp Arg Cys Asn Met Lys Asn Asn Phe Ile Cys
165170175
Lys Tyr Ala Asp Glu Lys Pro Ser Thr Thr Pro Ser Ile Arg Pro Gly
180185190
Gly Glu Ala Thr Glu Pro Pro Thr Pro Val Leu Pro Glu Glu Thr Gln
195200205
Lys Glu Asp Thr Lys Glu Thr Phe Lys Glu Ser Arg Glu Ala Ala Leu
210215220
Asn Leu Ala Tyr Ile Leu Ile Pro Ser Ile Pro Leu Phe Leu Leu Leu
225 230235240
Val Val Thr Ser Ala Ala Cys Trp Val Trp Ile Cys Arg Arg Arg Lys
245250255
Gln Glu Gln Pro Asp Pro Thr Thr Lys Glu Gln His Thr Ile Trp Pro
260265270
Thr Pro His Gln Glu Asn Ser Pro Asn Leu Asp Val Tyr Asn Val Ile
275280285
Arg Lys Gln Ser Glu Ala Asp Leu Thr Glu Pro Arg Pro Asp Leu Lys
290295300
Asn Ile Ser Phe Arg Val Cys Ser Ser Glu Ala Pro Pro Asp Asp Ile
305310315320
Ser Cys Asp Tyr Asp Asn Met Ala Val Asn Pro Ser Glu Ser Gly Phe
325330335
Val Thr Leu Ala Ser Met Glu Ser Gly Phe Val Thr Asn Asp Ile Tyr
340345350
Glu Phe Ser Pro Asp Arg Met Gly Arg Ser Lys Glu Ser Gly Trp Val
355360365
Glu Asn Glu Ile Tyr Tyr
370
<210> 306
<211> 376
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat Layilin NP_001178926
<400> 306
Met Gln Pro Gly Ala Ala Leu Gln Ala Met Leu Leu Ala Val Leu Leu
151015
Ala Lys Pro Arg Asp Ser Lys Gly His Leu Leu Ser Gly Asp Leu Asp
202530
Pro Arg Gly Gly Gln Arg Phe Cys Trp Glu Gly Thr Arg Arg Pro Cys
354045
Tyr Arg Val Ile Tyr Phe His Asp Thr Ser Gln Arg Arg Asn Phe Glu
505560
Glu Ala Lys Glu Ala Cys Met Lys Asp Gly Gly Gln Leu Ala Ser Ile
65707580
Glu Thr Ala Asp Glu Gln Arg Leu Ile Glu Asn Phe Ile Glu Ser Leu
859095
Gln Ala Ser Asp Gly Asp Phe Trp Ile Gly Leu Lys Arg Leu Glu Glu
100105110
Lys Gln His Asn Ser Thr Ala Cys Gln Asp Leu Tyr Ala Trp Thr Asp
115120125
Gly Ser Leu Ser Gln Phe Arg Asn Trp Tyr Met Asp Glu Pro Ser Cys
130135140
Glu Ser Glu Val Cys Val Val Met Tyr His Gln Pro Ser Ala Pro Pro
145150155160
Gly Ile Gly Gly Pro Tyr Met Phe Gln Trp Asn Asp Asp Arg Cys Asn
165170175
Thr Lys Lys Asn Phe Ile Cys Lys Tyr Ser Asp Asp Lys Pro Ser Thr
180185190
Thr Pro Ser Leu Ser Pro Gly Gly Glu Ala Thr Glu Pro Ala Ala Pro
195200205
Ile Leu Pro Glu Glu Thr Leu Glu Ile Asp Thr Lys Glu Arg Arg Glu
210215220
Ala Ala Leu Asn Leu Ala Tyr Ile Leu Ile Pro Ser Ile Pro Leu Phe
225230235240
Leu Leu Leu Val Val Thr Ser Ala Val Cys Trp Val Trp Ile Cys Arg
245250255
Arg Lys Arg Glu Gln Thr Asp Pro Pro Thr Lys Glu Gln His Thr Ile
260265270
Trp Pro Thr Pro His Gln Glu Asn Ser Pro Asp Leu Glu Val Tyr Asn
275280285
Val Ile Arg Lys Gln Ser Glu Ala Asp Leu Ala Glu Pro Arg Pro Asp
290295300
Leu Lys Asn Ile Ser Phe Arg Val Cys Ser Gly Glu Ala Met Pro Asp
305310315320
Asp Thr Ser Cys Asp Tyr Asp Asn Met Val Ile Asn Pro Ser Glu Ser
325330335
Gly Leu Val Thr Leu Ala Ser Met Glu Gly Arg Phe Val Thr Asn Asp
340345350
Ile Tyr Glu Phe Ser Pro Asp Arg Met Gly Arg Ser Lys Glu Ser Gly
355360365
Trp Val Glu Asn Glu Ile Tyr Tyr
370375
<210> 307
<211> 794
<212> PRT
<213> Mus musculus
<220>
<223> Mouse RHAMM Q00547
<400> 307
Met Ser Phe Pro Lys Ala Pro Leu Lys Arg Phe Asn Asp Pro Ser Gly
151015
Cys Ala Pro Ser Pro Gly Ala Tyr Asp Val Lys Thr Ser Glu Ala Thr
202530
Lys Gly Pro Val Ser Phe Gln Lys Ser Gln Arg Phe Lys Asn Gln Arg
354045
Glu Ser Gln Gln Asn Leu Asn Ile Asp Lys Asp Thr Thr Leu Leu Ala
505560
Ser Ala Lys Lys Ala Lys Lys Ser Val Ser Lys Lys Asp Ser Gln Lys
65707580
Asn Asp Lys Asp Val Lys Arg Leu Glu Lys Glu Ile Arg Ala Leu Leu
859095
Gln Glu Arg Gly Thr Gln Asp Lys Arg Ile Gln Asp Met Glu Ser Glu
100105110
Leu Glu Lys Thr Glu Ala Lys Leu Asn Ala Ala Val Arg Glu Lys Thr
115120125
Ser Leu Ser Ala Ser Asn Ala Ser Leu Glu Lys Arg Leu Thr Glu Leu
130135140
Thr Arg Ala Asn Glu Leu Leu Lys Ala Lys Phe Ser Glu Asp Gly His
145150155160
Gln Lys Asn Met Arg Ala Leu Ser Leu Glu Leu Met Lys Leu Arg Asn
165170175
Lys Arg Glu Thr Lys Met Arg Ser Met Met Val Lys Gln Glu Gly Met
180 185190
Glu Leu Lys Leu Gln Ala Thr Gln Lys Asp Leu Thr Glu Ser Lys Gly
195200205
Lys Ile Val Gln Leu Glu Gly Lys Leu Val Ser Ile Glu Lys Glu Lys
210215220
Ile Asp Glu Lys Cys Glu Thr Glu Lys Leu Leu Glu Tyr Ile Gln Glu
225230235240
Ile Ser Cys Ala Ser Asp Gln Val Glu Lys Cys Lys Val Asp Ile Ala
245250255
Gln Leu Glu Glu Asp Leu Lys Glu Lys Asp Arg Glu Ile Leu Ser Leu
260265270
Lys Gln Ser Leu Glu Glu Asn Ile Thr Phe Ser Lys Gln Ile Glu Asp
275280285
Leu Thr Val Lys Cys Gln Leu Leu Glu Thr Glu Arg Asp Asn Leu Val
290295300
Ser Lys Asp Arg Glu Arg Ala Glu Thr Leu Ser Ala Glu Met Gln Ile
305310315320
Leu Thr Glu Arg Leu Ala Leu Glu Arg Gln Glu Tyr Glu Lys Leu Gln
325330335
Gln Lys Glu Leu Gln Ser Gln Ser Leu Leu Gln Gln Glu Lys Glu Leu
340345350
Ser Ala Arg Leu Gln Gln Gln Leu Cys Ser Phe Gln Glu Glu Met Thr
355360365
Ser Glu Lys Asn Val Phe Lys Glu Glu Leu Lys Leu Ala Leu Ala Glu
370375380
Leu Asp Ala Val Gln Gln Lys Glu Glu Gln Ser Glu Arg Leu Val Lys
385390395400
Gln Leu Glu Glu Glu Thr Lys Ser Thr Ala Glu Gln Leu Thr Arg Leu
405410415
Asp Asn Leu Leu Arg Glu Lys Glu Val Glu Leu Glu Lys His Ile Ala
420425430
Ala His Ala Gln Ala Ile Leu Ile Ala Gln Glu Lys Tyr Asn Asp Thr
435440445
Ala Gln Ser Leu Arg Asp Val Thr Ala Gln Leu Glu Ser Val Gln Glu
450455460
Lys Tyr Asn Asp Thr Ala Gln Ser Leu Arg Asp Val Thr Ala Gln Leu
465470475480
Glu Ser Glu Gln Glu Lys Tyr Asn Asp Thr Ala Gln Ser Leu Arg Asp
485490495
Val Thr Ala Gln Leu Glu Ser Glu Gln Glu Lys Tyr Asn Asp Thr Ala
500505510
Gln Ser Leu Arg Asp Val Thr Ala Gln Leu Glu Ser Val Gln Glu Lys
515520525
Tyr Asn Asp Thr Ala Gln Ser Leu Arg Asp Val Thr Ala Gln Leu Glu
530535540
Ser Tyr Lys Ser Ser Thr Leu Lys Glu Ile Glu Asp Leu Lys Leu Glu
545550555560
Asn Leu Thr Leu Gln Glu Lys Val Ala Met Ala Glu Lys Ser Val Glu
565570575
Asp Val Gln Gln Gln Ile Leu Thr Ala Glu Ser Thr Asn Gln Glu Tyr
580585590
Ala Arg Met Val Gln Asp Leu Gln Asn Arg Ser Thr Leu Lys Glu Glu
595600605
Glu Ile Lys Glu Ile Thr Ser Ser Phe Leu Glu Lys Ile Thr Asp Leu
610615620
Lys Asn Gln Leu Arg Gln Gln Asp Glu Asp Phe Arg Lys Gln Leu Glu
625630635640
Glu Lys Gly Lys Arg Thr Ala Glu Lys Glu Asn Val Met Thr Glu Leu
645650655
Thr Met Glu Ile Asn Lys Trp Arg Leu Leu Tyr Glu Glu Leu Tyr Glu
660665670
Lys Thr Lys Pro Phe Gln Gln Gln Leu Asp Ala Phe Glu Ala Glu Lys
675680685
Gln Ala Leu Leu Asn Glu His Gly Ala Thr Gln Glu Gln Leu Asn Lys
690695700
Ile Arg Asp Ser Tyr Ala Gln Leu Leu Gly His Gln Asn Leu Lys Gln
705710715720
Lys Ile Lys His Val Val Lys Leu Lys Asp Glu Asn Ser Gln Leu Lys
725730735
Ser Glu Val Ser Lys Leu Arg Ser Gln Leu Val Lys Arg Lys Gln Asn
740745750
Glu Leu Arg Leu Gln Gly Glu Leu Asp Lys Ala Leu Gly Ile Arg His
755760765
Phe Asp Pro Ser Lys Ala Phe Cys His Ala Ser Lys Glu Asn Phe Thr
770775780
Pro Leu Lys Glu Gly Asn Pro Asn Cys Cys
785790
<210> 308
<211> 498
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat RHAMM Q9WUF7
<400> 308
Met Gly Gly Gly Val Ser Tyr Val Gly Trp Leu Glu Lys Ser Glu Thr
151015
Glu Lys Leu Leu Glu Tyr Ile Glu Glu Ile Ser Cys Ala Ser Asp Gln
202530
Val Glu Lys Tyr Lys Leu Asp Ile Ala Gln Leu Glu Glu Asp Leu Lys
354045
Glu Lys Asp Arg Glu Ile Leu Cys Leu Lys Gln Ser Leu Glu Glu Lys
505560
Val Ser Phe Ser Lys Gln Ile Glu Asp Leu Thr Val Lys Cys Gln Leu
65707580
Leu Glu Ala Glu Arg Asp Asp Leu Val Ser Lys Asp Arg Glu Arg Ala
859095
Glu Ser Leu Ser Ala Glu Met Gln Val Leu Thr Glu Lys Leu Leu Leu
100105110
Glu Arg Gln Glu Tyr Glu Lys Leu Gln Gln Asn Glu Leu Gln Ser Gln
115120125
Ser Leu Leu Gln Gln Glu Lys Glu Leu Ser Ala His Leu Gln Gln Gln
130135140
Leu Cys Ser Phe Gln Glu Glu Met Thr Ser Glu Arg Asn Val Phe Lys
145150155160
Glu Gln Leu Lys Leu Ala Leu Asp Glu Leu Asp Ala Val Gln Gln Lys
165170175
Glu Glu Gln Ser Glu Lys Leu Val Lys Gln Leu Glu Glu Glu Thr Lys
180185190
Ser Thr Ala Glu Gln Leu Arg Arg Leu Asp Asp Leu Leu Arg Glu Lys
195200205
Glu Ile Glu Leu Glu Lys Arg Thr Ala Ala His Ala Gln Ala Thr Val
210215220
Ile Ala Gln Glu Lys Tyr Ser Asp Thr Ala Gln Thr Leu Arg Asp Val
225230235240
Thr Ala Gln Leu Glu Ser Tyr Lys Ser Ser Thr Leu Lys Glu Ile Glu
245250255
Asp Leu Lys Leu Glu Asn Leu Thr Leu Gln Glu Lys Val Ala Met Ala
260265270
Glu Lys Arg Val Glu Asp Val Gln Gln Gln Ile Leu Thr Ala Glu Ser
275280285
Thr Asn Gln Glu Tyr Ala Lys Val Val Gln Asp Leu Gln Asn Ser Ser
290295300
Thr Leu Lys Glu Ala Glu Ile Lys Glu Ile Thr Ser Ser Tyr Leu Glu
305310315320
Lys Ile Thr Asp Leu Gln Asn Gln Leu Arg Gln Gln Asn Glu Asp Phe
325330335
Arg Lys Gln Leu Glu Glu Glu Gly Ala Lys Met Thr Glu Lys Glu Thr
340345350
Ala Val Thr Glu Leu Thr Met Glu Ile Asn Lys Trp Arg Leu Leu Tyr
355360365
Glu Glu Leu Tyr Asp Lys Thr Lys Pro Phe Gln Gln Gln Leu Asp Ala
370375380
Phe Glu Ala Glu Lys Gln Ala Leu Leu Asn Glu His Gly Ala Thr Gln
385390 395400
Glu Gln Leu Ser Lys Ile Arg Asp Ser Tyr Ala Gln Leu Leu Gly His
405410415
Gln Asn Leu Lys Gln Lys Ile Lys His Val Val Lys Leu Lys Asp Glu
420425430
Asn Ser Gln Leu Lys Ser Glu Val Ser Lys Leu Arg Ser Gln Leu Ala
435440445
Lys Arg Lys Gln Asn Glu Leu Arg Leu Gln Gly Glu Leu Asp Lys Ala
450455460
Leu Gly Ile Arg His Phe Asp Pro Pro Lys Ala Phe Cys His Glu Ser
465470475480
Lys Glu Asn Val Thr Leu Lys Thr Pro Leu Lys Glu Gly Asn Pro Asn
485490495
Cys Cys
<210> 309
<211> 907
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Inter-alpha-trypsin inhibitor heavy chain H1
Q61702
<400> 309
Met Glu Gly Ala Thr Gly Leu Arg Val Leu Leu Cys Leu Leu Pro Leu
151015
Leu Thr Leu Gln Ala Arg Pro Ala Leu Gly Leu Ala Thr Gly Arg Pro
202530
Arg Gly Ser Glu Lys Arg His Ala Val Asp Thr Ser Val Asn Gly Val
354045
Ser Ile Lys Ser Leu Lys Val Asn Cys Lys Val Thr Ser Arg Phe Ala
505560
His Tyr Val Ile Thr Ser Gln Val Val Asn Asn Ala Asp Lys Ala Arg
65707580
Glu Val Ala Phe Asp Val Glu Ile Pro Lys Thr Ala Phe Ile Ser Asp
859095
Phe Ala Ile Thr Ser Asp Gly Lys Ala Phe Ile Gly Asp Ile Lys Asp
100105110
Lys Val Thr Ala Trp Lys Gln Tyr Arg Lys Ala Ala Val Leu Gly Glu
115120125
Ser Ala Gly Leu Val Arg Ala Ser Gly Arg Asn Met Glu Gln Phe Thr
130135140
Ile His Ile Thr Val Gly Ala Gln Ser Lys Ala Thr Phe Arg Leu Thr
145150155160
Tyr Glu Glu Val Leu Lys Arg Arg Leu Met Gln Tyr Asp Ile Thr Ile
165170175
Lys Val Arg Pro Lys Gln Leu Val Gln His Phe Glu Ile Asp Val Asp
180185190
Ile Phe Glu Pro Gln Gly Ile Ser Lys Leu Asp Ala Gln Ala Ser Phe
195200205
Leu Ser Glu Glu Leu Ala Ala Gln Thr Ile Lys Lys Ser Phe Ser Gly
210215220
Lys Lys Gly His Val Leu Phe Arg Pro Thr Val Ser Gln Gln Gln Ser
225230235240
Cys Pro Thr Cys Ser Thr Ser Leu Leu Asn Gly Glu Phe Lys Val Thr
245250255
Tyr Asp Val Asn Arg Asp Lys Leu Cys Asp Leu Leu Val Ala Asn Asn
260265270
Tyr Phe Thr His Phe Phe Ala Pro Lys Asn Leu Thr Asn Met Ser Lys
275280285
Asn Leu Val Phe Val Ile Asp Ile Ser Gly Ser Met Glu Gly Gln Lys
290295300
Val Arg Gln Thr Lys Glu Ala Leu Leu Lys Ile Leu Glu Asp Met Arg
305310315320
Pro Val Asp Asn Phe Asp Leu Val Leu Phe Gly Ser Lys Val Gln Ser
325330335
Trp Lys Gly Ser Leu Val Pro Ala Ser Asn Ala Asn Leu Gln Ala Ala
340345350
Gln Asp Phe Val Arg Arg Phe Ser Leu Ala Gly Ala Thr Asn Leu Asn
355360365
Gly Gly Leu Leu Arg Gly Ile Glu Ile Leu Asn Lys Ala Gln Gly Ser
370375380
His Pro Glu Leu Ser Ser Pro Ala Ser Ile Leu Ile Met Leu Thr Asp
385390395400
Gly Glu Pro Thr Glu Gly Glu Thr Asp Arg Ser Gln Ile Leu Lys Asn
405410415
Val Arg Asn Ala Ile Arg Gly Arg Phe Pro Leu Tyr Asn Leu Gly Phe
420425430
Gly His Asp Leu Asp Phe Ser Phe Leu Glu Val Met Ser Thr Glu Asn
435440445
Asn Gly Trp Ala Gln Arg Ile Tyr Glu Asp His Asp Ala Thr Gln Gln
450455460
Leu Gln Gly Phe Tyr Asn Gln Val Ala Asn Pro Leu Leu Thr Asp Val
465470475480
Glu Leu Gln Tyr Pro Gln Asp Ala Val Leu Ala Leu Thr Gln His Arg
485490495
His Lys Gln Tyr Tyr Asp Gly Ser Glu Ile Val Val Ala Gly Arg Ile
500505510
Ala Asn His Lys Leu Asn Thr Phe Lys Ala Asp Val Arg Ala Arg Gly
515520525
Glu Lys Gln Glu Phe Arg Ala Thr Cys Leu Val Asp Glu Glu Glu Met
530535540
Lys Lys Leu Leu Arg Glu Arg Gly His Val Leu Glu Asn His Val Glu
545550555560
Arg Leu Trp Ala Tyr Leu Thr Ile Gln Glu Leu Leu Ala Lys Arg Met
565570575
Lys Thr Glu Gly Glu Glu Arg Ala Asn Leu Ser Ser Gln Val Leu Lys
580585590
Met Ser Leu Asp Tyr His Phe Val Thr Pro Leu Thr Ser Leu Thr Ile
595600605
Arg Gly Leu Thr Asp Glu Asp Gly Leu Glu Pro Thr Ile Asp Lys Pro
610615620
Leu Glu Asp Ser Gln Pro Leu Glu Met Val Gly Pro Arg Arg Thr Phe
625630635640
Val Leu Ser Ala Ile Gln Pro Ser Pro Thr Ala His Pro Ile Asp Ser
645650655
Lys Leu Pro Leu Arg Val Thr Gly Val Asp Thr Asp Pro His Phe Ile
660665670
Ile Tyr Val Pro Ser Lys Glu Asp Ser Leu Cys Phe Asn Ile Asn Glu
675680685
Glu Pro Gly Val Ile Leu Asn Leu Val Gln Asp Pro Asp Thr Gly Phe
690695700
Thr Val Asn Gly Gln Leu Ile Gly Asn Lys Ala Ser Ser Pro Gly Gln
705710715720
His Glu Ser Thr Tyr Phe Gly Arg Leu Gly Ile Ser Ser Pro Thr Ser
725730735
Asp Phe Gln Leu Glu Val Thr Pro Gln Asn Ile Thr Leu Asn Pro Ser
740745750
Ser Ser Gly Ser Met Phe Ser Trp Arg Asp Gln Ala Val Leu Gln Lys
755760765
Asp Gly Val Val Val Thr Ile Asn Lys Lys Arg Asn Leu Val Val Ser
770775780
Val Asp Asp Gly Ala Thr Phe Glu Ile Val Leu His Arg Thr Trp Lys
785790795800
Gly Ser Ala Val His Gln Asp Phe Leu Gly Phe Tyr Val Leu Asp Ser
805810815
Phe Arg Met Ser Ala Arg Thr Lys Gly Leu Leu Gly Gln Phe Phe Ser
820825830
Pro Leu Asp Phe Glu Val Phe Asp Leu His Pro Gly Ser Asp Pro Thr
835840845
Lys Thr Asp Ala Thr Met Val Val Lys Asn Arg Gln Leu Thr Val Thr
850855860
Arg Gly Leu Gln Lys Asp Tyr Ser Lys Asp Pro Arg His Gly Ala Glu
865870875880
Val Pro Cys Trp Phe Val His Asp Asn Gly Ala Gly Leu Ile Asp Gly
885890895
Val His Thr Asp Tyr Val Val Ser Asp Ile Phe
900905
<210> 310
<211> 946
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Inter-alpha-trypsin inhibitor heavy chain H2
Q61703
<400> 310
Met Gln Arg Pro Val Cys Leu Leu Ile Trp Leu Phe Leu Leu Glu Ala
151015
Gln Ala Phe Glu Ile Pro Ile Asn Gly Asn Ser Glu Phe Ala Glu Tyr
202530
Ser Asp Leu Val Glu Leu Ala Pro Asp Lys Leu Pro Phe Val Gln Glu
354045
Asn Gly Arg His Gln Arg Ser Leu Pro Glu Glu Ser Gly Glu Glu Thr
505560
Asp Thr Val Asp Pro Val Thr Leu Tyr Ser Tyr Lys Val Gln Ser Thr
65707580
Ile Thr Ser Arg Val Ala Thr Thr Thr Ile Gln Ser Lys Leu Val Asn
859095
Asn Ser Pro Leu Pro Gln Ser Val Val Phe Asp Val Gln Ile Pro Lys
100105110
Gly Ala Phe Ile Ser Asn Phe Thr Met Thr Val Asn Gly Met Thr Phe
115120125
Thr Ser Ser Ile Lys Glu Lys Thr Val Gly Arg Ala Leu Tyr Ser Gln
130135140
Ala Arg Ala Lys Gly Lys Thr Ala Gly Trp Val Arg Ser Arg Thr Leu
145150155160
Asp Met Glu Asn Phe Asn Thr Glu Val Asn Ile Pro Pro Gly Ala Lys
165170175
Val Gln Phe Glu Leu His Tyr Gln Glu Val Lys Trp Arg Lys Leu Gly
180185190
Ser Tyr Glu His Lys Ile His Leu Gln Pro Gly Lys Leu Ala Lys His
195200205
Leu Glu Val Asn Val Trp Ile Ile Glu Pro Gln Gly Met Arg Phe Leu
210215220
His Val Pro Asp Thr Phe Glu Gly His Phe Gln Gly Val Pro Val Ile
225230235240
Ser Lys Gly Gln Gln Lys Ala His Val Ser Phe Lys Pro Thr Val Ala
245250255
Gln Gln Arg Lys Cys Pro Asn Cys Thr Glu Thr Ala Val Asn Gly Glu
260265270
Leu Val Val Met Tyr Asp Val Asn Arg Glu Glu Lys Ala Gly Glu Leu
275280285
Glu Val Phe Asn Gly Tyr Phe Val His Phe Phe Ala Pro Glu Asn Leu
290295300
Asp Pro Ile Pro Lys Asn Ile Leu Phe Val Ile Asp Val Ser Gly Ser
305310315320
Met Trp Gly Ile Lys Met Lys Gln Thr Val Glu Ala Met Lys Thr Ile
325330335
Leu Asp Asp Leu Arg Thr Asp Asp Gln Phe Ser Val Val Asp Phe Asn
340345350
His Asn Val Arg Thr Trp Arg Asn Asp Leu Val Ser Ala Thr Lys Thr
355360365
Gln Ile Ala Asp Ala Lys Arg Tyr Ile Glu Lys Ile Gln Pro Ser Gly
370375380
Gly Thr Asn Ile Asn Glu Ala Leu Leu Arg Ala Ile Phe Ile Leu Asn
385390395400
Glu Ala Ser Asn Met Gly Leu Leu Asn Pro Asp Ser Val Ser Leu Ile
405410415
Ile Leu Val Ser Asp Gly Asp Pro Thr Val Gly Glu Leu Lys Leu Ser
420425430
Lys Ile Gln Lys Asn Val Lys Gln Ser Ile Gln Asp Asn Ile Ser Leu
435440445
Phe Ser Leu Gly Ile Gly Phe Asp Val Asp Tyr Asp Phe Leu Lys Arg
450455460
Leu Ser Asn Glu Asn Arg Gly Ile Ala Gln Arg Ile Tyr Gly Asn Gln
465470475480
Asp Thr Ser Ser Gln Leu Lys Lys Phe Tyr Asn Gln Val Ser Thr Pro
485490495
Leu Leu Arg Asn Val Gln Phe Asn Tyr Pro Gln Ala Ser Val Thr Asp
500505510
Val Thr Gln Asn Asn Phe His Asn Tyr Phe Gly Gly Ser Glu Ile Val
515520525
Val Ala Gly Lys Phe Asp Pro Ser Lys Leu Thr Glu Val Gln Ser Ile
530535540
Ile Thr Ala Thr Ser Ala Asn Thr Glu Leu Val Leu Glu Thr Leu Ser
545550555560
Gln Met Asp Asp Leu Glu Glu Phe Leu Ser Lys Asp Lys His Ala Asp
565570575
Pro Asp Phe Thr Lys Lys Leu Trp Ala Tyr Leu Thr Ile Asn Gln Leu
580585590
Leu Ala Glu Arg Ser Leu Ala Pro Thr Ala Ala Ile Lys Arg Lys Ile
595600605
Thr Lys Thr Ile Leu Gln Met Ser Leu Asp His His Ile Val Thr Pro
610615620
Leu Thr Ala Met Val Ile Glu Asn Asp Ala Gly Asp Glu Arg Met Leu
625630635640
Ala Asp Ser Pro Pro Gln Asp His Ser Cys Cys Ser Gly Ala Leu Tyr
645650655
Tyr Gly Thr Lys Val Ala Ser Gly Pro Ile Pro Ser Trp Ala Asn Pro
660665670
Ser Pro Thr Pro Met Ser Ala Met Leu Ala Val Gly Ala Lys Pro Leu
675680685
Glu Ser Thr Pro Pro Thr His Leu Asn Gln Val Glu Asn Asp Pro His
690695700
Phe Ile Ile Tyr Leu Pro Lys Ser Lys Arg Asn Ile Cys Phe Asn Ile
705710715720
Asp Ser Glu Pro Gly Lys Ile Leu Ser Leu Val Ser Asp Pro Glu Ser
725730735
Gly Ile Val Val Asn Gly Gln Leu Ile Gly Ala Lys Arg Ala Glu Asn
740745750
Gly Lys Leu Ser Thr Tyr Phe Gly Lys Leu Gly Phe Tyr Phe Gln Lys
755760765
Glu Gly Met Lys Ile Glu Ile Ser Thr Glu Thr Ile Thr Leu Ser Ser
770775780
Gly Ser Ser Thr Ser Arg Leu Ser Trp Ser Asp Thr Ala His Leu Gly
785790795800
Asn Ser Arg Val Leu Ile Ser Val Lys Lys Glu Lys Ser Val Thr Leu
805810815
Thr Leu Asn Lys Glu Leu Phe Phe Ser Val Leu Leu His Arg Val Trp
820825830
Arg Lys His Pro Val Asn Val Asp Phe Leu Gly Ile Tyr Ala Pro Pro
835840845
Ile Asp Lys Phe Ser Pro Arg Val His Gly Leu Leu Gly Gln Phe Met
850855860
Gln Glu Pro Ala Ile His Ile Phe Asn Glu Arg Pro Gly Lys Glu Pro
865870875880
Gly Lys Pro Glu Ala Ser Met Glu Val Lys Gly His Lys Leu Thr Val
885890895
Thr Arg Gly Leu Gln Lys Asp Tyr Arg Thr Asp Ile Val Phe Gly Thr
900905910
Asp Val Pro Cys Trp Phe Val His Asn Ser Gly Lys Gly Phe Ile Asp
915920925
Gly His Tyr Lys Asp Tyr Phe Val Pro Gln Leu Tyr Ser Phe Leu Lys
930935940
Arg Pro
945
<210> 311
<211> 889
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Inter-alpha-trypsin inhibitor heavy chain H3
Q61704
<400> 311
Met Arg Thr Met Trp Trp Pro Cys Leu Val Leu Ala Leu Leu Ser Gly
151015
Leu Glu Thr Ser Gly Phe Pro Arg Ser Pro Leu Gln Leu Leu Gly Lys
202530
Arg Ser Leu Pro Glu Gly Val Val Asp Gly Ile Glu Val Tyr Ser Thr
354045
Lys Ile Ser Cys Lys Val Thr Ser Arg Phe Ala His Asn Val Val Thr
505560
Thr Arg Ala Val Asn Arg Ala Asp Thr Ala Lys Glu Val Ser Phe Asp
65707580
Val Glu Leu Pro Lys Thr Ala Phe Ile Thr Asn Phe Thr Leu Thr Ile
859095
Asp Gly Val Thr Tyr Pro Gly Asn Val Lys Glu Lys Glu Val Ala Gln
100105110
Lys Gln Tyr Glu Lys Ala Val Ser Gln Gly Lys Thr Ala Gly Leu Val
115120125
Lys Ala Ser Gly Arg Lys Leu Glu Lys Phe Thr Val Ser Val Asn Val
130135140
Ala Ala Gly Ser Lys Val Thr Phe Glu Leu Thr Tyr Glu Glu Leu Leu
145150155160
Lys Arg Asn Lys Gly Lys Tyr Glu Met Tyr Leu Lys Val Gln Pro Lys
165170175
Gln Leu Val Arg His Phe Glu Ile Asp Ala His Ile Phe Glu Pro Gln
180185190
Gly Ile Ser Met Leu Asp Ala Glu Ala Ser Phe Ile Thr Asn Asp Leu
195200205
Leu Gly Ser Ala Leu Thr Lys Ser Phe Ser Gly Lys Lys Gly His Val
210215220
Ser Phe Lys Pro Ser Leu Asp Gln Gln Arg Ser Cys Pro Thr Cys Thr
225230235240
Asp Ser Leu Leu Asn Gly Asp Phe Thr Ile Val Tyr Asp Val Asn Arg
245250255
Glu Ser Pro Gly Asn Val Gln Ile Val Asn Gly Tyr Phe Val His Phe
260265270
Phe Ala Pro Gln Gly Leu Pro Val Val Pro Lys Asn Ile Val Phe Val
275280285
Ile Asp Val Ser Gly Ser Met Ser Gly Arg Lys Ile Gln Gln Thr Arg
290295300
Glu Ala Leu Leu Lys Ile Leu Asp Asp Val Lys Glu Asp Asp Tyr Leu
305310315320
Asn Phe Ile Leu Phe Ser Thr Asp Val Thr Thr Trp Lys Asp His Leu
325330335
Val Gln Ala Thr Pro Ala Asn Leu Lys Glu Ala Lys Thr Phe Val Lys
340345350
Asn Ile His Asp Gln Ser Met Thr Asn Ile Asn Asp Gly Leu Leu Lys
355360365
Gly Ile Glu Met Leu Asn Lys Ala Arg Glu Asp His Thr Val Pro Glu
370375380
Arg Ser Thr Ser Ile Ile Ile Met Leu Thr Asp Gly Asp Ala Asn Thr
385390395400
Gly Glu Ser Arg Pro Glu Lys Ile Gln Glu Asn Val Arg Asn Ala Ile
405410415
Gly Gly Lys Phe Pro Leu Tyr Asn Leu Gly Phe Gly Asn Asn Leu Asn
420425430
Tyr Asn Phe Leu Glu Thr Leu Ala Leu Glu Asn His Gly Leu Ala Arg
435440445
Arg Ile Tyr Glu Asp Ser Asp Ala Asn Leu Gln Leu Gln Gly Phe Tyr
450455460
Glu Glu Val Ala Asn Pro Leu Leu Thr Asn Val Glu Val Glu Tyr Pro
465470475480
Glu Asn Ala Ile Leu Asp Leu Thr Arg Asn Ser Tyr Pro His Phe Tyr
