CN107207577A - 用于治疗和预防炎症的组合物和方法 - Google Patents

用于治疗和预防炎症的组合物和方法 Download PDF

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CN107207577A
CN107207577A CN201580058020.7A CN201580058020A CN107207577A CN 107207577 A CN107207577 A CN 107207577A CN 201580058020 A CN201580058020 A CN 201580058020A CN 107207577 A CN107207577 A CN 107207577A
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普热梅斯瓦夫·萨皮哈
诺曼德·比利
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Abstract

本发明提供用于通过抑制NRP1依赖性细胞信号传导(i)治疗或预防炎症；和(ii)预防或降低先天免疫反应超活化的新型化合物组合物和方法。还提供了特异性抑制SEMA3A介导的细胞信号传导的化合物、组合物、和方法。

Description

用于治疗和预防炎症的组合物和方法
相关申请的交叉引用
本申请要求2014年9月5日提交的美国临时申请序列号US 62/046,459的优先权，其通过引用其全部内容而并入于此。
序列表
本申请包含计算机可读形式的序列表，标题为“12810_513_ST25”，创建于2015年9月8日，大小为580K字节。计算机可读形式通过引用并入本文。
关于联邦政府资助研究或开发的声明
不适用。
发明领域
本发明涉及炎症。更具体地，本发明涉及抑制NRP1途径用于预防或治疗炎症。
参考序列表
不适用
发明背景
局部急性炎症反应主要是有益的，并且构成机体抵抗宿主感染的第一道防线。相反，急性全身性炎症如感染性休克是发病和死亡的主要原因(58)。当慢性、低级别炎症持续时，其可以是几种全身性疾病——范围为II型糖尿病、关节炎、癌症、多种神经炎性状况等——的根源。
在所有细胞因子、受体和被认为有助于炎性过程的其它参与者中，一个已被大大忽略的范例是经典神经元导向因子(neuronal guidance cue)及其受体的影响。这些包括脑信号蛋白(semaphorin)3A(SEMA3A，例如mRNA：NM_006080；和蛋白质：NP_006071和图21)及其受体神经毡蛋白-1(NRP1，例如mRNA：NM_001024628；和蛋白质：NP_001019799，NM_003873和图22(同种型2或b，分泌的)和26(同种型1)。NRP1在淋巴和骨髓细胞上表达(59,31)。然而其在炎症中的作用在很大程度上是未知的，特别是在细胞因子产生的情况下。
脑信号蛋白最初被表征为胚胎形成期间轴突导向(axonal guidance)中的关键参与者。现在清楚的是，脑信号蛋白的作用延伸超过轴突导向并影响血管系统、肿瘤生长和免疫应答。脑信号蛋白家族总数至少21个脊椎动物基因和8个额外的无脊椎动物中的基因。所有脑信号蛋白都含有用于发信号所需的～500个氨基酸SEMA结构域。3型(class 3)脑信号蛋白(如SEMA3A)是家族中唯一的分泌成员。SEMA3A作为二硫键连接的同型二聚体而被合成，而二聚化对于发信号是必需的。
在神经元中，SEMA3A与其同源受体(cognate receptor，关联受体)神经毡蛋白-1(NRP1)的结合通过丛蛋白(plexin)引起细胞骨架塌陷(60)；内皮细胞中的转导机制仍然不清楚。NRP1具有通过其胞外结构域上的不同位位点结合两种结构不同的配体的特定能力(27-29)。它不仅结合引起细胞骨架塌陷的SEMA3A(46,47)，而且结合增强与VEGFR2的结合的VEGF165(28、29、47、61)并因此增加其血管生成潜力(62)。晶体学证据揭示VEGF165和SEMA3A不直接竞争NRP1，而是可以同时与NRP1在不同的、非重叠的位点结合(63)。此外，遗传研究表明NRP1明确调节VEGF和SEMA3A对神经元和血管发展的作用(64)。最后，还发现NRP1与TGF-β1结合并调节其潜伏形式。
NRP1是具有被细分为3个亚结构域(a1a2、b1b2和c)的大的860个氨基酸胞外结构域和短的40个氨基酸的胞内结构域(65)的单穿(single-pass，单通)跨膜受体。在神经元中，SEMA3A与NRP1的结合募集转导其胞内信号的丛蛋白(60)并引起细胞骨架塌陷。内皮细胞中的转导机制仍然不清楚。NRP1主要经由其a1a2(但也可能是b1-)结构域(引发细胞骨架塌陷)结合SEMA3A(46,47)和通过其b1b2结构域(增强与VEGFR2的结合)结合VEGF165(28,29,47,61)并因此增加其血管发生潜力(62)。因此，缺血性视网膜中SEMA3A的水平升高可通过使前进中的尖端细胞塌陷并使其脱离排斥指示(repellentcue)的来源而参与迫使新血管进入玻璃体(21)。
CNS长期以来被认为是免疫特权系统，但现在清楚的是，脑、视网膜和脊髓经历复杂的免疫监视(1，2)。CNS中的免疫活性主要依赖于先天免疫应答，并且在健康时存在而在疾病诸如糖尿病性视网膜病变、多发性硬化、肌萎缩性侧索硬化和阿尔茨海默病中升高。这在视网膜中是明显的，其中强化的、主要是基于小胶质细胞/巨噬细胞的免疫应答与若干视力威胁性疾病如糖尿病性视网膜病变(DR)(3-5)、年龄相关性黄斑变性(AMD)(6-8)和早产儿视网膜病变(ROP)(9,10)的发展相关。综上，这些视网膜疾病是造成工业化国家中失明的主要原因(6,11,12)。
许多炎性疾病和状况的当前治疗路线具有重大的副作用和缺乏的长期安全性。因此，仍然需要新颖的药物靶和治疗方法。
本说明书涉及多个文献，其内容通过引用整体并入本文。
发明内容
本发明人寻求确定骨髓驻留型(myeloid-resident，骨髓固有的)NRP1(骨髓-驻留型NRP1)在先天免疫反应的情况下的功能。
本发明人已经确定SEMA3A、VEGF和TGF-β充当表达NRP1受体的单核吞噬细胞(MP，例如，小胶质细胞和巨噬细胞)的有效引诱剂。显示在涉及包括增殖性视网膜病变、感染性休克和脑缺血/中风的先天免疫反应的超活化的各种状况下，先天免疫细胞中NRP1发信号的抑制导致保护免于MP依赖的炎症和组织损伤。此外，本发明人已经设计各种可溶性NRP1衍生的陷阱(trap)，其抑制SEMA3A发信号并显示SEMA3A的抑制显著地降低各种状况中的炎症反应。
因此，本发明涉及NRP1细胞信号转导(例如，NRP1和其配体)的抑制用以预防或治疗涉及先天免疫反应超活化(即，病理性活化)的炎性疾病和状况。此类疾病和状况的非限制性实例包含败血症、中风、脑缺血、和各种增殖性视网膜病变。
更具体地，在一方面，本发明涉及治疗或预防炎症的方法，其包括抑制NRP1依赖性细胞信号传导。
在另一方面，本发明涉及预防或降低先天免疫反应超活化的方法，包括抑制NRP1依赖性细胞信号传导。在一个实施方式中，先天免疫反应超活化包括i)IL-1β和TNFα的分泌和/或单核吞噬细胞(MP)的活化/募集。
在一个实施方式中，抑制NRP1依赖性细胞信号传导包括：a)降低NRP1表达或活性；和/或b)降低NRP1配体表达或活性。在一个实施方式中，NRP1配体是SEMA3A、VEGF165或TGF-β。在具体实施方式中，NRP1配体是SEMA3A。
在一个实施方式中，降低NRP1活性包括抑制NRP1与至少一种NRP1配体的结合。在一个实施方式中，抑制NRP1与至少一种NRP1配体的结合包括施用NRP1抗体(例如，SEMA3A抗体)。
在以上方法的另一实施方式中，降低NRP1活性包括施用有效量的NRP1陷阱，其包含可溶性NRP1多肽或其功能片段。在具体实施方式中，NRP1陷阱如图19或20所示。
在具体实施方式中，本发明的NRP1陷阱抑制SEMA3A与NPR-1结合但基本上不抑制VEGF与NRP1结合。在一个实施方式中，这样的NRP1陷阱包括NRP1的a1a2结构域但不包含NRP1的b1和/或b2亚域(一个或多个)。在另一实施方式中，这样的陷阱包括在对应于如图22中所示的NRP1氨基酸序列的酪氨酸297的位置处结构域b1中的突变，其降低或消除VEGF与陷阱结合。在具体的实施方式中，突变将位置297处的酪氨酸变为丙氨酸。
在具体的实施方式中，本发明的NRP1陷阱：a)包含NRP1的结构域a1、a2、b1、b2和c；b)包含NRP1的结构域a1、a2、b1和b2；c)包含NRP1的结构域a1、a2和b1；d)包含NRP1的结构域a1和a2；e)包含结构域b1，其中b1结构域包含对应于NRP1的酪氨酸297的氨基酸中的突变，其降低或消除与VEGF结合；f)包含结构域b1，其中b1结构域包含对应于NRP1的酪氨酸297的氨基酸中的突变，其将酪氨酸变为丙氨酸；g)不包含NRP1的结构域c；h)不包含NRP1的结构域b1；i)不包含NRP1的结构域b1和b2；或j)不包含NRP1的结构域b1、b2和c。
在以上方法的一个实施方式中，抑制NRP1配体表达或活性包括特异性抑制SEMA3A表达或SEMA3A与NRP1结合。在具体实施方式中，抑制SEMA3A与NRP1结合包括施用SEMA3A抗体。
在具体实施方式中，本发明的方法包括通过施用NRP1反义、shRNA或siRNA降低NRP1表达。
在另一实施方式中，方法包含通过施用SEMA3A反义、shRNA或siRNA降低SEMA3A表达。
在进一步的方面，本发明涉及用于预防或治疗炎症的化合物，其中化合物a)降低NRP1表达或活性；或b)降低NRP1配体表达或活性。
在另一方面，本发明涉及用于预防或降低先天免疫反应超活化的化合物，其中化合物a)降低NRP1表达或活性；或b)降低NRP1配体表达或活性。
在一个实施方式中，化合物是：i)SEMA3A抗体；ii)NRP1抗体；iii)NRP1陷阱；iv)SEMA3A反义、shRNA或siRNA；或v)NRP1反义、shRNA或siRNA。在另一特定实施方式中，化合物是NRP1抗体或NRP1陷阱，并且所述化合物基本上不降低VEGF与NRP1结合。
在具体实施方式中，化合物是NRP1陷阱。在一个实施方式中，NRP1陷阱如图19、20、27和表1中所示。
在另一实施方式中，本发明的NRP1陷阱抑制SEMA3A与NPR-1的结合，但基本上不抑制VEGF与NRP1的结合。在一个实施方式中，这样的NRP1陷阱包括NRP1的a1a2结构域，但不包括NRP1的b1和/或b2亚域(一个或多个)。在另一实施方式中，此陷阱包含如图22中所示的在对应于NRP1氨基酸序列的酪氨酸297的位置处结构域b1中的突变，其降低或消除VEGF与陷阱结合。在具体的实施方式中，突变将位置297处的酪氨酸变为丙氨酸。
在具体的实施方式中，本发明的NRP1陷阱：a)包含NRP1的结构域a1、a2、b1、b2和c；b)包含NRP1的结构域a1、a2、b1和b2；c)包含NRP1的结构域a1、a2和b1；d)包含NRP1的结构域a1和a2；e)包含结构域b1，其中b1结构域包含对应于NRP1的酪氨酸297的氨基酸中的突变，其降低或消除与VEGF的结合；f)包含结构域b1，其中b1结构域包含对应于NRP1的酪氨酸297的氨基酸中的突变，其将酪氨酸变为丙氨酸；g)不包含NRP1的结构域c；h)不包含NRP1的结构域b1；i)不包含NRP1的结构域b1和b2；或j)不包含NRP1的结构域b1、b2和c。