485490495
Asp Gly Ser Glu Ile Val Val Ala Gly Arg Leu Val Asp Arg Asn Met
500505510
Asp Asn Phe Lys Ala Asp Val Lys Gly His Gly Ala Leu Asn Asp Leu
515520525
Thr Phe Thr Glu Glu Val Asp Met Glu Glu Met Asp Ala Ala Leu Lys
530535540
Glu Gln Gly Tyr Ile Phe Gly Asp Tyr Ile Glu Arg Leu Trp Ala Tyr
545550555560
Leu Thr Ile Glu Gln Leu Leu Glu Lys Arg Lys Asn Ala Lys Gly Asp
565570575
Glu Lys Glu Asn Ile Thr Ala Glu Ala Leu Asp Leu Ser Leu Lys Tyr
580585590
His Phe Val Thr Pro Leu Thr Ser Met Val Val Thr Lys Pro Glu Asp
595600605
Asn Glu Asp Gln Thr Ser Ile Ala Asp Lys Pro Gly Glu Glu Ala Ile
610615620
Ala Glu Thr Thr Thr Met Ser Phe Leu Thr Thr Gln Gln Ser Ser Gln
625630635640
Ser Pro Tyr Tyr Tyr Val Asp Gly Asp Pro His Phe Ile Ile Gln Ile
645650655
Pro Gly Lys Asn Asp Ser Ile Cys Phe Asn Ile Asp Glu Lys Pro Gly
660665670
Thr Val Leu Arg Leu Ile Gln Asp Pro Val Thr Gly Ile Thr Val Thr
675680685
Gly Gln Ile Ile Gly Asp Lys Arg Ser Asn Ala Ser Ser Arg Thr Gly
690695700
Lys Thr Tyr Phe Gly Lys Leu Gly Ile Thr Asn Ala Trp Met Asp Phe
705710715720
Arg Val Glu Val Thr Thr Glu Lys Ile Ile Leu Gly Thr Gly Ala Glu
725730735
Leu Ser Thr Phe Ser Trp Leu Asp Thr Ile Thr Val Thr Gln Thr Gly
740745750
Leu Ser Val Thr Ile Asn Arg Lys Lys Asn Met Val Val Ser Phe Gly
755760765
Asp Gly Ile Ser Phe Val Ile Ile Leu His Gln Val Trp Lys Lys His
770775780
Pro Val His Gln Asp Phe Leu Gly Phe Tyr Val Val Asp Ser His Arg
785790795800
Met Ser Ala Gln Thr His Gly Leu Leu Gly Gln Phe Phe Gln Pro Phe
805810815
Asp Phe Lys Val Phe Gly Ile Arg Pro Gly Ser Asp Pro Thr Lys Pro
820825830
Asp Ala Thr Met Val Val Lys Asn His Arg Leu Thr Val Thr Arg Gly
835840845
Ser Gln Lys Asp Tyr Arg Lys Asp Ala Ser Val Gly Thr Lys Val Ile
850855860
Cys Trp Phe Val His Asn Asn Gly Glu Gly Leu Ile Asp Gly Val His
865870875880
Thr Asp Tyr Ile Val Pro Ser Leu Phe
885
<210> 312
<211> 906
<212> PRT
<213> Bos taurus
<220>
<223> Cow Inter-alpha-trypsin inhibitor heavy chain H1
Q0VCM5
<400> 312
Met Gly Leu Arg Gly Leu Leu Cys Val Cys Leu Val Ser Leu Leu Ala
151015
Leu Gln Ala Val Ala Ala Gln Gly Ser Pro Thr Arg Asn Pro Lys Gly
202530
Gly Lys Lys Arg Met Ala Val Asp Ala Ala Val Asp Gly Val Val Ile
354045
Arg Ser Leu Lys Val Asn Cys Lys Val Thr Ser Arg Phe Ala His Tyr
505560
Ile Ile Thr Ser Gln Val Val Asn Ser Ala Asp Thr Ala Lys Glu Val
65707580
Ser Phe Asn Val Glu Ile Pro Lys Thr Ala Phe Ile Ser Asp Phe Ala
859095
Ile Thr Ala Asp Glu Asn Ala Phe Thr Gly Asp Ile Lys Asp Lys Val
100105110
Thr Ala Trp Lys Gln Tyr Arg Lys Ala Ala Ile Ser Gly Glu Asn Ala
115120125
Gly Leu Val Arg Ala Ser Gly Arg Thr Met Glu Gln Phe Ser Ile His
130135140
Ile Ile Val Gly Pro Arg Ser Lys Ala Thr Phe Arg Leu Thr Tyr Glu
145150155160
Glu Val Leu Arg Arg Lys Leu Met Gln Tyr Asp Ile Val Ile Lys Val
165170175
Lys Pro Gln Gln Leu Val Gln His Phe Glu Ile Asp Val Asp Ile Phe
180185190
Glu Pro Gln Gly Ile Arg Lys Leu Asp Val Glu Ala Ser Phe Leu Pro
195200205
Lys Glu Leu Ala Ala Gln Leu Ile Lys Lys Ser Phe Ser Gly Lys Lys
210215220
Gly His Val Leu Phe Arg Pro Thr Val Ser Gln Gln Gln Thr Cys Pro
225230235240
Thr Cys Ser Thr Thr Leu Leu Asn Gly Asp Phe Lys Val Thr Tyr Asp
245250255
Val Asn Arg Asp Asp Ala Cys Asp Leu Leu Val Ala Asn Asn Tyr Phe
260265270
Ala His Phe Phe Ala Pro Gln Asn Leu Lys Lys Leu Asn Lys Asn Val
275280285
Val Phe Val Ile Asp Ile Ser Ser Ser Met Glu Gly Gln Lys Leu Lys
290295300
Gln Thr Lys Glu Ala Leu His Lys Ile Leu Gly Asp Met Arg Pro Gly
305310315320
Asp Tyr Phe Asp Leu Val Leu Phe Gly Ser Ala Val Gln Ser Trp Lys
325330335
Gly Ser Leu Val Gln Ala Ser Pro Ala Asn Leu Glu Ala Ala Arg Asn
340345350
Phe Val Gln Gln Phe Ser Leu Ala Gly Ala Thr Asn Leu Asn Gly Gly
355360365
Leu Leu Arg Gly Ile Glu Ile Leu Asn Lys Ala Gln Gln Ser Leu Pro
370375380
Glu Leu Ser Asn His Ala Ser Ile Leu Ile Met Leu Thr Asp Gly Glu
385390395400
Pro Thr Glu Gly Val Met Asp Arg Thr Gln Ile Leu Lys Asn Val Arg
405410415
Asp Gly Ile Lys Gly Arg Phe Pro Leu Tyr Asn Leu Gly Phe Gly His
420425430
Asp Val Asp Leu Asn Phe Leu Glu Val Met Ser Leu Glu Asn Asn Gly
435440445
Arg Val Gln Arg Ile Tyr Glu Asp His Asp Ala Thr Gln Gln Leu Gln
450455460
Gly Phe Tyr Glu Gln Val Ala Asn Pro Leu Leu Arg Asp Val Glu Leu
465470475480
Leu Tyr Pro Arg Glu Ala Val Ser Asp Leu Thr Gln His Arg His Lys
485490495
Gln Tyr Tyr Glu Gly Ser Glu Ile Met Val Ala Gly Arg Ile Ala Asp
500505510
His Lys Leu Ser Ser Phe Lys Ala Asp Val Arg Ala His Gly Glu Gly
515520525
Gln Glu Phe Met Thr Thr Cys Leu Val Asp Lys Glu Glu Met Lys Lys
530535540
Leu Leu Arg Glu Arg Gly His Met Leu Glu Asn His Val Glu Arg Leu
545550555560
Trp Ala Tyr Leu Thr Ile Gln Glu Leu Leu Ala Lys Arg Met Lys Leu
565570575
Glu Gly Gln Glu Lys Ala Asn Val Ser Ala Lys Ala Leu Gln Met Ser
580585590
Leu Ala Tyr Gln Phe Val Thr Pro Leu Thr Ser Met Thr Val Arg Gly
595600605
Met Thr Asp Gln Asp Gly Leu Glu Pro Ile Ile Asp Lys Pro Leu Asp
610615620
Asp Tyr Leu Pro Leu Glu Met Val Gly Pro Arg Lys Thr Phe Met Leu
625630635640
Gln Ala Ser Gln Pro Ala Pro Thr His Ser Ser Leu Asp Ile Lys Lys
645650655
Leu Pro Asp Gln Val Thr Gly Val Asp Thr Asp Pro His Phe Leu Ile
660665670
His Val Pro Gln Lys Glu Asp Thr Leu Cys Phe Asn Ile Asn Glu Glu
675680685
Pro Gly Val Val Leu Ser Leu Val Gln Asp Pro Asp Thr Gly Phe Ser
690695700
Val Asn Gly Gln Leu Ile Gly Asn Glu Ala Gly Ser Pro Gly Lys His
705710715720
Glu Gly Thr Tyr Phe Gly Arg Leu Gly Ile Ala Asn Pro Ala Thr Asp
725730735
Phe Gln Leu Glu Val Thr Pro Gln Asn Ile Thr Leu Asn Pro Gly Ser
740745750
Gly Gly Pro Val Phe Ser Trp Arg Asp Gln Ala Phe Leu Arg Gln Asn
755760765
Glu Val Leu Val Thr Ile Asn Arg Lys Arg Asn Leu Val Val Ser Val
770775780
Glu Asp Gly Gly Thr Phe Glu Val Val Leu His Arg Val Trp Arg Gly
785790795800
Ser Ala Val Arg Gln Asp Phe Leu Gly Phe Tyr Val Leu Asp Ser His
805810815
Arg Met Ser Ala Arg Thr His Gly Leu Leu Gly Gln Phe Phe His Pro
820825830
Phe Asp Tyr Lys Val Ser Asn Leu His Pro Gly Ser Asp Pro Thr Lys
835840845
Thr Asp Ala Thr Met Val Val Lys Asn Arg Arg Leu Thr Val Thr Arg
850855860
Gly Leu Gln Lys Asp Tyr Arg Lys Asp Pro Arg His Gly Ala Glu Val
865870875880
Thr Cys Trp Phe Ile His Asn Asn Gly Asp Gly Leu Ile Asp Gly Ile
885890895
His Thr Asp Tyr Ile Val Pro Asp Ile Phe
900905
<210> 313
<211> 946
<212> PRT
<213> Bos taurus
<220>
<223> Cow Inter-alpha-trypsin inhibitor heavy chain H2
NP_001091485
<400> 313
Met Lys Gly Leu Thr Cys Phe Phe Leu Cys Phe Phe Leu Ser Glu Ser
151015
Arg Gly Phe Glu Ile Pro Thr Asn Gly Leu Ser Glu Phe Ala Asp Tyr
202530
Gly Asp His Val Glu Leu Ala Pro Gly Lys Phe Gln Phe Val Pro Glu
354045
Asn Arg Arg Tyr Gln Arg Ser Ile Ser Gly Glu Ser Gly Glu Arg Thr
505560
Glu Asp Val Asp Gln Val Thr Val Tyr Ser Tyr Lys Val Gln Ser Thr
65707580
Ile Thr Ser Arg Val Ala Asn Thr Val Ile Gln Thr Lys Val Val Asn
859095
His Ser Pro Gln Pro Gln Asn Val Val Phe Asp Val Gln Ile Pro Lys
100105110
Gly Ala Phe Ile Ser Asn Phe Ser Met Thr Val Asp Gly Thr Thr Phe
115120125
Thr Ser Ser Ile Lys Glu Lys Thr Val Gly Arg Ala Leu Tyr Ala Gln
130135140
Ala Arg Ala Lys Gly Lys Thr Ala Gly Leu Val Arg Ser Arg Ala Leu
145150155160
Asp Met Glu Asp Phe Lys Thr Glu Val Ser Ile Ala Pro Gly Ala Lys
165170175
Val Gln Phe Glu Leu His Tyr Gln Glu Val Lys Trp Arg Lys Leu Gly
180185190
Ser Tyr Glu His Arg Leu His Leu Lys Pro Gly Arg Leu Ala Lys His
195200205
Leu Glu Val Asp Val Arg Ile Ile Glu Pro Gln Gly Leu Arg Ser Leu
210215220
His Val Leu Asp Thr Phe Asp Gly His Phe Asp Gly Val Pro Val Val
225230235240
Ser Lys Gly Pro Gln Lys Ala His Ile Ala Phe Lys Pro Thr Val Ala
245250255
Gln Gln Arg Lys Cys Leu Asn Cys Ser Glu Thr Met Val Asp Gly Glu
260265270
Leu Val Val Met Tyr Asp Val Asn Arg Glu Glu Lys Val Gly Glu Leu
275280285
Glu Val Phe Asn Gly Tyr Phe Val His Phe Phe Ala Pro Glu Asn Met
290295300
Asp Pro Ile Pro Lys Asn Ile Leu Phe Val Ile Asp Val Ser Gly Ser
305310315320
Met Trp Gly Ile Lys Met Lys Gln Thr Val Glu Ala Met Lys Thr Ile
325330335
Leu Asp Asp Leu Arg Thr Glu Asp His Phe Ser Val Val Asp Phe Asn
340345350
His Asn Val Arg Thr Trp Arg Asn Asp Leu Val Ser Ala Thr Lys Thr
355360365
Gln Val Ala Asp Ala Lys Asn Tyr Ile Glu Lys Ile Gln Pro Ser Gly
370375380
Gly Thr Asn Ile Asn Glu Ala Leu Leu Arg Ala Ile Phe Ile Leu Asn
385390395400
Glu Ala Asn Asn Leu Gly Met Leu Asp Pro Asn Ser Val Ser Leu Ile
405410415
Ile Leu Val Ser Asp Gly Asp Pro Thr Val Gly Glu Leu Lys Leu Ser
420425430
Lys Ile Gln Lys Asn Val Lys Gln Asn Ile Arg Asp Asn Ile Ser Leu
435440445
Phe Ser Leu Gly Ile Gly Phe Asp Val Asp Tyr Asp Phe Leu Lys Arg
450455460
Leu Ser Asn Asp Asn Arg Gly Ile Ala Gln Arg Ile Tyr Gly Asn Gln
465470475480
Asp Thr Ser Val Gln Leu Lys Lys Phe Tyr Asn Gln Val Ser Thr Pro
485490495
Leu Leu Arg Asn Val Gln Phe Asn Tyr Pro Gln Pro Ser Val Thr Asp
500505510
Val Thr Gln Asn Ser Phe His Asn Tyr Phe Gly Gly Ser Glu Ile Val
515520525
Val Ala Gly Lys Val Asp Pro Glu Lys Leu Gly Gln Leu Gln Ser Ile
530535540
Ile Thr Ala Thr Ser Ala Asn Ala Glu Leu Val Leu Glu Thr Leu Ala
545550555560
Glu Met Asp Gly Leu Glu Asp Phe Leu Ser Lys Asp Lys His Ala Asp
565570575
Pro Asp Phe Thr Lys Lys Leu Trp Ala Tyr Leu Thr Ile Asn Gln Leu
580585590
Leu Ala Glu Arg Ser Leu Ala Pro Thr Ala Ala Met Lys Arg Lys Ile
595600605
Thr Lys Thr Ile Leu Gln Met Ser Leu Asp His His Ile Val Thr Pro
610615620
Leu Thr Ala Met Val Ile Glu Asn Glu Ala Gly Asp Glu Arg Met Leu
625630635640
Ala Asp Ser Pro Pro Gln Asp His Ser Cys Cys Ser Gly Ala Leu Tyr
645650655
His Gly Ser Lys Val Ser Pro Asn Ser Val Pro Ser Trp Val Asn Pro
660665670
Ser Pro Ala Pro Val Leu Pro Met Pro Ala Val Gly Ala Gln Val Leu
675680685
Glu Ser Thr Pro Pro Pro His Val Met Arg Val Glu Asn Asp Pro His
690695700
Phe Ile Ile Tyr Leu Pro Lys Ser Gln Lys Asn Ile Cys Phe Asn Ile
705710715720
Asp Ser Glu Pro Gly Lys Ile Leu Asn Leu Val Ser Asp Pro Glu Leu
725730735
Gly Ile Leu Val Asn Gly Gln Leu Val Gly Ala Lys Lys Pro Lys Asn
740745750
Lys Lys Leu Ser Thr Tyr Phe Gly Lys Leu Gly Phe Tyr Phe Gln Arg
755760765
Glu Asp Val Lys Val Glu Ile Ser Thr Glu Thr Ile Ser Leu Ser Arg
770775780
Gly Ser Arg Thr Ser Val Leu Ser Trp Ser Asp Thr Ala His Val Leu
785790795800
Asn Gln Arg Val Leu Val Ser Val Lys Lys Glu Lys Thr Val Thr Val
805810815
Thr Leu Asp Lys Glu Met Phe Phe Ser Val Leu Leu His Arg Val Trp
820825830
Lys Lys His Pro Ile Asn Val Asp Phe Leu Gly Ile Tyr Ile Pro Pro
835840845
Thr Asn Lys Phe Ser Pro Asn Val His Gly Leu Ile Gly Gln Phe Met
850855860
Asn Glu Pro Lys Ile His Val Phe Asn Glu Arg Pro Gly Lys Asp Pro
865870875880
Glu Lys Pro Glu Ala Ser Met Glu Val Lys Gly Gln Lys Leu Val Val
885890895
Thr Arg Gly Leu Gln Lys Asp Tyr Arg Thr Asp Arg Val Phe Gly Thr
900905910
Asp Val Pro Cys Trp Phe Val His Asn Ser Gly Lys Gly Phe Ile Asp
915920925
Gly His Tyr Lys Asp Tyr Phe Val Pro Gln Leu Tyr Ser Phe Leu Arg
930935940
Arg Pro
945
<210> 314
<211> 891
<212> PRT
<213> Bos taurus
<220>
<223> Cow Inter-alpha-trypsin inhibitor heavy chain H3
P56652
<400> 314
Met Ala Leu Ala Gln Trp Pro Tyr Leu Ile Leu Ala Leu Leu Ser Gly
151015
Leu Ala Val Ser Gly Phe Pro Arg Asn Pro Ser Leu Leu Leu Gly Lys
202530
Arg Ser Leu Pro Gly Arg Ala Val Asp Gly Ile Glu Val Tyr Ser Thr
354045
Lys Val Asn Cys Lys Val Thr Ser Arg Phe Ala His Asn Val Val Thr
505560
Thr Arg Ala Val Asn His Ala Asn Thr Ala Lys Glu Val Ser Phe Asp
65707580
Val Glu Leu Pro Lys Thr Ala Phe Ile Thr Asn Phe Thr Leu Thr Ile
859095
Asp Gly Val Thr Tyr Pro Gly Lys Val Lys Glu Lys Glu Val Ala Lys
100105110
Lys Gln Tyr Glu Lys Ala Val Ser Gln Gly Lys Thr Ala Gly Leu Val
115120125
Lys Ala Ser Gly Arg Lys Leu Glu Lys Phe Thr Val Ser Val Asn Val
130135140
Ala Ala Gly Ser Lys Val Thr Phe Glu Leu Thr Tyr Glu Glu Leu Leu
145150155160
Lys Arg His Lys Gly Lys Tyr Glu Met Tyr Leu Lys Val Gln Pro Lys
165170175
Gln Leu Val Lys His Phe Glu Ile Thr Val Asp Ile Phe Glu Pro Gln
180185190
Gly Ile Ser Thr Leu Asp Ala Glu Ala Ser Phe Ile Thr Asn Asp Leu
195200205
Leu Gly Ser Ala Leu Thr Lys Ser Phe Ser Gly Lys Lys Gly His Val
210215220
Ser Phe Lys Pro Ser Leu Asp Gln Gln Arg Ser Cys Pro Thr Cys Thr
225230235240
Asp Ser Leu Leu Lys Gly Asp Phe Ile Ile Thr Tyr Asp Val Asn Arg
245250255
Glu Ser Pro Ala Asn Val Gln Ile Val Asn Gly Tyr Phe Val His Phe
260265270
Phe Ala Pro Gln Gly Leu Pro Val Val Pro Lys Ser Val Val Phe Val
275280285
Ile Asp Val Ser Gly Ser Met His Gly Arg Lys Met Glu Gln Thr Lys
290295300
Asp Ala Leu Leu Lys Ile Leu Glu Asp Val Lys Gln Asp Asp Tyr Leu
305310315320
Asn Phe Ile Leu Phe Ser Gly Asp Val Thr Thr Trp Lys Asp Ser Leu
325330335
Val Pro Ala Thr Pro Glu Asn Ile Gln Glu Ala Ser Lys Phe Val Met
340345350
Asp Ile Gln Asp Arg Gly Met Thr Asn Ile Asn Asp Ala Leu Leu Arg
355360365
Gly Ile Ser Met Leu Asn Lys Ala Arg Glu Glu His Thr Val Pro Glu
370375380
Arg Ser Thr Ser Ile Ile Ile Met Leu Thr Asp Gly Asp Ala Asn Val
385390395400
Gly Glu Ser Arg Pro Glu Lys Ile Gln Glu Asn Val Arg Asn Ala Ile
405410415
Gly Gly Lys Phe Pro Leu Tyr Asn Leu Gly Phe Gly Asn Asn Leu Asn
420425430
Tyr Asn Phe Leu Glu Asn Met Ala Leu Glu Asn His Gly Leu Ala Arg
435440445
Arg Ile Tyr Glu Asp Ser Asp Ala Asn Leu Gln Leu Gln Gly Phe Tyr
450455460
Glu Glu Val Ala Asn Pro Leu Leu Thr Gly Val Glu Val Glu Tyr Pro
465470475480
Gln Asn Ala Ile Leu Asp Leu Thr Gln Asn Ser Tyr Gln His Phe Tyr
485490495
Asp Gly Ser Glu Ile Val Val Ala Gly Arg Leu Ala Asp Glu Asp Met
500505510
Asn Ser Phe Lys Ala Ala Val Lys Gly His Gly Ala Ile Asn Asp Leu
515520525
Thr Phe Thr Glu Glu Val Asp Met Lys Glu Met Glu Lys Ala Leu Gln
530535540
Glu Arg Asp Tyr Ile Phe Gly Asp Tyr Ile Glu Arg Leu Trp Ala Tyr
545550555560
Leu Thr Ile Glu Gln Leu Leu Asp Lys Arg Lys Asn Ala Gln Gly Glu
565570575
Glu Lys Glu Ile Leu Thr Ala Gln Ala Leu Glu Leu Ser Leu Lys Tyr
580585590
His Phe Val Thr Pro Leu Thr Ser Met Val Val Thr Lys Pro Glu Asp
595600605
Asn Glu Asn Gln Thr Ala Ile Ala Asn Lys Pro Gly Glu Gly Pro Leu
610615620
Asp Ala Glu Glu Val Pro Ser Met Ala Tyr Leu Thr Ser Tyr Gln Ala
625630635640
Pro Gln Thr Pro Tyr Tyr Tyr Val Asp Gly Asp Pro His Phe Ile Ile
645650655
Gln Ile Pro Glu Lys Asp Asp Ala Ile Cys Phe Asn Ile Asp Glu Asp
660665670
Pro Gly Thr Val Leu Arg Leu Ile Gln Asp Pro Val Thr Gly Leu Thr
675680685
Val Asn Gly Gln Ile Ile Gly Glu Lys Thr Gly Arg Ser Asp Ser Gln
690695700
Thr Arg Arg Thr Tyr Phe Gly Lys Leu Gly Ile Ala Ser Ala Gln Met
705710715720
Asp Phe Arg Ile Glu Val Thr Arg Glu Asn Ile Thr Leu Trp Asn Gly
725730735
Asp Ser Leu Ser Thr Phe Ser Trp Leu Asp Thr Val Met Val Thr Gln
740745750
Asp Gly Leu Ser Val Met Ile Asn Arg Lys Lys Asn Met Val Val Ser
755760765
Phe Gly Asp Gly Val Thr Phe Val Val Val Leu His Gln Val Trp Lys
770775780
Lys Glu Pro Ala His His Asp Phe Leu Gly Phe Tyr Val Val Asn Ser
785790795800
Arg Gly Met Ser Ala Gln Thr His Gly Leu Leu Gly Gln Phe Phe His
805810815
Pro Phe Asp Phe Gln Val Ser Asp Val His Pro Gly Ser Asp Pro Thr
820825830
Lys Pro Asp Ala Thr Met Val Val Lys Asn His Gln Leu Thr Val Thr
835840845
Arg Gly Ser Gln Lys Asp Tyr Arg Lys Asp Ile Ser Val Gly Arg Asn
850855860
Val Ala Cys Trp Phe Val His Asn Asn Gly Gln Gly Leu Ile Asp Gly
865870875880
Ile His Arg Asp Tyr Ile Val Pro Asn Leu Phe
885890
<210> 315
<211> 928
<212> PRT
<213> Gallus gallus
<220>
<223> Chicken Interphotoreceptor matrix proteoglycan 1
SPACR Q8JIR8
<400> 315
Met His Leu Lys Thr Gly Leu Ile Phe Leu Ala Ile Cys Leu Ala Leu
151015
Gln Val Gln Gly Ser Arg Glu Ile Pro Ser Lys Thr Asn His Gly Glu
202530
Ala Lys Gln Leu Ala Asp Ala Ser Gly Ser Asp Lys Thr Glu Arg Thr
354045
Thr Lys Arg Ser Arg Val Ser Thr Ile Arg Arg Ile Phe Asp Met Ala
505560
Lys His Arg Thr Lys Arg Ser Pro Phe Phe Ser Thr Gly Val Lys Ile
65707580
Cys Pro Gln Glu Ser Val Lys Gln Ile Leu Ala Ser His Gln Ala Tyr
859095
Tyr Arg Leu Arg Val Cys Gln Glu Ala Val Trp Glu Ala Phe Arg Ile
100105110
Phe Leu Asp Arg Ile Pro Asp Thr Ser Glu Tyr Gln Asn Trp Val Thr
115120125
Ala Cys Gln Arg Glu Thr Phe Cys Ile Phe Asp Ile Gly Lys Asn Phe
130135140
Ser Asn Ser Gln Glu His Leu Glu Ile Ile Gln Arg Arg Val Lys His
145150155160
Arg Thr Phe Gln Glu Arg Lys Asp Glu Ile Ser Thr Asp Lys Thr Gly
165170175
Gly Lys Lys Leu Glu Asp Ile Pro Ser Val Ser Thr Gly Pro Pro Ser
180185190
Ala Ser Leu Ser Thr Tyr Thr Leu Val Pro Asn Gly Thr Leu Leu Asn
195200205
Glu Ile Val Asn Glu Thr Lys Thr Pro Val Lys Glu Leu Gly Thr Asn
210215220
Thr Val Pro Glu Leu Pro Ala Glu Gln Met Val Glu Phe Ser Val Thr
225230235240
Leu Thr Asp Gln Glu Tyr Thr Ala Glu Leu Ser Asp Pro Asn Ser Pro
245250255
Gln Tyr Arg Gln Leu Ala Ala Lys Phe Gln Leu Gln Met Gln Lys Ile
260265270
Phe Glu Lys Leu Pro Gly Phe Lys Glu Ile His Val Leu Gly Phe Lys
275280285
Gln Lys Lys Glu Lys Asp Gly Ser Ser Ser Thr Ile Ala Arg Tyr Met
290295300
Val Asn Phe Glu Arg Asp Gly Ser Glu Ile Lys Ser Thr Ala Asp Asp
305310315320
Ile Ser Thr Ile Gly Ser Asn Lys Val Glu Asn Glu Lys Val Pro Leu
325330335
Ser Ala Lys Glu Glu Arg Glu Ile Ser Ala Thr Lys Leu Thr Val Thr
340345350
Asp Leu Gln Gln Leu Val Ala Thr Ala Leu His Glu Asp Arg Ser Leu
355360365
Pro Val Asp Leu Gly Thr Leu Arg Phe Thr Asp Glu Pro Ile Lys Pro
370375 380
Ser Ser Asp Phe Asp Asn Asp Ile Gln Gly Met Val Thr Ile Pro Leu
385390395400
Ala Gly Pro Asp Leu Asp Asp Thr Ile Ser Ala Glu Leu Pro Leu Val
405410415
Tyr Pro Ser Pro Ile Thr Val Asp Gln Thr Arg Asp Ile Phe Val Asp
420425430
Glu Phe Thr Thr Gly Ile Thr Asp Leu Ser Arg Glu Ile Gly Gly Pro
435440445
Glu Asp Phe Asp Ser Asn Phe Ile Thr Ser Glu Pro Ala Phe Pro Thr
450455460
Lys Pro Ser Arg Glu Pro Pro His Asp Arg Ser Pro Asp Thr Glu Asp
465470475480
Ile Thr Thr Asp Tyr Gln Arg Phe Thr Val Pro Phe Ser Ala Leu Val
485490495
Ser Thr Asp Ser Pro Ala Lys Pro Glu Asp Ser Tyr Leu Pro Pro Pro
500505510
Ala Asp Glu Ser Asp Ser Asn Asp Leu Ile Thr Asp Glu Ser Pro Thr
515520525
Glu Gln Val Ile Thr Pro Ala Val Tyr Thr Thr Gly Ser Phe Thr Leu
530535540
Pro Thr Phe Leu Gln Ala Thr Asp Lys Asp Thr Glu Ala Glu Met Lys
545550555560
Lys Glu Leu Val Gly Val Thr Glu Pro Leu Phe Lys Glu Ala Asp Arg
565570575
Asp Ser Leu Ser Gly Gln Ala Val Lys Met Met Asp Glu Leu Glu Ser
580585590
Ser Gly Asp Asp Ile Leu Val Thr Thr Ser Thr Tyr Lys Thr Leu Pro
595600605
Phe Leu Ile Gly Ser Ser Asp Leu Phe Ala Thr Gln Pro Glu Val Thr
610615620
Phe Ala Ala Ala Leu Pro Pro Asp Gln Thr Leu Leu Pro Thr Val Thr
625630635640
Ser Pro Phe Tyr Ser His Ser Val Val Ile Asp Gln Ser Pro Glu Val
645650655
Pro Asp Thr Leu Met Pro Ala Ala Ala Ser Ala Leu Pro Asp Arg Ala
660665670
Ser Thr Gly Val Gln Asp Ile Ala Ala Glu Leu Asp Gly Ala Gly Val
675680685
Lys Ser Thr Ala Val Leu Asp Glu Ala Glu His Gly Ser Gly Tyr Ile
690 695700
Ser Val Gln Thr Thr Glu Pro Ala Glu Val Thr Gln Ala Pro Thr Leu
705710715720
Lys Tyr Val Thr Thr Ser Ser Met Thr Thr Ala Ala Lys Gly Lys Glu
725730735
Leu Val Val Phe Phe Ser Leu Arg Val Thr Asn Met His Phe Ser Asp
740745750
Asp Leu Phe Asn Arg Ser Ser Gln Glu Tyr Lys Ala Leu Glu Gln Gln
755760765
Phe Met Gln Leu Leu Leu Pro Tyr Leu Gln Ser Asn Leu Thr Gly Phe
770775780
Lys Gln Leu Glu Ile Leu Asn Phe Arg Asn Gly Ser Val Ile Val Asn
785790795800
Ser Lys Met Lys Phe Ala Arg Thr Val Pro Tyr Asn Ile Thr Glu Ala
805810815
Val His Cys Val Leu Glu Asp Phe Cys Asp Ala Ala Ala Gln His Leu
820825830
Asn Leu Glu Ile Asp Ser Tyr Ser Leu Asp Ile Glu Pro Ala Asp Gln
835840845
Ala Asp Pro Cys Lys Phe Met Ala Cys Asp Glu Phe Ser Lys Cys Ile
850855860
Met Asn Glu Trp Thr Lys Glu Ala Asp Cys Leu Cys Lys Pro Gly Tyr
865870875880
Ala Ser Gln Asp Gly Leu Pro Cys Arg Ser Leu Cys Glu Met Glu Pro
885890895
His Leu Cys Asp Asn Gly Gly Lys Cys Glu Leu Val Pro Gly Arg Gly
900905910
Ala Val Cys Arg Ser Pro Asp Gln Phe Thr Glu Pro Gly Leu Thr Ser
915920925
<210> 316
<211> 798
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Interphotoreceptor matrix proteoglycan 1
SPACR Q8RIW8
<400> 316
Met Asn Leu Gln Ile Lys His Ala Ile Phe Val Leu Gly Ile Phe Leu
151015
Gln Val Gln Gly Ile Lys Asp Thr Ser Ile Lys Ile Phe Ser Ser Glu
202530
Ile Lys Asn Ile Asp Lys Thr Pro Arg Ile Glu Thr Ile Glu Ser Thr
354045
Ser Thr Val His Lys Val Ser Thr Met Lys Arg Ile Phe Asp Leu Pro
505560
Lys Leu Arg Thr Lys Arg Ser Ala Leu Phe Pro Ala Ala Asn Ile Cys
65707580
Pro Gln Glu Ser Leu Arg Gln Ile Leu Ala Ser Leu Gln Glu Tyr Tyr
859095
Arg Leu Arg Val Cys Gln Glu Val Val Trp Glu Ala Tyr Arg Ile Phe
100105110
Leu Asp Arg Ile Pro Asp Thr Glu Glu Tyr Gln Asp Trp Val Ser Leu
115120125
Cys Gln Lys Glu Thr Phe Cys Leu Phe Asp Ile Gly Lys Asn Phe Ser
130135140
Asn Ser Gln Glu His Leu Asp Leu Leu Gln Gln Arg Ile Lys Gln Arg
145150155160
Ser Phe Pro Gly Arg Lys Asp Glu Thr Ala Ser Met Glu Thr Leu Glu
165170175
Ala Pro Thr Glu Ala Pro Val Val Pro Thr Asp Val Ser Arg Met Ser
180185190
Leu Gly Pro Phe Pro Leu Pro Ser Asp Asp Thr Asp Leu Lys Glu Ile
195200205
Leu Ser Val Thr Leu Lys Asp Ile Gln Lys Pro Thr Thr Glu Ser Lys
210215220
Thr Glu Pro Ile His Val Ser Glu Phe Ser Ser Glu Glu Lys Val Glu
225230235240
Phe Ser Ile Ser Leu Pro Asn His Arg Phe Lys Ala Glu Leu Thr Asn
245250255
Ser Gly Ser Pro Tyr Tyr Gln Glu Leu Val Gly Gln Ser Gln Leu Gln
260265270
Leu Gln Lys Ile Phe Lys Lys Leu Pro Gly Phe Gly Glu Ile Arg Val
275280285
Leu Gly Phe Arg Pro Lys Lys Glu Glu Asp Gly Ser Ser Ser Thr Glu
290295300
Ile Gln Leu Met Ala Ile Phe Lys Arg Asp His Ala Glu Ala Lys Ser
305310315320
Pro Asp Ser His Leu Leu Ser Leu Asp Ser Asn Lys Ile Glu Ser Glu
325330335
Arg Ile His His Gly Val Ile Glu Asp Lys Gln Pro Glu Thr Tyr Leu
340345350
Thr Ala Thr Asp Leu Lys Lys Leu Ile Ile Gln Leu Leu Asp Gly Asp
355360365
Leu Ser Leu Val Glu Gly Lys Ile Pro Phe Gly Asp Glu Val Thr Gly
370375380
Thr Leu Phe Arg Pro Val Thr Glu Pro Asp Leu Pro Lys Pro Leu Ala
385390395400
Asp Val Thr Glu Asp Ala Thr Leu Ser Pro Glu Leu Pro Phe Val Glu
405410415
Pro Arg Leu Glu Ala Val Asp Arg Glu Gly Ser Glu Leu Pro Gly Met
420425430
Ser Ser Lys Asp Ser Ser Trp Ser Pro Pro Val Ser Ala Ser Ile Ser
435440445
Arg Ser Glu Asn Leu Pro Ser Phe Thr Pro Ser Ile Phe Ser Leu Asp
450455460
Ala Gln Ser Pro Pro Pro Leu Met Thr Thr Gly Pro Thr Ala Leu Ile
465470475480
Pro Lys Pro Thr Leu Pro Thr Ile Asp Tyr Ser Thr Ile Arg Gln Leu
485490495
Pro Leu Glu Ser Ser His Trp Pro Ala Ser Ser Ser Asp Arg Glu Leu
500505510
Ile Thr Ser Ser His Asp Thr Ile Arg Asp Leu Asp Gly Met Asp Val
515520525
Ser Asp Thr Pro Ala Leu Ser Glu Ile Ser Glu Leu Ser Gly Tyr Asp
530535540
Ser Ala Ser Gly Gln Phe Leu Glu Met Thr Thr Pro Ile Pro Thr Val
545550555560
Arg Phe Ile Thr Thr Ser Ser Glu Thr Ile Ala Thr Lys Gly Gln Glu
565570575
Leu Val Val Phe Phe Ser Leu Arg Val Ala Asn Met Pro Phe Ser Tyr
580585590
Asp Leu Phe Asn Lys Ser Ser Leu Glu Tyr Gln Ala Leu Glu Gln Arg
595600605
Phe Thr Asp Leu Leu Val Pro Tyr Leu Arg Ser Asn Leu Thr Gly Phe
610615620
Lys Gln Leu Glu Ile Leu Ser Phe Arg Asn Gly Ser Val Ile Val Asn
625630635640
Ser Lys Val Arg Phe Ala Lys Ala Val Pro Tyr Asn Leu Thr Gln Ala
645650655
Val Arg Gly Val Leu Glu Asp Leu Arg Ser Thr Ala Ala Gln Gly Leu
660665670
Asn Leu Glu Ile Glu Ser Tyr Ser Leu Asp Ile Glu Pro Ala Asp Gln
675680685
Ala Asp Pro Cys Lys Leu Leu Asp Cys Gly Lys Phe Ala Gln Cys Val
690695700
Lys Asn Glu Trp Thr Glu Glu Ala Glu Cys Arg Cys Arg Gln Gly His
705710715720
Glu Ser His Gly Thr Leu Asp Tyr Gln Thr Leu Asn Leu Cys Pro Pro
725730735
Gly Lys Thr Cys Val Ala Gly Arg Glu Gln Ala Thr Pro Cys Arg Pro
740745750
Pro Asp His Ser Thr Asn Gln Ala Gln Glu Pro Gly Val Lys Lys Leu
755760765
Arg Gln Gln Asn Lys Val Val Lys Lys Arg Asn Ser Lys Leu Ser Ala
770775780
Ile Gly Phe Glu Glu Phe Glu Asp Gln Asp Trp Glu Gly Asn
785790795
<210> 317
<211> 1243
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Interphotoreceptor matrix proteoglycan 2
SPACRCAN Q80XH2
<400> 317
Met Ile Met Phe Leu Pro Val Gly Arg Met Ser Leu Gly Ile Leu Ile
151015
Leu Phe Leu Thr Gly Gly Asn Leu Val Ser Ala Ser Glu Glu Arg Gln
202530
Glu Pro Met His Ala Val Ser Val Leu Ser Pro Glu Lys Ser Thr Asp
354045
Leu Ser Leu Pro Thr Arg Lys Arg Gln Leu Leu Asp Ala Thr Glu Thr
505560
Gly Arg Arg Trp Leu Leu Arg Arg Arg Arg Ser Ile Leu Phe Pro Asn
65707580
Gly Val Lys Ile Cys Ser Ser Glu Thr Val Ala Glu Ala Val Ala Asn
859095
His Val Lys Tyr Phe Lys Ala Arg Val Cys Gln Glu Ala Ile Trp Glu
100105110
Ala Phe Arg Thr Phe Trp Asp Arg Leu Pro Gly Arg Asp Glu Tyr Arg
115120125
His Trp Met Asn Leu Cys Glu Asp Gly Val Thr Ser Val Phe Glu Met
130135140
Gly Ala His Phe Ser Gln Ser Val Glu His Arg Asn Leu Ile Met Lys
145150155160
Lys Leu Ala Tyr Thr Arg Glu Ala Glu Ser Ser Ser Cys Lys Asp Gln
165170175
Ser Cys Gly Pro Glu Leu Ser Phe Pro Val Pro Ile Gly Glu Thr Ser
180185190
Thr Leu Thr Gly Ala Val Ser Ser Ala Ser Tyr Pro Gly Leu Ala Ser
195200205
Glu Ser Ser Ala Ala Ser Pro Gln Glu Ser Ile Ser Asn Glu Ile Glu
210215220
Asn Val Thr Glu Glu Pro Thr Gln Pro Ala Ala Glu Gln Ile Ala Glu
225230235240
Phe Ser Ile Gln Leu Leu Gly Lys Arg Tyr Ser Glu Glu Leu Arg Asp
245250255
Pro Ser Ser Ala Leu Tyr Arg Leu Leu Val Glu Glu Phe Ile Ser Glu
260265270
Val Glu Lys Ala Phe Thr Gly Leu Pro Gly Tyr Lys Gly Ile Arg Val
275280285
Leu Glu Phe Arg Ala Pro Glu Glu Asn Asp Ser Gly Ile Asp Val His
290295300
Tyr Ala Val Thr Phe Asn Gly Glu Ala Ile Ser Asn Thr Thr Trp Asp
305310315320
Leu Ile Ser Leu His Ser Asn Lys Val Glu Asn His Gly Leu Val Glu
325330335
Met Asp Asp Lys Pro Thr Ala Val Tyr Thr Ile Ser Asn Phe Arg Asp
340345350
Tyr Ile Ala Glu Thr Leu His Gln Asn Phe Leu Met Gly Asn Ser Ser
355360365
Leu Asn Pro Asp Pro Lys Ser Leu Gln Leu Ile Asn Val Arg Gly Val
370375380
Leu Leu Pro Gln Thr Glu Asp Ile Val Trp Asn Thr Gln Ser Ser Ser
385390395400
Leu Gln Val Thr Thr Ser Ser Ile Leu Asp Asn Thr Leu Gln Ala Glu
405410415
Trp Leu Ser Ala Asp Thr Thr Thr Thr Thr Thr Thr Thr Ile Ser Pro
420425430
Phe Gly Phe Ser Ser Ser Ser Pro Ser Ala Thr Gly Arg Glu Leu Gln
435440445
Ser Gln Ser Ala Leu Arg Asp Val Val Ser Thr Ser Lys Leu Ala Ser
450455460
Pro Thr Lys Val Val Leu Ser Ser Leu Pro Glu Ile Leu Gly Gly Ser
465470475480
Ser Leu Thr Leu His Ser Val Thr Pro Ala Val Leu Gln Pro Asp Leu
485490495
Pro Val Ala Pro Glu Gly Arg Thr Ser Gly Ser Phe Ile Leu Glu Asp
500505510
Gly Leu Ala Ser Thr Glu Glu Leu Glu Asp Thr Ser Ile Asp Gly Leu
515520525
Pro Ser Ser Pro Leu Ile Gln Pro Val Pro Lys Glu Thr Val Pro Pro
530535540
Met Glu Asp Ser Asp Thr Ala Leu Leu Ser Thr Pro His Leu Thr Ser
545550555560
Ser Ala Ile Glu Asp Leu Thr Lys Asp Ile Gly Thr Pro Ser Gly Leu
565570575
Glu Ser Leu Ala Ser Asn Ile Ser Asp Gln Leu Glu Val Ile Pro Trp
580585590
Phe Pro Asp Thr Ser Val Glu Lys Asp Phe Ile Phe Glu Ser Gly Leu
595600605
Gly Ser Gly Ser Gly Lys Asp Val Asp Val Ile Asp Trp Pro Trp Ser
610615620
Glu Thr Ser Leu Glu Lys Thr Thr Lys Pro Leu Ser Lys Ser Trp Ser
625630635640
Glu Glu Gln Asp Ala Leu Leu Pro Thr Glu Gly Arg Glu Lys Leu His
645650655
Ile Asp Gly Arg Val Asp Ser Thr Glu Gln Ile Ile Glu Ser Ser Glu
660665670
His Arg Tyr Gly Asp Arg Pro Ile His Phe Ile Glu Glu Glu Ser His
675680685
Val Arg Ser Thr Ile Pro Ile Phe Val Glu Ser Ala Thr Pro Pro Thr
690695700
Ser Pro Ile Phe Ser Lys His Thr Ser Asp Val Pro Asp Ile Asp Ser
705710715720
Tyr Ser Leu Thr Lys Pro Pro Phe Leu Pro Val Thr Ile Ala Ile Pro
725730735
Ala Ser Thr Lys Lys Thr Asp Glu Val Leu Lys Glu Asp Met Val His
740745750
Thr Glu Ser Ser Ser His Lys Glu Leu Asp Ser Glu Val Pro Val Ser
755760765
Arg Pro Asp Met Gln Pro Val Trp Thr Met Leu Pro Glu Ser Asp Thr
770775780
Val Trp Thr Arg Thr Ser Ser Leu Gly Lys Leu Ser Arg Asp Thr Leu
785790795800
Ala Ser Thr Pro Glu Ser Thr Asp Arg Leu Trp Leu Lys Ala Ser Met
805810815
Thr Gln Ser Thr Glu Leu Pro Ser Thr Thr His Ser Thr Gln Leu Glu
820825830
Glu Glu Val Ile Met Ala Val Gln Asp Ile Ser Leu Glu Leu Asp Gln
835840845
Val Gly Thr Asp Tyr Tyr Gln Ser Glu Leu Thr Glu Glu Gln His Gly
850855860
Lys Ala Asp Ser Tyr Val Glu Met Ser Thr Ser Val His Tyr Thr Glu
865870875880
Met Pro Ile Val Ala Leu Pro Thr Lys Gly Gly Val Leu Ser His Thr
885890895
Gln Thr Ala Gly Ala Leu Val Val Phe Phe Ser Leu Arg Val Thr Asn
900905910
Met Leu Phe Ser Glu Asp Leu Phe Asn Lys Asn Ser Leu Glu Tyr Lys
915920925
Ala Leu Glu Gln Arg Phe Leu Glu Leu Leu Val Pro Tyr Leu Gln Ser
930935940
Asn Leu Ser Gly Phe Gln Asn Leu Glu Ile Leu Ser Phe Arg Asn Gly
945950955960
Ser Ile Val Val Asn Ser Arg Val Arg Phe Ala Glu Ser Ala Pro Pro
965970975
Asn Val Asn Lys Ala Met Tyr Arg Ile Leu Glu Asp Phe Cys Thr Thr
980985990
Ala Tyr Gln Thr Met Asn Leu Asp Ile Asp Lys Tyr Ser Leu Asp Val
99510001005
Glu Ser Gly Asp Glu Ala Asn Pro Cys Lys Phe Gln Ala Cys Asn Glu
101010151020
Phe Ser Glu Cys Leu Val Asn Pro Trp Ser Gly Glu Ala Lys Cys Lys
1025103010351040
Cys Tyr Pro Gly Tyr Leu Ser Val Asp Glu Leu Pro Cys Gln Ser Leu
104510501055
Cys Asp Leu Gln Pro Asp Phe Cys Leu Asn Asp Gly Lys Cys Asp Ile
106010651070
Met Pro Gly His Gly Ala Ile Cys Arg Cys Arg Val Gly Ser Asn Trp
107510801085
Trp Tyr Arg Gly Gln His Cys Glu Glu Phe Val Ser Glu Pro Phe Val
109010951100
Ile Gly Ile Thr Ile Ala Ser Val Val Ser Phe Leu Leu Val Ala Ser
1105111011151120
Ala Val Val Phe Phe Leu Val Lys Met Leu Gln Ala Gln Asn Val Arg
112511301135
Arg Glu Arg Gln Arg Pro Thr Ser Ser Ser Arg His Pro Asp Ser Leu
114011451150
Ser Ser Val Glu Asn Ala Met Lys Tyr Asn Pro Ala Tyr Glu Ser His
115511601165
Leu Ala Gly Cys Glu Leu Tyr Glu Lys Ser Tyr Ser Gln His Pro Phe
117011751180
Tyr Ser Ser Ala Ser Glu Glu Val Ile Gly Gly Leu Ser Arg Glu Glu
1185119011951200
Ile Arg Gln Met Tyr Glu Ser Ser Asp Leu Ser Lys Glu Glu Ile Gln
120512101215
Glu Arg Met Arg Ile Leu Glu Leu Tyr Ala Asn Asp Pro Glu Phe Ala
122012251230
Ala Phe Val Arg Glu His Gln Met Glu Glu Leu
12351240
<210> 318
<211> 1241
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat Interphotoreceptor matrix proteoglycan 2
SPACRCAN P70628
<400> 318
Met Ile Met Phe Leu Pro Leu Gly Arg Ile Ser Leu Gly Ile Leu Ile
151015
Leu Phe Leu Thr Gly Gly Asn Leu Val Ser Val Ser Glu Glu Ile Gln
202530
Asp Arg Met His Ala Val Ala Val Leu Ser Pro Lys Glu Ser Thr Asp
354045
Leu Ser Leu Pro Thr Arg Lys Arg Gln Leu Leu Asp Ala Thr Glu Thr
505560
Gly Arg Arg Trp Pro Leu Arg Arg Arg Arg Ser Ile Leu Phe Pro Asn
65707580
Gly Val Arg Ile Cys Pro Ser Asp Thr Val Ala Glu Ala Val Ala Asn
859095
His Val Lys Tyr Phe Lys Ala Arg Val Cys Gln Glu Ala Ile Trp Glu
100105110
Ala Phe Arg Thr Phe Trp Asp Arg Leu Pro Gly Arg Glu Glu Tyr Gln
115120125
Tyr Trp Met Asn Leu Cys Glu Asp Gly Val Thr Ser Val Phe Glu Met
130135140
Gly Thr Gln Phe Ser Gln Ser Val Glu His Arg His Leu Ile Met Glu
145150155160
Lys Leu Thr Tyr Thr Lys Glu Ala Glu Ser Ser Ser Cys Lys Asp Gln
165170175
Ala Cys Gly Pro Glu Leu Ser Ser Pro Val Pro Ile Gly Glu Thr Ser
180185190
Thr Leu Ala Gly Ala Val Ser Ser Ala Ser Tyr Pro Gly Ala Ala Ser
195200205
Glu Arg Ser Ala Ala Ser Pro Gln Glu Ser Ile Ser Asn Glu Ile Glu
210215220
Asn Val Thr Glu Gln Pro Thr Pro Pro Ala Ala Glu Gln Ile Ala Glu
225230235240
Phe Ser Ile Gln Leu Leu Gly Lys Gln Tyr Ser Glu Glu Leu Arg Asp
245250255
Pro Ser Ser Ala Leu Tyr Arg Leu Leu Val Glu Glu Phe Ile Ser Glu
260265270
Val Glu Lys Ala Phe Thr Gly Leu Pro Gly Tyr Lys Gly Ile His Val
275280285
Leu Asp Phe Arg Ser Pro Lys Glu Asn Gly Ser Gly Ile Asp Val His
290295300
Tyr Ala Val Thr Phe Asn Gly Glu Ala Ile Ser Asn Thr Thr Trp Asp
305310315320
Leu Ile Ser Leu His Ser Asn Lys Val Glu Asn His Gly Leu Val Glu
325330335
Leu Asp Asp Lys Pro Thr Ala Val Tyr Thr Ile Ser Asn Phe Arg Asp
340345350
Tyr Ile Ala Glu Thr Leu His Gln Asn Phe Leu Met Gly Asn Ser Ser
355360365
Leu Asn Pro Asp Pro Lys Ser Leu Gln Leu Ile Asn Val Arg Gly Val
370375380
Leu Leu Pro Gln Thr Glu Glu Ile Val Trp Asn Thr Gln Ser Ser Ser
385390395400
Leu Gln Val Thr Thr Ser Ser Ile Leu Asp Asn Thr Leu Gln Ala Glu
405410415
Trp Leu Ser Ala Asp Glu Ser Ile Thr Thr Thr Thr Thr Thr Thr Ile
420425430
Ser Pro Phe Gly Phe Ser Ser Gly Pro Pro Ser Ala Thr Gly Arg Glu
435440445
Leu His Ser Glu Ser Thr Leu Gly Asp Ile Val Ser Thr Pro Lys Leu
450455460
Ala Ser Pro Ser Lys Val Val Leu Ser Ser Ser Pro Glu Val Leu Gly
465470475480
Gly Ser Ser Leu Thr Leu His Ser Val Thr Pro Ala Val Leu Gln Ile
485490495
Asp Leu Pro Val Ala Pro Glu Gly Arg Thr Ser Gly Ser Ser Ile Leu
500505510
Glu Asp Asp Asn Thr Glu Glu Ser Glu Asp Val Ser Ile Asp Val Leu
515520525
Pro Ser Ser Ser Leu Ile Gln Pro Val Pro Lys Glu Thr Val Pro Pro
530535540
Met Glu Asp Ser Asp Met Ile Leu Leu Thr Ser Ser Pro His Leu Thr
545550555560
Ser Ser Val Ile Glu Asp Leu Ala Lys Asp Ile Thr Thr Pro Ser Gly
565570575
Leu Asp Ser Leu Ala Ser Arg Val Ser Asp Lys Leu Asp Val Ser Pro
580585590
Trp Phe Pro Asp Thr Ser Val Glu Lys Glu Phe Ile Phe Glu Ser Gly
595600605
Leu Gly Ser Gly Ser Gly Lys Asn Val Asp Val Ile Asp Trp Pro Trp
610615620
Ser Glu Thr Ser Leu Glu Lys Thr Thr Glu Pro Leu Ser Lys Ser Trp
625630635640
Ser Glu Glu Gln Asp Thr Leu Leu Pro Thr Glu Ser Ile Glu Lys Leu
645650655
His Met Tyr Phe Thr Glu Gln Met Ile Glu Pro Ser Ala His Arg Tyr
660665670
Gly Asp Gly Pro Ile Tyr Phe Thr Glu Glu Glu Ser His Val Arg Ser
675680685
Thr Ile Pro Ile Phe Ala Glu Ser Ala Thr Gln Pro Thr Ser Leu Ile
690695700
Ser Ser Lys His Thr Ser Asp Val Pro Asp Ile Asp Ser Tyr Ser Val
705710715720
Thr Lys Ala Pro Phe Leu Leu Ala Thr Ile Ala Asn Thr Ala Ser Thr
725730735
Lys Glu Thr Asp Glu Val Asn Thr Leu Leu Lys Lys Gly Met Val Gln
740745750
Thr Glu Pro Ser Ser Pro Lys Gly Leu Asp Ser Lys Ile Ser Val Ala
755760765
Arg Pro Asp Met Gln Pro Val Trp Thr Ile Leu Pro Glu Ser Asp Thr
770775780
Val Trp Ala Arg Thr Ser Ser Leu Gly Lys Leu Ser Arg Asp Thr Leu
785790795800
Val Ser Thr Pro Glu Ser Ala Asp Arg Leu Trp Leu Lys Ala Ser Met
805810815
Thr Gln Pro Ala Glu Leu Pro Pro Ser Thr His Ser Ile Gln Leu Glu
820825830
Asp Glu Val Ile Met Ala Val Gln Asn Ile Ser Leu Glu Leu Asp Gln
835840845
Val Gly Thr Asp Tyr Tyr Gln Pro Glu Leu Thr Gln Glu Gln Asn Gly
850855860
Lys Val Asp Ser Tyr Val Glu Met Pro Thr His Val His Tyr Thr Glu
865870875880
Met Pro Leu Val Ala Gln Pro Thr Lys Gly Gly Val Leu Ser Arg Thr
885890895
Gln Thr Ala Gly Ala Leu Val Val Phe Phe Ser Leu Arg Val Thr Asn
900905910
Met Leu Phe Ser Glu Asp Leu Phe Asn Lys Asn Ser Leu Glu Tyr Lys
915920925
Ala Leu Glu Gln Arg Phe Leu Glu Leu Leu Val Pro Tyr Leu Gln Ser
930935940
Asn Leu Ser Gly Phe Gln Asn Leu Glu Ile Leu Asn Phe Arg Asn Gly
945950955960
Ser Ile Val Val Asn Ser Arg Val Lys Phe Ala Glu Ser Val Pro Pro
965970975
Asn Val Asn Asn Ala Ile Tyr Met Ile Leu Glu Asp Phe Cys Thr Thr
980985990
Ala Tyr Gln Thr Met Asn Leu Asp Ile Asp Lys Tyr Ser Leu Asp Val
99510001005
Glu Ser Gly Asp Asp Ala Asn Pro Cys Lys Phe Gln Ala Cys Asn Glu
101010151020
Phe Ser Glu Cys Leu Val Asn Pro Trp Ser Gly Glu Ala Lys Cys Lys
1025103010351040
Cys His Pro Gly Tyr Leu Ser Val Asp Glu Leu Pro Cys Gln Ser Val
104510501055
Cys Asp Leu Gln Pro Asp Phe Cys Leu Asn Asp Gly Lys Cys Asp Val
10601065 1070
Met Pro Gly His Gly Ala Ile Cys Arg Cys Arg Val Gly Ser Asn Trp
107510801085
Trp Tyr Arg Gly Gln His Cys Glu Glu Phe Val Ser Glu Pro Phe Val
109010951100
Ile Gly Ile Thr Ile Ala Ser Val Val Ser Leu Leu Leu Val Ala Ser
1105111011151120
Ala Val Val Phe Phe Leu Ala Lys Met Leu Gln Ala Gln Asn Val Arg
112511301135
Arg Glu Arg Gln Arg Pro Thr Asn Arg Gln Pro Asp Ser Leu Ser Ser
114011451150
Val Glu Asn Ala Met Lys Tyr Asn Pro Ala Tyr Glu Ser Arg Leu Ala
115511601165
Gly Cys Glu Gln Tyr Glu Lys Pro Tyr Ser Gln His Pro Phe Tyr Ser
117011751180
Ser Ala Ser Glu Glu Val Ile Gly Gly Leu Ser Arg Glu Glu Ile Arg
1185119011951200
Gln Met Tyr Glu Ser Ser Asp Leu Ser Lys Glu Glu Ile Gln Glu Arg
120512101215
Met Arg Ile Leu Glu Leu Tyr Ala Asn Asp Pro Glu Phe Ala Ala Phe
122012251230
Val Arg Glu His Glu Met Glu Glu Leu
12351240
<210> 319
<211> 1423
<212> PRT
<213> Gallus gallus
<220>
<223> Chicken Interphotoreceptor matrix proteoglycan 2
SPACRCAN Q1XI86
<220>
<221> VARIANT
<222> 491, 606, 623, 812, 842
<223> Xaa = any amino acid
<400> 319
Met Phe Ala Phe Leu Trp Lys Ile Ser Leu Cys Leu Leu Val Leu Gly
151015
Val Ile Thr Gly Asp Pro Gln Ala Val Ala Ala Glu Glu Lys Gln Ala
202530
Lys Asp Ala Ser Pro Thr Pro Gln Leu Gly Val Trp Gln Phe Ala Ser
354045
Pro Ser Leu Pro Pro Glu Leu Arg Lys Leu His Gly Ile Val Glu Ala
505560
Glu Gln Val Asn Arg His Leu Leu Arg Arg Arg Lys Arg Ser Ile Leu
65707580
Phe Pro Ser Gly Val Lys Ile Cys Pro Asp Glu Ser Val Glu Gln Ala
859095
Ile Ala Asn His Leu Lys Tyr Phe Arg Leu Arg Val Cys Gln Glu Thr
100105110
Val Trp Glu Val Phe Lys Thr Phe Trp Asp Arg Leu Pro Glu Arg Glu
115120125
Glu Tyr His Thr Trp Met Ser Leu Cys Glu Glu Gly Thr Met Ser Ile
130135140
Phe Glu Met Gly Met Asn Phe Ser Gln Ser Glu Glu His Arg Ser Leu
145150155160
Ile Val Lys Lys Leu Ser Tyr Thr Lys Glu Ala Met Ala Gly Ser Cys
165170175
Thr Asp Trp Ser Cys Gly Gly Thr Pro Thr Pro Ala Ser Asp Ala Asp
180185190
Ala Thr Thr Leu Arg Asp Ala Ala Ala Asn Val Pro Pro Pro His Glu
195200205
Val Ser Ile Glu Ser Pro Pro Gly Gly Thr Ser His Glu Ile Glu Asp
210215220
Ala Asp Thr Thr Ile Asn Asn Glu Ile Lys Lys Glu Asp Glu Ile Pro
225230235240
Val Arg Pro Val Thr Glu Gln Met Ile Glu Phe Ser Ile Val Ile Ala
245250255
Gly Glu Lys Tyr Ser Glu Glu Leu Ser Asp Pro Asp Thr Ala Lys Tyr
260265270
Gln Leu Leu Ser Glu Gln Phe Val Ser Gln Ile Gln Asn Val Phe Glu
275280285
Gly Leu Pro Gly Tyr Lys Asn Ile His Val Leu Glu Phe Ser Ser Pro
290295300
Glu Glu Asp Ser Gly Val Glu Val His Tyr Ala Val Thr Phe Asp Gly
305310315320
Glu Ala Ile Ser Asn Ala Thr Trp Asp Leu Ile Asn Leu His Ser Asn
325330335
Lys Val Glu Asp Asn Ser Phe Met Gly Ile Glu Asp Asn Pro Thr Val
340345350
Val Tyr Thr Ile Ser Asp Phe Gln Asp Tyr Ile Ala Glu Ile Leu Gln
355360365
Lys Asn Ala Leu Leu Glu Asn Thr Ser Leu Thr Leu Asp Pro Asn Ser
370375380
Leu Gln Leu Ile Asn Val Lys Glu Ile Leu His Pro Thr Gln Glu Asp
385390395400
Pro Ser Trp Ile Thr Glu His Pro Thr Val Leu Glu His Val Glu Phe
405410415
Asp Asp Asn Thr Phe Ser Ala Glu Arg Pro Ser Ala Asp Glu Ser Thr
420425430
Val Ser Asn Thr Leu Pro Phe Asp Phe Thr Lys Pro Asp Ser Thr Leu
435440445
Asp Ser Glu Glu Ser Asp Asp Asn Glu Ile Arg Pro Arg Pro Glu Ser
450455460
Leu Asp Ser Glu Val Ser Leu Ile Pro Glu Ala Pro Leu Ser Ser Glu
465470475480
Ala Asp Val Thr Ser Leu Pro Asp Gly Leu Xaa Leu Ala Asp Trp Asn
485490495
Gln Thr Pro Ala Leu Val Thr Ala Pro Val Ile Glu His Asp Ser Leu
500505510
Asp Ser Leu Glu Trp Leu Ser Ala Pro Asp Ser Ser Asp Glu Phe Glu
515520525
Asp Thr Gly Leu Ser Asp Asp Phe Leu Leu Pro Ser Ser Pro Ser Ser
530535540
His Leu Val Pro Glu Glu Pro Pro Ser Thr Asp Asp Tyr Thr Ala Pro
545550555560
Leu Leu Ser Ala Pro Thr Val Ala Ser Ser Ser Val Ile Glu Thr Asp
565570575
Thr Lys Arg Thr Val Thr Ala Glu Lys Glu Val Val Thr Gln Gly Ser
580585590
Pro Ala Asp Ser Ser Ser Ala Asp Ser Leu Leu His Glu Xaa Val Glu
595600605
Glu Ser Pro Phe Pro Leu Glu Val His Pro Val Glu Gly Glu Xaa Asp
610615620
Ile Tyr Leu Gly Asp Arg Met Ile Phe Asp Asp Gly Ser Gly Ser Ala
625630635640
Phe Asp Gly Ser Gly Lys Gly Met Glu Pro Ser Ile Trp Pro Trp Asp
645650655
Val Ala Thr Leu Glu Pro Val Phe Tyr Pro Gly Pro Asp Ser Trp Leu
660665670
Asp Asp Asp Asn Asp Ser Leu Pro Phe Arg Thr Glu Asp Ile Pro Glu
675680685
Gly Leu Ile Leu Asp Tyr Ile Leu Asn Ser Gly Asn Lys Leu Asp Asp
690695700
Asp Pro Ser Lys Asp Glu Asn Glu Gly Val Ala Ser Ile Lys Glu Asn
705710715720
Phe Leu Asp Glu Ser Glu Ile Phe Val Phe Pro Glu Thr Thr Thr Gln
725730735
Gln Val Pro Leu Leu Gln Thr Gly Glu Pro Ser Ser Val Glu Thr Ser
740745750
Thr Gln Met Glu Thr Leu Ser Met Asp Asp Asp Ser Phe Val Lys Pro
755760765
Ser Phe Val Leu Glu Pro Pro Glu Asp Tyr Ser Phe Ala Asp Leu Pro
770775780
Thr Gly Glu Asp Leu Phe Leu Pro His Ser Thr Gly Val Ser Val Glu
785790795800
Asp Thr Leu Leu Thr Ser Thr Val Thr Leu Gly Xaa Glu Asp Ser Leu
805810815
Leu Thr Ser Thr Val Ala Phe Ser Val Glu Gln Pro Glu Glu Ser Ser
820825830
Val Gly Gln Glu Ile Ile Ser Glu Ala Xaa Glu His Gln Asn Glu Asp
835840845
Arg Pro Thr Val Glu Glu Leu Phe Thr Ala Gly Gln Ser Asn Val Gly
850855860
Glu Ala Ala Thr Val Gly Tyr Leu Asp Lys Ser Ser Leu Glu Thr Val
865870875880
Leu Thr Ala Glu Pro Phe Glu Val Ser Thr Asp Thr Ser Thr Glu Glu
885890895
Gln Gln Ser Leu Asp Ser Ser Leu Ala Asp Arg Asp Thr Gly Leu Ala
900905910
Ile Arg Lys Pro Ala Asp Val Trp Pro Thr Asp Arg Val Leu Glu Lys
915920925
Thr Leu Asp Gln Thr Val Gln Ser Ala Val Pro Thr Ala Ala Gln Val
930935940
Ser Thr Ala Val Pro Ser Leu Ile His Gln Ala Thr Ala Leu Glu Gly
945950955960
Phe Ala Gly Gln Asp Gly Thr Glu His Asp Thr His Val Ser Met Ser
965970975
Ile Ser Thr Ile Leu Asn Ser Tyr Val Thr Ile Thr Ala Asp Thr Val
980985990
Glu Leu Pro Ser His Leu Pro Pro Met Thr Thr Thr Val Ser Ser Ser
99510001005
Val Val Thr Leu Ala Lys Val Gly Asp Glu Thr Thr Arg Val Leu Asp
101010151020
Val Ser Val Asp Leu Asp His Val Ser Met Val Ser Phe Ser Pro Glu
1025103010351040
Pro Ser Glu Glu Ala Lys Ser Met Thr Asp Ser His Met Glu Leu Thr
104510501055
Thr His Ala His Ser Thr Glu Met Ala Gly Val Ala Trp Pro Thr His
106010651070
Glu Ile His Asn Ser Thr Pro Val Pro Ser Arg Ala Leu Val Val Phe
107510801085
Phe Ser Leu Arg Val Thr Asn Met Met Phe Ser Glu Asp Leu Phe Asn
109010951100
Lys Asn Ser Pro Glu Tyr Lys Ala Leu Glu Gln Arg Phe Leu Glu Leu