在一个实施方式中，本发明的NRP1陷阱包含：(i)图26中所示的NRP1多肽的氨基酸1-856(优选地，22至856)(SEQ ID NO：69)；(ii)图26中所示的NRP1多肽的氨基酸1至583(优选地22至583)(SEQ ID NO：69)；(iii)图26中所示的NRP1多肽的氨基酸1至424(优选地22-424)(SEQ ID NO：69)；(iv)图26中所示的NRP1多肽的氨基酸1至265(优选地22至265)(SEQID NO：69)；(v)图26中所示的NRP1多肽的1至430和584至856(优选地22-430和584-856)(SEQ ID NO：69)；(vi)图26中所示的NRP1多肽的氨基酸1至274和584至856(优选地22-274和584至856)(SEQ ID NO：69)；(vii)图26中所示的NRP1多肽的氨基酸1至430和584(优选地22至430和584至856)(SEQ ID NO：69)。在具体实施方式中，以上指出的陷阱包含一个或多个突变以降低VEGF或SEMA3A的结合，如上所述。
在另一方面，本发明提供用于i)治疗和预防炎症或ii)预防或降低先天免疫反应超活化的组合物，其包含本发明的一种或多种化合物连同药物载体(carrier，运载体)。
本发明也涉及本发明的一种或多种化合物在生产用于i)治疗和预防炎症或ii)预防或降低先天免疫反应超活化的药物中的应用。
在相关的方面，本发明涉及本发明的一种或多种化合物用于i)治疗和预防炎症或ii)预防或降低先天免疫反应超活化的应用。
在具体实施方式中，本发明的方法、化合物(例如，NRP1多肽陷阱、编码其的核酸、载体、包含载体的细胞等)、组合物和应用是用于治疗或预防选自以下的炎性疾病和状况：感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症(cutaneous skin inflammation)、糖尿病、葡萄膜炎(uveitis)、糖尿病性视网膜病变、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病或中风。
在一个实施方式中，本发明的方法、化合物、组合物和应用是用于治疗或预防感染性休克、脑缺血或中风。
更具体地，根据本发明，提供了以下项：
1.治疗或预防炎症的方法，包括抑制受试者中的NRP1依赖性细胞信号传导。
2.预防或降低先天免疫反应超活化的方法，包括抑制受试者中的NRP1依赖性细胞信号传导。
3.项2所述的方法，其中所述先天免疫反应超活化包括i)IL-6、IL-1β和TNFα的分泌和/或单核吞噬细胞(MP)的募集。
4.项1-3中任一项所述的方法，其中抑制NRP1依赖性细胞信号传导包括：(a)降低NRP1表达或活性；和/或(b)降低NRP1配体表达或活性；其中所述NRP1配体是SEMA3A、VEGF和/或TGF-β。
5.项4所述的方法，其中所述方法包括(i)通过抑制NRP1与至少一种NRP1配体的结合降低NRP1活性。
6.项5所述的方法，其中NRP1配体是SEMA3A、VEGF或TGF-β。
7.项5或6所述的方法，其中抑制NRP1与至少一种NRP1配体的结合包括施用抗NRP1抗体或NRP1陷阱，其中所述陷阱包含NRP1多肽或其功能片段或变体。
8.项7所述的方法，其中所述NRP1多肽对应于可溶性NRP1同种型2(NRP1 isoform2)。
9.项8所述的方法，其中所述可溶性NRP1同种型2包括或基本上由具有如图22所示的氨基酸序列而无信号肽的多肽组成。
10.项7所述的方法，其中所述NRP1多肽对应于NRP1同种型1多肽的胞外结构域。
11.项10所述的方法，其中所述NRP1同种型1多肽如图26所示，并且其中所述胞外结构域包含对应于图26所示的NRP1多肽的氨基酸22至859(SEQ ID NO：66)。
12.项7至11中任一项所述的方法，其中所述NRP1陷阱包含NRP1多肽，其包含(i)如SEQ ID NO：65所示的NRP1多肽的氨基酸22至609；(ii)如SEQ ID NO：66中所示的NRP1多肽的氨基酸22至859；(iii)如SEQ ID NO：69中所示的NRP1多肽的氨基酸22至859(iv)或(i)、(ii)或(iii)的功能片段或功能变体。
13.项7至12中任一项所述的方法，其中所述抗NRP1抗体抑制SEMA3A与NPR-1的结合，但基本上不抑制VEGF与NRP1的结合，并且其中所述NRP1陷阱与SEMA3A结合，但基本上不与VEGF165结合或具有与SEMA3A结合亲和力相比降低的对VEGF165结合亲和力。
14.项13所述的方法，其中所述NRP1陷阱(i)完全或部分地缺少NRP1的结构域b1和/或b2；或(ii)包含抑制VEGF与NRP1结合的至少一个氨基酸点突变。
15.项13所述的方法，其中所述抗NRP1抗体不与NRP1的结构域b1和/或b2结合。
16.项14所述的方法，其中所述点突变包含(a)在对应于图22或图26中所示的NRP1氨基酸序列的酪氨酸297的氨基酸残基处的结构域b1中的氨基酸取代或缺失；(b)在对应于图22或图26中所示的NRP1氨基酸序列的天冬氨酸320的氨基酸残基处的结构域b1中的氨基酸取代或缺失；和/或(c)在对应于图22或图26中所示的NRP1氨基酸序列的谷氨酸319的氨基酸残基处的结构域b1中的氨基酸取代或缺失。
17.项16所述的方法，其中所述点突变是Y297A取代；D320K取代和/或E319K取代。
18.项7至12中任一项所述的方法，其中所述NRP1陷阱：(a)包含所述NRP1多肽的结构域a1、a2、b1、b2、和c；(b)包含所述NRP1多肽的结构域a1、a2、b1和b2；(c)包含所述NRP1多肽的结构域a1、a2和b1；(d)包含所述NRP1多肽的结构域a1和a2；(f)包含所述NRP1多肽的结构域b1，其中所述结构域b1包含：在对应于包括如图26中所示的氨基酸序列的NRP1多肽的(i)酪氨酸297；(ii)天冬氨酸320和/或(iii)谷氨酸319的氨基酸残基处的至少一个点突变，其中所述至少一个突变降低或消除与VEGF165的结合；(g)完全或部分地缺少所述NRP1多肽的结构域c；(h)完全或部分地缺少所述NRP1多肽的结构域b1；(i)完全或部分地缺少所述NRP1多肽的结构域b2；(j)缺少所述NRP1多肽的结构域b1和b2；或(k)缺少所述NRP1多肽的结构域b1、b2和c。
19.项18所述的方法，其中(i)所述结构域a1包含对应于如图26中所示的NRP1多肽的氨基酸27至141的氨基酸序列或基本上由对应于如图26中所示的NRP1多肽的氨基酸27至141的氨基酸序列组成；(ii)所述结构域a2包含对应于如图26中所示的NRP1多肽的氨基酸147至265的氨基酸序列；(iii)所述结构域b1包含对应于如图26中所示的NRP1多肽的氨基酸275至424的氨基酸序列；(iv)所述结构域b2包含对应于如图26中所示的NRP1多肽的氨基酸431至583的氨基酸序列；和/或(v)所述结构域c结构域包含对应于如图26中所示的NRP1多肽的氨基酸645至811的氨基酸序列。
20.项18所述的方法，其中(i)所述结构域a1包含对应于如图26中所示的NRP1多肽的氨基酸22至148的氨基酸序列或基本上由对应于如图26中所示的NRP1多肽的氨基酸22至148的氨基酸序列组成；(ii)所述结构域a2包含对应于如图26中所示的NRP1多肽的氨基酸149至275的氨基酸序列；(iii)所述结构域b1包含对应于如图26中所示的NRP1多肽的氨基酸276至428的氨基酸序列；(iv)所述结构域b2包含对应于如图26中所示的NRP1多肽的氨基酸429至589的氨基酸序列；和/或(v)所述结构域c结构域包含对应于如图26中所示的NRP1多肽的氨基酸590至859的氨基酸序列。
21.项7所述的方法，其中所述方法包括通过施用基本上由如表1中所示的陷阱或其功能变体组成的NRP1陷阱而抑制NRP1与至少一种NRP1配体的结合。
22.项7至20中任一项所述的方法，其中所述NRP1陷阱进一步包含蛋白质纯化结构域。
23.22所述的方法，其中所述纯化结构域是聚组氨酸标签。
24.项7至20中任一项所述的方法，其中所述NRP1陷阱进一步包含FC结构域。
25.项22至24中任一项所述的方法，其中所述NRP1陷阱包含能够使所述蛋白质纯化结构域或FC结构域从所述NRP1陷阱移除的蛋白酶或肽酶切割位点。
26.项25所述的方法，其中所述蛋白酶或肽酶是TEV蛋白酶切割位点。
27.项26所述的方法，其中所述TEV蛋白酶切割位点包含氨基酸序列GSKENLYFQG。
28.项4所述的方法，其中所述方法包括降低NRP1配体表达或活性，并且其中NRP1配体是SEMA3A。
29.项28所述的方法，其包括通过施用与SEMA3A的SEMA结构域结合的抗SEMA3A抗体抑制SEMA3A与NRP1的结合而降低SEMA3A活性[增加了对于特定结构域的支持]。
30.4所述的方法，其中所述方法包括通过施用NRP1反义、shRNA或siRNA降低NRP1表达。
31.4所述的方法，其中所述方法包括通过施用SEMA3A反义、shRNA或siRNA降低SEMA3A表达。
32.包含NRP1多肽或其功能片段或变体的NRP1多肽陷阱，其与SEMA3A、VEGF165和/或TGF-β结合。
33.项32所述的NRP1多肽陷阱，其中所述NRP1多肽对应于可溶性NRP1同种型2。
34.项33所述的NRP1多肽陷阱，其中所述可溶性NRP1同种型2包含或基本上由具有如图22中所示的氨基酸序列的多肽组成而无信号肽。
35.项34所述的NRP1多肽陷阱，其中所述NRP1多肽对应于NRP1同种型1多肽的胞外结构域。
36.项35所述的NRP1多肽陷阱，其中所述NRP1同种型1多肽如图26中所示，并且其中所述胞外结构域对应于氨基酸22至859。
37.项32至36中任一项所述的NRP1多肽陷阱，其中所述NRP1陷阱包含NRP1多肽，其包含(i)SEQ ID NO：65中所示的NRP1多肽的氨基酸22至609；(ii)SEQ ID NO：66中所示的NRP1多肽的氨基酸22至859；(iii)SEQ ID NO：69中所示的NRP1多肽的氨基酸22至859(iv)或(i)、(ii)或(iii)的功能片段或功能变体。
38.项32至37中任一项所述的NRP1多肽陷阱，其中NRP1陷阱与SEMA3A结合但基本上不与VEGF165结合或具有与SEMA3A结合亲和力相比降低的对VEGF165的结合亲和力。
39.项38所述的NRP1多肽陷阱，其中所述NRP1陷阱(i)完全或部分地缺少NRP1的结构域b1和/或b2；或(ii)包含至少一个氨基酸点突变，其抑制VEGF与NRP1的结合。
40.项39所述的NRP1多肽陷阱，其中所述点突变包含(a)在对应于图22或图26中所示的NRP1氨基酸序列的酪氨酸297的氨基酸残基处的结构域b1中的氨基酸取代或缺失；(b)在对应于图22或图26中所示的NRP1氨基酸序列的天冬氨酸320的氨基酸残基处的结构域b1中的氨基酸取代或缺失；和/或(c)在对应于图22或图26中所示的NRP1氨基酸序列的谷氨酸319的氨基酸残基处的结构域b1中的氨基酸取代或缺失。
41.项40所述的NRP1多肽陷阱，其中所述突变点是Y297A取代；D320K取代和/或E319K取代。
42.项32至38中任一项所述的NRP1多肽陷阱，其中所述陷阱：(a)包含所述NRP1多肽的结构域a1、a2、b1、b2、和c；(b)包含所述NRP1多肽的结构域a1、a2、b1和b2；(c)包含所述NRP1多肽的结构域a1、a2、和b1；(d)包含所述NRP1多肽的结构域a1和a2；(e)包含所述NRP1多肽的结构域b1，其中所述结构域b1包含在对应于包含如图26中所示的氨基酸序列的NRP1多肽的(i)酪氨酸297；(ii)天冬氨酸320和/或(iii)谷氨酸319的氨基酸残基处的至少一个点突变，其中所述至少一个突变降低或消除与VEGF165的结合；(f)完全或部分地缺少所述NRP1多肽的结构域c；(g)完全或部分地缺少所述NRP1多肽的结构域b1；(h)完全或部分地缺少所述NRP1多肽的结构域b2；(i)缺少所述NRP1多肽的结构域b1和b2；或(j)缺少所述NRP1多肽的结构域b1、b2和c。
43.项42所述的NRP1多肽陷阱，其中(i)所述结构域a1包含对应于如图26中所示的NRP1多肽的氨基酸27至141的氨基酸序列或基本上由对应于如图26中所示的NRP1多肽的氨基酸27至141的氨基酸序列组成；(ii)所述结构域a2包含对应于如图26中所示的NRP1多肽的氨基酸147至265的氨基酸序列；(iii)所述结构域b1包含对应于如图26中所示的NRP1多肽的氨基酸275至424的氨基酸序列；(iv)所述结构域b2包含对应于如图26中所示的NRP1多肽的氨基酸431至583的氨基酸序列；和/或(v)所述结构域c结构域包含对应于如图26中所示的NRP1多肽的氨基酸645至811的氨基酸序列[相应于N.Beaulieu传送的可选的不同结构域的定义-SEQ ID NO：71-75]。
44.项42所述的NRP1多肽陷阱，其中(i)所述结构域a1包含对应于如图26中所示的NRP1多肽的氨基酸22至148的氨基酸序列或基本上由对应于如图26中所示的NRP1多肽的氨基酸22至148的氨基酸序列组成；(ii)所述结构域a2包含对应于如图26中所示的NRP1多肽的氨基酸149至275的氨基酸序列；(iii)所述结构域b1包含对应于如图26中所示的NRP1多肽的氨基酸276至428的氨基酸序列；(iv)所述结构域b2包含对应于如图26中所示的NRP1多肽的氨基酸429至589的氨基酸序列；和/或(v)所述结构域c结构域包含对应于如图26中所示的NRP1多肽的氨基酸590至859的氨基酸序列。
45.项32所述的NRP1多肽陷阱，其中所述陷阱基本上由如表1中所示的陷阱或其功能变体组成。
46.项32至44中任一项所述的NRP1多肽陷阱，其中所述陷阱进一步包含蛋白质纯化结构域。
47.项46所述的NRP1多肽陷阱，其中所述纯化结构域是聚组氨酸标签。
48.项32至47中任一项所述的NRP1多肽陷阱，其中所述NRP1陷阱进一步包含FC结构域。
49.项46至48中任一项所述的NRP1多肽陷阱，其中所述NRP1陷阱包含能够使所述蛋白质纯化结构域或FC结构域从所述NRP1陷阱移除的蛋白酶或肽酶切割位点。
50.项49所述的NRP1多肽陷阱，其中所述蛋白酶或肽酶切割位点是TEV蛋白酶切割位点。
51.项50所述的NRP1多肽陷阱，其中所述TEV蛋白酶切割位点包含氨基酸序列GSKENLYFQG。
52.编码项32-51中任一项所述的NRP1多肽陷阱的核酸。
53.包含项52所述的核酸的表达载体。
54.包含项53所述的载体的宿主细胞。
55.包含项32至51中任一项所述的NRP1多肽陷阱、项52所述的核酸、项53所述的载体或项54所述的宿主细胞和适合的载体的组合物。
56.项55所述的组合物用于(ii)预防或治疗炎症，或(ii)防止或降低先天免疫反应超活化。
57.用于预防或治疗炎症的化合物，其中所述化合物：(a)降低NRP1表达或活性；和/或(b)降低NRP1配体表达或活性。
58.用于预防或降低先天免疫反应超活化的化合物，其中所述化合物：(a)降低NRP1表达或活性；和/或(b)降低NRP1配体表达或活性。
59.项57或58所述的化合物，其中所述化合物是：(i)抗SEMA3A抗体；(ii)抗VEGF165抗体；(iii)抗NRP1抗体；(iv)NRP1陷阱；(v)SEMA3A反义、shRNA或siRNA；(vi)NRP1反义、shRNA或siRNA；或(vii)VEGF反义、shRNA或siRNA。
60.项59所述的化合物，其中所述化合物是NRP1多肽陷阱。
61.用于治疗或预防炎症的组合物，其包含项57-60中任一项中所限定的化合物和适合的载体。
62.用于预防或降低先天免疫反应超活化的组合物。其包含项57-60中任一项中所限定的化合物和适合的载体。
63.项32-51中任一项所述的NRP1多肽陷阱、项52所述的核酸、项53所述的载体、项54所述的宿主细胞、项57-60中任一项所述的化合物或项55、61和62中任一项所述的组合物在制备用于预防或治疗炎症的药物中的应用。
64.项32-51中任一项所述的NRP1多肽陷阱、项52所述的核酸、项53所述的载体、项54所述的宿主细胞、项57-60中任一项所述的化合物或项55、61和62中任一项所述的组合物在制备用于预防或治疗炎症的药物的应用。
65.项32-51中任一项所述的NRP1多肽陷阱、项52所述的核酸、项53所述的载体、项54所述的宿主细胞、项57-60中任一项所限定的化合物或项55、61和62中任一项所限定的组合物用于预防或治疗先天免疫反应超活化的应用。
66.项32-51中任一项所述的NRP1多肽陷阱、项52所述的核酸、项53所述的载体、项54所述的宿主细胞、项57-60中任一项所限定的化合物或项55、61和62中任一项所限定的组合物用于预防或降低先天免疫反应超活化的应用。
67.项1-31中任一项所述的方法，其中所述受试者患有或可能患有感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症、糖尿病、葡萄膜炎、糖尿病性视网膜病变、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病或中风。
68.项1-31中任一项所述的方法、项32-51中任一项所述的NRP1多肽陷阱、项52所述的核酸、项53所述的载体、项54所述的宿主细胞、项57-60中任一项所限定的化合物或项55、61和62中任一项所限定的组合物，其中所述方法、NRP1多肽陷阱、核酸、载体、宿主细胞、化合物、组合物或应用是用于治疗或预防感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症、糖尿病、葡萄膜炎、糖尿病性视网膜病变、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病或中风。
69.项1-31中任一项所述的方法、项32-51中任一项所述的NRP1多肽陷阱、项52所述的核酸、项53所述的载体、项54所述的宿主细胞、项57-60中任一项所限定的化合物或项55、61和62中任一项所限定的组合物，其中所述方法、NRP1多肽陷阱、核酸、载体、宿主细胞、化合物、组合物或应用是用于治疗或预防感染性休克或中风。
在阅读以下仅通过示例的方式参考附图给出的其具体实施方式的非限制性描述之后，本发明的其它目标、优点和特征将会变得更加明显。
附图说明
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在附图中：
图1显示NRP1鉴定继发于血管损伤转移(mobilized)的小胶质细胞群。(A).氧诱导视网膜病变(retinopathy，视网膜病)(OIR)的小鼠模型的示意图。第一阶段(出生后7-12天(P7-P12))，在75％氧下，诱导血管闭塞(vasoobliteration)。出生后12至17天(P7-P17)的第二阶段(在室内空气下)允许达到最大的视网膜前新血管形成。(B、E和H)显示在P10(B)、P14(E)和P17(H)时从WT OIR和含氧量正常的对照小鼠收集的视网膜中的CD11b+/F4-80+/Gr-1-细胞(小胶质细胞)的代表性FACS图。(C、F和I)显示在P10(C)、P14(F)和P17(I)时含氧量正常(N)和OIR中的视网膜小胶质细胞数目的倍数变化。视网膜小胶质细胞的数目在OIR中在所有分析点(C、F和I)显著地增加；n＝7-8(含氧量正常，(N))，n＝7-8(OIR)(每个条件总共28-32个视网膜；每个“n”包含4个视网膜)。(D、G和J)显示在P10(D)、P14(G)和P17(J)时NRP1阳性MP数目的倍数变化。在OIR视网膜(D、G和J)中观察到NRP1阳性小胶质细胞数目成比例增加；n＝3-5(含氧量正常，(N))，n＝3-5(OIR)(每个条件总共12-20个视网膜；每个“n”包括4个视网膜)。(K).为了研究MP驻留型NRP1的作用，产生在视网膜小胶质细胞中具有显著受损(compromised)NRP1表达的LysM-Cre/Nrp1fl/fl小鼠(n＝3(WT)，n＝4(LysM-Cre/Nrp1fl/fl，每个条件总共12-16个视网膜)。左侧框显示通过FACS(右侧框)确定的WT(LysM-Cre/NRP1+/+)和其骨髓细胞中缺乏NRP1的小鼠(LysM-Cre/Nrp1fl/fl)中的NPR-1阳性MP的％。(L、N和P)，在P10(L)、P14(N)和P17(P)时的FACS分析，以量化含氧量正常和OIR中LysM-Cre/Nrp1fl/fl小鼠视网膜中的MP的数目。(M、O和Q)显示含氧量正常和OIR中LysM-Cre/Nrp1fl/fl小鼠视网膜中的MP的数目的倍数变化。在OIR增殖阶段期间在P10和P14时的FACS分析(L，N)揭示MP驻留型NRP1是MP渗入至缺血性视网膜必不可少的，因为LysM-Cre/Nrp1fl/fl小鼠没有显示在这些时间点时OIR中的CD11b+/F4-80+/Gr-1-细胞数目的增加(M，O)。在P17时，MP渗入独立于NRP1(P，Q)。n＝7-8(N)，n＝7-9(OIR)(每个条件总共28-36个视网膜；每个“n”包括4个视网膜)。(R)在OIR过程中WT和LysM-Cre/Nrp1fl/fl小鼠中视网膜中的MP积累的总结图。(S，T)描述Gr1-/CD11b+/F4/80+细胞表达高水平CX3CR1及中/低水平的CD45的代表性FACS图。CX3CR1高和CD45低细胞表达WT视网膜中的NRP1(S)而不表达来自LysM-Cre/Nrp1fl/fl小鼠的视网膜中的NRP1(T)。数据被表示为相对于对照的倍数变化±SEM。*P<0.05、**P<0.001、***P>0.0001；
图2显示NRP1+骨髓细胞定位于视网膜中病理新血管形成的位点。异凝集素B4(血管和小胶质细胞染色)和NRP1染色的视网膜铺片(flatmount)在P14时与WT(A)和LysM-Cre/Nrp1fl/fl小鼠(G)中的出芽(budding)新生血管簇以及在P17时与WT(D)和LysM-Cre/Nrp1fl /fl小鼠(J)中的成熟簇的共聚焦图像。高倍放大图像揭示在WT小鼠中通过3D重建(C，D)确认的NRP1阳性小胶质细胞(IBA1)与新生(B)和成熟簇(E)两者的共定位。(C、F、I、L)显示组织的3D重建。(A，右侧框)中的白色箭头指向萌芽簇。(B，E)中的白色箭头指向与簇相关联的NRP1+MP。LysM-Cre/Nrp1fl/fl小鼠具有较少的MP和较少的簇绒(tufting)(G-K)。对于所有的IHC，显示了三个独立实验的代表性图像。比例尺(A、D、G、J)：100μm，(B、E、H、K)：50μm；
图3显示NRP1配体——SEMA3A——在患有增殖糖尿病性视网膜病变的患者中被诱导。造影、眼底镜、光谱域光学相干层析成像(spectral-domain optical coherencetomography，SD-OCT)和三维(3D)视网膜图从被选择用于研究的患者获得。对照患者具有非血管性病理并且与具有增殖糖尿病性视网膜病变(PDR)的患者比较。对照ERM患者显示非糖尿病相关的视网膜损伤的标记，如继发于(C)纤维化组织(白色箭头)、玻璃体后脱离(箭头)和黄斑膨胀(造影和3D图)的脉管系统(箭头)上的(A，B)牵引张力。来自PDR患者的视网膜具有(E)新血管形成(插图)与(D)由荧光染料的渗漏所证明的高渗透性微血管(插图)、(F)微动脉瘤(microaneurysm)(插图箭头)和(G)纤维性瘢痕组织(箭头)，指示晚期视网膜病变。(H)PDR患者显示黄斑水肿的一些证据，包括囊形成(白色箭头)——由于外渗液的焦点聚结。(I)通过ELISA分析的玻璃体显示在具有PDR的患者中SEMA3A蛋白水平增加5倍；对照n＝17并且PDR也为17。(J)等体积的玻璃体的蛋白质印迹分析证实相对于对照具有PDR的患者中SEMA3A(～125KDa和95KDa)增加；