1105111011151120
Leu Val Pro Tyr Leu Gln Ser Asn Leu Thr Gly Phe Gln Asn Leu Glu
112511301135
Ile Leu Asn Phe Arg Asn Gly Ser Ile Val Val Asn Ser Arg Met Lys
114011451150
Phe Ala Lys Pro Val Pro Arg Asn Val Thr Asn Ala Val Tyr Met Ile
115511601165
Leu Glu Asp Phe Cys Asn Thr Ala Tyr His Thr Met Asn Leu Ala Ile
117011751180
Asp Lys Tyr Ser Leu Asp Val Glu Ser Gly Glu Gln Ala Asp Pro Cys
1185119011951200
Lys Phe Gln Ala Cys Asn Glu Phe Ser Glu Cys Leu Val Asn Arg Trp
120512101215
Ser Gly Glu Ala Glu Cys Val Cys Asn Pro Gly Tyr Leu Ser Ile Asp
122012251230
Gly Leu Pro Cys Asn Ser Ile Cys Asp Leu Gln Pro Asn Phe Cys Leu
123512401245
Asn Asp Gly Lys Cys Asp Ile Ser Pro Gly Gln Gly Ala Ile Cys Arg
125012551260
Cys Arg Val Gly Glu Asn Trp Trp Tyr Arg Gly Glu His Cys Glu Glu
1265127012751280
Tyr Val Ser Glu Pro Leu Val Val Gly Ile Ala Ile Ala Ser Val Ala
128512901295
Gly Phe Leu Leu Val Ala Ser Ala Val Ile Phe Phe Leu Ala Arg Thr
130013051310
Leu Arg Asp Gln Tyr Thr Lys Ser Asp Thr Glu Asp Ser Gln Gly Gln
131513201325
Gly Asp Ser Leu Ser Ser Ile Glu Asn Ala Val Lys Tyr Asn Pro Met
133013351340
Tyr Glu Ser Asp Thr Thr Gly Tyr Ser His Tyr Tyr Arg Arg Tyr Pro
1345135013551360
Gln Leu Thr Ser Tyr Ser Ser Thr Ser Ala Glu Thr Ser Thr Asp Tyr
136513701375
Ser Ser Glu Glu Ile Arg His Ile Tyr Glu Asn Ser Glu Leu Thr Lys
138013851390
Glu Glu Ile Gln Asp Arg Ile Arg Ile Ile Glu Leu Tyr Ala Lys Asp
139514001405
Arg Gln Phe Ala Glu Phe Val Arg Gln His Gln Met Lys Leu Leu
141014151420
<210> 320
<211> 304
<212> PRT
<213> Mus musculus
<220>
<223> Mouse CD38 P56528
<400> 320
Met Ala Asn Tyr Glu Phe Ser Gln Val Ser Gly Asp Arg Pro Gly Cys
151015
Arg Leu Ser Arg Lys Ala Gln Ile Gly Leu Gly Val Gly Leu Leu Val
202530
Leu Ile Ala Leu Val Val Gly Ile Val Val Ile Leu Leu Arg Pro Arg
354045
Ser Leu Leu Val Trp Thr Gly Glu Pro Thr Thr Lys His Phe Ser Asp
505560
Ile Phe Leu Gly Arg Cys Leu Ile Tyr Thr Gln Ile Leu Arg Pro Glu
65707580
Met Arg Asp Gln Asn Cys Gln Glu Ile Leu Ser Thr Phe Lys Gly Ala
859095
Phe Val Ser Lys Asn Pro Cys Asn Ile Thr Arg Glu Asp Tyr Ala Pro
100105110
Leu Val Lys Leu Val Thr Gln Thr Ile Pro Cys Asn Lys Thr Leu Phe
115120125
Trp Ser Lys Ser Lys His Leu Ala His Gln Tyr Thr Trp Ile Gln Gly
130135140
Lys Met Phe Thr Leu Glu Asp Thr Leu Leu Gly Tyr Ile Ala Asp Asp
145150155160
Leu Arg Trp Cys Gly Asp Pro Ser Thr Ser Asp Met Asn Tyr Val Ser
165170175
Cys Pro His Trp Ser Glu Asn Cys Pro Asn Asn Pro Ile Thr Val Phe
180185190
Trp Lys Val Ile Ser Gln Lys Phe Ala Glu Asp Ala Cys Gly Val Val
195200205
Gln Val Met Leu Asn Gly Ser Leu Arg Glu Pro Phe Tyr Lys Asn Ser
210215220
Thr Phe Gly Ser Val Glu Val Phe Ser Leu Asp Pro Asn Lys Val His
225230235240
Lys Leu Gln Ala Trp Val Met His Asp Ile Glu Gly Ala Ser Ser Asn
245250255
Ala Cys Ser Ser Ser Ser Leu Asn Glu Leu Lys Met Ile Val Gln Lys
260265270
Arg Asn Met Ile Phe Ala Cys Val Asp Asn Tyr Arg Pro Ala Arg Phe
275280285
Leu Gln Cys Val Lys Asn Pro Glu His Pro Ser Cys Arg Leu Asn Thr
290295300
<210> 321
<211> 303
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat CD38 Q64244
<400> 321
Met Ala Asn Tyr Glu Phe Ser Gln Val Ser Glu Asp Arg Pro Gly Cys
151015
Arg Leu Thr Arg Lys Ala Gln Ile Gly Leu Gly Val Gly Leu Leu Leu
202530
Leu Val Ala Leu Val Val Val Val Val Ile Val Leu Trp Pro Arg Ser
354045
Pro Leu Val Trp Lys Gly Lys Pro Thr Thr Lys His Phe Ala Asp Ile
505560
Ile Leu Gly Arg Cys Leu Ile Tyr Thr Gln Ile Leu Arg Pro Glu Met
65707580
Arg Asp Gln Asp Cys Lys Lys Ile Leu Ser Thr Phe Lys Arg Gly Phe
859095
Ile Ser Lys Asn Pro Cys Asn Ile Thr Asn Glu Asp Tyr Ala Pro Leu
100105110
Val Lys Leu Val Thr Gln Thr Ile Pro Cys Asn Lys Thr Leu Phe Trp
115120125
Ser Lys Ser Lys His Leu Ala His Gln Tyr Thr Trp Ile Gln Gly Lys
130135140
Met Phe Thr Leu Glu Asp Thr Leu Leu Gly Tyr Ile Ala Asp Asp Leu
145150155160
Arg Trp Cys Gly Asp Pro Ser Thr Ser Asp Met Asn Tyr Asp Ser Cys
165170175
Pro His Trp Ser Glu Asn Cys Pro Asn Asn Pro Val Ala Val Phe Trp
180185190
Asn Val Ile Ser Gln Lys Phe Ala Glu Asp Ala Cys Gly Val Val Gln
195200205
Val Met Leu Asn Gly Ser Leu Ser Glu Pro Phe Tyr Arg Asn Ser Thr
210215220
Phe Gly Ser Val Glu Val Phe Asn Leu Asp Pro Asn Lys Val His Lys
225230235240
Leu Gln Ala Trp Val Met His Asp Ile Lys Gly Thr Ser Ser Asn Ala
245250255
Cys Ser Ser Pro Ser Ile Asn Glu Leu Lys Ser Ile Val Asn Lys Arg
260265270
Asn Met Ile Phe Ala Cys Gln Asp Asn Tyr Arg Pro Val Arg Phe Leu
275280285
Gln Cys Val Lys Asn Pro Glu His Pro Ser Cys Arg Leu Asn Val
290295300
<210> 322
<211> 298
<212> PRT
<213> Oryctolagus cuniculus
<220>
<223> Rabbit CD38 Q0MZ03
<400> 322
Met Pro Asp Tyr Glu Phe Ser Pro Ala Ser Gly Asp Arg Pro Arg Ser
151015
Trp Ile Ser Lys Gln Val Leu Ile Val Leu Gly Val Cys Leu Pro Val
202530
Ile Leu Ala Leu Ala Ile Trp Val Gly Val Leu Thr Trp Arg Gln Ser
354045
Ser Met Gly Ala Thr Asp His Val Ser Ala Ile Val Leu Gly Arg Cys
505560
Leu Thr Tyr Thr Arg Asn Met His Pro Glu Leu Arg Asn Gln Asp Cys
65707580
Lys Lys Ile Leu Asn Thr Phe Thr Ser Ala Phe Val Ser Lys Asp Pro
859095
Cys Asn Ile Thr Lys Glu Asp Tyr Gln Pro Leu Ile Asp Leu Val Thr
100105110
Gln Thr Val Pro Cys Asn Lys Thr Leu Phe Trp Ser Arg Ser Lys Glu
115120125
Leu Ala His Gln Tyr Ser Gly Ile Gln Lys Glu Met Phe Thr Leu Glu
130135140
Asp Thr Leu Leu Gly Tyr Ile Ala Asp Asn Leu Val Trp Cys Gly Asp
145150155160
Pro Arg Thr Ser Glu Val Lys Glu Glu Phe Cys Pro Tyr Arg Asn Glu
165170175
Asn Cys Ser Ser Thr Ala Thr Ser Val Phe Trp Thr Val Val Ser Gln
180185190
Lys Phe Ala Glu Ser Ala Cys Gly Thr Val Tyr Val Met Leu Asn Gly
195200205
Ser Arg Thr Thr Ala Phe Ser Lys Ala Ser Thr Phe Gly Ser Val Glu
210215220
Val Phe Asn Leu His Pro Asp Arg Val His Thr Leu His Ala Trp Val
225230235240
Met His Asp Ile Gly Gly Val Glu Arg Asp Ser Cys Leu Gly Ser Ser
245250255
Ile Lys Glu Leu Lys Ser Ile Val Asn Gln Arg Asn Ile Ser Phe Phe
260265270
Cys Gln Asp Asp Tyr Arg Pro Ala Arg Phe Val Gln Cys Val Arg His
275280285
Pro Glu His Pro Ser Cys Ser Val Leu Met
290295
<210> 323
<211> 301
<212> PRT
<213> Macaca fascicularis
<220>
<223> Cynomolgus monkey CD38 Q5VAN0
<400> 323
Met Ala Asn Cys Glu Phe Ser Pro Val Ser Gly Asp Lys Pro Cys Cys
151015
Arg Leu Ser Arg Arg Ala Gln Val Cys Leu Gly Val Cys Leu Leu Val
202530
Leu Leu Ile Leu Val Val Val Val Ala Val Val Leu Pro Arg Trp Arg
354045
Gln Gln Trp Ser Gly Ser Gly Thr Thr Ser Arg Phe Pro Glu Thr Val
505560
Leu Ala Arg Cys Val Lys Tyr Thr Glu Val His Pro Glu Met Arg His
65707580
Val Asp Cys Gln Ser Val Trp Asp Ala Phe Lys Gly Ala Phe Ile Ser
859095
Lys Tyr Pro Cys Asn Ile Thr Glu Glu Asp Tyr Gln Pro Leu Val Lys
100105110
Leu Gly Thr Gln Thr Val Pro Cys Asn Lys Thr Leu Leu Trp Ser Arg
115120125
Ile Lys Asp Leu Ala His Gln Phe Thr Gln Val Gln Arg Asp Met Phe
130135140
Thr Leu Glu Asp Met Leu Leu Gly Tyr Leu Ala Asp Asp Leu Thr Trp
145150155160
Cys Gly Glu Phe Asn Thr Phe Glu Ile Asn Tyr Gln Ser Cys Pro Asp
165170175
Trp Arg Lys Asp Cys Ser Asn Asn Pro Val Ser Val Phe Trp Lys Thr
180185190
Val Ser Arg Arg Phe Ala Glu Thr Ala Cys Gly Val Val His Val Met
195200205
Leu Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys Asn Ser Thr Phe Gly
210215220
Ser Val Glu Val His Asn Leu Gln Pro Glu Lys Val Gln Ala Leu Glu
225230235240
Ala Trp Val Ile His Gly Gly Arg Glu Asp Ser Arg Asp Leu Cys Gln
245250255
Asp Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile Ser Lys Arg Asn Ile
260265270
Arg Phe Phe Cys Lys Asn Ile Tyr Arg Pro Asp Lys Phe Leu Gln Cys
275280285
Val Lys Asn Pro Glu Asp Ser Ser Cys Leu Ser Gly Ile
290295300
<210> 324
<211> 411
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Intracellular hyaluronan-binding protein 4
Q9JKS5
<400> 324
Met Lys Gly Ala Leu Gly Ser Pro Val Ala Ala Ala Gly Ala Ala Met
151015
Gln Glu Thr Phe Gly Cys Val Val Ala Asn Arg Phe His Gln Leu Leu
202530
Asp Asp Glu Ser Asp Pro Phe Asp Ile Leu Arg Glu Ala Glu His Arg
354045
Arg Gln Gln Gln Leu Gln Arg Lys Arg Arg Asp Glu Ala Ala Ala Ala
505560
Ser Gly Ala Gly His Arg Gly Gly Arg Ser Pro Ala Val Ala Ser Gly
65707580
His Arg Pro Gly Ala Gly Gly Arg Arg Glu Ser Gln Lys Glu Arg Lys
859095
Ser Leu Ala Ala Ser Gly Ala Gln Gln Pro Asp Ser Pro Gly Gly Pro
100105110
Gln Pro Pro Gly Gln Lys Arg Thr Pro Arg Arg Gly Glu Gln Gln Gly
115120125
Trp Asn Asp Asn Arg Gly Thr Asp Val Val Leu Glu Arg Ala Glu Arg
130135140
Arg Ser Tyr Arg Glu Tyr Arg Pro Tyr Glu Thr Glu Arg Gln Ala Asp
145150155160
Leu Pro Val Glu Lys Phe Thr Asp Glu Lys Pro Val Asp Arg Phe Asp
165170175
Arg Asp Arg Pro Leu Arg Gly Arg Gly Gly Pro Arg Gly Gly Leu Arg
180185190
Ser Arg Gly Arg Gly Gly Pro Gly Asn Arg Ala Phe Asp Ser Phe Asp
195200205
Gln Arg Gly Lys Arg Asp Phe Glu Arg Tyr Ser Ser Asn Asp Lys Thr
210215220
Asn Arg Met Glu Asp Ser Met Gly Gly Cys Gly Ile Arg Pro Trp Gly
225230235240
Ser Gly Lys Asp Thr Ser Asp Thr Glu Pro Pro Ala Pro Met Glu Glu
245250255
Thr Ser Met Met Glu Glu Cys Gln Gly Thr Leu Asp Glu Glu Ser Ala
260265270
Ala Lys Val Pro Glu Leu Glu Val Glu Glu Glu Asn Gln Val Gln Glu
275280285
Met Thr Leu Asp Glu Trp Lys Asn Leu Gln Glu Gln Thr Arg Pro Lys
290295300
Pro Glu Phe Asn Ile Arg Lys Pro Glu Ser Thr Val Pro Ser Lys Ala
305310315320
Val Val Ile His Lys Ser Arg Tyr Arg Asp Asp Met Val Lys Glu Asp
325330335
Tyr Glu Asp Glu Ser His Val Phe Arg Lys Ala Ala Asn Asp Ile Thr
340345350
Ser Gln Leu Glu Ile Asn Phe Gly Asn Leu Pro Arg Pro Gly Arg Gly
355360365
Ala Arg Gly Ser Thr Arg Gly Gly Arg Gly Arg Met Arg Arg Thr Glu
370375380
Asn Tyr Gly Pro Arg Ala Glu Val Val Thr Gln Asp Val Ala Pro Asn
385390395400
Pro Asp Asp Pro Glu Asp Phe Pro Ala Leu Ala
405410
<210> 325
<211> 357
<212> PRT
<213> Gallus gallus
<220>
<223> Chicken Intracellular hyaluronan-binding protein 4
Q9I9R0
<400> 325
Met Met Lys Gly Ala Met Gly Cys Pro Val Ala Ala Val Met Glu Gly
151015
Ser Phe Ser Cys Thr Val Ala Asn Arg Phe Tyr Gln Leu Leu Asp Asp
202530
Glu Ser Asp Pro Phe Asp Asn Leu Arg Glu Ala Glu Arg Cys Trp Gln
354045
Gln Arg Lys Asn Leu Ser Lys Val Val Ala Arg Arg Gly Asp Pro Gly
505560
Ser Arg Gly Cys Ala Thr Arg Arg Glu Leu Gln Lys Gln Arg Lys Gln
65707580
Leu Gly Thr Pro Ala Pro Pro Pro Gln Pro Gly Gln Lys Gln Ala Pro
859095
Lys Gln Glu Glu Cys Gly Gly Lys Asp Asn Ser Arg Ala Glu Lys Glu
100105110
His Lys Thr Ala Trp Arg Pro Ser Phe Met Glu Tyr Leu Ser Ser Glu
115120125
Thr Glu Ser Gln Ala Glu Leu Thr Ala Gln Ser Leu Phe Arg Pro Thr
130135140
Ala Lys Leu Asn Tyr Glu Arg Pro Arg Gly Cys Gly Arg Gly Arg Gly
145150155160
Gly Met Gln Gly Arg Gly Arg Gly Gly Gly Ile Asn Lys Ser Phe Asp
165170175
Gly Phe Asp Gln Arg Gly Lys Arg Glu Phe Gly Arg Gln Asn Asp Asn
180185190
Asp Lys Ile Glu Met Glu Leu Thr Ala Pro Met Glu Ala Thr Ala Lys
195200205
Thr Ala Lys Ser Pro Gly Val Ser Glu Gly Glu Leu Leu Asn Lys Val
210215220
Ala Glu Gly Lys Pro Arg Glu Glu Val Val Gln Glu Met Thr Leu Asp
225230235240
Glu Trp Lys Asn Leu Gln Gln Gln Asn Arg Pro Lys His Glu Phe Asn
245250255
Ile Arg Arg Pro Glu Ser Thr Val Pro Ser Lys Ala Val Val Ile His
260265270
Lys Ser Lys Tyr Ser Asp Asp Ile Gln Lys Gly Glu Leu Glu Asp Asp
275280285
Tyr His Ile Phe Arg Arg Ala Val Asn Asp Ile Thr Phe Gln Leu Asp
290295300
Ile Asn Phe Gly Ser Leu Pro Arg Pro Gly Cys Gly Ser Arg Gly Ala
305310315320
Arg Gly Arg Gly Arg Gly Arg Gln Met Glu Glu Thr Gly Pro Gln Pro
325330335
Glu Ala Met Val Gln Ile Val Ala Pro Asn Pro Asp Asp Pro Glu Asp
340345350
Phe Pro Ala Leu Thr
355
<210> 326
<211> 506
<212> PRT
<213> Saccharomyces cerevisiae
<220>
<223> Saccharomyces cerevisiae Baker's yeast CDC37
P06101
<400> 326
Met Ala Ile Asp Tyr Ser Lys Trp Asp Lys Ile Glu Leu Ser Asp Asp
151015
Ser Asp Val Glu Val His Pro Asn Val Asp Lys Lys Ser Phe Ile Lys
202530
Trp Lys Gln Gln Ser Ile His Glu Gln Arg Phe Lys Arg Asn Gln Asp
354045
Ile Lys Asn Leu Glu Thr Gln Val Asp Met Tyr Ser His Leu Asn Lys
505560
Arg Val Asp Arg Ile Leu Ser Asn Leu Pro Glu Ser Ser Leu Thr Asp
65707580
Leu Pro Ala Val Thr Lys Phe Leu Asn Ala Asn Phe Asp Lys Met Glu
859095
Lys Ser Lys Gly Glu Asn Val Asp Pro Glu Ile Ala Thr Tyr Asn Glu
100105110
Met Val Glu Asp Leu Phe Glu Gln Leu Ala Lys Asp Leu Asp Lys Glu
115120125
Gly Lys Asp Ser Lys Ser Pro Ser Leu Ile Arg Asp Ala Ile Leu Lys
130135140
His Arg Ala Lys Ile Asp Ser Val Thr Val Glu Ala Lys Lys Lys Leu
145150155160
Asp Glu Leu Tyr Lys Glu Lys Asn Ala His Ile Ser Ser Glu Asp Ile
165170175
His Thr Gly Phe Asp Ser Ser Phe Met Asn Lys Gln Lys Gly Gly Ala
180185190
Lys Pro Leu Glu Ala Thr Pro Ser Glu Ala Leu Ser Ser Ala Ala Glu
195200205
Ser Asn Ile Leu Asn Lys Leu Ala Lys Ser Ser Val Pro Gln Thr Phe
210215220
Ile Asp Phe Lys Asp Asp Pro Met Lys Leu Ala Lys Glu Thr Glu Glu
225230235240
Phe Gly Lys Ile Ser Ile Asn Glu Tyr Ser Lys Ser Gln Lys Phe Leu
245250255
Leu Glu His Leu Pro Ile Ile Ser Glu Gln Gln Lys Asp Ala Leu Met
260265270
Met Lys Ala Phe Glu Tyr Gln Leu His Gly Asp Asp Lys Met Thr Leu
275280285
Gln Val Ile His Gln Ser Glu Leu Met Ala Tyr Ile Lys Glu Ile Tyr
290295300
Asp Met Lys Lys Ile Pro Tyr Leu Asn Pro Met Glu Leu Ser Asn Val
305310315320
Ile Asn Met Phe Phe Glu Lys Val Ile Phe Asn Lys Asp Lys Pro Met
325330335
Gly Lys Glu Ser Phe Leu Arg Ser Val Gln Glu Lys Phe Leu His Ile
340345350
Gln Lys Arg Ser Lys Ile Leu Gln Gln Glu Glu Met Asp Glu Ser Asn
355360365
Ala Glu Gly Val Glu Thr Ile Gln Leu Lys Ser Leu Asp Asp Ser Thr
370375380
Glu Leu Glu Val Asn Leu Pro Asp Phe Asn Ser Lys Asp Pro Glu Glu
385390395400
Met Lys Lys Val Lys Val Phe Lys Thr Leu Ile Pro Glu Lys Met Gln
405410415
Glu Ala Ile Met Thr Lys Asn Leu Asp Asn Ile Asn Lys Val Phe Glu
420425430
Asp Ile Pro Ile Glu Glu Ala Glu Lys Leu Leu Glu Val Phe Asn Asp
435440445
Ile Asp Ile Ile Gly Ile Lys Ala Ile Leu Glu Asn Glu Lys Asp Phe
450455460
Gln Ser Leu Lys Asp Gln Tyr Glu Gln Asp His Glu Asp Ala Thr Met
465470475480
Glu Asn Leu Ser Leu Asn Asp Arg Asp Gly Gly Gly Asp Asn His Glu
485490495
Glu Val Lys His Thr Ala Asp Thr Val Asp
500505
<210> 327
<211> 389
<212> PRT
<213> Drosophila melanogaster
<220>
<223> Fruit fly CDC37 Q24276
<400> 327
Met Val Asp Tyr Ser Lys Trp Lys Asn Ile Glu Ile Ser Asp Asp Glu
151015
Asp Asp Thr His Pro Asn Ile Asp Thr Pro Ser Leu Phe Arg Trp Arg
202530
His Gln Ala Arg Val Glu Arg Met Ala Glu Met Asp His Glu Lys Asp
354045
Glu Leu Lys Lys Lys Arg Gln Ser Tyr Gln Ala Arg Leu Met Asp Val
505560
Lys Glu Arg Ile Ser Lys Lys Asp Gly Asp Glu Glu Ala Leu Lys Lys
65707580
Glu Leu Glu Lys Ile Glu Ala Glu Gly Lys Glu Leu Asp Arg Ile Glu
859095
Ser Glu Met Ile Lys Lys Glu Lys Lys Thr Pro Trp Asn Val Asp Thr
100105110
Ile Ser Lys Pro Gly Phe Glu Lys Thr Val Ile Asn Lys Lys Ala Gly
115120125
Arg Lys Pro Asp Glu Asn Leu Ser Glu Glu Glu Arg Glu Gln Arg Met
130135140
Lys Gln Phe Val Lys Glu Asn Glu Lys Leu Cys Gln Gln Tyr Gly Met
145150155160
Leu Arg Lys Tyr Asp Asp Ser Lys Arg Phe Leu Gln Glu His Leu His
165170175
Leu Val Gly Glu Glu Thr Ala Asn Tyr Leu Val Ile Trp Ser Ile Asn
180185190
Leu Glu Met Glu Glu Lys His Glu Leu Met Ala His Val Ala His Gln
195200205
Cys Ile Cys Met Gln Tyr Ile Leu Glu Leu Ala Lys Gln Leu Asp Val
210215220
Asp Pro Arg Ala Cys Val Ser Ser Phe Phe Ser Lys Ile Gln His Cys
225230235240
His Pro Glu Tyr Arg Ala Gln Phe Asp Ser Glu Ile Glu Gly Phe Lys
245250255
Gly Arg Ile Gln Lys Arg Ala Gln Glu Lys Ile Gln Glu Ala Ile Ala
260265270
Gln Ala Glu Glu Glu Glu Arg Lys Glu Arg Leu Gly Pro Gly Gly Leu
275280285
Asp Pro Ala Asp Val Phe Glu Ser Leu Pro Asp Glu Leu Lys Ala Cys
290295300
Phe Glu Ser Arg Asp Val Glu Leu Leu Gln Lys Thr Ile Ala Ala Met
305310315320
Pro Val Asp Val Ala Lys Leu His Met Lys Arg Cys Val Asp Ser Gly
325330335
Leu Trp Val Pro Asn Ala Ala Asp Leu Glu Gly Asp Lys Lys Glu Glu
340345350
Asp Asp Ser Asp Asp Val Ala Gly Gly Glu Glu Lys Thr Asp Asp Ala
355360365
Lys Ser Glu Ser Ala Ala Lys Glu Glu Pro Ile Tyr Thr Gly Val Ser
370375380
Thr Glu Asp Val Asp
385
<210> 328
<211> 379
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat CDC37 Q63692
<400> 328
Met Val Asp Tyr Ser Val Trp Asp His Ile Glu Val Ser Asp Asp Glu
151015
Asp Glu Thr His Pro Asn Ile Asp Thr Ala Ser Leu Phe Arg Trp Arg
202530
His Gln Ala Arg Val Glu Arg Met Glu Gln Phe Gln Lys Glu Lys Glu
354045
Glu Leu Asp Arg Gly Cys Arg Glu Cys Lys Arg Lys Val Ala Glu Cys
505560
Gln Arg Lys Leu Lys Glu Leu Glu Val Ala Glu Gly Gly Gly Gln Val
65707580
Glu Leu Glu Arg Leu Arg Ala Glu Ala Gln Gln Leu Arg Lys Glu Glu
859095
Arg Ser Trp Glu Gln Lys Leu Glu Asp Met Arg Lys Lys Glu Lys Asn
100105110
Met Pro Trp Asn Val Asp Thr Leu Ser Lys Asp Gly Phe Ser Lys Ser
115120125
Met Val Asn Thr Lys Pro Glu Lys Ala Glu Glu Asp Ser Glu Glu Ala
130135140
Arg Glu Gln Lys His Lys Thr Phe Val Glu Lys Tyr Glu Lys Gln Ile
145150155160
Lys His Phe Gly Met Leu His Arg Trp Asp Asp Ser Gln Lys Tyr Leu
165170175
Ser Asp Asn Val His Leu Val Cys Glu Glu Thr Ala Asn Tyr Leu Val
180185190
Ile Trp Cys Ile Asp Leu Glu Val Glu Glu Lys Cys Ala Leu Met Glu
195200205
Gln Val Ala His Gln Thr Met Val Met Gln Phe Ile Leu Glu Leu Ala
210215220
Lys Ser Leu Lys Val Asp Pro Arg Ala Cys Phe Arg Gln Phe Phe Thr
225230235240
Lys Ile Lys Thr Ala Asp Gln Gln Tyr Met Glu Gly Phe Lys Tyr Glu
245250255
Leu Glu Ala Phe Lys Glu Arg Val Arg Gly Arg Ala Lys Leu Arg Ile
260265270
Glu Lys Ala Met Lys Glu Tyr Glu Glu Glu Glu Arg Lys Lys Arg Leu
275280285
Gly Pro Gly Gly Leu Asp Pro Val Glu Val Tyr Glu Ser Leu Pro Glu
290295300
Glu Leu Gln Lys Cys Phe Asp Val Lys Asp Val Gln Met Leu Gln Asp
305310315320
Ala Ile Ser Lys Met Asp Pro Thr Asp Ala Lys Tyr His Met Gln Arg
325330335
Cys Ile Asp Ser Gly Leu Trp Val Pro Asn Ser Lys Ser Gly Glu Ala
340345350
Lys Glu Gly Glu Glu Ala Gly Pro Gly Asp Pro Leu Leu Glu Ala Val
355360365
Pro Lys Ala Gly Asn Glu Lys Asp Ile Ser Ala
370375
<210> 329
<211> 379
<212> PRT
<213> Mus musculus
<220>
<223> Mouse CDC37 Q61081
<400> 329
Met Val Asp Tyr Ser Val Trp Asp His Ile Glu Val Ser Asp Asp Glu
151015
Asp Glu Thr His Pro Asn Ile Asp Thr Ala Ser Leu Phe Arg Trp Arg
202530
His Gln Ala Arg Val Glu Arg Met Glu Gln Phe Gln Lys Glu Lys Glu
354045
Glu Leu Asp Arg Gly Cys Arg Glu Cys Lys Arg Lys Val Ala Glu Cys
505560
Gln Arg Lys Leu Lys Glu Leu Glu Val Ala Glu Ser Asp Gly Gln Val
65707580
Glu Leu Glu Arg Leu Arg Ala Glu Ala Gln Gln Leu Arg Lys Glu Glu
859095
Arg Ser Trp Glu Gln Lys Leu Glu Asp Met Arg Lys Lys Glu Lys Asn
100105110
Met Pro Trp Asn Val Asp Thr Leu Ser Lys Asp Gly Phe Ser Lys Ser
115120125
Met Val Asn Thr Lys Pro Glu Lys Ala Glu Glu Asp Ser Glu Glu Ala
130135140
Arg Glu Gln Lys His Lys Thr Phe Val Glu Lys Tyr Glu Lys Gln Ile
145150155160
Lys His Phe Gly Met Leu His Arg Trp Asp Asp Ser Gln Lys Tyr Leu
165170175
Ser Asp Asn Val His Leu Val Cys Glu Glu Thr Ala Asn Tyr Leu Val
180185190
Ile Trp Cys Ile Asp Leu Glu Val Glu Glu Lys Cys Ala Leu Met Glu
195200205
Gln Val Ala His Gln Thr Met Val Met Gln Phe Ile Leu Glu Leu Ala
210215220
Lys Ser Leu Lys Val Asp Pro Arg Ala Cys Phe Arg Gln Phe Phe Thr
225230235240
Lys Ile Lys Thr Ala Asp His Gln Tyr Met Glu Gly Phe Lys Tyr Glu
245250255
Leu Glu Ala Phe Lys Glu Arg Val Arg Gly Arg Ala Lys Leu Arg Ile
260265270
Glu Lys Ala Met Lys Glu Tyr Glu Glu Glu Glu Arg Lys Lys Arg Leu
275280285
Gly Pro Gly Gly Leu Asp Pro Val Glu Val Tyr Glu Ser Leu Pro Glu
290295300
Glu Leu Gln Lys Cys Phe Asp Val Lys Asp Val Gln Met Leu Gln Asp
305310315320
Ala Ile Ser Lys Met Asp Pro Thr Asp Ala Lys Tyr His Met Gln Arg
325330335
Cys Ile Asp Ser Gly Leu Trp Val Pro Asn Ser Lys Ser Gly Glu Ala
340345350
Lys Glu Gly Glu Glu Ala Gly Pro Gly Asp Pro Leu Leu Glu Ala Val
355360365
Pro Lys Ala Gly Asn Glu Lys Asp Val Ser Ala
370375
<210> 330
<211> 466
<212> PRT
<213> Schizosaccharomyces pombe
<220>
<223> Fission yeast CDC37 O94740
<400> 330
Met Ala Ile Asp Tyr Ser Lys Trp Asp Lys Leu Glu Leu Ser Asp Asp
151015
Ser Asp Ile Glu Val His Pro Asn Val Asp Lys Lys Ser Phe Ile Arg
202530
Trp Arg Gln Arg Asp Ile His Glu Lys Arg Ala Val Arg Lys Gln Lys
354045
Met Glu Asp Ile Lys Gly Ala Met Ala Met Asn Arg Arg Leu Leu Ser
505560
Arg Ile Ser Glu Met Glu Thr Val Leu Glu Lys Glu Ser Pro Ser Asp
65707580
Pro Tyr Val Leu Leu Gly Ser Phe Leu Glu Ala Lys Lys Ser Glu Asp
859095
Met Asp Ser Ala Ile Pro Gly Gly Met Ser Tyr His His Met Leu Met
100105110
Ser Leu Leu Lys Val Ile Lys Asp Ala Glu Asp Thr Thr Glu Glu Lys
115120125
Ser Met Asp Asp Ser Asp Lys Cys Leu Arg Arg Leu Lys Ser His Lys
130135140
Glu Arg Leu Leu Lys Leu Leu Glu Asp Ala Gln Lys Glu Tyr Asp Thr
145150155160
Leu Glu Ala Glu Ser Lys Asn Tyr Ile Thr Ser Glu Asp Leu His Leu
165 170175
Gly Phe Asp Ser Thr Tyr Val Gln Lys Lys Glu Pro Glu Lys Pro Lys
180185190
Lys Thr Lys Thr Lys Lys Glu Thr Ile Gln Val Ile Glu Ser Leu Asn
195200205
Asn Pro Thr Pro Pro Thr Asp Phe Pro Gly Ala Lys Glu Gln Ala Ser
210215220
Thr Gly Asn Ala Pro Lys Asn Pro Val Asn Glu Asn Glu Ser Glu Asp
225230235240
Glu Glu Gly Leu Ser Leu Ser Glu Asp Gly Lys Lys Phe Ala Asn Ile
245250255
Asp Phe Gly Asp Tyr Ser Ser Ser Glu Glu Phe Leu Lys Glu His Leu
260265270
Asn Ile Leu Ala Asp Glu Glu Glu Ser Asp Ala Ile Leu Leu Glu Ala
275280285
Phe Asn Ala Glu Leu Glu Gly Lys Pro Ser Leu Ala Lys Gln Tyr Val
290295300
His Gln Ala Leu Leu Ile Ser Tyr Cys Arg Gln Leu Gly Pro Asn Gly
305310315320
Leu Ser Ile Phe Phe Gln Lys Ile Lys Asp Pro Asn His Gln Ser Gln
325330335
Arg Leu Phe Leu Glu Asp Val His Asn Thr Tyr Val Arg Ile His Glu
340345350
Arg Ser Ala Ala Ile Ser Lys Glu Gln Ala Glu Ser Gly Glu Gly Val
355360365
Glu Gln Ile Gln Leu Cys Ala Val Asp Pro Asn Thr Lys Leu Ser Ile
370375380
Thr Ile Pro Glu Ala Gly Ser Thr Asp Pro Glu Thr Gln Lys Ala Arg
385390395400
Ala Ala Phe Glu Ser Phe Pro Pro Asn Leu Gln Lys Ala Leu Met Thr
405410415
Asn Asp Leu Asp Lys Ile Asn Val Val Leu Gly Lys Met Ala Val Glu
420425430
Asn Ala Glu Glu Val Val Glu Lys Leu Ser Ser Thr Gly Met Leu Ser
435440445
Ile Glu Glu Gly Ile Ile Asp Thr Thr Lys Gly Glu Thr Ile Pro Gln
450455460
Leu Ser
465
<210> 331
<211> 399
<212> PRT
<213> Drosophila virilis
<220>
<223> Drosophila virilis Fruit fly CDC37 Q24740
<400> 331
Met Val Asp Tyr Ser Lys Trp Lys Asn Ile Glu Ile Ser Asp Asp Glu
151015
Asp Glu Thr His Pro Asn Ile Asp Thr Pro Ser Leu Phe Arg Trp Arg
202530
His Gln Ala Arg Val Glu Arg Met Ala Glu Ser Glu Lys Glu Lys Glu
354045
Glu Leu Lys Lys Lys Arg Gln Ser Tyr Gln Ala Arg Leu Ile Asn Val
505560
Lys Glu Leu Ile Ser Lys Lys Glu Gly Asp Glu Val Ala Leu Lys Lys
65707580
Glu Leu Glu Lys Ile Glu Asn Glu Gly Lys Glu Leu Asp Arg Gln Glu
859095
Asn Glu Leu Leu Lys Arg Glu Lys Lys Thr Pro Trp Asn Val Asp Thr
100105110
Ile Ser Lys Pro Gly Phe Glu Lys Thr Val Ile Asn Lys Lys Pro Pro
115120125
Arg Lys Ala Ala Glu Asp Leu Thr Glu Glu Glu Arg Glu Gln Arg Met
130135140
Lys Gln Phe Val Lys Glu Asn Glu Lys Leu Cys Lys Gln Tyr Gly Met
145150155160
Leu Arg Lys Tyr Asp Asp Ser Lys Arg Phe Leu Gln Glu His Leu Asp
165170175
Leu Val Cys Glu Glu Thr Ala Asn Tyr Leu Val Ile Trp Ser Ile Asn
180185190
Leu Glu Met Glu Glu Lys His Asp Leu Met Ala His Val Ala His Gln
195200205
Cys Ile Cys Met Gln Tyr Ile Leu Glu Leu Ala Lys Gln Leu Asp Val
210215220
Asp Pro Arg Ala Cys Val Ser Ser Phe Phe Ser Lys Ile Gln Gln Cys
225230235240
Val Pro Glu Tyr Arg Gln Gln Phe Glu Ser Glu Ile Glu Gly Phe Lys
245250255
Glu Arg Ile Gln Lys Arg Ala Gln Glu Lys Leu Gln Glu Ala Met Ala
260265270
Gln Leu Glu Glu Glu Glu Lys Gln Glu Arg Met Gly Pro Gly Gly Leu
275280285
Asp Pro Ala Asp Val Phe Glu Ser Leu Pro Glu Glu Leu Lys Ala Cys
290295300
Phe Glu Ser Arg Asp Ile Glu Leu Leu Gln Lys Thr Ile Ala Thr Met
305310315320
Pro Val Asp Gln Ala Lys Tyr His Met Lys Arg Cys Val Asp Ser Gly
325330335
Leu Trp Val Pro Asn Ala Ala Asp Val Gln Leu Gly Asn Asp Glu Thr
340345350
Glu Ala Lys Asp Asp Glu Thr Thr Thr Ala Thr Asn Glu Thr Pro Thr
355360365
Glu Lys Glu Asn Ser Lys Ser Gln Asn Glu Lys Ser Ala Asp Ala Ala
370375380
Lys Glu Glu Pro Leu Tyr Ala Gly Val Ser Thr Asp Asp Val Asp
385390395
<210> 332
<211> 393
<212> PRT
<213> Gallus gallus
<220>
<223> Chicken CDC37 Q57476
<400> 332
Met Val Asp Tyr Ser Val Trp Asp His Ile Glu Val Ser Asp Asp Glu
151015
Asp Glu Thr His Pro Asn Ile Asp Thr Ala Ser Leu Phe Arg Trp Arg
202530
His Gln Ala Arg Val Glu Arg Met Glu Gln Phe Gln Lys Glu Lys Glu
354045
Glu Leu Asp Lys Gly Cys Arg Glu Cys Lys Arg Lys Leu Ala Glu Cys
505560
Gln Lys Lys Leu Lys Glu Leu Glu Val Ala Glu Pro Gly Gly Gly Ser
65707580
Gly Gly Gly Arg Gly Glu Arg Glu Arg Leu Gln Ala Glu Ala Gln Gln
859095
Leu Arg His Glu Glu Arg Asn Trp Glu Ser Lys Met Glu Glu Leu Arg
100105110
Lys Lys Glu Lys Asn Met Pro Trp Asn Val His Thr Leu Ser Lys Asp
115120125
Gly Phe Ser Lys Ser Val Phe Asn Val Lys Ala Glu Glu Lys Glu Glu
130135140
Thr Glu Glu Gln Lys Glu Gln Lys His Lys Thr Phe Val Glu Arg His
145150155160
Glu Lys Gln Ile Lys His Phe Gly Met Leu Arg Arg Trp Asp Asp Ser
165170175
Gln Lys Tyr Leu Ser Asp Asn Pro His Leu Val Cys Glu Glu Thr Ala
180185190
Asn Tyr Leu Val Ile Trp Cys Ile Asp Leu Glu Val Glu Glu Lys Gln
195200205
Ala Leu Met Glu Gln Val Ala His Gln Thr Ile Val Met Gln Phe Ile
210215220
Leu Glu Leu Ala Lys Ser Leu Lys Val Asp Pro Arg Ala Cys Phe Arg
225230235240
Gln Phe Phe Thr Lys Ile Lys Thr Ala Asp Gln Gln Tyr Met Glu Gly
245250255
Phe Asn Asp Glu Leu Glu Ala Phe Lys Glu Arg Val Arg Gly Arg Ala
260265270
Lys Ala Arg Ile Glu Arg Ala Met Arg Glu Tyr Glu Glu Glu Glu Arg
275280285
Gln Lys Arg Leu Gly Pro Gly Gly Leu Asp Pro Val Asp Val Tyr Glu
290295300
Ser Leu Pro Pro Glu Leu Gln Lys Cys Phe Asp Ala Lys Asp Val Gln
305310315320
Met Leu Gln Asp Thr Ile Ser Arg Met Asp Pro Thr Glu Ala Lys Tyr
325330335
His Met Gln Arg Cys Ile Asp Ser Gly Leu Trp Val Pro Asn Ala Lys
340345350
Ala Ala Ala Glu Gly Gly Gly Gln Gly Gly Ala His Gly Gln Pro Gly
355360365
Gly Ala Asp Ser Glu Ala Leu Tyr Glu Glu Ile Pro Lys Glu Ser Gly
370375380
Glu Glu Glu Gly Gly Glu Gly Lys Ala
385390
<210> 333
<211> 380
<212> PRT
<213> Bos taurus
<220>
<223> Cow CDC37 Q5EAC6
<400> 333
Met Val Asp Tyr Ser Val Trp Asp His Ile Glu Val Ser Asp Asp Glu
151015
Asp Glu Thr His Pro Asn Ile Asp Thr Ala Ser Leu Phe Arg Trp Arg
202530
His Gln Ala Arg Val Glu Arg Met Glu Gln Phe Gln Lys Glu Lys Glu
354045
Glu Leu Asp Arg Gly Cys Arg Glu Cys Lys Arg Lys Val Ala Glu Cys
505560
Gln Arg Lys Leu Lys Glu Leu Glu Val Ala Glu Gly Glu Gly Gly Lys
65707580
Ala Glu Leu Glu Arg Leu Gln Ala Glu Ala Gln Gln Leu Arg Lys Glu
859095
Glu Arg Ser Trp Glu Gln Lys Leu Glu Glu Met Arg Lys Lys Glu Lys
100105110
Ser Met Pro Trp Asn Val Asp Thr Leu Ser Lys Asp Gly Phe Ser Lys
115120125
Ser Met Val Asn Thr Lys Pro Glu Gln Ala Glu Glu Glu Ser Glu Glu
130135140
Val Arg Glu Gln Lys His Lys Thr Phe Val Glu Lys Tyr Glu Lys Gln
145150155160
Ile Lys His Phe Gly Met Leu Arg Arg Trp Asp Asp Ser Gln Lys Tyr
165170175
Leu Ser Asp Asn Val His Leu Val Cys Glu Glu Thr Ala Asn Tyr Leu
180185190
Val Ile Trp Cys Ile Asp Leu Glu Val Glu Glu Lys Cys Ala Leu Met
195200205
Glu Gln Val Ala His Gln Thr Ile Val Met Gln Phe Ile Leu Glu Leu
210215220
Ala Lys Ser Leu Lys Val Asp Pro Arg Ala Cys Phe Arg Gln Phe Phe
225230235240
Thr Lys Ile Lys Thr Ala Asp Arg Gln Tyr Met Glu Gly Phe Asn Asp
245250255
Glu Leu Glu Ala Phe Lys Asp Arg Val Arg Gly Arg Ala Lys Leu Arg
260265270
Ile Glu Lys Ala Met Lys Glu Tyr Glu Glu Glu Glu Arg Lys Lys Arg
275280285
Leu Gly Pro Gly Gly Leu Asp Pro Val Glu Val Tyr Glu Ser Leu Pro
290295300
Glu Glu Leu Gln Lys Cys Phe Asp Ala Lys Asp Val Gln Met Leu Gln
305310315320
Asp Ala Ile Ser Lys Met Asp Pro Thr Asp Ala Lys Tyr His Met Gln
325330335
Arg Cys Ile Asp Ser Gly Leu Trp Val Pro Asn Ser Lys Ser Ser Glu
340345350
Ala Lys Asp Gly Glu Glu Ala Gly Thr Gly Asp Pro Leu Leu Glu Ala
355360365
Thr Ser Lys Ser Gly Asp Glu Lys Asp Val Ser Val
370375380
<210> 334
<211> 508
<212> PRT
<213> Candida albicans
<220>
<223> Candida albicans Yeast CDC37 Q8X1E6
<400> 334
Met Pro Ile Asp Tyr Ser Lys Trp Asp Lys Ile Glu Ile Ser Asp Asp
151015
Ser Asp Val Glu Val His Pro Asn Val Asp Lys Gln Ser Phe Ile Arg
202530
Trp Lys Gln Arg Asp Ile His Glu Lys Arg Met Gln Arg Asn Ile Glu
354045
Ile Lys Ser Ile Leu Ile Gln Leu Thr Met Tyr Ala Lys Leu Asn Glu
505560
Arg Val Asp Tyr Leu Leu Glu Lys Leu Thr Ser Thr Glu Leu Leu Asp
65707580
Ser Glu Lys Val Met Ser Lys Leu Asn Ser Glu Phe Asp Pro Gln Glu
859095
Lys Phe Asp Tyr Asp Lys Leu Ile Lys Asp Lys Gly Ser Thr Leu Arg
100105110
Lys Gly Leu Lys Asp Leu Lys Phe Asp Arg Glu Glu Ile Glu Asn Thr
115120125
Pro Cys Tyr Asn Glu Met Ile Glu Asp Leu Phe Val Gln Ile Lys Asp
130135140
Asp His Pro Glu Thr Lys Thr Asp Gly Asp Lys Leu Ile Glu Tyr Leu
145150155160
Lys Glu His Arg Asn Arg Ile Asp Asp Val Leu Ser Lys Gln Thr Ile
165170175
Lys Leu Asp Asp Leu Leu Tyr Gln Lys Ala Gln Leu Ile Val Ser Asp
180185190
Asp Leu His Thr Gly Phe Asp Arg Ser Phe Leu Asn Lys Asp Lys Pro
195200205
Glu Glu Lys Glu Glu Asn Gln Asp Lys Pro Lys Ala Pro Glu Ala Lys
210215220
Lys Thr Thr Val Thr Thr Thr Glu Thr Ile Asn Ser Pro Lys Pro Val
225230235240
Glu Glu Asn Thr Asp Lys Glu Ile Leu Asp Glu Leu Glu Ile Leu Pro
245250255
Ala Thr Lys Glu Phe Ala Lys Ile Pro Ser Asp Asn Leu Ser Lys Ala
260265270
Ala Glu Phe Leu Ile Lys His Pro Ser Ile Cys Thr Glu Gln Gln Lys
275280285
Asp Ala Leu Ile Met Thr Ala Phe Asp Leu Gln Leu Glu Asn Lys Ser
290295300
Asp Glu Ala Lys His Ile Val His Gln Ser Leu Leu Leu Gln Tyr Val
305310315320
Gly Gln Leu Ser Asp Asn Gly Lys Ala Ala Pro Ala Asn Val Ile Asn
325330335
Ala Ile Lys Leu Phe Phe Ser Lys Ile Ala Ala Glu Ser Ser Pro Ala
340345350
Lys His Ala Phe Leu Glu Asp Val Asn Gln Thr Phe Asn His Ile Lys
355360365
Gly Arg Cys Glu Ile Ile Lys Glu Glu Gln Lys Gln Asn Ala Ala Asn
370375380
Lys Glu Gly Thr Gly Glu Glu Glu Glu Glu Glu Ala Leu Ile Gln Leu
385390395400
Lys Ala Leu Asp Asp Asn Thr Glu Leu Ser Val Asn Ile Pro Gln Glu
405410415
Gly Thr Lys Glu Tyr Glu Ile Phe Thr Thr Lys Leu Pro Ile Glu Phe
420425430
Gln Asn Ala Ile Lys Thr Glu Ser Ile Asp Glu Val Asn Lys Glu Phe
435440445
Ala Lys Leu Lys Ile Glu Asp Ala Glu Arg Ile Leu Glu Ile Phe Asn
450455460
Glu Cys Gly Val Ile Gly Ile Ser Gly Tyr Ile Glu Asp Glu Lys Glu
465470475480
Phe Glu Glu Leu Lys Lys Glu Tyr Ala His Glu Thr Ala Asn Gln Glu
485490495
Glu Asp Gln Ser Ala Ser Val Glu Asp Thr Val Asp
500505
<210> 335
<211> 370
<212> PRT
<213> Caenorhabditis elegans
<220>
<223> Caenorhabditis elegans CDC37 O02108
<400> 335
Met Pro Ile Asp Tyr Ser Lys Trp Lys Asp Ile Glu Val Ser Asp Asp
151015
Glu Asp Asp Thr His Pro Asn Ile Asp Thr Pro Ser Leu Phe Arg Trp
202530
Arg His Gln Ala Arg Leu Glu Arg Met Ala Glu Lys Lys Met Glu Gln
354045
Glu Lys Ile Asp Lys Glu Lys Gly Thr Thr Ser Lys Lys Met Glu Glu
505560
Leu Glu Lys Lys Leu Ala Ala Ala Asp Val Thr Asp Lys Ser Asp Ile
65707580
Gln Lys Gln Ile Asp Glu Val Lys Ala Gln Glu Glu Ala Trp Arg Lys
859095
Lys Glu Ala Glu Leu Glu Glu Lys Glu Arg Leu Glu Pro Trp Asn Val
100105110
Asp Thr Ile Gly His Glu Ala Phe Ser Thr Ser Arg Ile Asn Lys Ile
115120125
Thr Glu Lys Lys Pro Gln Ala Pro Lys Thr Asp Glu Glu Asp Thr His
130135140
Ala Met Ser Thr Phe Phe Glu Thr His Glu Ser Leu Leu Glu Lys Met
145150155160
Ala Val Leu Lys Asn Gly Ala Lys Ser Thr Glu Leu Phe Leu Ala Glu
165170175
His Pro His Met Ala Ser Glu Tyr Thr Ala Asn Trp Leu Thr Ile Glu
180185190
Ala Leu Asn Ala Ala Ile Asp Phe Asn Glu Glu Lys Met Lys Thr Met
195200205
Ala Glu Gln Cys Ile Ile Ile Gln Tyr Leu Leu Glu Leu Ser Lys Ser
210215220
Leu Asn Ala Val Ala Thr Asn Thr Thr Val Gln Lys Gln Phe Phe Lys
225230235240
Lys Phe Glu Ala Ala Glu Pro Val Tyr Met Lys His Tyr Gln Asp Glu
245250255
Val Lys Ala Phe Glu Asp Arg Leu Arg Thr Arg Ala Gln Thr Lys Arg
260265270
Asp Ala Ala Met Glu Glu Ala Glu Ala Glu Glu Lys Ala Glu Arg Met
275280285
Lys Ser Ala Pro Gly Gly Ile Asp Pro Gln Glu Val Phe Glu Gln Leu
290295300
Pro Glu Glu Met Arg Lys Cys Phe Glu Ala His Asp Ile Glu Ala Leu
305310315320
Lys Gly Val Ala Gln Lys Met Asp Glu Glu Val Phe Lys Tyr His Phe
325330 335
Asp Arg Cys Ile Ala Ser Gly Leu Trp Val Pro Gly Lys Ala Asp Asp
340345350
Asp Asp Asp Asp Glu Glu Ala Ala Pro Ala Glu Glu Glu Pro Thr Thr
355360365
Ser Ser
370
<210> 336
<211> 377
<212> PRT
<213> Tetraodon fluviatilis
<220>
<223> Tetraodon fluviatilis Green pufferfish CDC37
Q9DGQ7
<400> 336
Met Ser Arg Ile Asp Tyr Ser Val Trp Asp His Ile Glu Val Ser Asp
151015
Asp Glu Asp Val Ser His Pro Asn Ile Asp Thr Pro Ser Leu Phe Arg
202530
Trp Arg His Gln Ala Arg Val Glu Arg Met Glu Asp Phe Lys Lys Lys
354045
Gly Asp Asp Leu Asn Lys Gly Leu Gln Glu Cys Arg Arg Lys Leu Ala
505560
Glu Ala Gln Lys Lys Val Arg Glu Leu Ser Ile Ser Ala Ala Gly Asp
65707580
Ala Lys Ala Glu Leu Thr Lys Thr Gln Thr Glu Glu Lys Lys Leu Lys
859095
Lys Glu Glu Arg Asp Trp Ala Arg Lys Leu Glu Glu His Asn His Glu
100105110
Glu Lys Lys Met Pro Trp Asn Val Asp Thr Leu Ser Lys Asp Gly Phe
115120125
Ser Lys Ser Ile Val Asn Val Lys Ala Asp Ser Ala Glu Asp Thr Glu
130135140
Glu Glu Lys Glu Lys Lys His Lys Thr Phe Val Glu Arg Tyr Glu Lys
145150155160
Gln Ile Lys His Phe Gly Met Leu His Arg Trp Asp Asp Ser Gln Arg
165170175
Tyr Leu Ser Asp Asn Pro Asp Leu Val Cys Glu Glu Thr Ala Asn Tyr
180185190
Leu Val Ile Met Cys Ile Asp Leu Glu Val Glu Glu Lys His Ala Leu
195200205
Met Glu Gln Val Ala His Gln Thr Ile Val Met Gln Phe Ile Leu Glu
210215220
Leu Ala Lys Ser Leu Lys Val Asp Pro Arg Gly Cys Phe Arg Gln Phe
225230235240
Phe Glu Lys Ile Lys Thr Ala Asp Gln Gln Tyr Gln Asp Ala Phe Asn
245250255
Asp Glu Leu Glu Ser Phe Lys Glu Arg Val Arg Gly Arg Ala Lys Ile
260265270
Arg Ile Glu Lys Ala Met Lys Glu Tyr Glu Glu Glu Glu Arg Gln Lys
275280285
Arg Leu Gly Pro Gly Gly Leu Asp Pro Val Glu Val Tyr Glu Ser Leu
290295300
Pro Pro Glu Met Gln Lys Cys Phe Asp Glu Lys Asp Ile Gln Met Leu
305310315320
Gln Asp Val Ile Thr Lys Met Asp Pro Thr Glu Ala Lys Ala His Met
325330335
Lys Arg Cys Ile Asp Ser Gly Leu Trp Val Pro Asn Ser Lys Met Asp
340345350
Glu Ser Asp Glu Lys Glu Asp Gly Ser Thr Tyr Glu Glu Val Lys Gln
355360365
Glu Gln Glu Glu Pro Ala Lys Lys Glu
370375
<210> 337
<211> 558
<212> PRT
<213> Mus musculus
<220>
<223> Mouse Hyaluronan-binding protein 2 Q8K0D2
<400> 337
Met Phe Val Arg Met Leu Val Phe Arg Val Leu Leu Leu Ile Ala Leu
151015
Val Gly Lys Ser Val Ile Gly Leu Ser Leu Met Ser Phe Ile Ala Pro
202530
Pro Asp Pro Asp Trp Thr Pro Asp Asp Tyr Tyr Tyr Ser Tyr Glu Gln
354045
Ser Ser Pro Asp Glu Asp Pro Ser Val Thr Gln Thr Thr Pro Glu Asn
505560
Pro Asp Trp Tyr Tyr Glu Asp Asp Asp Pro Cys Gln Ser Asn Pro Cys
65707580
Glu His Gly Gly Asp Cys Ile Ile Arg Gly Asp Thr Phe Ser Cys Ser
859095
Cys Pro Ala Pro Phe Ser Gly Ser Arg Cys Gln Thr Ala Gln Asn Lys
100105110
Cys Lys Asp Asn Pro Cys Val His Gly Asp Cys Leu Ile Thr Gln Lys
115120125
His Pro Tyr Tyr Arg Cys Ala Cys Lys Tyr Pro Tyr Thr Gly Pro Asp
130135140
Cys Ser Lys Val Leu Pro Ala Cys Arg Pro Asn Pro Cys Gln Asn Gly
145150 155160
Gly Val Cys Ser Arg His Arg Arg Arg Ser Arg Phe Thr Cys Ala Cys
165170175
Pro Asp Gln Tyr Lys Gly Lys Phe Cys Glu Ile Gly Pro Asp Asp Cys
180185190
Tyr Val Gly Asp Gly Tyr Ser Tyr Arg Gly Lys Val Ser Lys Thr Val
195200205
Asn Gln Asn Pro Cys Leu Tyr Trp Asn Ser His Leu Leu Leu Gln Glu
210215220
Thr Tyr Asn Met Phe Met Glu Asp Ala Glu Thr His Gly Ile Ala Glu
225230235240
His Asn Phe Cys Arg Asn Pro Asp Gly Asp His Lys Pro Trp Cys Phe
245250255
Val Lys Val Asn Ser Glu Lys Val Lys Trp Glu Tyr Cys Asp Val Thr
260265270
Val Cys Pro Val Pro Asp Thr Pro Asn Pro Val Glu Ser Leu Leu Glu
275280285
Pro Val Met Glu Leu Pro Gly Phe Glu Ser Cys Gly Lys Thr Glu Val
290295300
Ala Glu His Ala Val Lys Arg Ile Tyr Gly Gly Phe Lys Ser Thr Ala
305310315320
Gly Lys His Pro Trp Gln Val Ser Leu Gln Thr Ser Leu Pro Leu Thr
325330335
Thr Ser Met Pro Gln Gly His Phe Cys Gly Gly Ala Leu Ile His Pro
340345350
Cys Trp Val Leu Thr Ala Ala His Cys Thr Asp Ile Asn Thr Lys His
355360365
Leu Lys Val Val Leu Gly Asp Gln Asp Leu Lys Lys Thr Glu Ser His
370375380
Glu Gln Thr Phe Arg Val Glu Lys Ile Leu Lys Tyr Ser Gln Tyr Asn
385390395400
Glu Arg Asp Glu Ile Pro His Asn Asp Ile Ala Leu Leu Lys Leu Lys
405410415
Pro Val Gly Gly His Cys Ala Leu Glu Ser Arg Tyr Val Lys Thr Val
420425430
Cys Leu Pro Ser Asp Pro Phe Pro Ser Gly Thr Glu Cys His Ile Ser
435440445
Gly Trp Gly Val Thr Glu Thr Gly Glu Gly Ser Arg Gln Leu Leu Asp
450455460
Ala Lys Val Lys Leu Ile Ala Asn Pro Leu Cys Asn Ser Arg Gln Leu
465 470475480
Tyr Asp His Thr Ile Asp Asp Ser Met Ile Cys Ala Gly Asn Leu Gln
485490495
Lys Pro Gly Ser Asp Thr Cys Gln Gly Asp Ser Gly Gly Pro Leu Thr
500505510
Cys Glu Lys Asp Gly Thr Tyr Tyr Val Tyr Gly Ile Val Ser Trp Gly
515520525
Gln Glu Cys Gly Lys Lys Pro Gly Val Tyr Thr Gln Val Thr Lys Phe
530535540
Leu Asn Trp Ile Lys Thr Thr Met His Arg Glu Ala Gly Leu
545550555
<210> 338
<211> 558
<212> PRT
<213> Rattus norvegicus
<220>
<223> Rat Hyaluronan-binding protein 2 Q6L711
<400> 338
Met Ser Val Val Met Leu Val Phe Arg Val Leu Leu Leu Ile Ala Leu
151015
Val Gly Asn Ser Ala Ile Gly Leu Ser Leu Met Pro Phe Ile Ala Pro
202530
Pro Asp Pro Asp Trp Thr Pro Asp Asp Tyr Tyr Tyr Ser Tyr Glu Gln
354045
Ser Ser Pro Asp Lys Asp Ala Ser Val Thr Gln Thr Ser Pro Glu Asn
505560
Pro Asp Trp Tyr Tyr Glu Asp Asp Asp Pro Cys Gln Ser Asn Pro Cys
65707580
Glu His Gly Gly Asp Cys Ile Ile Arg Gly Asn Thr Phe Ser Cys Ser
859095
Cys Pro Ala Pro Phe Ser Gly Ser Arg Cys Gln Thr Val Gln Asn Lys
100105110
Cys Lys Asp Asn Pro Cys Val Gln Gly Asp Cys Leu Ile Thr Gln Thr
115120125
Pro Pro Tyr Tyr Arg Cys Ala Cys Lys Tyr Pro Tyr Thr Gly Pro Asp
130135140
Cys Ser Lys Val Leu Pro Val Cys Arg Pro Asn Pro Cys Gln Asn Gly
145150155160
Gly Val Cys Ser Arg His Arg Arg Arg Ser Arg Phe Ser Cys Ala Cys
165170175
Pro Asp Gln Tyr Lys Gly Arg Phe Cys Glu Ile Gly Pro Asp Asp Cys
180185190
Tyr Val Gly Asp Gly Tyr Ser Tyr Arg Gly Lys Val Ser Arg Thr Val
195200205
Asn Gln Asn Pro Cys Leu Tyr Trp Asn Ser His Leu Leu Leu Gln Glu
210215220
Asn Tyr Asn Met Phe Met Glu Asp Ala Glu Thr His Gly Ile Ala Asp
225230235240
His Asn Phe Cys Arg Asn Pro Asp Gly Asp His Lys Pro Trp Cys Phe
245250255
Val Lys Val Asn Ser Glu Lys Val Lys Trp Glu Tyr Cys Asn Val Glu
260265270
Val Cys Pro Glu Ser Asp Ala Ala Asn Pro Val Gly Ser Leu Gln Glu
275280285
Pro Val Met Glu Leu Pro Gly Phe Asp Ser Cys Gly Lys Thr Glu Met
290295300
Thr Glu His Ala Val Lys Arg Ile Tyr Gly Gly Phe Lys Ser Thr Ala
305310315320
Gly Lys His Pro Trp Gln Val Ser Leu Gln Thr Ser Leu Pro Leu Thr
325330335
Thr Ser Met Pro Gln Gly His Phe Cys Gly Gly Ser Leu Ile His Pro
340345350
Cys Trp Val Leu Thr Ala Ala His Cys Thr Asp Met Ser Thr Lys His
355360365
Leu Lys Val Val Leu Gly Asp Gln Asp Leu Lys Lys Thr Glu Ser His
370375380
Glu Gln Thr Phe Arg Val Glu Lys Ile Leu Lys Tyr Ser Gln Tyr Asn
385390395400
Glu Arg Asp Glu Ile Pro His Asn Asp Ile Ala Leu Leu Lys Leu Lys
405410415
Pro Val Gly Gly His Cys Ala Leu Glu Ser Lys Tyr Val Lys Thr Val
420425430
Cys Leu Pro Ser Asp Pro Phe Pro Ser Gly Thr Glu Cys His Ile Ser
435440445
Gly Trp Gly Val Thr Glu Thr Gly Glu Gly Ser Arg Gln Leu Leu Asp
450455460
Ala Lys Val Lys Leu Ile Ala Asn Ala Leu Cys Asn Ser Arg Gln Leu
465470475480
Tyr Asp His Thr Ile Asp Asp Ser Met Ile Cys Ala Gly Asn Leu Gln
485490495
Lys Pro Gly Ser Asp Thr Cys Gln Gly Asp Ser Gly Gly Pro Leu Thr
500505510
Cys Glu Lys Asp Gly Thr Tyr Tyr Val Tyr Gly Ile Val Ser Trp Gly
515520525
Gln Glu Cys Gly Lys Lys Pro Gly Val Tyr Thr Gln Val Thr Lys Phe
530535540
Leu Asn Trp Ile Lys Thr Thr Met His Lys Glu Ala Gly Leu
545550555
<210> 339
<211> 558
<212> PRT
<213> Bos taurus
<220>
<223> Cow Hyaluronan-binding protein 2 Q5E9Z2
<400> 339
Met Phe Ala Arg Met Ser Asp Leu His Val Leu Leu Leu Met Val Leu
151015
Ala Gly Lys Thr Ala Phe Gly Leu Ser Leu Leu Ser Phe Leu Thr Glu
202530
Pro Asp Pro Asp Trp Thr Pro Asp Gln Tyr Glu Tyr Ser Gln Glu Tyr
354045
Asn Asn Gln Glu Glu Asn Ala Ser Ser Thr Thr Ala Tyr Ser Asp Asn
505560
Pro Asp Trp Tyr Tyr Glu Glu Asp Asp Pro Cys Leu Ser Asn Pro Cys
65707580
Thr His Gly Gly Asp Cys Leu Val Ser Gly Ala Thr Phe Thr Cys Arg
859095
Cys Pro Asp Pro Phe Ser Gly Asn Arg Cys Gln Asn Val Gln Asn Lys
100105110
Cys Lys Asn Asn Pro Cys Gly Arg Gly Asp Cys Leu Ile Thr Gln Ser
115120125
Pro Pro Tyr His Arg Cys Ala Cys Lys His Pro Tyr Arg Gly Ser Asp
130135140
Cys Ser Arg Val Val Pro Val Cys Arg Pro Asn Pro Cys Gln Asn Gly
145150155160
Gly Thr Cys Ser Arg Gln Arg Arg Arg Ser Lys Phe Thr Cys Ala Cys
165170175
Pro Asp Gln Phe Lys Gly Lys Leu Cys Glu Ile Gly Pro Asp Asp Cys
180185190
Tyr Val Asp Asp Gly Tyr Ser Tyr Arg Gly Arg Val Ser Lys Thr Ile
195200205
His Gln His Thr Cys Leu Tyr Trp Asn Ser His Leu Leu Leu Gln Glu
210215220
Lys Tyr Asn Met Phe Met Glu Asp Ala Glu Ala His Gly Ile Gly Glu
225230235240
His Asn Phe Cys Arg Asn Pro Asp Gly Asp Lys Lys Pro Trp Cys Phe
245250255
Ile Lys Val Asn Asn Val Lys Val Lys Trp Glu Tyr Cys Asp Val Pro
260265270
Ala Cys Ser Ala Leu Asp Val Ala Asn Pro Glu Gly Arg Pro Thr Glu
275280285
Pro Leu Thr Lys Phe Pro Glu Phe Gly Ser Cys Gly Arg Thr Glu Ile
290295300
Ala Glu Lys Lys Val Lys Arg Ile Phe Gly Gly Phe Lys Ser Thr Ala
305310315320
Gly Lys His Pro Trp Gln Ala Ser Leu Gln Thr Ser Leu Arg Leu Thr
325330335
Val Ser Thr Pro Gln Gly His Tyr Cys Gly Gly Ala Leu Ile His Pro