图4显示在OIR期间在视网神经节细胞层中NRP1的配体被诱导。(A，B)在P10和P17之间收集来自在含氧量正常的条件下或在OIR中的WT和骨髓缺乏NRP1敲除小鼠(LysM-Cre/Nrp1fl/fl小鼠)的视网膜并通过RT-qPCR进行分析(在实施例11、表2中公开了使用的寡核苷酸)。SEMA3A mRNA(A)表达在WT和LysM-Cre/Nrp1fl/fl视网膜两者中在整个OIR期间被诱导，而VEGF(B)在基因敲除小鼠(LysM-Cre/Nrp1fl/fl)中相比于WT视网膜被显著较少地诱导(星号)。数据被表示为各个时间点相对于各自含氧量正常的对照的倍数变化±SEM；n＝4-7；*p<0.05，**p<0.01，***p<0.001。(C)小心地对P14小鼠进行激光捕获显微切割(LCM)以选择OIR中的无血管视网膜区域。(D，E)对照和OIR无血管区域中的视网膜层的LCM的RT-qPCR显示与含氧量正常的视网膜相比在OIR视网膜期间的神经节细胞层(GCL)中SEMA3A(D)和VEGF(E)mRNA的诱导。VEGF在OIR视网膜(E)的内核层中也被诱导。数据被表示为相对于含氧量正常的GCL的倍数变化±SEM；
图5显示在血管损伤后NRP1+MP没有在视网膜中增殖。获自在P14时从在P13时注射有BrdU的WTOIR(右侧框)和含氧量正常的(左侧框)对照小鼠中收集的视网膜(A)和脾(B)的CD11b+/F4-80+/Gr-1-细胞的代表性FACS直方图。BrdU+细胞的数目在脾中相当高，但是在OIR和含氧量正常的小鼠之间没有显著地变化(C)。n＝4(含氧量正常的，N)，n＝4(OIR)(每个条件总共16个视网膜；每个“n”包括4个视网膜)。数据被表达为BrdU+Gr-1-/CD11b+/F4-80+细胞的百分比±SEM；
图6显示SEMA3A和VEGF经NRP1对巨噬细胞具有化学吸引。(A，B)从WT或骨髓缺乏NRP1基因敲除小鼠(LysM-Cre/Nrp1fl/fl小鼠)分离原代巨噬细胞并且进行添加至下室(lower chamber)的媒介物(vehicle)、MCP-1(100ng/ml)、SEMA3A(100ng/ml)或VEGF(50ng/ml)的transwell迁移测定。用DAPI染色的迁移细胞的代表性图像被显示(A)。SEMA3A或VEGF以与阳性对照MCP-1相似的程度促进巨噬细胞迁移(B)。为了确定SEMA3A和VEGF正在刺激巨噬细胞趋化性，用消除趋化性的选择性ROCK抑制剂Y-27632(100μg/ml)预处理细胞(B)。来自LysM-Cre/Nrp1fl/fl小鼠的巨噬细胞不对SEMA3A或VEGF响应而对MCP-1响应(C)。数据被表达为相对于对照(未处理细胞)的倍数变化；n＝6–22；**p<0.01，***p<0.001。比例尺：100μm(A)；
图7显示Nrp1+巨噬细胞促进离体脉络膜外植体中的微血管生长。(A)从LysM-Cre/Nrp1+/+和LysM-Cre/Nrp1fl/fl小鼠中分离的脉络膜外植体的定量和代表性图像(n＝6；p＝0.018)。(B，C)来自LysM-Cre/Nrp1+/+(B)和LysM-Cre/Nrp1fl/fl(C)小鼠——氯膦酸(chlodronate)脂质体治疗后(以耗尽巨噬细胞)并且随后添加外源巨噬细胞(Ma)——的脉络膜外植体的代表性图像。(D，E)来自B和C中所描述的LysM-Cre/Nrp1+/+(D)和LysM-Cre/Nrp1fl/fl(E)的脉络膜微脉管萌芽的定量(n＝6，n.s.：无显著性差异，*p<0.05，**p<0.01，***p<0.001)；
图8显示骨髓驻留型NRP1的缺乏降低视网膜病变中的血管变性和病理新血管形成。使野生型、LysMCre/Nrp1+/+和LysM-Cre/Nrp1fl/fl小鼠经历OIR并且在P12和P17时收集视网膜，用异凝集素B4铺片和染色。与对照WT(#1)或对照LysMCre/Nrp1+/+小鼠(#2)两者相比，LysM-Cre/Nrp1fl/fl小鼠在P12时具有较少血管闭塞(A、B中的#3)，在P17时具有降低的无血管面积(C、D中的#3)和视网膜前新血管形成(E、F中的#3)。结果被表达为无血管或新生血管面积与全部视网膜面积的百分比；n＝5–19。比例尺：B&D：1mm和F：500μm。**p<0.01，***p<0.001；
图9显示治疗性玻璃体内施用可溶性NRP1降低视网膜病变中的MP浸润和病理新血管形成。使WT小鼠经历OIR并在P12时玻璃体内注射可溶重组小鼠NRP1(包含结构域a1、a2、b1、b2和c的rmNRP1，同时参见图19C和20R)作为陷阱，以隔离OIR诱导的NRP1配体。在P14时，FACS分析揭示在注射rmNRP1的视网膜中视网膜MP数目减少超过30％(A)。数据被表达为相对于对照(注射媒介物的视网膜)的倍数变化±SEM；n＝3-4(每个条件总共12-16个视网膜；每个“n”包括4个视网膜)。当与注射媒介物的眼睛比较时，用rmNRP1治疗有效地减少在P17时的病理新血管形成(B，C)。结果被表达为新生血管面积与全部视网膜面积的百分比；n＝11。比例尺：500μm。*p<0.05，**p<0.01；
图10是本发现的示意图，其示例在缺血性视网膜病变(如糖尿病视网膜病变)期间，视网膜、缺血性神经元和神经组织的无血管区域产生NRP1配体(SEMA3A和VEGF)，其反过来充当促血管生成小胶质细胞的有效的化学吸引剂。NRP1+小胶质细胞随后参与增殖性视网膜病变的发病机理；
图11显示在感染性休克期间SEMA3A在若干器官中被上调。在小鼠中LPS诱导(15mg/kg)败血症后，通过qRT-PCR评价SEMA3A(左侧框)和VEGF(右侧框)的mRNA水平。用β-肌动蛋白表达将SEMA3A和VEGF mRNA水平归一化，在LPS施用后0、6、12和24小时确定mRNA水平的倍数变化。A.小鼠脑中的SEMA3A(左侧框)和VEGF(右侧框)的倍数变化。B.小鼠肾中的SEMA3A(左侧框)和VEGF(右侧框)的倍数变化。C.小鼠肺中的SEMA3A(左侧框)和VEGF(右侧框)的倍数变化。D。小鼠肝中的SEMA3A(左侧框)和VEGF(右侧框)的倍数变化；
图12显示在LPS诱导败血症后的细胞因子表达。在小鼠中LPS诱导败血症(15mg/kg)后通过qRT-PCR评价TNF-α和IL-1β的mRNA水平。用β-肌动蛋白表达将mRNA水平归一化并且在LPS施用后0、6、12和24小时确定mRNA水平的倍数变化。A.小鼠脑中的TNF-α(左侧框)和IL-1β(右侧框)的倍数变化。B.小鼠肾中的TNF-α(左侧框)和IL-1β(右侧框)的倍数变化。C.小鼠肺中的TNF-α(左侧框)和IL-1β(右侧框)的倍数变化。D.小鼠肝中的TNF-α(左侧框)和IL-1β(右侧框)的倍数变化；
图13显示SEMA3A通过NRP1诱导骨髓细胞中的促炎性细胞因子分泌。用SEMA3A(100ng/nml)或媒介物处理野生型和NRP1敲除(LyzM/NRP1fl/fl)骨髓细胞，并且通过流式微珠阵列(Cytometric Bead Array，CBA)分析IL-6(A)、TNF-α(B)和IL-1β(C)蛋白质分泌；
图14显示缺乏NRP1的骨髓在体内败血症期间降低炎性细胞因子的产生。施用NRP1敲除小鼠(LyzM/NRP1fl/fl)和对照野生型小鼠媒介物或LPS(15mg/kg)，以诱导败血症。LPS注射后6小时收集脑和肝并提取mRNA。通过实时RT-PCR分析TNF-α(A，C)和IL-1β(B，D)表达并用β-肌动蛋白表达水平归一化水平；
图15显示NRP1活性的体内抑制阻止败血症诱导的屏障功能损坏。施用小鼠i)媒介物；ii)LPS(15mg/kg)；或iii)LPS(15mg/kg)和NRP1陷阱(陷阱-1，图19C和20R(但无FC结构域)，NP_032763，4ug/0.2mg/kg，静脉注射)。随后使用Evan蓝色渗透试验(Evan bluepermeation assay，EBP)评估脑(A)、肾(B)和肝(C)的血管通透性；
图16显示NRP1活性的体内抑制保护免于败血症。(A)施用i)高剂量的LPS(腹腔注射，25/mg/kg)；或ii)NRP1陷阱(静脉注射，0.2mg/kg的陷阱-1，图19C和20R(但无FC结构域)，NP_032763)，随后高剂量的LPS(腹腔注射，25/mg/kg)的对照小鼠的存活率。(B)施用高剂量的LPS(腹腔注射，25/mg/kg)的骨髓驻留型NRP1敲除小鼠(LyzM/NRP1fl/fl)和对照小鼠之间的存活率的比较；
图17显示NRP1衍生陷阱的施用或缺乏NRP1的骨髓降低感染性休克中的炎性细胞因子产生。施用野生型小鼠i)媒介物(n＝3)，ii)LPS(15mg/kg，n＝3)或iii)LPS和NRP1陷阱(陷阱-1，图19C和20R(但无FC结构域)，NP_032763)。施用具有缺乏NRP1的骨髓细胞(LyzM-Cre/Nrpfl/fl)的小鼠LPS(15mg/kg，n＝3)。LPS注射后6小时收集脑并且测量TNF-α(A)和IL-6(B)的产生；
图18显示NRP1衍生陷阱的施用保护免于缺血性中风。小鼠经历短暂的大脑中动脉闭塞(middlecerebral artery occlusion，MCAO)并且施用媒介物或NRP1陷阱，以及在用甲酚紫染色的冠状脑切片上测量梗塞(中风)的尺寸。未染色面积对应于损伤面积。(A)用媒介物治疗的MCAO小鼠的冠状脑切片。(B)用NRP1陷阱-1(参见图19C和20R(但无FC结构域)，NP_032763)治疗的MCAO小鼠的冠状脑切片。(C)在MCAO后用媒介物或NRP1陷阱治疗的小鼠中的平均梗塞尺寸的图示。(D)在MCAO后1h用媒介物或NRP1陷阱治疗的小鼠的神经损伤(神经学评分)。(E)在MCAO后24h用媒介物或NRP1陷阱治疗的小鼠的神经损伤(神经学评分)；
图19显示本发明的NRP1蛋白质和NRP1-陷阱的实施方式的图示。(A).显示SEMA3A结合结构域(大部分a1a2和一小部分b1)和VEGF结合结构域(b1b2)的WT NRP1示例。c-结构域是被认为促进NRP与其它共受体二聚化的MEM结构域。(B-F)人衍生NRP1(C)和小鼠衍生NRP1陷阱的图示；
图20显示图19B和C中所示的NRP1陷阱的核酸和蛋白质序列。(A)陷阱1/陷阱peA-全NRP1-FC氨基酸(SEQ ID NO：114)和核苷酸(SEQ ID NO：2)序列；(B)陷阱2-NRP1-FC-Δc-氨基酸序列(SEQ ID NO：115)；(C)陷阱2-NRP1-FC-Δc-核苷酸序列(SEQ ID NO：4)；(D)陷阱3-NRP1-FC-Δb2c-氨基酸序列(SEQ ID NO：116)；(E).陷阱3-NRP1-FC-Δb2c-核苷酸序列(SEQ ID NO：6)；(F)陷阱4-NRP1-FC-Δb1b2c-氨基酸序列(SEQ ID NO：117)；(G)陷阱4-NRP1-FC-Δb1b2c-核苷酸序列(SEQ ID NO：8)；(H)陷阱5/陷阱I-NRP1-FCΔc-短-氨基酸(SEQ ID NO：118)和核苷酸(SEQ ID NO：10)序列；(I)陷阱6/陷阱D-NRP1-FCΔb2c-短-氨基酸(SEQ ID NO：119)和核苷酸(SEQ ID NO：12)序列；(J)陷阱7/陷阱C-NRP1-FCΔb1b2c-短-氨基酸(SEQ ID NO：120)和核苷酸(SEQ ID NO：14)序列；(K)陷阱8/陷阱J-全NRP1-FC-VEGF低-氨基酸(SEQ ID NO：121)和核苷酸(SEQ ID NO：16)序列；(L)陷阱9-NRP1-FC-Δc-VEGF低-氨基酸序列(SEQ ID NO：122)；(M)陷阱9-NRP1-FC-Δc-VEGF低-核苷酸序列(SEQ IDNO：18)；(N)陷阱10-NRP1-FC-Δb2c-VEGF低-氨基酸序列(SEQ ID NO：123)；(O)陷阱10-NRP1-FC-Δb2c-VEGF低-核苷酸序列(SEQ ID NO：20)；(P)陷阱11/陷阱L-NRP1-FC-Δc-VEGF低–短-氨基酸(SEQ ID NO：124)和核苷酸(SEQ ID NO：22)序列；(Q)陷阱12/陷阱K-NRP1-FC-Δb2c-VEGF低–短-氨基酸(SEQ ID NO：125)和核苷酸(SEQ ID NO：24)序列。(R)小鼠陷阱1-全Nrp1-mFC氨基酸(SEQ ID NO：126)和核苷酸(SEQ ID NO：26)序列。(S)小鼠陷阱2-Nrp1-mFCΔc-短氨基酸(SEQ ID NO：127)和核苷酸(SEQ ID NO：28)序列。(T)小鼠陷阱3-Nrp1-FCΔb2c-短氨基酸(SEQ ID NO：128)和核苷酸(SEQ ID NO：30)序列；