340345350
Cys Trp Val Leu Thr Ala Ala His Cys Thr Glu Ile Lys Thr Lys Tyr
355360365
Leu Lys Val Val Leu Gly Asp Gln Asp Leu Thr Lys Thr Glu Phe His
370375380
Glu Gln Ser Phe Gly Val Gln Lys Ile Phe Lys Tyr Ser His Tyr Ile
385390395400
Glu Ile Asp Asp Ile Pro Tyr Asn Asp Ile Ala Leu Leu Lys Leu Lys
405410415
Pro Val Asp Gly His Cys Ala Leu Glu Ser Lys Tyr Val Lys Thr Val
420425430
Cys Leu Pro Asp Gly Pro Phe Leu Ser Gly Thr Glu Cys Tyr Ile Ser
435440445
Gly Trp Gly Val Thr Glu Thr Gly Glu Gly Ser Arg His Leu Leu Asp
450455460
Ala Lys Val Lys Leu Ile Ser Asn Thr Ile Cys Asn Ser Arg Gln Leu
465470475480
Tyr Asp His Ser Ile Asp Asp Asn Met Ile Cys Ala Gly Asn Leu Gln
485490495
Lys Pro Gly Gln Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro Leu Thr
500505510
Cys Glu Lys Asp Gly Thr Ser Tyr Ile Tyr Gly Ile Val Ser Trp Gly
515520525
Leu Glu Cys Gly Lys Arg Pro Gly Val Tyr Thr Gln Val Thr Lys Phe
530535540
Leu Thr Trp Ile Lys Ala Thr Met Glu Lys Glu Ala Ser Phe
545550555
<210> 340
<211> 2315
<212> PRT
<213> Homo sapiens
<220>
<223> human Phosphacan NP_002842
<400> 340
Met Arg Ile Leu Lys Arg Phe Leu Ala Cys Ile Gln Leu Leu Cys Val
151015
Cys Arg Leu Asp Trp Ala Asn Gly Tyr Tyr Arg Gln Gln Arg Lys Leu
202530
Val Glu Glu Ile Gly Trp Ser Tyr Thr Gly Ala Leu Asn Gln Lys Asn
354045
Trp Gly Lys Lys Tyr Pro Thr Cys Asn Ser Pro Lys Gln Ser Pro Ile
505560
Asn Ile Asp Glu Asp Leu Thr Gln Val Asn Val Asn Leu Lys Lys Leu
65707580
Lys Phe Gln Gly Trp Asp Lys Thr Ser Leu Glu Asn Thr Phe Ile His
859095
Asn Thr Gly Lys Thr Val Glu Ile Asn Leu Thr Asn Asp Tyr Arg Val
100105110
Ser Gly Gly Val Ser Glu Met Val Phe Lys Ala Ser Lys Ile Thr Phe
115120125
His Trp Gly Lys Cys Asn Met Ser Ser Asp Gly Ser Glu His Ser Leu
130135140
Glu Gly Gln Lys Phe Pro Leu Glu Met Gln Ile Tyr Cys Phe Asp Ala
145150155160
Asp Arg Phe Ser Ser Phe Glu Glu Ala Val Lys Gly Lys Gly Lys Leu
165170175
Arg Ala Leu Ser Ile Leu Phe Glu Val Gly Thr Glu Glu Asn Leu Asp
180185190
Phe Lys Ala Ile Ile Asp Gly Val Glu Ser Val Ser Arg Phe Gly Lys
195200205
Gln Ala Ala Leu Asp Pro Phe Ile Leu Leu Asn Leu Leu Pro Asn Ser
210215220
Thr Asp Lys Tyr Tyr Ile Tyr Asn Gly Ser Leu Thr Ser Pro Pro Cys
225230235240
Thr Asp Thr Val Asp Trp Ile Val Phe Lys Asp Thr Val Ser Ile Ser
245250255
Glu Ser Gln Leu Ala Val Phe Cys Glu Val Leu Thr Met Gln Gln Ser
260265270
Gly Tyr Val Met Leu Met Asp Tyr Leu Gln Asn Asn Phe Arg Glu Gln
275280285
Gln Tyr Lys Phe Ser Arg Gln Val Phe Ser Ser Tyr Thr Gly Lys Glu
290295300
Glu Ile His Glu Ala Val Cys Ser Ser Glu Pro Glu Asn Val Gln Ala
305310315320
Asp Pro Glu Asn Tyr Thr Ser Leu Leu Val Thr Trp Glu Arg Pro Arg
325330335
Val Val Tyr Asp Thr Met Ile Glu Lys Phe Ala Val Leu Tyr Gln Gln
340345350
Leu Asp Gly Glu Asp Gln Thr Lys His Glu Phe Leu Thr Asp Gly Tyr
355360365
Gln Asp Leu Gly Ala Ile Leu Asn Asn Leu Leu Pro Asn Met Ser Tyr
370375380
Val Leu Gln Ile Val Ala Ile Cys Thr Asn Gly Leu Tyr Gly Lys Tyr
385390395400
Ser Asp Gln Leu Ile Val Asp Met Pro Thr Asp Asn Pro Glu Leu Asp
405410415
Leu Phe Pro Glu Leu Ile Gly Thr Glu Glu Ile Ile Lys Glu Glu Glu
420425430
Glu Gly Lys Asp Ile Glu Glu Gly Ala Ile Val Asn Pro Gly Arg Asp
435440445
Ser Ala Thr Asn Gln Ile Arg Lys Lys Glu Pro Gln Ile Ser Thr Thr
450455460
Thr His Tyr Asn Arg Ile Gly Thr Lys Tyr Asn Glu Ala Lys Thr Asn
465470475480
Arg Ser Pro Thr Arg Gly Ser Glu Phe Ser Gly Lys Gly Asp Val Pro
485490495
Asn Thr Ser Leu Asn Ser Thr Ser Gln Pro Val Thr Lys Leu Ala Thr
500505510
Glu Lys Asp Ile Ser Leu Thr Ser Gln Thr Val Thr Glu Leu Pro Pro
515520525
His Thr Val Glu Gly Thr Ser Ala Ser Leu Asn Asp Gly Ser Lys Thr
530535540
Val Leu Arg Ser Pro His Met Asn Leu Ser Gly Thr Ala Glu Ser Leu
545550555560
Asn Thr Val Ser Ile Thr Glu Tyr Glu Glu Glu Ser Leu Leu Thr Ser
565570575
Phe Lys Leu Asp Thr Gly Ala Glu Asp Ser Ser Gly Ser Ser Pro Ala
580585590
Thr Ser Ala Ile Pro Phe Ile Ser Glu Asn Ile Ser Gln Gly Tyr Ile
595600605
Phe Ser Ser Glu Asn Pro Glu Thr Ile Thr Tyr Asp Val Leu Ile Pro
610615620
Glu Ser Ala Arg Asn Ala Ser Glu Asp Ser Thr Ser Ser Gly Ser Glu
625630635640
Glu Ser Leu Lys Asp Pro Ser Met Glu Gly Asn Val Trp Phe Pro Ser
645650655
Ser Thr Asp Ile Thr Ala Gln Pro Asp Val Gly Ser Gly Arg Glu Ser
660665670
Phe Leu Gln Thr Asn Tyr Thr Glu Ile Arg Val Asp Glu Ser Glu Lys
675680685
Thr Thr Lys Ser Phe Ser Ala Gly Pro Val Met Ser Gln Gly Pro Ser
690695700
Val Thr Asp Leu Glu Met Pro His Tyr Ser Thr Phe Ala Tyr Phe Pro
705710715720
Thr Glu Val Thr Pro His Ala Phe Thr Pro Ser Ser Arg Gln Gln Asp
725730735
Leu Val Ser Thr Val Asn Val Val Tyr Ser Gln Thr Thr Gln Pro Val
740745750
Tyr Asn Gly Glu Thr Pro Leu Gln Pro Ser Tyr Ser Ser Glu Val Phe
755760765
Pro Leu Val Thr Pro Leu Leu Leu Asp Asn Gln Ile Leu Asn Thr Thr
770775780
Pro Ala Ala Ser Ser Ser Asp Ser Ala Leu His Ala Thr Pro Val Phe
785790795800
Pro Ser Val Asp Val Ser Phe Glu Ser Ile Leu Ser Ser Tyr Asp Gly
805810815
Ala Pro Leu Leu Pro Phe Ser Ser Ala Ser Phe Ser Ser Glu Leu Phe
820825830
Arg His Leu His Thr Val Ser Gln Ile Leu Pro Gln Val Thr Ser Ala
835840845
Thr Glu Ser Asp Lys Val Pro Leu His Ala Ser Leu Pro Val Ala Gly
850855860
Gly Asp Leu Leu Leu Glu Pro Ser Leu Ala Gln Tyr Ser Asp Val Leu
865870875880
Ser Thr Thr His Ala Ala Ser Glu Thr Leu Glu Phe Gly Ser Glu Ser
885890895
Gly Val Leu Tyr Lys Thr Leu Met Phe Ser Gln Val Glu Pro Pro Ser
900905910
Ser Asp Ala Met Met His Ala Arg Ser Ser Gly Pro Glu Pro Ser Tyr
915920925
Ala Leu Ser Asp Asn Glu Gly Ser Gln His Ile Phe Thr Val Ser Tyr
930935940
Ser Ser Ala Ile Pro Val His Asp Ser Val Gly Val Thr Tyr Gln Gly
945950955960
Ser Leu Phe Ser Gly Pro Ser His Ile Pro Ile Pro Lys Ser Ser Leu
965970975
Ile Thr Pro Thr Ala Ser Leu Leu Gln Pro Thr His Ala Leu Ser Gly
980985990
Asp Gly Glu Trp Ser Gly Ala Ser Ser Asp Ser Glu Phe Leu Leu Pro
99510001005
Asp Thr Asp Gly Leu Thr Ala Leu Asn Ile Ser Ser Pro Val Ser Val
101010151020
Ala Glu Phe Thr Tyr Thr Thr Ser Val Phe Gly Asp Asp Asn Lys Ala
1025103010351040
Leu Ser Lys Ser Glu Ile Ile Tyr Gly Asn Glu Thr Glu Leu Gln Ile
104510501055
Pro Ser Phe Asn Glu Met Val Tyr Pro Ser Glu Ser Thr Val Met Pro
106010651070
Asn Met Tyr Asp Asn Val Asn Lys Leu Asn Ala Ser Leu Gln Glu Thr
107510801085
Ser Val Ser Ile Ser Ser Thr Lys Gly Met Phe Pro Gly Ser Leu Ala
109010951100
His Thr Thr Thr Lys Val Phe Asp His Glu Ile Ser Gln Val Pro Glu
1105111011151120
Asn Asn Phe Ser Val Gln Pro Thr His Thr Val Ser Gln Ala Ser Gly
112511301135
Asp Thr Ser Leu Lys Pro Val Leu Ser Ala Asn Ser Glu Pro Ala Ser
114011451150
Ser Asp Pro Ala Ser Ser Glu Met Leu Ser Pro Ser Thr Gln Leu Leu
115511601165
Phe Tyr Glu Thr Ser Ala Ser Phe Ser Thr Glu Val Leu Leu Gln Pro
117011751180
Ser Phe Gln Ala Ser Asp Val Asp Thr Leu Leu Lys Thr Val Leu Pro
1185119011951200
Ala Val Pro Ser Asp Pro Ile Leu Val Glu Thr Pro Lys Val Asp Lys
120512101215
Ile Ser Ser Thr Met Leu His Leu Ile Val Ser Asn Ser Ala Ser Ser
122012251230
Glu Asn Met Leu His Ser Thr Ser Val Pro Val Phe Asp Val Ser Pro
123512401245
Thr Ser His Met His Ser Ala Ser Leu Gln Gly Leu Thr Ile Ser Tyr
125012551260
Ala Ser Glu Lys Tyr Glu Pro Val Leu Leu Lys Ser Glu Ser Ser His
1265127012751280
Gln Val Val Pro Ser Leu Tyr Ser Asn Asp Glu Leu Phe Gln Thr Ala
128512901295
Asn Leu Glu Ile Asn Gln Ala His Pro Pro Lys Gly Arg His Val Phe
130013051310
Ala Thr Pro Val Leu Ser Ile Asp Glu Pro Leu Asn Thr Leu Ile Asn
131513201325
Lys Leu Ile His Ser Asp Glu Ile Leu Thr Ser Thr Lys Ser Ser Val
133013351340
Thr Gly Lys Val Phe Ala Gly Ile Pro Thr Val Ala Ser Asp Thr Phe
1345135013551360
Val Ser Thr Asp His Ser Val Pro Ile Gly Asn Gly His Val Ala Ile
136513701375
Thr Ala Val Ser Pro His Arg Asp Gly Ser Val Thr Ser Thr Lys Leu
138013851390
Leu Phe Pro Ser Lys Ala Thr Ser Glu Leu Ser His Ser Ala Lys Ser
139514001405
Asp Ala Gly Leu Val Gly Gly Gly Glu Asp Gly Asp Thr Asp Asp Asp
141014151420
Gly Asp Asp Asp Asp Asp Asp Arg Gly Ser Asp Gly Leu Ser Ile His
1425143014351440
Lys Cys Met Ser Cys Ser Ser Tyr Arg Glu Ser Gln Glu Lys Val Met
144514501455
Asn Asp Ser Asp Thr His Glu Asn Ser Leu Met Asp Gln Asn Asn Pro
146014651470
Ile Ser Tyr Ser Leu Ser Glu Asn Ser Glu Glu Asp Asn Arg Val Thr
147514801485
Ser Val Ser Ser Asp Ser Gln Thr Gly Met Asp Arg Ser Pro Gly Lys
149014951500
Ser Pro Ser Ala Asn Gly Leu Ser Gln Lys His Asn Asp Gly Lys Glu
1505151015151520
Glu Asn Asp Ile Gln Thr Gly Ser Ala Leu Leu Pro Leu Ser Pro Glu
152515301535
Ser Lys Ala Trp Ala Val Leu Thr Ser Asp Glu Glu Ser Gly Ser Gly
154015451550
Gln Gly Thr Ser Asp Ser Leu Asn Glu Asn Glu Thr Ser Thr Asp Phe
155515601565
Ser Phe Ala Asp Thr Asn Glu Lys Asp Ala Asp Gly Ile Leu Ala Ala
157015751580
Gly Asp Ser Glu Ile Thr Pro Gly Phe Pro Gln Ser Pro Thr Ser Ser
1585159015951600
Val Thr Ser Glu Asn Ser Glu Val Phe His Val Ser Glu Ala Glu Ala
160516101615
Ser Asn Ser Ser His Glu Ser Arg Ile Gly Leu Ala Glu Gly Leu Glu
162016251630
Ser Glu Lys Lys Ala Val Ile Pro Leu Val Ile Val Ser Ala Leu Thr
163516401645
Phe Ile Cys Leu Val Val Leu Val Gly Ile Leu Ile Tyr Trp Arg Lys
165016551660
Cys Phe Gln Thr Ala His Phe Tyr Leu Glu Asp Ser Thr Ser Pro Arg
1665167016751680
Val Ile Ser Thr Pro Pro Thr Pro Ile Phe Pro Ile Ser Asp Asp Val
168516901695
Gly Ala Ile Pro Ile Lys His Phe Pro Lys His Val Ala Asp Leu His
170017051710
Ala Ser Ser Gly Phe Thr Glu Glu Phe Glu Thr Leu Lys Glu Phe Tyr
171517201725
Gln Glu Val Gln Ser Cys Thr Val Asp Leu Gly Ile Thr Ala Asp Ser
173017351740
Ser Asn His Pro Asp Asn Lys His Lys Asn Arg Tyr Ile Asn Ile Val
1745175017551760
Ala Tyr Asp His Ser Arg Val Lys Leu Ala Gln Leu Ala Glu Lys Asp
176517701775
Gly Lys Leu Thr Asp Tyr Ile Asn Ala Asn Tyr Val Asp Gly Tyr Asn
178017851790
Arg Pro Lys Ala Tyr Ile Ala Ala Gln Gly Pro Leu Lys Ser Thr Ala
179518001805
Glu Asp Phe Trp Arg Met Ile Trp Glu His Asn Val Glu Val Ile Val
181018151820
Met Ile Thr Asn Leu Val Glu Lys Gly Arg Arg Lys Cys Asp Gln Tyr
1825183018351840
Trp Pro Ala Asp Gly Ser Glu Glu Tyr Gly Asn Phe Leu Val Thr Gln
184518501855
Lys Ser Val Gln Val Leu Ala Tyr Tyr Thr Val Arg Asn Phe Thr Leu
186018651870
Arg Asn Thr Lys Ile Lys Lys Gly Ser Gln Lys Gly Arg Pro Ser Gly
187518801885
Arg Val Val Thr Gln Tyr His Tyr Thr Gln Trp Pro Asp Met Gly Val
189018951900
Pro Glu Tyr Ser Leu Pro Val Leu Thr Phe Val Arg Lys Ala Ala Tyr
1905191019151920
Ala Lys Arg His Ala Val Gly Pro Val Val Val His Cys Ser Ala Gly
192519301935
Val Gly Arg Thr Gly Thr Tyr Ile Val Leu Asp Ser Met Leu Gln Gln
194019451950
Ile Gln His Glu Gly Thr Val Asn Ile Phe Gly Phe Leu Lys His Ile
195519601965
Arg Ser Gln Arg Asn Tyr Leu Val Gln Thr Glu Glu Gln Tyr Val Phe
197019751980
Ile His Asp Thr Leu Val Glu Ala Ile Leu Ser Lys Glu Thr Glu Val
1985199019952000
Leu Asp Ser His Ile His Ala Tyr Val Asn Ala Leu Leu Ile Pro Gly
200520102015
Pro Ala Gly Lys Thr Lys Leu Glu Lys Gln Phe Gln Leu Leu Ser Gln
202020252030
Ser Asn Ile Gln Gln Ser Asp Tyr Ser Ala Ala Leu Lys Gln Cys Asn
203520402045
Arg Glu Lys Asn Arg Thr Ser Ser Ile Ile Pro Val Glu Arg Ser Arg
205020552060
Val Gly Ile Ser Ser Leu Ser Gly Glu Gly Thr Asp Tyr Ile Asn Ala
2065207020752080
Ser Tyr Ile Met Gly Tyr Tyr Gln Ser Asn Glu Phe Ile Ile Thr Gln
208520902095
His Pro Leu Leu His Thr Ile Lys Asp Phe Trp Arg Met Ile Trp Asp
210021052110
His Asn Ala Gln Leu Val Val Met Ile Pro Asp Gly Gln Asn Met Ala
211521202125
Glu Asp Glu Phe Val Tyr Trp Pro Asn Lys Asp Glu Pro Ile Asn Cys
213021352140
Glu Ser Phe Lys Val Thr Leu Met Ala Glu Glu His Lys Cys Leu Ser
2145215021552160
Asn Glu Glu Lys Leu Ile Ile Gln Asp Phe Ile Leu Glu Ala Thr Gln
216521702175
Asp Asp Tyr Val Leu Glu Val Arg His Phe Gln Cys Pro Lys Trp Pro
218021852190
Asn Pro Asp Ser Pro Ile Ser Lys Thr Phe Glu Leu Ile Ser Val Ile
219522002205
Lys Glu Glu Ala Ala Asn Arg Asp Gly Pro Met Ile Val His Asp Glu
221022152220
His Gly Gly Val Thr Ala Gly Thr Phe Cys Ala Leu Thr Thr Leu Met
2225223022352240
His Gln Leu Glu Lys Glu Asn Ser Val Asp Val Tyr Gln Val Ala Lys
224522502255
Met Ile Asn Leu Met Arg Pro Gly Val Phe Ala Asp Ile Glu Gln Tyr
226022652270
Gln Phe Leu Tyr Lys Val Ile Leu Ser Leu Val Ser Thr Arg Gln Glu
227522802285
Glu Asn Pro Ser Thr Ser Leu Asp Ser Asn Gly Ala Ala Leu Pro Asp
229022952300
Gly Asn Ile Ala Glu Ser Leu Glu Ser Leu Val
230523102315
<210> 341
<211> 159
<212> PRT
<213> Homo sapiens
<220>
<223> CD44 Hyaluronan-binding domain
<400> 341
Ala Gln Ile Asp Leu Asn Ile Thr Cys Arg Phe Ala Gly Val Phe His
151015
Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg Thr Glu Ala Ala Asp
202530
Leu Cys Lys Ala Phe Asn Ser Thr Leu Pro Thr Met Ala Gln Met Glu
354045
Lys Ala Leu Ser Ile Gly Phe Glu Thr Cys Arg Tyr Gly Phe Ile Glu
505560
Gly His Val Val Ile Pro Arg Ile His Pro Asn Ser Ile Cys Ala Ala
65707580
Asn Asn Thr Gly Val Tyr Ile Leu Thr Ser Asn Thr Ser Gln Tyr Asp
859095
Thr Tyr Cys Phe Asn Ala Ser Ala Pro Pro Glu Glu Asp Cys Thr Ser
100105110
Val Thr Asp Leu Pro Asn Ala Phe Asp Gly Pro Ile Thr Ile Thr Ile
115120125
Val Asn Arg Asp Gly Thr Arg Tyr Val Gln Lys Gly Glu Tyr Arg Thr
130135140
Asn Pro Glu Asp Ile Tyr Pro Ser Asn Pro Thr Asp Asp Asp Val
145150155
<210> 342
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 342
Gly Gly Gly Gly Gly
15
<210> 343
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 343
Gly Gly Gly Gly Ser
15
<210> 344
<211> 5
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 344
Ser Ser Ser Ser Gly
15
<210> 345
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 345
Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser
1510
<210> 346
<211> 15
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 346
Gly Gly Ser Thr Ser Gly Ser Gly Lys Ser Ser Glu Gly Lys Gly
151015
<210> 347
<211> 19
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 347
Gly Ser Thr Ser Gly Ser Gly Lys Ser Ser Ser Glu Gly Ser Gly Ser
151015
Thr Lys Gly
<210> 348
<211> 18
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 348
Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Thr
151015
Lys Gly
<210> 349
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 349
Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Glu Phe
1510
<210> 350
<211> 4
<212> PRT
<213> Artificial Sequence
<220>
<223> linker
<400> 350
Ala Ala Pro Ala
1
<210> 351
<211> 27
<212> DNA
<213> Artificial Sequence
<220>
<223> Gly4Ser with NcoI ends
<400> 351
ccatgggcgg cggcggctct gccatgg27
<210> 352
<211> 42
<212> DNA
<213> Artificial Sequence
<220>
<223> (Gly4Ser)2with NcoI ends
<400> 352
ccatgggcgg cggcggctct ggcggcggcg gctctgccat gg42
<210> 353
<211> 75
<212> DNA
<213> Artificial Sequence
<220>
<223> (Ser4Gly)4 with NcoI ends
<400> 353
ccatggcctc gtcgtcgtcg ggctcgtcgt cgtcgggctc gtcgtcgtcg ggctcgtcgt 60
cgtcgggcgc catgg75
<210> 354
<211> 45
<212> DNA
<213> Artificial Sequence
<220>
<223> (Ser4Gly)2with NcoI ends
<400> 354
ccatggcctc gtcgtcgtcg ggctcgtcgt cgtcgggcgc catgg45
<210> 355
<211> 330
<212> PRT
<213> Homo sapiens
<220>
<223> hIgG1 heavy chain constant
<400> 355
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
151015
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
202530
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
354045
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
505560
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65707580
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
859095
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
100105110
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
115120125
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
130135140
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
145150155160
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
165170175
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
180185190
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
195200205
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
210215220
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
225230235240
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
245250255
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
260265270
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275280285
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
290295300
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
305310315320
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
325330
<210> 356
<211> 326
<212> PRT
<213> Homo sapiens
<220>
<223> hIgG2 heavy chain constant
<400> 356
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
151015
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
202530
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
354045
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
505560
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
65707580
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
859095
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
100105110
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
115120125
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
130135140
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
145150155 160
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
165170175
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
180185190
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
195200205
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
210215220
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
225230235240
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
245250255
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
260265270
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
275280285
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
290295300
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
305310315320
Ser Leu Ser Pro Gly Lys
325
<210> 357
<211> 377
<212> PRT
<213> Homo sapiens
<220>
<223> hIgG3 heavy chain constant
<400> 357
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
151015
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
202530
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
354045
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
505560
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
65707580
Tyr Thr Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
859095
Arg Val Glu Leu Lys Thr Pro Leu Gly Asp Thr Thr His Thr Cys Pro
100105110
Arg Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg
115120125
Cys Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys
130135140
Pro Glu Pro Lys Ser Cys Asp Thr Pro Pro Pro Cys Pro Arg Cys Pro
145150155160
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
165170175
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
180185190
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Lys Trp Tyr
195200205
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
210215220
Gln Tyr Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Leu His
225230235240
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
245250255
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln
260265270
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
275280285
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
290295300
Ser Asp Ile Ala Val Glu Trp Glu Ser Ser Gly Gln Pro Glu Asn Asn
305310315320
Tyr Asn Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu
325330335
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Ile
340345350
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn Arg Phe Thr Gln
355360365
Lys Ser Leu Ser Leu Ser Pro Gly Lys
370375
<210> 358
<211> 327
<212> PRT
<213> Homo sapiens
<220>
<223> hIgG4 heavy chain constant
<400> 358
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
151015
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
202530
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
354045
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
505560
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65707580
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
859095
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
100105110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115120125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130135140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145150155160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165170175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180185190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195200205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210215220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225230235240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245250255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260265270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275280285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290295300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305310315320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 359
<211> 231
<212> PRT
<213> Artificial Sequence
<220>
<223> hIgG1 Fc
<400> 359
Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
151015
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
202530
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
354045
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
505560
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
65707580
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
859095
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
100105110
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
115120125
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
130135140
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
145150155160
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
165170175
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
180185190
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
195200205
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
210215220
Leu Ser Leu Ser Pro Gly Lys
225230
<210> 360
<211> 93
<212> PRT
<213> Homo sapiens
<220>
<223> TSG-6 Link domain
<400> 360
Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys Leu Thr Tyr
151015
Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His Leu Ala Thr
202530
Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His Val Cys Ala
354045
Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile Val Lys Pro
505560
Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp Tyr Gly Ile
65707580
Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
8590
<210> 361
<211> 93
<212> PRT
<213> Homo sapiens
<220>
<223> TSG-6 Link domain variant K20A/K34A/K41A
<400> 361
Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys Leu Thr Tyr
15 1015
Ala Glu Ala Ala Ala Val Cys Glu Phe Glu Gly Gly His Leu Ala Thr
202530
Tyr Ala Gln Leu Glu Ala Ala Arg Ala Ile Gly Phe His Val Cys Ala
354045
Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile Val Lys Pro
505560
Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp Tyr Gly Ile
65707580
Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
8590
<210> 362
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> c-jun leucine zipper
<400> 362
Arg Ile Ala Arg Leu Glu Glu Lys Val Lys Thr Leu Lys Ala Gln Asn
151015
Ser Glu Leu Ala Ser Thr Ala Asn Met Leu Arg Glu Gln Val Ala Gln
202530
Leu Lys Gln Lys Val Met Asn
35
<210> 363
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> c-fos leucine zipper
<400> 363
Leu Thr Asp Thr Leu Gln Ala Glu Thr Asp Gln Leu Glu Asp Glu Lys
151015
Ser Ala Leu Gln Thr Glu Ile Ala Asn Leu Leu Lys Glu Lys Glu Lys
202530
Leu Glu Phe Ile Leu Ala Ala
35
<210> 364
<211> 33
<212> PRT
<213> Artificial Sequence
<220>
<223> GCN4 leucine zipper
<400> 364
Arg Met Lys Gln Leu Glu Asp Lys Val Glu Glu Leu Leu Ser Lys Asn
151015
Tyr His Leu Glu Asn Glu Val Ala Arg Leu Lys Lys Leu Val Gly Glu
202530
Arg
<210> 365
<211> 33
<212> PRT
<213> Artificial Sequence
<220>
<223> GCN4 leucine zipper- trimer
<400> 365
Arg Met Lys Gln Ile Glu Asp Lys Ile Glu Glu Ile Leu Ser Lys Ile
151015
Tyr His Ile Glu Asn Glu Ile Ala Arg Ile Lys Lys Leu Ile Gly Glu
202530
Arg
<210> 366
<211> 33
<212> PRT
<213> Artificial Sequence
<220>
<223> GCN4 leucine zipper- tetramer
<400> 366
Arg Met Lys Gln Ile Glu Asp Lys Leu Glu Glu Ile Leu Ser Lys Leu
151015
Tyr His Ile Glu Asn Glu Leu Ala Arg Ile Lys Lys Leu Leu Gly Glu
202530
Arg
<210> 367
<211> 44
<212> PRT
<213> Artificial Sequence
<220>
<223> R subunit of protein kinase A (PKA)
<400> 367
Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly Tyr
151015
Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe Ala
202530
Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
3540
<210> 368
<211> 17
<212> PRT
<213> Artificial Sequence
<220>
<223> AD subunit
<400> 368
Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile Gln Gln
151015
Ala
<210> 369
<211> 45
<212> PRT
<213> Artificial Sequence
<220>
<223> modified R subunit of protein kinase A (PKA)
<400> 369
Cys Ser His Ile Gln Ile Pro Pro Gly Leu Thr Glu Leu Leu Gln Gly
151015
Tyr Thr Val Glu Val Leu Arg Gln Gln Pro Pro Asp Leu Val Glu Phe
202530
Ala Val Glu Tyr Phe Thr Arg Leu Arg Glu Ala Arg Ala
354045
<210> 370
<211> 21
<212> PRT
<213> Artificial Sequence
<220>
<223> modified AD subunit
<400> 370
Cys Gly Gln Ile Glu Tyr Leu Ala Lys Gln Ile Val Asp Asn Ala Ile
151015
Gln Gln Ala Gly Cys
20
<210> 371
<211> 93
<212> PRT
<213> Homo sapiens
<220>
<223> Stabilin-1 Link domain
<400> 371
Gly Val Phe His Leu Gln Ala Thr Ser Gly Pro Tyr Gly Leu Asn Phe
151015
Ser Glu Ala Glu Ala Ala Cys Glu Ala Gln Gly Ala Val Leu Ala Ser
202530
Phe Pro Gln Leu Ser Ala Ala Gln Gln Leu Gly Phe His Leu Cys Leu
354045
Met Gly Trp Leu Ala Asn Gly Ser Thr Ala His Pro Val Val Phe Pro
505560
Val Ala Asp Cys Gly Asn Gly Arg Val Gly Ile Val Ser Leu Gly Ala
65707580
Arg Lys Asn Leu Ser Glu Arg Trp Asp Ala Tyr Cys Phe
8590
<210> 372
<211> 93
<212> PRT
<213> Homo sapiens
<220>
<223> Stabilin-2 Link domain
<400> 372
Gly Val Phe His Leu Arg Ser Pro Leu Gly Gln Tyr Lys Leu Thr Phe
151015
Asp Lys Ala Arg Glu Ala Cys Ala Asn Glu Ala Ala Thr Met Ala Thr
202530
Tyr Asn Gln Leu Ser Tyr Ala Gln Lys Ala Lys Tyr His Leu Cys Ser
354045
Ala Gly Trp Leu Glu Thr Gly Arg Val Ala Tyr Pro Thr Ala Phe Ala
505560
Ser Gln Asn Cys Gly Ser Gly Val Val Gly Ile Val Asp Tyr Gly Pro
65707580
Arg Pro Asn Lys Ser Glu Met Trp Asp Val Phe Cys Tyr
8590
<210> 373
<211> 93
<212> PRT
<213> Homo sapiens
<220>
<223> CAB61358 Link domain
<400> 373
Gly Val Phe His Leu Arg Ser Pro Leu Gly Gln Tyr Lys Leu Thr Phe
151015
Asp Lys Ala Arg Glu Ala Cys Ala Asn Glu Ala Ala Thr Met Ala Thr
202530
Tyr Asn Gln Leu Ser Tyr Ala Gln Lys Ala Lys Tyr His Leu Cys Ser
354045
Ala Gly Trp Leu Glu Thr Gly Arg Val Ala Tyr Pro Thr Ala Phe Ala
505560
Ser Gln Asn Cys Gly Ser Gly Val Val Gly Ile Val Asp Tyr Gly Pro
65707580
Arg Pro Asn Lys Ser Glu Met Trp Asp Val Phe Cys Tyr
8590
<210> 374
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> KIAA0527 Link domain
<400> 374
Lys Leu Phe Val Leu Glu Ser Gln Asn Gly Ser Gln Gly Leu Gln Leu
151015
Glu Ala Ala Arg Leu Ser Cys Lys Ser Arg Gly Ala His Leu Ala Ser
202530
Ala Asp Glu Leu Arg Arg Val Val Gln Asp Cys Ser Phe Ala Val Cys
354045
Thr Thr Gly Trp Leu Ala Asp Gly Thr Leu Gly Thr Thr Val Cys Ser
505560
Lys Gly Ser Gly Glu Gln Gln Ile Met Arg Ala Val Asp Val Arg Ile
65707580
Glu Ser Asn Pro Val Pro Gly Gly Thr Tyr Ser Ala Leu Cys Ile
859095
<210> 375
<211> 88
<212> PRT
<213> Homo sapiens
<220>
<223> CD44 Link domain
<400> 375
Gly Val Phe His Val Glu Lys Asn Gly Arg Tyr Ser Ile Ser Arg Thr
151015
Glu Ala Ala Asp Leu Cys Lys Ala Phe Asn Ser Thr Leu Pro Thr Met
202530
Ala Gln Met Glu Lys Ala Leu Ser Ile Gly Phe Glu Thr Cys Arg Tyr
354045
Gly Phe Ile Glu Gly His Val Val Ile Pro Arg Ile His Pro Asn Ser
505560
Ile Cys Ala Ala Asn Asn Thr Gly Val Tyr Ile Leu Thr Ser Asn Thr
65707580
Ser Gln Tyr Asp Thr Tyr Cys Phe
85
<210> 376
<211> 90
<212> PRT
<213> Homo sapiens
<220>
<223> LYVE-1 Link domain
<400> 376
Gly Ile Thr Leu Val Ser Lys Lys Ala Asn Gln Gln Leu Asn Phe Thr
151015
Glu Ala Lys Glu Ala Cys Arg Leu Leu Gly Leu Ser Leu Ala Gly Lys
202530
Asp Gln Val Glu Thr Ala Leu Lys Ala Ser Phe Glu Thr Cys Ser Tyr
354045
Gly Trp Val Gly Asp Gly Phe Val Val Ile Ser Arg Ile Ser Pro Asn
505560
Pro Lys Cys Gly Lys Asn Gly Val Gly Val Leu Ile Trp Lys Val Pro
65707580
Val Ser Arg Gln Phe Ala Ala Tyr Cys Tyr
8590
<210> 377
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN1 Link domain 1
<400> 377
Val Val Phe Pro Tyr Phe Pro Arg Leu Gly Arg Tyr Asn Leu Asn Phe
151015
His Glu Ala Gln Gln Ala Cys Leu Asp Gln Asp Ala Val Ile Ala Ser
202530
Phe Asp Gln Leu Tyr Asp Ala Trp Arg Gly Gly Leu Asp Trp Cys Asn
354045
Ala Gly Trp Leu Ser Asp Gly Ser Val Gln Tyr Pro Ile Thr Lys Pro
505560
Arg Glu Pro Cys Gly Gly Gln Asn Thr Val Pro Gly Val Arg Asn Tyr
65707580
Gly Phe Trp Asp Lys Asp Lys Ser Arg Tyr Asp Val Phe Cys Phe
859095
<210> 378
<211> 92
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN1 Link domain 2
<400> 378
Gly Arg Phe Tyr Tyr Leu Ile His Pro Thr Lys Leu Thr Tyr Asp Glu
151015
Ala Val Gln Ala Cys Leu Asn Asp Gly Ala Gln Ile Ala Lys Val Gly
202530
Gln Ile Phe Ala Ala Trp Lys Ile Leu Gly Tyr Asp Arg Cys Asp Ala
354045
Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Ser Arg Pro Arg
505560
Arg Arg Cys Ser Pro Thr Glu Ala Ala Val Arg Phe Val Gly Phe Pro
65707580
Asp Lys Lys His Lys Leu Tyr Gly Val Tyr Cys Phe
8590
<210> 379
<211> 94
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN2 Link domain 1
<400> 379
Val Val Phe Pro Tyr Gln Pro Ser Arg Gly Arg Tyr Gln Phe Asn Tyr
151015
Tyr Glu Ala Lys Gln Ala Cys Glu Glu Gln Asp Gly Arg Leu Ala Thr
202530
Tyr Ser Gln Leu Tyr Gln Ala Trp Thr Glu Gly Leu Asp Trp Cys Asn
354045
Ala Gly Trp Leu Leu Glu Gly Ser Val Arg Tyr Pro Val Leu Thr Ala
505560
Arg Ala Pro Cys Gly Gly Arg Gly Arg Pro Gly Ile Arg Ser Tyr Gly
65 707580
Pro Arg Asp Arg Met Arg Asp Arg Tyr Asp Ala Phe Cys Phe
8590
<210> 380
<211> 90
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN2 Link domain 2
<400> 380
Gly Gln Phe Phe Val Pro Gly Arg Leu Thr Leu Ser Glu Ala His Ala
151015
Ala Cys Arg Arg Arg Gly Ala Val Val Ala Lys Val Gly His Leu Tyr
202530
Ala Ala Trp Lys Phe Ser Gly Leu Asp Gln Cys Asp Gly Gly Trp Leu
354045
Ala Asp Gly Ser Val Arg Phe Pro Ile Thr Thr Pro Arg Pro Arg Cys
505560
Gly Gly Leu Pro Asp Pro Gly Val Arg Ser Phe Gly Phe Pro Arg Pro
65707580
Gln Gln Ala Ala Tyr Gly Thr Tyr Cys Tyr
8590
<210> 381
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> APLN3 Link domain 1
<400> 381
Val Val Phe Pro Tyr Gln Ser Pro Asn Gly Arg Tyr Gln Phe Asn Phe
151015
His Glu Gly Gln Gln Val Cys Ala Glu Gln Ala Ala Val Val Ala Ser
202530
Phe Glu Gln Leu Phe Arg Ala Trp Glu Glu Gly Leu Asp Trp Cys Asn
354045
Ala Gly Trp Leu Gln Asp Ala Thr Val Gln Tyr Pro Ile Met Leu Pro
505560
Arg Gln Pro Cys Gly Gly Pro Gly Leu Ala Pro Gly Val Arg Ser Tyr
65707580
Gly Pro Arg His Arg Arg Leu His Arg Tyr Asp Val Phe Cys Phe
859095
<210> 382
<211> 92
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN3 Link domain 2
<400> 382
Gly Arg Val Tyr Tyr Leu Glu His Pro Glu Lys Leu Thr Leu Thr Glu
151015
Ala Arg Glu Ala Cys Gln Glu Asp Asp Ala Thr Ile Ala Lys Val Gly
202530
Gln Leu Phe Ala Ala Trp Lys Phe His Gly Leu Asp Arg Cys Asp Ala
354045
Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Val Val His Pro His
505560
Pro Asn Cys Gly Pro Pro Glu Pro Gly Val Arg Ser Phe Gly Phe Pro
65707580
Asp Pro Gln Ser Arg Leu Tyr Gly Val Tyr Cys Tyr
8590
<210> 383
<211> 105
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN4 Link domain 1
<400> 383
Val Val Phe Pro Tyr His Pro Arg Gly Gly Arg Tyr Lys Leu Thr Phe
151015
Ala Glu Ala Gln Arg Ala Cys Ala Glu Gln Asp Gly Ile Leu Ala Ser
202530
Ala Glu Gln Leu His Ala Ala Trp Arg Asp Gly Leu Asp Trp Cys Asn
354045
Ala Gly Trp Leu Arg Asp Gly Ser Val Gln Tyr Pro Val Asn Arg Pro
505560
Arg Glu Pro Cys Gly Gly Leu Gly Gly Thr Gly Ser Ala Gly Gly Gly
65707580
Gly Asp Ala Asn Gly Gly Leu Arg Asn Tyr Gly Tyr Arg His Asn Ala
859095
Glu Glu Arg Tyr Asp Ala Phe Cys Phe
100105
<210> 384
<211> 92
<212> PRT
<213> Homo sapiens
<220>
<223> HAPLN4 Link domain 2
<400> 384
Gly Arg Val Phe Phe Leu Lys Pro Leu Arg Pro Val Pro Phe Ser Gly
151015
Ala Ala Arg Ala Cys Ala Ala Arg Gly Ala Ala Val Ala Lys Val Gly
202530
Gln Leu Phe Ala Ala Trp Lys Leu Gln Leu Leu Asp Arg Cys Thr Ala
3540 45
Gly Trp Leu Ala Asp Gly Ser Ala Arg Tyr Pro Ile Val Asn Pro Arg
505560
Ala Arg Cys Gly Gly Arg Arg Pro Gly Val Arg Ser Leu Gly Phe Pro
65707580
Asp Ala Thr Arg Arg Leu Phe Gly Val Tyr Cys Tyr
8590
<210> 385
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> Aggrecan Link domain 1
<400> 385
Ile Val Phe His Tyr Arg Ala Ile Ser Thr Arg Tyr Thr Leu Asp Phe
151015
Asp Arg Ala Gln Arg Ala Cys Leu Gln Asn Ser Ala Ile Ile Ala Thr
202530
Pro Glu Gln Leu Gln Ala Ala Tyr Glu Asp Gly Phe His Gln Cys Asp
354045
Ala Gly Trp Leu Ala Asp Gln Thr Val Arg Tyr Pro Ile His Thr Pro
505560
Arg Glu Gly Cys Tyr Gly Asp Lys Asp Glu Phe Pro Gly Val Arg Thr
65707580
Tyr Gly Ile Arg Asp Thr Asn Glu Thr Tyr Asp Val Tyr Cys Phe
859095
<210> 386
<211> 96
<212> PRT
<213> Homo sapiens
<220>
<223> Aggrecan Link domain 2
<400> 386
Glu Val Phe Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu Ala
151015
Ala Asn Glu Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly Gln
202530
Leu Tyr Leu Ala Trp Gln Ala Gly Met Asp Met Cys Ser Ala Gly Trp
354045
Leu Ala Asp Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro Asn
505560
Cys Gly Gly Asn Leu Leu Gly Val Arg Thr Val Tyr Val His Ala Asn
65707580
Gln Thr Gly Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys Tyr
859095
<210> 387
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> Aggrecan Link domain 3
<400> 387
Val Val Phe His Tyr Arg Pro Gly Pro Thr Arg Tyr Ser Leu Thr Phe
151015
Glu Glu Ala Gln Gln Ala Cys Leu Arg Thr Gly Ala Val Ile Ala Ser
202530
Pro Glu Gln Leu Gln Ala Ala Tyr Glu Ala Gly Tyr Glu Gln Cys Asp
354045
Ala Gly Trp Leu Arg Asp Gln Thr Val Arg Tyr Pro Ile Val Ser Pro
505560
Arg Thr Pro Cys Val Gly Asp Lys Asp Ser Ser Pro Gly Val Arg Thr
65707580
Tyr Gly Val Arg Pro Ser Thr Glu Thr Tyr Asp Val Tyr Cys Phe
859095
<210> 388
<211> 96
<212> PRT
<213> Homo sapiens
<220>
<223> Aggrecan Link domain 4
<400> 388
Glu Val Phe Phe Ala Thr Arg Leu Glu Gln Phe Thr Phe Gln Glu Ala
151015
Leu Glu Phe Cys Glu Ser His Asn Ala Thr Leu Ala Thr Thr Gly Gln
202530
Leu Tyr Ala Ala Trp Ser Arg Gly Leu Asp Lys Cys Tyr Ala Gly Trp
354045
Leu Ala Asp Gly Ser Leu Arg Tyr Pro Ile Val Thr Pro Arg Pro Ala
505560
Cys Gly Gly Asp Lys Pro Gly Val Arg Thr Val Tyr Leu Tyr Pro Asn
65707580
Gln Thr Gly Leu Pro Asp Pro Leu Ser Arg His His Ala Phe Cys Phe
859095
<210> 389
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> Brevican Link domain 1
<400> 389
Val Val Phe Leu Tyr Arg Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe
151015
Ser Gly Ala Gln Glu Ala Cys Ala Arg Ile Gly Ala His Ile Ala Thr
202530
Pro Glu Gln Leu Tyr Ala Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp
354045
Ala Gly Trp Leu Ser Asp Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro
505560
Arg Glu Ala Cys Tyr Gly Asp Met Asp Gly Phe Pro Gly Val Arg Asn
65707580
Tyr Gly Val Val Asp Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr
859095
<210> 390
<211> 96
<212> PRT
<213> Homo sapiens
<220>
<223> Brevican Link domain 2
<400> 390
Glu Leu Phe Leu Gly Asp Pro Pro Glu Lys Leu Thr Leu Glu Glu Ala
151015
Arg Ala Tyr Cys Gln Glu Arg Gly Ala Glu Ile Ala Thr Thr Gly Gln
202530
Leu Tyr Ala Ala Trp Asp Gly Gly Leu Asp His Cys Ser Pro Gly Trp
354045
Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Val Thr Pro Ser Gln Arg
505560
Cys Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro Asn
65707580
Gln Thr Gly Phe Pro Asn Lys His Ser Arg Phe Asn Val Tyr Cys Phe
859095
<210> 391
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> Versican Link domain 1
<400> 391
Val Val Phe His Tyr Arg Ala Ala Thr Ser Arg Tyr Thr Leu Asn Phe
151015
Glu Ala Ala Gln Lys Ala Cys Leu Asp Val Gly Ala Val Ile Ala Thr
202530
Pro Glu Gln Leu Phe Ala Ala Tyr Glu Asp Gly Phe Glu Gln Cys Asp
354045
Ala Gly Trp Leu Ala Asp Gln Thr Val Arg Tyr Pro Ile Arg Ala Pro
505560
Arg Val Gly Cys Tyr Gly Asp Lys Met Gly Lys Ala Gly Val Arg Thr
65707580
Tyr Gly Phe Arg Ser Pro Gln Glu Thr Tyr Asp Val Tyr Cys Tyr
859095
<210> 392
<211> 96
<212> PRT
<213> Homo sapiens
<220>
<223> Versican Link domain 2
<400> 392
Asp Val Phe His Leu Thr Val Pro Ser Lys Phe Thr Phe Glu Glu Ala
151015
Ala Lys Glu Cys Glu Asn Gln Asp Ala Arg Leu Ala Thr Val Gly Glu
202530
Leu Gln Ala Ala Trp Arg Asn Gly Phe Asp Gln Cys Asp Tyr Gly Trp
354045
Leu Ser Asp Ala Ser Val Arg His Pro Val Thr Val Ala Arg Ala Gln
505560
Cys Gly Gly Gly Leu Leu Gly Val Arg Thr Leu Tyr Arg Phe Glu Asn
65707580
Gln Thr Gly Phe Pro Pro Pro Asp Ser Arg Phe Asp Ala Tyr Cys Phe
859095
<210> 393
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> Neurocan Link domain 1
<400> 393
Val Val Phe His Tyr Arg Ser Ala Arg Asp Arg Tyr Ala Leu Thr Phe
151015
Ala Glu Ala Gln Glu Ala Cys Arg Leu Ser Ser Ala Ile Ile Ala Ala
202530
Pro Arg His Leu Gln Ala Ala Phe Glu Asp Gly Phe Asp Asn Cys Asp
354045
Ala Gly Trp Leu Ser Asp Arg Thr Val Arg Tyr Pro Ile Thr Gln Ser
505560
Arg Pro Gly Cys Tyr Gly Asp Arg Ser Ser Leu Pro Gly Val Arg Ser
65707580
Tyr Gly Arg Arg Asn Pro Gln Glu Leu Tyr Asp Val Tyr Cys Phe
859095
<210> 394
<211> 96
<212> PRT
<213> Homo sapiens
<220>
<223> Neurocan Link domain 2
<400> 394
Glu Val Phe Tyr Val Gly Pro Ala Arg Arg Leu Thr Leu Ala Gly Ala
151015
Arg Ala Gln Cys Arg Arg Gln Gly Ala Ala Leu Ala Ser Val Gly Gln
202530
Leu His Leu Ala Trp His Glu Gly Leu Asp Gln Cys Asp Pro Gly Trp
354045
Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Gln Thr Pro Arg Arg Arg
505560
Cys Gly Gly Pro Ala Pro Gly Val Arg Thr Val Tyr Arg Phe Ala Asn
65707580
Arg Thr Gly Phe Pro Ser Pro Ala Glu Arg Phe Asp Ala Tyr Cys Phe
859095
<210> 395
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HAS1 Forward primer
<400> 395
tacaaccaga agttcctggg20
<210> 396
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HAS1 Reverse primer
<400> 396
ctggaggtgt acttggtagc20
<210> 397
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> HAS2 forward primer
<400> 397
gtatcagttt ggtttacaat c21
<210> 398
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> HAS2 reverse primer
<400> 398
gcaccatgtc atattgttgt c21
<210> 399
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HAS3 forward primer
<400> 399
cttaagggtt gcttgcttgc20
<210> 400
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HAS3 reverse primer
<400> 400
gttcgtggga gatgaaggaa20
<210> 401
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HYAL1 forward primer
<400> 401
gtgctgccct atgtccagat20
<210> 402
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HYAL1 reverse primer
<400> 402
attttcccag ctcacccaga20
<210> 403
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> HYAL2 forward primer
<400> 403
tctaccattg gcgagagtg19
<210> 404
<211> 18
<212> DNA
<213> Artificial Sequence
<220>
<223> HYAL2 reverse primer
<400> 404
gcagccgtgt caggtaat18
<210> 405
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> GAPDH forward primer
<400> 405
tgcaccacca actgcttagc20
<210> 406
<211> 21
<212> DNA
<213> Artificial Sequence
<220>
<223> GAPDH reverse primer
<400> 406
ggcatggact gtggtcatga g21
<210> 407
<211> 277
<212> PRT
<213> Homo sapiens
<220>
<223> human TSG-6 preprotein Q144R
<220>
<221> SIGNAL
<222> (1)...(17)
<223> signal sequence
<400> 407
Met Ile Ile Leu Ile Tyr Leu Phe Leu Leu Leu Trp Glu Asp Thr Gln
151015
Gly Trp Gly Phe Lys Asp Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Arg Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Glu Asp Asn Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu Asp Asp Pro Gly Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Asp Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Ala Met Asp Pro Val Ser Lys Ser Ser Gln Gly
245250255
Lys Asn Thr Ser Thr Thr Ser Thr Gly Asn Lys Asn Phe Leu Ala Gly
260265270
Arg Phe Ser His Leu
275
<210> 408
<211> 277
<212> PRT
<213> Pan troglodytes
<220>
<223> chimpanzee TSG-6 protein
<400> 408
Met Ile Ile Leu Ile Tyr Leu Phe Leu Leu Leu Trp Glu Asp Thr Gln
151015
Gly Trp Gly Phe Lys Asp Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Arg Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Val Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Glu Asp Asn Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu Asp Asp Pro Gly Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Asp Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Ala Met Asp Pro Val Ser Lys Ser Ser Gln Gly
245250255
Lys Asn Thr Ser Thr Thr Ser Thr Gly Asn Lys Asn Phe Leu Ala Gly
260265270
Arg Phe Ser His Leu
275
<210> 409
<211> 277
<212> PRT
<213> Equus caballus
<220>
<223> horse TSG-6 protein
<400> 409
Met Ile Ile Leu Ile Tyr Val Leu Val Leu Leu Trp Glu Glu Ala His
151015
Gly Trp Gly Phe Lys Asn Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Gln Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Tyr Glu Gly Gly His