图21显示人SEMA3A前体蛋白质序列(SEQ ID NO：31)。将此序列被进一步加工成为成熟形式。残基1-20对应于信号肽；
图22显示人可溶神经毡蛋白-1(NRP1)受体蛋白质序列(例如，GenBank登录号AAH07737.1-SEQ ID NO：32)。结构域a1、a2、b1、b2和c被显示。结构域a1由氨基酸23-148组成；结构域a2由氨基酸149-270组成；结构域b1由氨基酸271-428组成；结构域b2由氨基酸429-590组成，和结构域c由氨基酸591-609组成；
图23显示SEMA3A陷阱在氧诱导视网膜病变模型中的缺血性小鼠视网膜中加速血管再生并降低病理性血管生成。(A)显示视网膜病变的四个主要阶段(即，含氧量正常、血管损失/血管闭塞、增殖/新血管形成和新生血管性(NV)退化)的氧诱导视网膜病变(OIR)的小鼠模型示意图。(B)在玻璃体内注射组氨酸标记的陷阱G或陷阱M(陷阱G-HIS(SEQ ID NO：38)和陷阱M-HIS(SEQ ID NO：42))之后的P17时的无血管面积(相对于媒介物)的平均百分比(％)。显示每个组的显示无血管面积的代表性视网膜的照片。(C)在玻璃体内注射组氨酸标记的陷阱G和陷阱M之后的P17时的新生血管面积(相对于媒介物)的平均百分比。显示每个组的显示新生血管面积的代表性视网膜的照片。*p<0,05，**p<0,01，***p<0,001。n＝8-13动物/组；
图24显示SEMA3A陷阱阻止糖尿病视网膜中的血管渗漏(vascular leakage)和水肿。(A).在链脲霉素(streptozotocin，STZ)治疗前(0周)和在STZ治疗后3周的小鼠血糖水平(糖尿病状况)。(B).在STZ施用后6和7周玻璃体内注射有0.5ug/ml的陷阱G、陷阱M或80μg(1ul)的抗VEGF164抗体(AF-493-NA，R&D)的小鼠视网膜上的视网膜Evans蓝色渗透试验(在第8周测量)。(C)在STZ治疗后12和13周玻璃体内注射有0.5ug/ml的陷阱G或陷阱M或抗VEGF164抗体(AF-493-NA，Novus Biologicals)的小鼠视网膜上的视网膜Evans蓝色渗透试验(在第14周测量)。*p<0,05，n＝4，来自12个动物；
图25显示NRP1衍生陷阱(抗SEMA3A和VEGF)降低年龄相关的黄斑变性(AMD)的模型中的脉络膜新血管形成。(A)用于诱导小鼠眼中的脉络膜新血管形成的方法的图示。(B)激光烧伤后14天的脉络膜新血管形成(平均灌注的FITC/凝集素面积)。在激光烧伤后立即用陷阱G玻璃体内地注射小鼠眼；
图26显示大鼠(登录号EDL96784，NP_659566)、人(SEQ ID NO：68，登录号NM003873)和小鼠(SEQ ID NO：67，登录号NP_032763)连同NRP1共有序列(SEQ ID NO：69)之间的比对。鉴定NRP1信号结构域(氨基酸1-21)、SEMA3a结合结构域a1(氨基酸22-148，SEQID NO：78)、a2(氨基酸149-175，SEQ ID NO：79)、VEGF结合结构域b1(氨基酸276-428，SEQID NO：80)和b2(氨基酸429-589，SEQ ID NO：81)、结构域c(氨基酸590-859，SEQ ID NO：82)、跨膜结构域(氨基酸860-883，SEQID NO：77)和细胞质结构域(氨基酸884-923)；和
图27显示图19中所示的本发明示例性陷阱(但无任意组氨酸或FC标签)之间的蛋白质序列比对。(A).包含6X His标签纯化结构域的本发明的的示例性陷阱——但缺少6XHis标签纯化结构域(G(SEQ ID NO：100)、R(SEQ ID NO：101)、Z(SEQ ID NO：102)、AB(SEQID NO：103)、AC(SEQ ID NO：104)、O(SEQ ID NO：105)、Q(SEQ ID NO：106)、M(SEQ ID NO：107)、P(SEQ ID NO：108)、N(SEQ ID NO：109)、W(SEQIDNO：110)、X(SEQ ID NO：111)和Y(SEQID NO：112))——之间的蛋白质序列比对。(B)本发明的示例性陷阱——但缺少FC结构域((A(SEQ ID NO：100)、I(SEQ ID NO：105)、D(SEQ ID NO：107)、C(SEQ ID NO：109)、J(SEQID NO：101)、L(SEQ ID NO：106)、K(SEQ ID NO：108)、S(SEQ ID NO：113)、U(SEQ ID NO：111)、V(SEQ ID NO：112))——之间的蛋白质序列比对。
具体实施方式
本发明人已经鉴定单核吞噬细胞(MP)的亚群，其响应在中枢神经元、血管和免疫细胞之间保守的局部趋化信号(local chemotactic cue)如SEMA3A。显示表达NRP1的MP进入损伤部位并且促进炎性状况模型中的(i)组织损伤和/或(ii)先天免疫反应的病理性活化，所述炎性状况包括各种形式的炎性、增殖性视网膜病变(例如，增殖糖尿病性视网膜病变、早产儿视网膜病变和年龄相关的黄斑变性)、感染性休克和脑缺血/中风。
本发明人证实紧张的(stessed)视网膜神经元和神经组织具有通过非常规趋化剂调节局部先天免疫反应的固有能力。发现小胶质细胞上的NRP1是SEMA3A的有效的趋化性受体，并且先天免疫细胞中的VEGF和NRP1信号转导的抑制(例如，利用NRP1衍生陷阱或NRP1或SEMA3A抗体)导致保护免于MP诱导的炎症和组织损伤。
患有晚期增殖糖尿病性视网膜病变(PDR)的患者显示产生升高水平的SEMA3A，其反而(counterintuitively，违反直觉地)充当神经毡蛋白-1(NRP1)阳性MP的有效的引诱剂。这些促血管生成MP响应于局部产生的SEMA3A以及VEGF和TGF-β被选择性地募集至病理新血管形成的部位。此外，显示SEMA3A在感染性休克期间在若干器官中上调并且通过MP诱导炎性细胞因子分泌。NRP1的抑制也降低败血症中的促炎性细胞因子的产生。
最后，NRP1阳性MP被显示在炎性疾病进展中起到至关重要的作用。显示NRP1骨髓依赖性活性的抑制/消除保护免于继发于脑缺血/中风的新生血管性视网膜疾病(血管变性和病理新血管形成)、感染性休克和神经损伤。
综合来看，这些发现强调了NRP1阳性MP和其配体在炎症中(并且特别在神经性炎症中)的作用，并且证实抑制NRP1细胞信号传导以限制先天免疫反应超活化(例如，通过小胶质细胞/巨噬细胞的募集和/或诱导促炎性细胞因子的产生和/或分泌在损伤部位处的组织损伤，和/或血管渗漏/水肿)的治疗益处。本发现发现在由涉及MP募集和促炎性细胞因子产生和分泌的持续(例如，慢性、持久)或过度/病理性的炎症表征的疾病和状况的预防和治疗中的应用，所述疾病和状况如感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症、糖尿病、葡萄膜炎和神经炎性状况如糖尿病性视网膜病变、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病和中风。
NRP1介导的细胞活性的抑制
本发明人已发现通过抑制NRP1依赖性细胞信号传导(并且特别是SEMA3A介导的细胞信号传导)，可以保护防止(阻止或治疗)炎性疾病和状况，如涉及先天免疫反应超活化的疾病和状况。特别地，NRP1介导的细胞信号传导的抑制降低不需要的(病理学的)单核吞噬细胞(MP，例如，小胶质细胞、巨噬细胞)的募集和促炎性细胞因子——其促进组织损伤(例如，增加的血管变性、病理新血管形成、细胞死亡或细胞损伤)、炎症和水肿——的产生/分泌。
因此，在一个方面，本发明涉及治疗或预防炎症的方法，包括抑制NRP1依赖性细胞信号传导。在具体方面，炎症是神经性炎症。
如本发明中所用的，术语“炎症”指的是涉及先天免疫反应活化的疾病或状况，其包括i)在炎症或损伤部位处表达NRP1受体的单核吞噬细胞(例如，小胶质细胞或巨噬细胞)的募集；和/或ii)促炎性细胞因子(例如，IL-1β、TNF-α、IL-6)的NRP1依赖性产生/分泌。急性炎症的典型标志是痛、发热、发红、肿胀和功能丧失。炎症可以被归类为急性或慢性。急性炎症是身体对有害刺激的初始反应，并且通过血浆和白细胞(特别是粒细胞)从血液到损伤组织中的增加的运动实现。生化事件的级联使炎症反应扩散和成熟，涉及损伤组织内的局部血管系统、免疫系统和各种细胞。长期的(持续的)炎症——被称为慢性炎症——导致存在于炎症部位的细胞类型的进行性变化，并且其特征在于来自炎症过程的组织的同时破坏和愈合。可依照本发明的方法治疗或预防的炎性状况的非限制性实例包括感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症、糖尿病、葡萄膜炎和神经炎性状况，如糖尿病性视网膜病变(包含增殖糖尿病性视网膜病变(PDR))、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病和中风。
在具体实施方式中，炎性疾病或状况不是视网膜病变。在另一实施方式中，炎性疾病或状况不是糖尿病性视网膜病变。在另一实施方式中，炎性疾病或状况不是黄斑水肿。在另一实施方式中，炎性疾病或状况不是糖尿病黄斑水肿。
在相关方面，本发明涉及抑制先天免疫反应超活化(或病理性活化)的方法，其包括抑制NRP1依赖性细胞信号传导。此类先天免疫反应超活化通常与免疫系统的任何给定细胞群(先天性和适应性，例如器官/组织中的单核细胞募集)的急性或慢性活化超过维持组织稳态所需的水平相关。这通常伴有细胞因子(例如TNF-α，IL-6)的产生增加、血管通透性增加，并且可导致组织功能受损。
在另一方面，本发明涉及治疗或预防血管变性的方法，其包括抑制NRP1依赖性细胞信号传导。
在进一步的方面，本发明涉及治疗或预防病理新血管形成的方法，其包括抑制NRP1依赖性细胞信号传导。
在另一方面，本发明涉及治疗或预防感染性休克的方法，其包括抑制NRP1依赖性细胞信号传导。
在又一方面，本发明涉及治疗或预防继发于脑缺血/中风的神经损伤的方法，其包括抑制NRP1依赖性细胞信号传导。
由于NRP1介导的细胞信号传导(例如，MP募集和促炎性细胞因子的产生/分泌)取决于NRP1与其配体(例如，SEMA3A、VEGF和/或TGF-β)的结合，所以可以以下面至少两种方式来实现NRP1介导的细胞信号传导的抑制：i)通过直接地靶向NRP1的表达或活性(通过使用NRP1抗体、NRP1衍生陷阱或类似物)；或ii)通过靶向其一种或多种配体(例如，SEMA3A、VEGF和/或TGF-β)的表达或活性。
在实施方式中，以上方法包括优选地或特异性地抑制SEMA3A介导细胞信号传导。“优选地抑制”指的是SEMA3A介导的细胞信号传导的抑制水平比其它NRP1配体(例如，VEGF165和TGF-β)更大。在某些方面，本发明的方法基本上不降低或抑制VEGF(例如，VEGF165)和/或TGF-β介导的细胞信号传导——其通过与NRP1相互作用而发生。在实施方式中，本发明的化合物(例如，NRP1陷阱)超过其它配体地与一种配体“优选地结合”(例如，超过VEGF优选地结合SEMA3A)。通过测量每种配体的解离常数(Kd)可确定此类优选相互作用。在实施方式中，对一种配体(例如，SEMA3A)的相互作用超过其它配体(例如，VEGF)至少1.5、2、3、4、5、6、7、8、9、10、12、15、28、20、22、25、30、35、40、45、50、60、75、80、100、200、300、400、500、1000倍或更多。在实施方式中，一种配体的kD(例如，nM)小于一种或多种其它配体(例如，VEGF)的kD至少1.5、2、3、4、5、6、7、8、9、10、12、15、28、20、22、25、30、35、40、45、50、60、75、80、100、200、300、400、500、1000倍。