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Ile Phe Thr Asp Thr Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Asp Asp Asn Gln Val
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu Asp Asp Thr Gly Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Glu Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Ala Val Asp Pro Pro Ser Lys Pro Ser Gln Gly
245250255
Lys Asn Thr Ser Thr Thr Ser Thr Gly Asn Lys Ser Phe Leu Ala Pro
260265270
Ser Phe Thr His Leu
275
<210> 410
<211> 277
<212> PRT
<213> Canis lupis
<220>
<223> dog TSG-6 protein
<400> 410
Met Ile Ile Phe Ile Ser Leu Phe Val Leu Leu Trp Glu Glu Ala His
151015
Gly Trp Gly Phe Asn Asn Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Gln Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Arg Tyr Arg
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly Arg
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
657075 80
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Val Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Asp Asp Asn Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Val Lys Tyr Gly Gln Arg Val His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu Asp Asp Pro Ala Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Glu Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Ile Ala Val Asp Pro Leu Ser Lys Ser Ser Gln Gly
245250255
Lys Asn Thr Ser Thr Thr Ser Thr Gly Asn Lys Asn Phe Leu Ala Gly
260265270
Arg Phe Ser His Leu
275
<210> 411
<211> 275
<212> PRT
<213> Mus musculus
<220>
<223> mouse TSG-6 protein
<400> 411
Met Val Val Leu Leu Cys Leu Cys Val Leu Leu Trp Glu Glu Ala His
151015
Gly Trp Gly Phe Lys Asn Gly Ile Phe His Asn Ser Ile Trp Leu Glu
202530
Gln Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ala Gly Arg Tyr Lys
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly Arg
505560
Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys Arg
130135140
Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Asp Asp Asn Gln Val
145150155160
Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu Ser
165170175
Phe Leu Asp Phe Asp Leu Glu His Asp Pro Gly Cys Leu Ala Asp Tyr
180185190
Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly Arg
195200205
Tyr Cys Gly Asp Glu Leu Pro Glu Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Lys Tyr Val Thr Val Asp Pro Ala Ser Lys Ser Ser Gln Ala
245250255
Lys Asn Thr Ser Thr Thr Gly Asn Lys Lys Phe Leu Pro Gly Arg Phe
260265270
Ser His Leu
275
<210> 412
<211> 275
<212> PRT
<213> Gallus gallus
<220>
<223> chicken TSG-6 protein
<400> 412
Met Ile Ala Leu Ile Phe Phe Ser Ala Leu Leu Trp Asp Glu Ala Gln
151015
Ala Trp Gly Phe Lys Asp Gly Val Leu His Asn Ser Ile Trp Leu Glu
202530
Arg Ala Ala Gly Val Tyr His Arg Glu Ser Arg Ser Gly Lys Tyr Gln
354045
Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Tyr Glu Gly Gly His
505560
Leu Ala Thr Tyr Gln Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Ala Gly Ala Asn Cys Gly Phe Gly Arg Thr Gly Ile Val Asp
100105110
Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro Asn Gly Lys Glu Cys Gly Gly Val Phe Thr Asp Ser Lys His
130135140
Val Phe Lys Ser Pro Gly Tyr Pro Asn Glu Tyr Glu Asn Asp Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Val Lys Tyr Gly Gln Arg Ile His Leu Gln
165170175
Phe Leu Glu Phe Asp Val Glu Asp Asp Thr Ala Cys Met Ala Asp Tyr
180185190
Leu Glu Ile Tyr Asp Ser Tyr Asp Asp Ile Asn Gly Phe Val Gly Arg
195200205
Phe Cys Gly Asp Glu Leu Pro Asp Asp Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly Phe
225230235240
Gln Ile Arg Tyr Val Thr Ile Asp Leu Pro Ser Lys Ala Gly Asp Gly
245250255
Lys Asn Thr Thr Ser Gln Gly Lys Ala Asn Phe Leu Ser Gly Lys Phe
260265270
Gly Ile Met
275
<210> 413
<211> 266
<212> PRT
<213> Xenopus laevis
<220>
<223> African clawed frog TSG-6 protein
<400> 413
Met Lys Thr Met Ile Phe Leu Val Leu Val Phe Leu Asp Glu Thr Phe
151015
Gly Trp Gly Phe Lys Asn Gly Val Leu His Asn Ser Ile Trp Leu Glu
202530
Gln Ala Ala Gly Val Tyr His Arg Glu Ser Arg Asn Gly Lys Tyr Lys
354045
Leu Thr Tyr Arg Glu Ala Lys Ala Val Cys Glu Tyr Glu Gly Gly Arg
505560
Leu Ala Thr Tyr Glu Gln Leu Glu Ala Ala Arg Gln Ile Gly Phe His
65707580
Val Cys Ala Ala Gly Trp Leu His Lys Gly Arg Val Gly Tyr Pro Ile
859095
Val Lys Pro Thr Phe Asn Cys Gly Phe Gly Lys Lys Gly Ile Ile Asp
100105110
Tyr Gly Phe Arg Leu Asn Lys Ser Glu Arg Trp Asp Ala Tyr Cys Tyr
115120125
Asn Pro His Ala Lys Glu Cys Gly Gly Val Leu Thr Glu Gln Glu Arg
130135140
Ile Ile Lys Ser Pro Gly Tyr Pro Asp His Tyr Glu Asn Asp Gln Ile
145150155160
Cys Tyr Trp His Ile Arg Val Asn Tyr Gly Gln Arg Ile Phe Ile Glu
165170175
Phe Leu Asp Leu Asp Ile Glu Glu Asp Ile Asp Cys Leu Ser Asp Tyr
180185190
Phe Glu Ile Tyr Asp Ser Tyr Asp Asp Leu His Gly Leu Val Gly Arg
195200205
Tyr Cys Gly Tyr Glu Leu Pro Asp Arg Ile Ile Ser Thr Gly Asn Val
210215220
Met Thr Leu Lys Phe Leu Ser Asp Gly Ser Val Ile Gly Gly Gly Phe
225230235240
Gln Ile Lys Tyr Thr Ala Val Asp Ser Glu Arg Asn Glu Thr Asn Ala
245250255
Ser Ser Glu Pro Tyr Asn Glu Phe Glu Tyr
260265
<210> 414
<211> 271
<212> PRT
<213> Danio rerio
<220>
<223> zebrafish TSG-6 protein
<400> 414
Met Ser His Cys Gly Leu Arg Ala Met Arg Ala Leu Thr Ala Val Phe
151015
Gly Val Leu Ile Val Leu Lys Glu Thr Glu Ala Trp Gly Tyr Lys Asn
202530
Gly Ile Leu His Asn Ser Ile Trp Leu Glu Gln Ala Ala Gly Val Tyr
354045
His Arg Glu Ser Arg Lys Gly Arg Tyr Gln Leu Thr Tyr Lys Glu Ala
505560
Lys Ala Val Cys Asn Phe Glu Gly Gly Thr Leu Ala Thr Phe Asp Gln
65 707580
Leu Glu Ala Ala Arg Gln Ile Gly Phe His Val Cys Ala Ala Gly Trp
859095
Leu Asp Lys Gly Arg Val Gly Tyr Pro Ile Val Lys Ala Gly Ser Asn
100105110
Cys Gly Phe Gly Lys Val Gly Ile Ile Asp Tyr Gly Tyr Arg Leu Asn
115120125
Lys Ser Glu Arg Trp Asp Val Tyr Cys Tyr Asn Pro Val Ala Lys Glu
130135140
Cys Gly Gly Val His Thr Asp Pro Glu Lys Val Leu Val Ser Pro Gly
145150155160
Tyr Pro Asp Glu Tyr Gln Asp Glu Gln Ile Cys Tyr Trp His Ile Arg
165170175
Val Arg Phe Gly His Arg Ile Arg Leu His Phe Leu Asp Phe Asp Ile
180185190
Glu Glu Asp Thr Asp Cys Leu Ser Asp His Leu Glu Ile Tyr Asp Ser
195200205
Tyr Asp Asp Val Ser Gly Phe Val Gly Arg Tyr Cys Gly Asp Gln Leu
210215220
Pro Asp Asp Phe Ile Ser Thr Gly Asn Val Met Thr Leu Lys Phe Leu
225230235240
Ser Asp Ser Ser Val Thr Ala Gly Gly Phe Lys Leu Gln Tyr Ile Ser
245250255
Val Asn Ser Ser Gln Leu Phe Asp Leu Leu Ala Asp Ser Phe Ser
260265270
<210> 415
<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> V5 tag
<400> 415
Gly Lys Pro Ile Pro Asn Pro Leu Leu Gly Leu Asp Ser Thr
1510
<210> 416
<211> 95
<212> PRT
<213> Homo sapiens
<220>
<223> TSG-6 link domain aa 35-129 variant K21A/K35A/K42A
<400> 416
Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys Leu Thr
151015
Tyr Ala Glu Ala Ala Ala Val Cys Glu Phe Glu Gly Gly His Leu Ala
202530
Thr Tyr Ala Gln Leu Glu Ala Ala Arg Ala Ile Gly Phe His Val Cys
354045
Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile Val Lys
505560
Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp Tyr Gly
65707580
Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr Asn
859095
<210> 417
<211> 94
<212> PRT
<213> Homo sapeins
<220>
<223> TSG-6 link domain aa 36-129
<400> 417
Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys Leu Thr Tyr
151015
Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His Leu Ala Thr
202530
Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His Val Cys Ala
354045
Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile Val Lys Pro
505560
Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp Tyr Gly Ile
65707580
Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr Asn
8590
<210> 418
<211> 97
<212> PRT
<213> Homo sapiens
<220>
<223> TSG-6 link domain aa 36-132
<400> 418
Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr Lys Leu Thr Tyr
151015
Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly His Leu Ala Thr
202530
Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe His Val Cys Ala
354045
Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro Ile Val Lys Pro
505560
Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile Asp Tyr Gly Ile
65707580
Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys Tyr Asn Pro His
859095
Ala
<210> 419
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> c-myc Tag
<400> 419
Glu Gln Lys Leu Ile Ser Glu Glu Asp Leu
1510
<210> 420
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> Hemagglutinin tag
<400> 420
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala
15
<210> 421
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> VSV-G Tag
<400> 421
Tyr Thr Asp Ile Glu Met Asn Arg Leu Gly Lys
1510
<210> 422
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> HSV Tag
<400> 422
Gln Pro Glu Leu Ala Pro Glu Asp Pro Glu Asp
1510
<210> 423
<211> 308
<212> PRT
<213> Homo sapiens
<220>
<223> Aggrecan G1 domain
<400> 423
Thr Ser Leu Thr Ile Pro Cys Tyr Phe Ile Asp Pro Met His Pro Val
151015
Thr Thr Ala Pro Ser Thr Ala Pro Leu Ala Pro Arg Ile Lys Trp Ser
202530
Arg Val Ser Lys Glu Lys Glu Val Val Leu Leu Val Ala Thr Glu Gly
354045
Arg Val Arg Val Asn Ser Ala Tyr Gln Asp Lys Val Ser Leu Pro Asn
505560
Tyr Pro Ala Ile Pro Ser Asp Ala Thr Leu Glu Val Gln Ser Leu Arg
65707580
Ser Asn Asp Ser Gly Val Tyr Arg Cys Glu Val Met His Gly Ile Glu
859095
Asp Ser Glu Ala Thr Leu Glu Val Val Val Lys Gly Ile Val Phe His
100105110
Tyr Arg Ala Ile Ser Thr Arg Tyr Thr Leu Asp Phe Asp Arg Ala Gln
115120125
Arg Ala Cys Leu Gln Asn Ser Ala Ile Ile Ala Thr Pro Glu Gln Leu
130135140
Gln Ala Ala Tyr Glu Asp Gly Phe His Gln Cys Asp Ala Gly Trp Leu
145150155160
Ala Asp Gln Thr Val Arg Tyr Pro Ile His Thr Pro Arg Glu Gly Cys
165170175
Tyr Gly Asp Lys Asp Glu Phe Pro Gly Val Arg Thr Tyr Gly Ile Arg
180185190
Asp Thr Asn Glu Thr Tyr Asp Val Tyr Cys Phe Ala Glu Glu Met Glu
195200205
Gly Glu Val Phe Tyr Ala Thr Ser Pro Glu Lys Phe Thr Phe Gln Glu
210215220
Ala Ala Asn Glu Cys Arg Arg Leu Gly Ala Arg Leu Ala Thr Thr Gly
225230235240
Gln Leu Tyr Leu Ala Trp Gln Ala Gly Met Asp Met Cys Ser Ala Gly
245250255
Trp Leu Ala Asp Arg Ser Val Arg Tyr Pro Ile Ser Lys Ala Arg Pro
260265270
Asn Cys Gly Gly Asn Leu Leu Gly Val Arg Thr Val Tyr Val His Ala
275280285
Asn Gln Thr Gly Tyr Pro Asp Pro Ser Ser Arg Tyr Asp Ala Ile Cys
290295300
Tyr Thr Gly Glu
305
<210> 424
<211> 306
<212> PRT
<213> Homo sapiens
<220>
<223> Bervican G1 domain
<400> 424
Gly Ala Leu Thr Ile Pro Cys His Val His Tyr Leu Arg Pro Pro Pro
151015
Ser Arg Arg Ala Val Leu Gly Ser Pro Arg Val Lys Trp Thr Phe Leu
202530
Ser Arg Gly Arg Glu Ala Glu Val Leu Val Ala Arg Gly Val Arg Val
354045
Lys Val Asn Glu Ala Tyr Arg Phe Arg Val Ala Leu Pro Ala Tyr Pro
505560
Ala Ser Leu Thr Asp Val Ser Leu Ala Leu Ser Glu Leu Arg Pro Asn
65707580
Asp Ser Gly Ile Tyr Arg Cys Glu Val Gln His Gly Ile Asp Asp Ser
859095
Ser Asp Ala Val Glu Val Lys Val Lys Gly Val Val Phe Leu Tyr Arg
100105110
Glu Gly Ser Ala Arg Tyr Ala Phe Ser Phe Ser Gly Ala Gln Glu Ala
115120125
Cys Ala Arg Ile Gly Ala His Ile Ala Thr Pro Glu Gln Leu Tyr Ala
130135140
Ala Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp
145150155160
Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro Arg Glu Ala Cys Tyr Gly
165170 175
Asp Met Asp Gly Phe Pro Gly Val Arg Asn Tyr Gly Val Val Asp Pro
180185190
Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Asp Leu Asn Gly Glu
195200205
Leu Phe Leu Gly Asp Pro Pro Glu Lys Leu Thr Leu Glu Glu Ala Arg
210215220
Ala Tyr Cys Gln Glu Arg Gly Ala Glu Ile Ala Thr Thr Gly Gln Leu
225230235240
Tyr Ala Ala Trp Asp Gly Gly Leu Asp His Cys Ser Pro Gly Trp Leu
245250255
Ala Asp Gly Ser Val Arg Tyr Pro Ile Val Thr Pro Ser Gln Arg Cys
260265270
Gly Gly Gly Leu Pro Gly Val Lys Thr Leu Phe Leu Phe Pro Asn Gln
275280285
Thr Gly Phe Pro Asn Lys His Ser Arg Phe Asn Val Tyr Cys Phe Arg
290295300
Asp Ser
305
<210> 425
<211> 312
<212> PRT
<213> Homo sapiens
<220>
<223> Versican G1 domain
<400> 425
Gly Lys Val Ser Leu Pro Cys His Phe Ser Thr Met Pro Thr Leu Pro
151015
Pro Ser Tyr Asn Thr Ser Glu Phe Leu Arg Ile Lys Trp Ser Lys Ile
202530
Glu Val Asp Lys Asn Gly Lys Asp Leu Lys Glu Thr Thr Val Leu Val
354045
Ala Gln Asn Gly Asn Ile Lys Ile Gly Gln Asp Tyr Lys Gly Arg Val
505560
Ser Val Pro Thr His Pro Glu Ala Val Gly Asp Ala Ser Leu Thr Val
657075 80
Val Lys Leu Leu Ala Ser Asp Ala Gly Leu Tyr Arg Cys Asp Val Met
859095
Tyr Gly Ile Glu Asp Thr Gln Asp Thr Val Ser Leu Thr Val Asp Gly
100105110
Val Val Phe His Tyr Arg Ala Ala Thr Ser Arg Tyr Thr Leu Asn Phe
115120125
Glu Ala Ala Gln Lys Ala Cys Leu Asp Val Gly Ala Val Ile Ala Thr
130135140
Pro Glu Gln Leu Phe Ala Ala Tyr Glu Asp Gly Phe Glu Gln Cys Asp
145150155160
Ala Gly Trp Leu Ala Asp Gln Thr Val Arg Tyr Pro Ile Arg Ala Pro
165170175
Arg Val Gly Cys Tyr Gly Asp Lys Met Gly Lys Ala Gly Val Arg Thr
180185190
Tyr Gly Phe Arg Ser Pro Gln Glu Thr Tyr Asp Val Tyr Cys Tyr Val
195200205
Asp His Leu Asp Gly Asp Val Phe His Leu Thr Val Pro Ser Lys Phe
210215220
Thr Phe Glu Glu Ala Ala Lys Glu Cys Glu Asn Gln Asp Ala Arg Leu
225230235240
Ala Thr Val Gly Glu Leu Gln Ala Ala Trp Arg Asn Gly Phe Asp Gln
245250255
Cys Asp Tyr Gly Trp Leu Ser Asp Ala Ser Val Arg His Pro Val Thr
260265270
Val Ala Arg Ala Gln Cys Gly Gly Gly Leu Leu Gly Val Arg Thr Leu
275280285
Tyr Arg Phe Glu Asn Gln Thr Gly Phe Pro Pro Pro Asp Ser Arg Phe
290295300
Asp Ala Tyr Cys Phe Lys Pro Lys
305310
<210> 426
<211> 307
<212> PRT
<213> Homo sapiens
<220>
<223> Neurocan G1 domain
<400> 426
Glu Leu Val Ala Leu Pro Cys Leu Phe Thr Leu Gln Pro Arg Pro Ser
151015
Ala Ala Arg Asp Ala Pro Arg Ile Lys Trp Thr Lys Val Arg Thr Ala
202530
Ser Gly Gln Arg Gln Asp Leu Pro Ile Leu Val Ala Lys Asp Asn Val
354045
Val Arg Val Ala Lys Ser Trp Gln Gly Arg Val Ser Leu Pro Ser Tyr
505560
Pro Arg Arg Arg Ala Asn Ala Thr Leu Leu Leu Gly Pro Leu Arg Ala
65707580
Ser Asp Ser Gly Leu Tyr Arg Cys Gln Val Val Arg Gly Ile Glu Asp
859095
Glu Gln Asp Leu Val Pro Leu Glu Val Thr Gly Val Val Phe His Tyr
100105110
Arg Ser Ala Arg Asp Arg Tyr Ala Leu Thr Phe Ala Glu Ala Gln Glu
115120125
Ala Cys Arg Leu Ser Ser Ala Ile Ile Ala Ala Pro Arg His Leu Gln
130135140
Ala Ala Phe Glu Asp Gly Phe Asp Asn Cys Asp Ala Gly Trp Leu Ser
145150155160
Asp Arg Thr Val Arg Tyr Pro Ile Thr Gln Ser Arg Pro Gly Cys Tyr
165170175
Gly Asp Arg Ser Ser Leu Pro Gly Val Arg Ser Tyr Gly Arg Arg Asn
180185190
Pro Gln Glu Leu Tyr Asp Val Tyr Cys Phe Ala Arg Glu Leu Gly Gly
195200205
Glu Val Phe Tyr Val Gly Pro Ala Arg Arg Leu Thr Leu Ala Gly Ala
210215220
Arg Ala Gln Cys Arg Arg Gln Gly Ala Ala Leu Ala Ser Val Gly Gln
225230235240
Leu His Leu Ala Trp His Glu Gly Leu Asp Gln Cys Asp Pro Gly Trp
245250255
Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile Gln Thr Pro Arg Arg Arg
260265270
Cys Gly Gly Pro Ala Pro Gly Val Arg Thr Val Tyr Arg Phe Ala Asn
275280285
Arg Thr Gly Phe Pro Ser Pro Ala Glu Arg Phe Asp Ala Tyr Cys Phe
290295300
Arg Ala His
305

Claims (61)

1.一种TSG-6-连接模块(LM)多聚体，其包含：
第一多肽，其包含直接或通过接头间接连接至第一多聚化结构域的TSG-6LM；以及
第二多肽，其包含直接或通过接头间接连接至第二多聚化结构域的TSG-6连接模块，
其中所述第一和第二多聚化结构域相互作用以形成包含两个或更多个TSG-6连接模块的多聚体；
所述第一和第二多肽不包含TSG-6的全长序列；并且
所述TSG-6多聚体对乙酰透明质酸(HA)具有结合亲和力，其结合常数为至少107M-1。
2.权利要求1的TSG-6-LM多聚体，其中所述连接模块是所述第一多肽和所述第二多肽的唯一TSG-6部分。
3.权利要求1或2的TSG-6多聚体，其中所述第一和第二连接模块相同或不同。
4.权利要求1或2的TSG-6多聚体，其中所述连接模块由SEQ ID NO:207、360、417或418所示的氨基酸序列组成。
5.权利要求1的TSG-6多聚体，其中修饰所述TSG-6连接模块以减少或消除对肝素的结合。
6.权利要求5的TSG-6多聚体，其中对肝素的结合减少至少1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。
7.权利要求1的TSG-6多聚体，其中所述TSG-6连接模块在对应于SEQ ID NO:360所示的氨基酸残基20、34、41、54、56、72或84的氨基酸位置处包含氨基酸置换，其中通过与SEQ IDNO:360所示的TSG-6-LM比对来鉴定相应的氨基酸残基。
8.权利要求7的TSG-6多聚体，其中所述氨基酸置换是置换为选自以下的非碱性氨基酸残基：Asp(D)、Glu(E)、Ser(S)、Thr(T)、Asn(N)、Gln(Q)、Ala(A)、Val(V)、Ile(I)、Leu(L)、Met(M)、Phe(F)、Tyr(Y)和Trp(W)。
9.权利要求8的TSG-6多聚体，其中所述TSG-6连接模块包含对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A或K41A的氨基酸置换。
10.权利要求9的TSG-6多聚体，其中所述TSG-6连接模块包含对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A和K41A的氨基酸置换。
11.权利要求10的TSG-6多聚体，其中所述连接模块由SEQ ID NO:361或416所示的氨基酸序列组成。
12.权利要求1的TSG-6多聚体，其中所述多聚化结构域选自免疫球蛋白恒定区(Fc)、亮氨酸拉链、互补疏水区、互补亲水区、相容的蛋白-蛋白相互作用结构域、在两个分子之间形成分子间二硫键的游离硫醇以及形成稳定多聚体的相同或相似大小的突起成腔和补偿腔。
13.权利要求12的TSG-6多聚体，其中所述多聚化结构域为Fc结构域或其实现多聚化的变体。
14.权利要求1的TSG-6多聚体，其中所述第一和第二多肽包含TSG-6连接模块和免疫球蛋白Fc结构域。
15.权利要求14的TSG-6多聚体，其包含SEQ ID NO:212或215的氨基酸24-349所示的氨基酸序列，或者包含表现出与SEQ ID NO:212或215的氨基酸24-349至少85％氨基酸序列相同性的氨基酸序列。
16.权利要求14的TSG-6多聚体，其中所述TSG-6多聚体包含SEQ ID NO:211、214或217中任一个所示的核苷酸序列编码的氨基酸序列，或者包含表现出与SEQ ID NO:211、214或217中任一个所示的核苷酸序列至少85％序列相同性的核苷酸序列编码的氨基酸序列。
17.权利要求1的TSG-6多聚体，其对HA的结合亲和力具有至少1x108M-1的结合常数(Ka)。
18.一种核酸分子，其编码权利要求1-17中任一项的TSG-6多聚体，其中
所述核酸分子编码融合多肽，所述融合多肽包含直接或通过接头间接连接至多聚化结构域的TSG-6连接模块；并且
所述多聚化结构域为自身相互作用以形成稳定的蛋白-蛋白相互作用的多肽，由此编码的蛋白形成包含至少两个TSG-6连接模块的多聚体。
19.权利要求18的核酸分子，其由SEQ ID NO:211、214或217中任一个所示的核苷酸序列组成。
20.一种载体，其包含权利要求18的核酸分子。
21.一种分离的细胞或细胞培养物，其包含权利要求18的核酸分子。
22.一种制备TSG-6多聚体的方法，其包括：
将权利要求18的核酸分子引入细胞；
将所述细胞在所述细胞表达融合多肽的条件下进行培养；以及
回收所述TSG-6多聚体。
23.一种试剂盒或组合，其包含：
权利要求1-17中任一项的TSG-6多聚体；以及
抗乙酰透明质酸剂。
24.权利要求23的试剂盒或组合，其还包含用于检测TSG-6多聚体的试剂。
25.权利要求23的试剂盒或组合，其中所述抗乙酰透明质酸剂为乙酰透明质酸降解酶或抑制乙酰透明质酸合成的物质。
26.权利要求25的试剂盒或组合，其中所述抗乙酰透明质酸剂为乙酰透明质酸降解酶。
27.权利要求26的试剂盒或组合，其中所述乙酰透明质酸降解酶为透明质酸酶。
28.权利要求27的试剂盒或组合，其中所述乙酰透明质酸降解酶为PH20透明质酸酶或者其缺少C-末端糖基磷脂酰肌醇(GPI)粘附位点或一部分GPI粘附位点的截短形式。
29.权利要求28的试剂盒或组合，其中所述PH20或其截短形式包含SEQ ID NO:4-9、47、48、150-170和183-189中任一个所示的氨基酸序列。
30.权利要求23的试剂盒或组合，其中所述抗乙酰透明质酸剂为通过缀合至聚合物而进行修饰的乙酰透明质酸降解酶。
31.权利要求30的试剂盒或组合，其中所述聚合物为PEG，并且所述乙酰透明质酸降解酶是聚乙二醇化的。
32.权利要求1-17中任一项的TSG-6-LM多聚体在制备用于选择用抗乙酰透明质酸剂治疗肿瘤的对象的组合物中的用途。
33.权利要求1-17中任一项的TSG-6-LM多聚体在制备用于预测用抗乙酰透明质酸剂治疗对象的效力的组合物中的用途。
34.权利要求1-17中任一项的TSG-6-LM多聚体在制备用于根据包括以下的方法来选择用抗乙酰透明质酸剂治疗肿瘤的对象的组合物中的用途：
使之前获得自患有肿瘤或癌症的对象的组织或体液样品与所述组合物接触；以及
检测所述乙酰透明质酸结合蛋白对所述样品的结合，从而确定所述样品中乙酰透明质酸的量，其中如果所述样品中乙酰透明质酸的量为或高于预定的阈值水平，则选择所述对象用抗乙酰透明质酸剂进行治疗。
35.权利要求1-17中任一项的TSG-6-LM多聚体在制备用于根据包括以下的方法来预测用抗乙酰透明质酸剂治疗对象的效力的组合物中的用途：
使之前获得自正在或已经用抗乙酰透明质酸剂治疗的对象的组织或体液样品与所述组合物接触，其中所述HABP不是制备自或分离自动物软骨；
检测所述乙酰透明质酸结合蛋白对所述样品的结合，从而确定所述样品中乙酰透明质酸的量，其中与用所述抗乙酰透明质酸剂治疗或所述抗乙酰透明质酸剂上次的剂量之前相比检测到乙酰透明质酸的减少表明治疗是有效的。
36.权利要求1-17中任一项的TSG-6-LM多聚体在制备用于根据包括以下的方法来诊断乙酰透明质酸相关疾病或疾病状况的组合物中的用途：
使之前获得自对象的组织或体液样品与所述组合物接触；以及
检测所述TSG-6-LM多聚体对所述样品的结合，从而确定所述样品中乙酰透明质酸的量，其中如果所述乙酰透明质酸的量高于预定水平或高于参考样品的乙酰透明质酸水平，则诊断所述对象患有乙酰透明质酸相关疾病或疾病状况。
37.权利要求34的用途，其中来自所述对象的样品包含高HA。
38.权利要求34的用途，其中：
所述样品中HA的预定水平或量为至少或高于0.025μg HA/ml样品、0.030μg/ml、0.035μg/ml、0.040μg/ml、0.045μg/ml、0.050μg/ml、0.055μg/ml、0.060μg/ml、0.065μg/ml、0.070μg/ml、0.08μg/ml、0.09μg/ml、0.1μg/ml、0.2μg/ml、0.3μg/ml或更高；或者
所述样品为肿瘤组织样品，并且所述预定水平为至少+2(HA+2)或至少+3(HA+3)的HA评分；或者
所述样品为肿瘤组织样品，并且所述预定水平是至少肿瘤(细胞和基质)中HA阳性像素比肿瘤组织中总染色的百分比为至少10％、10％-25％或大于25％。
39.权利要求38的用途，其中所述预定的阈值水平为至少+3(HA+3)的HA评分(高水平)。
40.权利要求35的用途，其中所述乙酰透明质酸相关疾病或疾病状况为肿瘤或癌症。
41.权利要求32-36中任一项的用途，其中修饰所述TSG-6连接模块以减少或消除对肝素的结合。
42.权利要求32-36中任一项的用途，其中
所述TSG-6-LM多聚体的多聚化结构域为Fc；并且
所述TSG-6-LM-Fc由SEQ ID NO:212或215的氨基酸24-349所示的氨基酸序列组成。
43.权利要求32-36中任一项的用途，其中
所述TSG-6-LM多聚体的多聚化结构域为Fc；并且
所述TSG-6-LM-Fc由SEQ ID NO:211、214或217中任一个所示的核苷酸序列编码的氨基酸序列组成。
44.权利要求32-35中任一项的用途，其中所述抗乙酰透明质酸剂为乙酰透明质酸降解酶或抑制乙酰透明质酸合成的物质。
45.权利要求44的用途，其中所述抗乙酰透明质酸剂为乙酰透明质酸降解酶。
46.权利要求45的用途，其中所述乙酰透明质酸降解酶为透明质酸酶。
47.权利要求46的用途，其中所述乙酰透明质酸降解酶为PH20透明质酸酶或者其缺少C-末端糖基磷脂酰肌醇(GPI)粘附位点或一部分GPI粘附位点的截短形式。
48.权利要求47的用途，其中所述PH20或其截短形式包含SEQ ID NO:4-9、47、48、150-170和183-189中任一个所示的氨基酸序列，或者包含表现出与SEQ ID NO:4-9、47、48、150-170和183-189中任一个的至少85％序列相同性的氨基酸序列。
49.权利要求44-48中任一项的用途，其中所述抗乙酰透明质酸剂为通过缀合至聚合物而进行修饰的乙酰透明质酸降解酶。
50.权利要求49的用途，其中所述聚合物为PEG，并且所述乙酰透明质酸降解酶是聚乙二醇化的。
51.权利要求36的用途，其中所述预定或参考水平是来自对照对象群体的健康或正常组织或流体样品中存在的乙酰透明质酸的中值水平。
52.权利要求36的用途，其中：
所述预定的阈值水平大于0.015μg HA/ml样品；或者
所述样品是肿瘤组织样品，并且所述预定的阈值水平为HA+1、HA+2或HA+3的HA评分。
53.权利要求41的用途，其中对肝素的结合减少至少1.2倍、1.5倍、2倍、3倍、4倍、5倍、6倍、7倍、8倍、9倍、10倍、20倍、30倍、40倍、50倍、100倍或更多倍。
54.权利要求41的用途，其中TSG-6连接模块包含选自对应于SEQ ID NO:360所示的TSG-6-LM中氨基酸置换K20A、K34A和K41A的氨基酸置换，或者在另一TSG-6-LM中相应残基处的置换。
55.权利要求34-36中任一项的用途，其中所述TSG-6-LM多聚体以具有至少低于或低于1x10-7M的解离常数(Kd)的结合亲和力特异性结合HA。
56.权利要求34-36中任一项的用途，其中所述TSG-6-LM多聚体缀合至可检测地标记或可以被检测的可检测部分。
57.权利要求34-36中任一项的用途，其中
所述样品为基质组织样品；或者
所述样品为流体样品，所述流体样品为血液、血清、尿、汗液、精液、唾液、脑脊液或淋巴样品。
58.权利要求34-36中任一项的用途，其中所述样品为来自肿瘤的基质组织样品。
59.权利要求34-36中任一项的用途，其中所述肿瘤为选自以下的癌症：乳腺癌、胰腺癌、卵巢癌、结肠癌、肺癌、非小细胞肺癌、原位癌(ISC)、鳞状细胞癌(SCC)、甲状腺癌、子宫颈癌、子宫癌、前列腺癌、睾丸癌、脑癌、膀胱癌、胃癌、肝癌、黑素瘤、神经胶质瘤、视网膜母细胞瘤、间皮瘤、骨髓瘤、淋巴瘤和白血病。
60.权利要求34-36中任一项的用途，其中所述肿瘤为癌症，所述癌症为晚期癌症、转移癌症和未分化的癌症。
61.权利要求34-36中任一项的用途，其中通过固相结合测定、组织化学或体内成像检测乙酰透明质酸。
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US9458442B2 (en) 2016-10-04
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BR112014009797A2 (pt) 2020-10-27
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US20150218544A9 (en) 2015-08-06
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