在一个实施方式中，本发明的方法包括向可能患有炎症(例如，可能患有炎性疾病或状况)的受试者施用。在其它实施方式中，本发明的方法包括向诊断有炎症(例如，可能患有炎性疾病或状况)的受试者施用。在一个实施方式中，受试者是哺乳动物，优选是人。
在具体的实施方式中，依照该方法使用化合物。
NRP1陷阱
可以使用本发明的NRP1陷阱实现NRP1介导的细胞信号传导的抑制。如本发明中所用的，术语，“NRP1陷阱”或“NRP1多肽陷阱”包括天然存在的可溶性NRP1多肽(例如，如NRP1分泌的同种型b，图22，SEQ ID NO：65))和合成的(例如，重组产生的)NRP1多肽陷阱，其包括NRP1的任意功能性可溶片段(例如，NRP1同种型1或2)或NRP1的任意功能性变体——其与用于配体结合的内源性NRP1竞争。在一个实施方式中，本发明的NRP1陷阱在自然中不存在(即，不是天然存在的)，但“衍生”自天然存在的NRP1多肽(即，其是合成的；例如，包括NRP1同种型1的胞外结构域或其片段或变体的NRP1陷阱)。本发明的NRP1陷阱初始包括图26(例如，SEQ ID NO：69)中所示的NRP1的其N末端(例如，氨基酸1-21(SEQ ID NO：70)处的信号肽，其在被细胞分泌时被切割。因此，当作为纯化的多肽被施用时或当作为包含纯化的或基本上纯化形式的药物组合物被制备时，本发明的NRP1多肽陷阱缺少氨基酸1-21。编码本发明的NRP1陷阱的核酸(例如，SEQ ID NO：2、4、6、8、10、12、14、16、18、20、22、24、26、28、34、32、34、36、39、41、43、45、47等。同样参见表1)在5'中包含编码信号肽(在N末端编码前21个氨基酸的前63个核苷酸)的多核苷酸序列，其将允许NRP1陷阱由细胞合成和分泌。在具体实施方式中，信号肽对应于SEQ ID NO：65(图22)或SEQ ID NO：69(图26)中所示的NRP1多肽的前20个氨基酸。本发明的NRP1陷阱包括相应地“野生型”NRP1多肽或其片段的功能变体(例如，多态性变异在种群中自然发现)。
本发明的NRP1陷阱可或不可包括另外的多肽结构域(例如，纯化结构域)。缺少纯化结构域并且仅包含NRP1衍生序列的示例性陷阱在图27中显示。可依照本发明使用的NRP1陷阱的非限制性实例在图19B-F、图20、图27中给出并且在下面表1列出。
表1：依照本发明进行制备的示例性NRP1衍生陷阱。
SP：信号肽
鉴于NRP1明显地调节其配体对信号转导和细胞反应的作用，特异性抑制一种特异性配体与NRP1的结合而不抑制其它特异性配体的结合可能是有利的。例如，如本文所示，在视网膜疾病的早期时间点，其中SEMA3A水平升高，VEGF保持低水平并且与非糖尿病对照相比相对未改变。同样，在感染性休克中，SEMA3A是在诱导败血症后唯一具有长效作用并且持续上调多于24小时的NRP1配体。因此，鉴于每种配体表达动力学的不同和一种配体(例如，VEGF)的中和在某些状况中可能无效(或与不期望的副作用有关)的事实，特异性抑制一种配体(例如，SEMA3A)与NRP1的结合(但不抑制其它配体(一种或多种)(例如，VEGF))是有优势的。因此，在本发明方法的某些方面，通过提供对SEMA3比VEGF具有更大亲合力或不与VEGF(例如，VEGF165)结合或基本上不与VEGF(例如，VEGF165)结合的NRP1陷阱来完成SEMA3A介导的细胞信号传导的抑制。
因此，在一个实施方式中，本发明的可溶性NRP1多肽或其功能片段或变体(NRP1陷阱)结合所有的NRP1的天然配体(例如，SEMA3A、VEGF和TGF-β，例如，包含胞外结构域(例如，SEQ ID NO：66或69的氨基酸22-856或22-959)、陷阱1(SEQ ID NO：1)或陷阱G(SEQ ID NO：38)的可溶性NRP1陷阱，同样参见图19和27和表1)。在一个实施方式中，本发明的NRP1衍生陷阱通过与SEMA3A和VEGF两者结合而抑制SEMA3和VEGF信号传导。
在另一实施方式中，本发明的NRP1陷阱是与SEMA3A结合而不与VEGF结合的多肽。例如，NRP1陷阱可包含与SEMA3A结合的a1(例如，SEQ ID NO：71)和/或a2亚域(一种或多种)(例如，SEQ ID NO：72)，但不包含VEGF结合所需的b1(例如，SEQ ID NO：73)和/或b2(例如，SEQ ID NO：74)亚域(一种或多种)(例如，陷阱M，(SEQ ID NO：42)、陷阱N(SEQ ID NO：44)、陷阱12/陷阱K(SEQ ID NO：23)、陷阱4(SEQ ID NO：7)、陷阱7/C(SEQ ID NO：13)，同样参见图19和27和表1)。在一个实施方式中，NRP1衍生陷阱包含结构域a1和a2，其对应于图26中所示的NRP1氨基酸序列的氨基酸22至275(例如，SEQ ID NO：66的氨基酸22-275或SEQ ID NO：69的SEQ ID NO：22-275)。NRP1陷阱也可包含显著地消除或降低VEGF与NRP1结合但不消除或降低SEMA3A与NRP1结合的突变(例如，缺失或取代)(例如，陷阱8/陷阱J(SEQ ID NO：15)、陷阱9(SEQ ID NO：17)、陷阱10(SEQ ID NO：19)、陷阱11/L(SEQ ID NO：21)、陷阱12/K(SEQID NO：23)、陷阱U(SEQ ID NO：34)、陷阱R(SEQ ID NO：46)、陷阱Q(SEQ ID NO：48)、陷阱P(SEQ ID NO：50、陷阱X(SEQ ID NO：54、陷阱AC(SEQ ID NO：60)、陷阱Z(SEQ ID NO：62)，同样参见图19和27和表1)。此类突变的一个非限制性实例是NRP1的b1结构域中的酪氨酸297处的取代(例如，Y297A，图19B-D、图27和表1，例如，陷阱8、9、10、11、12、V、R、Q、P和X)。此类突变的其它实例包括NRP1中的位置319处的谷氨酸和位置320处的天冬氨酸的取代(例如，如陷阱AC和Z(SEQ ID NO：60，62)中的E319K和D320K)。
在另一实施方式中，NRP1陷阱是与VEGF结合但不与SEMA3A结合的可溶性NRP1多肽或其功能片段或变体。例如，NRP1陷阱可包含与VEGF结合的b1(例如，SEQ ID NO：73)和/或b2(例如，SEQ ID NO：74)结构域(一个或多个)，但不包含与SEMA3A结合的a1(例如，SEQ IDNO：71)和/或a2(例如，SEQ ID NO：72)亚域(一个或多个)。在一个实施方式中，NRP1陷阱包含结构域b1b2，其对应于图26中所示的NRP1氨基酸序列的氨基酸276至589(例如，SEQ IDNO：66的氨基酸276-589或SEQ ID NO：69的276-289)。在另一实施方式中，NRP1陷阱可包含降低或消除SEMA3A结合而不是VEGF结合的突变。此类突变的一个非限制性实例是NRP1的丝氨酸346和/或谷氨酸348处的取代(例如，如陷阱AB(SEQID NO：58)中的S346A和E348K突变，同样参见图19和27)。
在一个实施方式中，可溶性NRP1多肽或其功能片段包括如图19B-F、20、27和表1中所示的陷阱或由如图19B-F、20、27和表1中所示的陷阱组成。
在优选的实施方式中，本发明的NRP1陷阱缺少在例如NRP1同种型1中发现的跨膜结构域(例如，对应于图26中所示NRP1多肽序列的氨基酸残基860至883(如SEQ ID NO：66和69))和胞质结构域(例如，对应于图26中显示的NRP1多肽同种型1序列(如SEQ ID NO：66和69)的氨基酸残基884-923)。在实施方式中，本发明的NRP1陷阱完全或部分地缺少NRP1的结构域c。NRP1同种型1包含更长的c结构域(参见图26)，而同种型2的c结构域较短(例如，图22中所示的氨基酸序列VLATEKPTVIDSTIQSGIK(SEQ ID NO：99))。具体地，结构域c不是SEMA3A和VEGF结合所必须的并且因此可从用于抑制NRP1依赖性细胞信号传导(或SEMA3A介导的细胞信号传导)的NRP1陷阱中排除。在一个实施方式中，NRP1陷阱缺少对应于图26中所示的NRP1氨基酸序列的氨基酸590至859(例如，SEQ ID NO：66或SEQ ID NO：69的氨基酸590至859)的c结构域。在实施方式中，本发明的NRP1陷阱完全或部分地缺少如图22中所示的同种型2的c结构域(例如，SEQ ID NO：99)。在实施方式中，本发明的NRP1陷阱包含NRP1同种型2的结构域c。在另一实施方式中，NRP1衍生陷阱缺少对应于SEQ ID NO：75中所示的氨基酸的结构域c的部分。
本发明的可溶性NRP1多肽或其功能片段或变体可包含一种或多种另外的多肽结构域(一个或多个)以增加体内稳定性和/或促进纯化。例如，本发明的NRP1陷阱可包含FC结构域(或其部分如SEQ ID NO：37中所示的人FC结构域)或纯化标签(例如，6X-组氨酸标签)。可直接或间接地(通过连接体)将此类另外的多肽结构域(一个或多个)连接至可溶性NRP1多肽或其功能片段。
本发明的可溶性NRP1多肽或其功能片段可任选地包含一个或多个多肽连接体。此类连接体可用于将一个或多个另外的多肽结构域(一种或多种)连接至本发明的可溶多肽(例如，增加多肽体内稳定性的多肽结构域和/或促进多肽纯化的结构域)。连接体序列可任选地包含肽酶或蛋白酶切割位点，其可被用于移除一个或多个多肽片段或结构域(例如，在体内施用可溶性NRP1多肽或其功能片段之前纯化标签的移除)。能够切割多肽和移除，例如，多肽结构域(一个或多个)(例如，6×组氨酸(his)标签纯化结构域)的连接体或结构域的一个非限制性实例包括包含TEV蛋白酶切割位点(例如，GSKENLYFQ’G，SEQ ID NO：76)的多肽。很多其它TEV切割位点和很多其它蛋白酶/肽酶切割位点是技术人员已知的，并且可被引入至本发明的多肽以任选地移除一个或多个多肽结构域或片段。
多肽连接体也可被用于完全或部分地替代一般在野生型NRP1多肽中发现但在本发明的可溶性NRP1多肽或其功能片段中不存在的结构域。例如，在本发明的NRP1陷阱中，合成的连接体可完全或部分地替代结构域a1、a2、b1、b2和c。连接体的长度可对应于移除的结构域的全部长度或对应于其部分。此类连接体可增加蛋白质折叠、稳定性或与NRP1配体结合。图19和20中显示了包含连接体的NRP1陷阱的非限制性实例(例如，表1中所列的陷阱2、陷阱3、陷阱4、陷阱9和陷阱10)。有用多肽连接体的一个非限制性实例是聚精氨酸多肽。其它连接体在本领域中已知并且可依照本发明进行使用。
在实施方式中，本发明的NRP1陷阱包括：(i)图26中所示的NRP1多肽(SEQ ID NO：69)的氨基酸1-856(优选地，22至856)；(ii)图26中所示的NRP1多肽(SEQ ID NO：69)的氨基酸1至583(优选地22至583)；(iii)图26中所示的NRP1多肽(SEQ ID NO：69)的氨基酸1至424(优选地22-424)；(iv)图26中所示的NRP1多肽(SEQ ID NO：69)的氨基酸1至265(优选地22至265)；(v)图26中所示的NRP1多肽(SEQ ID NO：69)的1至430和584至856(优选地22-430和584-856)；(vi)图26中所示的NRP1多肽(SEQ ID NO：69)的氨基酸1至274和584至856(优选地22-274和584至856)；(vii)图26中所示的NRP1多肽(SEQ ID NO：69)的氨基酸1至430和584(优选地22至430和584至856)。在具体实施方式中，以上指出的陷阱包含一个或多个突变以降低如上所述的VEGF或SEMA3A结合。
在相关方面，本发明提供编码NRP1陷阱(例如，表1中所列和图19、20和27上所示的陷阱)的核酸。此类核酸可被包含在用于在细胞中表达的表达载体中。因此，本发明进一步涉及包含编码可溶性NRP1多肽或其功能片段的核酸的载体和包含此类表达载体的细胞。编码本发明的可溶性NRP1多肽或其功能片段(即，NRP衍生陷阱)的核酸可包括编码用于细胞分泌的信号序列(例如，编码SEQ ID NO：65、66或69或SEQ ID NO：70的氨基酸1-21)的多核苷酸部分。此外，本发明的核酸包括在其3’端具有和不具有翻译终止”终止”密码子的核酸。可提供翻译终止终止密码子——例如，通过本发明的核酸可被克隆到其中的表达载体。
如本发明中所用的，NRP1的“功能片段”或“功能变体”(例如，本发明的可溶性NRP1多肽或多核苷酸的功能片段，如NRP1)是指基本上保持与原始分子相同的期望活性的分子，但其经任意修饰，和/或氨基酸/核苷酸取代、缺失或添加(例如，与另一个多肽融合)而不同。修饰可在任何地方发生，包括多肽/多核苷酸主链(例如，氨基酸序列、氨基酸侧链和氨基或羧基末端)。此类取代、缺失或添加可涉及一个或多个氨基酸或在多核苷酸的情况下，一个或多个核苷酸。取代优选是地保守的，即，氨基酸被本领域普通技术人员所熟知的具有相似理化性质(大小、疏水性、电荷/极性等)的另一种氨基酸所替代。可溶性NRP1的功能片段包括可溶性NRP1多肽的片段或部分(例如，a1和/或a2结构域(一个或多个))或NRP1的同源物或等位基因变体的片段或部分，其保持抑制活性——即，与SEMA3A、VEGF和/或TGF-β结合和抑制NRP1介导的细胞活性的转导。NRP1介导的细胞活性的非限制性实例包括i)血管通透性过高；ii)MP活化和募集；iii)凋亡的诱导；iv)促炎性细胞因子(例如，TNF-α，IL-1β)产生和/或分泌的诱导。在实施方式中，NRP1多肽与图22的多肽序列(NRP1同种型2，SEQ IDNO：65)或图26中所示的NRP1同种型1(SEQ ID NO：66和69)的氨基酸1-859或22-859具有至少80、85、88、90、95、98或99％的同一性。在实施方式中，NRP1功能片段包括亚域a1、a2、b1、b2和/c，其与图22或26中所示的NRP1(分别地SEQ ID NO：65和66)的亚域(一个或多个)a1(例如，SEQ ID NO：71或SEQ ID NO：66的氨基酸22-148)、a2(例如，SEQ ID NO：72，或SEQ IDNO：66的氨基酸149-275)、b1(例如，SEQ ID NO：73或氨基酸)、b2(例如，SEQ ID NO：74或SEQID NO：66的氨基酸429-589)和/或c(例如，SEQ ID NO：75或SEQ ID NO：66的氨基酸590-859)具有至少80、85、88、90、95、98或99％的同一性。在一个实施方式中，NRP1是包括在大鼠、小鼠和人NRP1之间不保守的氨基酸中的变异(保守或非保守取代(一个或多个)和/或缺失(一个或多个))的功能变体(参见图26和SEQ ID NO：69中所示的共有序列)。优选地，NRP1多肽/多核苷酸或其片段是人的。
表2：本发明的可溶性NRP1多肽/NRP1陷阱中的取代的非限制性实例。
抗体
通过使用阻断NRP1与一种或多种其配体(例如，SEMA3A、VEGF和/或TGF-β)的结合的剂可以抑制NRP1细胞活性。此类剂的一个实例是与NRP1结合并且阻断NRP1与SEMA3A、VEGF和/或TGF-β结合的抗体。
可选地，通过使用阻断NRP1配体与NRP1多肽结合的剂可以实现NRP1介导的细胞信号传导的抑制。此类剂的非限制性实例包括与SEMA3A、VEGF或TGF-β结合并且阻断其与NRP1各自结合的抗体。
在本发明的具体方面，靶向NRP1的抗体阻断SEMA3A与受体的结合但是基本上不干扰VEGF和/或TGF-β与NRP1结合。在一个实施方式中，抗NRP1抗体与NRP1多肽的a1a2结构域结合。在另一实施方式中，抗NRP1抗体与NRP1多肽的亚域a1或a2结合。
如上指出的，抗SEMA3A抗体可被用于通过阻断SEMA3A与NRP1结合而抑制(即，完全或部分地降低)NRP1介导的细胞信号传导。有用的抗SEMA3A抗体与SEMA3A的SEMA结构域结合并且阻断与NRP1的相互作用。在实施方式中，依照本发明使用的抗SEMA3A抗体包括与SEMA3A多肽结构域结合的抗体，所述SEMA3A多肽结构域包含SEMA3A的氨基酸残基252-260、359-366或363-380。抑制SEMA3A与NRP1结合的SEMA3A抗体在本领域是已知的并且可依照本发明进行使用。
如本发明中所用的，表述“抗NRP1抗体”是指这样的抗体，其特异性地与NRP1蛋白质结合(与NRP1蛋白质相互作用)并且显示基本上不与除了与NRP1蛋白质共有相同抗原决定簇的蛋白质之外的其它天然存在的蛋白质结合。类似地，表述“抗SEMA3A抗体”、“抗VEGF抗体”或“抗TGF-β抗体”是指这样的抗体，其分别与SEMA3A、VEGF或TGF-β蛋白质特异性地结合(与SEMA3A、VEGF或TGF-β蛋白质相互作用)和显示基本上不与除了与所靶向的SEMA3A/VEGF/TGF-β蛋白质共有相同抗原决定簇的蛋白质的其它天然存在的蛋白质结合。
可以依照本发明使用的抗体包括多克隆、单克隆、人源化以及嵌合抗体。术语抗体或免疫球蛋白被以最广泛的含义使用，并且涵盖了单克隆抗体(包括全长单克隆抗体)、多克隆抗体、多特异性抗体和抗体片段——只要其显示期望的生物学活性。抗体片段包括全长抗体的部分，通常包括抗原结合或其可变区。抗体片段的实例包含由抗体片段形成的Fab、Fab'、F(ab')2和Fv片段、双抗体、线性抗体、单链抗体分子、单结构域抗体(例如来自骆驼科)、纳米抗体、鲨鱼NAR单结构域抗体、和多特异性抗体。抗体片段也可以是指包括CDR或抗原结合结构域的结合部分，其包括但不限于，VH区(VH，VH-VH)、anticalin、PepBodiesTM、抗体T细胞表位融合(Troybodies)或肽抗体(Peptidodies)。
抗人NRP1/sem3A/VEGF/TGF-β抗体已被在先制备并且也可商业得自各种货源，包括Santa Cruz、AbCam和Cell Signaling。
总而言之，制备抗体(包括当其序列已知时的单克隆抗体、杂交瘤和人源化抗体)和利用抗体检测抗原的技术是本领域所熟知的并且各种协议是熟知和可获得的。
NRP1或NRP1配体表达的抑制
可利用各种方法来降低NRP1或其配体(例如，SEMA3A、VEGF或TGF-β)的表达(在mRNA或蛋白质水平)以抑制NRP1介导的细胞信号传导并且因此降低炎症和先天免疫反应超活化(即，i)促炎性细胞因子的产生和/或分泌；ii)单核吞噬细胞(MP)的募集；iii)血管超透化(hyperpermeabilization)；和/或iv)水肿；v)神经元损伤、脉络膜新血管形成等)。非限制性实例包括使用靶向NRP1、SEMA3A、VEGF或Tgf-β启动子或类似物的小发夹shRNA(RNAi)、反义、核酶、TAL效应子。
通过质粒的递送或通过病毒(例如，慢病毒载体)或细菌载体可以获得shRNA、siRNA、反义寡核苷酸或类似物在细胞中的的表达。
因此，在可选的实施方式中，本发明提供用于外源施用的反义、shRNA分子和核酶以引起感兴趣的mRNA的翻译的减少和/或抑制。优选地，反义、shRNA分子和核酶靶向人NRP1、SEMA3A、VEGF和/或Tgf-β表达。治疗性反义寡核苷酸应用的实例包括：美国专利号5,135,917，发布于1992年8月4日；美国专利号5,098,890，发布于1992年3月24日；美国专利号5,087,617，发布于1992年2月11日；美国专利号5,166,195，发布于1992年11月24日；美国专利号5,004,810，发布于1991年4月2日；美国专利号5,194,428，发布于1993年3月16日；美国专利号4,806,463，发布于1989年2月21日；美国专利号5,286,717，发布于1994年2月15日；美国专利号5,276,019和美国专利号5,264,423；BioWorld Today，1994年4月29日，第3页。
优选地，在反义分子中，对于感兴趣的mRNA存在足够程度的互补性，以避免反义分子与非靶向序列的非特异性结合——在其中期望特异性结合的情况下，如在体内测定或治疗性处理的情况下或体外测定的情况下的生理条件下；在进行测定的条件下。用于反义结合的靶mRNA不仅可包含编码蛋白质的信息，还有相关的核糖核苷酸，其例如形成5'-非翻译区、3'-非翻译区、5'帽区和内含子/外显子连接核糖核苷酸。可被用于提供此类分子作为本发明的Shc抑制剂的筛选反义和核酶核酸的方法在美国专利号5,932,435中被公开。
本发明的反义分子(寡核苷酸)可包括包含糖间主链键合如磷酸三酯、甲基膦酸酯、短链烷基或环烷基糖间键合或短链杂原子或杂环糖间键合、硫代磷酸酯的那些和具有CH2--NH--O--CH2、CH2--N(CH3)--O--CH2(被称为亚甲基(甲基亚胺基)或MMI主链)、CH2--O--N(CH3)--CH2、CH2--N(CH3)--N(CH3)--CH2和O--N(CH3)--CH2--CH2主链(其中磷酸二酯是O--P--O--CH2)的那些。也可使用具有吗啉代主链结构的寡核苷酸(美国专利号5,034,506)。在可选的实施方式中，反义寡核苷酸可具有肽核酸(PNA，有时称为“蛋白质核酸”)主链，其中寡核苷酸的磷酸二酯主链可用聚酰胺主链替代，其中核苷碱基被直接或间接地结合至聚酰胺主链中的氮杂原子或亚甲基基团(Nielsen等，1991，Science 254：1497和美国专利号5,539,082)。磷酸二酯键可以被手性和对映异构体特异性的结构取代。本领域普通技术人员将能够选择其它键合用于本发明的实践中。
寡核苷酸也可包括含有至少一种修饰的核苷酸碱基的物质。因此，可以使用通常在自然界中发现的嘌呤和嘧啶以外的嘌呤和嘧啶。类似地，也可发生核苷酸亚基的呋喃戊糖基(pentofuranosyl)部分上的修饰。此类修饰的实例是2'-O-烷基-和2'-卤素取代的核苷酸。本发明中有用的糖部分的2'位置处的修饰的一些具体实例是OH、SH、SCH3、F、OCN、O(CH2)nNH2或O(CH2)nCH3，其中n为1至约10；C1至C10低级烷基、取代的低级烷基、烷芳基或芳烷基；Cl；Br；CN；CF3；OCF3；O-、S-、或N-烷基；O-、S-、或N-烯基；SOCH3；SO2CH3；ONO2；NO2；N3；NH2；杂环烷基；杂环烷芳基；氨基烷基氨基；聚烷基氨基；取代的甲硅烷基；RNA切割基团；报告基因基团；嵌入剂；提高寡核苷酸的药代动力学性质的基团；或提高寡核苷酸的药效学性质的基团和具有相似性质的其它取代基。一个或多个呋喃戊糖基基团可被另一种糖、被糖模拟物(sugar mimic)如环丁基或被取代糖的另一个部分所代替。
在一些实施方式中，根据本发明的反义寡核苷酸可包含约5至约100个核苷酸单元。如将会理解的，核苷酸单元是通过磷酸二酯或形成主链结构的其它键适当地结合至相邻核苷酸单元的碱基-糖组合(或类似结构的组合)。
在进一步的实施方式中，可使用RNA干扰(RNAi)技术(一类转录后的基因沉默)抑制或阻止编码感兴趣多肽(例如，SEMA3A或NRP1)或其片段的核酸表达。RNAi可被用于产生假的“敲除”，即这样的系统，其中由感兴趣的基因或编码区编码的产物的表达被降低，导致系统中编码的产物的活性全部降低。如此，可以进行RNAi靶向感兴趣的核酸或其片段或变体，以反过来降低其表达和其编码的产物的活性水平。此类系统可被用于产物的功能研究，以及治疗涉及此类产物活性的障碍。RNAi被描述于例如公开的美国专利申请20020173478(Gewirtz；21，2002年11月21日公开)和20020132788(Lewis等；2002年11月7日公开)。用于进行RNAi的试剂和试剂盒可市售自例如Ambion Inc.(Austin，TX，USA)和New EnglandBiolabs Inc.(Beverly，MA，USA)。
一些系统中的RNAi起始剂是对应于靶核酸的dsRNA分子。dsRNA(例如，shRNA)随后认为被裂解成短的干扰RNA(siRNA)，其长度为21-23个核苷酸(19-21bp双链体，每个具有2个核苷酸3’悬突)。认为影响此第一裂解步骤的酶已被称为“Dicer”并且被归类为dsRNA特异性核糖核酸酶的核糖核酸酶III家族的成员。可选地，可通过直接引入细胞中或通过将此类siRNA或siRNA样分子的适合前体(例如编码前体(一种或多种)的载体等)引入细胞中而在细胞内生成来进行(effect，引起)RNAi。siRNA可随后与其它胞内成分缔合以形成RNA诱导的沉默复合物(RISC)。由此形成的RISC可随后通过其siRNA成分和靶向转录物之间的碱基配对相互作用凭借同源性而靶向感兴趣的转录物，导致靶向转录物从siRNA的3’端裂解大约12个核苷酸。因此，靶mRNA被裂解并且其编码的蛋白质产物的水平降低。
可通过将适合的体外合成的siRNA(shRNA)或siRNA样分子引入至细胞中来进行(effect，引起)RNAi。例如可利用化学合成的RNA进行RNAi。可选地，适合的表达载体可被用于体外或体内转录此类RNA。可利用例如T7RNA聚合酶进行有义和反义链(由存在于相同载体或分离载体上的序列编码)的体外转录，在该情况下载体可包含可操作地连接至T7启动子的适合编码序列。体外转录的RNA可在实施方式中被体外加工(例如使用大肠杆菌核糖核酸酶III)至有益于RNAi的大小。将有义和反义转录物结合以形成RNA双链体，其被引入至感兴趣的靶向细胞中。可以使用表达可以被处理成siRNA样分子的小发夹RNA(shRNA)的其它载体。各种基于载体的方法和将此类载体引入至细胞中的各种方法(体外或体内)(例如基因治疗)在本领域中是已知的。
因此，在一个实施方式中，可以通过将siRNA或siRNA样分子引入至细胞内或在细胞内产生siRNA或siRNA样分子抑制编码感兴趣的多肽(或其片段例如，可溶性NRP1、NRP1衍生陷阱)的核酸的表达，所述siRNA或siRNA样分子对应于编码感兴趣的多肽(例如SEMA3A或NRP1)的核酸，或其片段，或对应于与其同源的核酸。“siRNA样分子”是指与siRNA相似的(例如在大小和结构上)并且能够诱发siRNA活性，即引起RNAi介导的表达抑制的核酸分子。在各种实施方式中，此类方法可能需要将siRNA或siRNA样分子直接施用至细胞中，或使用上述基于载体的方法。在一个实施方式中，siRNA或siRNA样分子长度小于约30个核苷酸。在进一步的实施方式中，siRNA或siRNA样分子长度为约21-23个核苷酸。在一个实施方式中，siRNA或siRNA样分子包含19-21bp双链体部分，每条链具有2个核苷酸3’悬突。在实施方式中，siRNA或siRNA样分子与编码感兴趣的多肽，或其片段或变体(或变体的片段)的核酸基本上相同。此类变体能够编码具有与感兴趣的多肽类似的活性的蛋白质。
多种病毒载体可以被用于获得细胞中的shRNA/RNAi表达，包括腺相关病毒(AAV)、腺病毒、和慢病毒。使用腺相关病毒和腺病毒，基因组保持游离(episomal)。这是有优势的，因为避免了插入诱变。其不利之处在于细胞的后代将通过细胞分裂快速失去病毒，除非细胞分裂非常缓慢。AAV与腺病毒的不同之处在于病毒基因已被除去并且它们具有减少的包装能力。慢病毒整合到转录活性染色质的部分中，并因此传递给后代细胞。使用这种方法，存在插入诱变增加的风险；然而，可以通过使用整合酶缺陷型慢病毒来降低风险。
药物组合物和试剂盒
本发明的抑制NRP1依赖性细胞信号传导的剂(即，NRP1抑制剂)可以通过其自身或在药物组合物中——其中其与剂量下的适合的载体或赋形剂(一种或多种)混合——施用至人受试者，以治疗或预防靶向的疾病或状况或提高所期望的细胞反应。
这些化合物(例如，NRP1陷阱、抗体、显性失活(dominant negative)的小抑制肽或类似物)的混合物也可以作为简单混合物或以适合的制剂药物组合物施用至受试者。治疗有效剂量进一步是指足以导致预防或治疗靶向的炎性疾病或状况(例如，如感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症、糖尿病、葡萄膜炎和神经炎性状况如糖尿病性视网膜病变、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病)或提供所期望的细胞或生理反应的化合物或多种化合物的量(例如，所述量足以i)降低水肿；ii)降低单核吞噬细胞(例如，小胶质细胞或巨噬细胞)的活化/募集；iii)降低炎性细胞因子(例如，IL-1β、TNF-α、IL-6等)的产生或分泌；iv)降低病理新血管形成；v)降低血管变性等)。
如本发明中所用的“药学可接受载体”或“赋形剂”包含任意和所有的生理上可相容的溶剂、分散介质、包衣、抗细菌和抗真菌剂、生理介质、和类似物。在实施方式中，载体适合于眼部施用。在其它实施方式中，载体适合于全身施用。在其它实施方式中，载体适合于口服施用。
药学可接受载体包括无菌水溶液或分散体和用于临时制备无菌可注射溶液或分散体的无菌粉末。此类介质和剂的使用——如用于眼部、全身或口服应用——在本领域中是熟知的。除非任何常规介质或剂与本发明的化合物不相容，否则考虑将其用于本发明的组合物中。补充活性化合物也可以掺入组合物中。
在“Remington's Pharmaceutical Sciences”Mack Publishing Co.,Easton，PA(最新版)中可以发现配制和施用本申请的化合物的技术。
本发明也涉及用于本发明的方法的试剂盒或商业包装。此类试剂盒可包含本发明的化合物(例如，抑制NRP1细胞信号传导——包含SEMA3A介导的细胞信号传导——的化合物，如陷阱、抗体、shRNA、细胞、载体、核酸)，及可选地使用该试剂盒的说明书。
施用/配制的途径
适合的施用途径可，例如，包括全身用、口服和眼(滴眼或眼内注射)。优选的施用途径包含用于眼状况的滴眼和眼内注射施用、用于慢性炎性状况的口服施用和用于败血症和某些神经元状况如中风的全身施用。制剂也可以是持续释放制剂的形式。
因此，可以利用一种或多种包括促进将活性化合物加工成可以药学使用的制剂的赋形剂和助剂的生理可接受载体，以传统方式配置依照本发明使用的药物组合物。适当的制剂取决于所选择的施用途径。对于注射，可以水溶液——优选在生理上可相容的缓冲液如Hanks's溶液、Ringer's溶液、或生理盐水缓冲液——来配制本发明的剂。
化合物可被配制用于眼施用例如，滴眼或眼注射。注射用制剂可以单位剂型(例如，在安瓿或多剂量容器中)存在，添加防腐剂。组合物可采取在油性或水性媒介物中的悬浮液、溶液或乳液的形式，并且可包含配制剂如助悬剂、稳定剂和/或分散剂。此外，某人可以在靶向药物递送系统——例如用细胞特异性抗体包被的脂质体——或其它递送系统中施用药物(例如以靶向例如特定组织(例如脑)或细胞类型(例如，小胶质细胞或巨噬细胞))。纳米系统和乳液是药物递送媒介物或载体的另外熟知的实例。另一个实例是用于眼睛疾病的来自Neurotech的微囊化细胞疗法(Encapsulated Cell Therapy，ECT)递送系统。ECT是一种基因工程眼部植入物，其能够向眼连续产生治疗性蛋白质2年以上。此外，通过简单地移除植入物，治疗是可逆的。将ECT植入物通过单个切口插入玻璃体并在20分钟的门诊手术操作中适当地被缝合。
有效剂量
适合用于本发明的药物组合物包括其中包含有效量活性成分以实现其预期目的组合物。更具体地，治疗有效量是指有效阻止被治疗受试者的现有症状的发展或减轻被治疗受试者的现有症状的量。有效量的确定完全在本领域技术人员的能力范围内。
有效剂量的化合物抑制NRP1的细胞信号传导功能，足以降低或阻止一种或多种生理或细胞反应(例如，血管通透性过高、血液视网膜屏障渗漏、水肿、MP活化和/或募集、促炎性细胞因子产生和/或分泌、新血管形成、神经元损伤等)或预防或治疗给定的炎性疾病或状况，而不引起明显的负面影响。可以通过确定NRP1介导的细胞信号传导抑制剂(例如，直接靶向NRP1的表达或活性的剂或靶向NRP1配体的表达或活性(例如，结合)的剂)的剂量依赖性抑制的体外检验鉴定具有此类活性的某些化合物。
对于本发明的方法中所使用的任意化合物，可以根据细胞检验初步估计治疗有效剂量。例如，可以在细胞和动物模型中配制剂量以实现包括在细胞检验中测定的IC50的循环浓度范围(即，通常响应于炎性介导剂如IL-1β或其它活化刺激如缺氧、局部缺血、细胞应激、ER应激等，实现NRP1的细胞信号传导功能的半最大抑制的测试化合物的浓度)。
治疗有效量是指致使受试者症状改善的化合物的量。类似地，预防有效量是指阻止或延缓患者症状(例如，NRP1介导的血管通透性过高、斑点和/或模糊视觉、周细胞损失、黄斑水肿、视网膜肿胀、血液视网膜屏障渗漏、单核吞噬细胞募集、促炎性细胞因子的产生和分泌、血管变性、病理新血管形成、神经元损伤等)所必须的量。此类化合物的毒性和治疗功效可以通过细胞培养物或实验动物中的标准药学程序确定，例如确定最大耐受剂量(MTD)和ED(50％最大反应的有效剂量)。毒性和治疗效果之间的剂量比是治疗指数，并且其可以表达为MTD和ED 50之间的比率。显示高治疗指数的化合物是优选的。确切的制剂、施用途径和剂量可以由个体医生根据患者的状况来选择。
可以单独调整剂量的量和间隔以提供足以维持NRP1调节作用或最小有效浓度(MEC)的活性化合物的水平。MEC对于每种化合物将不同，但可以从体外数据估计；例如实现SEMA3A表达或活性(例如，与NRP1受体的结合)大量抑制所必需的浓度。实现MEC所必需的剂量将取决于个体特征和施用途径。
当然，施用的组合物的量将取决于被治疗的受试者，取决于受试者的体重、痛苦的严重程度、施用方式和处方医师的判断。
定义
为明确起见，在本发明的上下文中提供了以下术语的定义。
如本发明中所用的，术语“神经毡蛋白-1受体”或“NRP1”受体是指神经毡蛋白-1和其同种型，和等位基因/多晶型物(例如，HGNC：8004；Entrez Gene：8829；Ensembl：ENSG00000099250；OMIM：602069；和UniProtKB：O14786；GenBank登录号AAH07737.1，图22，SEQ ID NO：65)。NRP1是非酪氨酸激酶多功能受体，其具有通过其胞外结构域上的不同位点结合三种结构上不同的配体的特定能力。其结合SEMA3A18,19(例如引起细胞骨架塌陷)和VEGF165，增强与VEGFR2的结合(例如增加其血管生成潜能)。它还结合TGF-β。此外，遗传研究表明NRP1明确调节VEGF和SEMA3A对神经元和血管发育的影响。因此，根据配体，NRP1介导的细胞反应不同。
神经毡蛋白-1的基本结构包含5个结构域：三个胞外结构域(a1a2(CUB)、b1b2(FV/FVIII)和c(MAM))、跨膜结构域和胞质结构域(参见图19A和22和SEQ ID NO：65和66和68)。a1a2结构域与通常包含4个形成二硫键的半胱氨酸残基的补体成分C1r和C1s(CUB)同源。此结构域结合SEMA3A。结构域b1b2(FV/FVIII)与VEGF结合。亚域b1中的氨基酸Y297对于与VEGF的结合是重要的，因为将Y297取代为丙氨酸显著地降低VEGF与NRP1结合。存在NRP1的几种剪接变体同种型和可溶形式，其均包括在本发明中。
“同源性”和“同源”是指两种肽或两种核酸分子之间的序列相似性。可以通过比较比对序列中的每个位置来确定同源性。核酸之间或氨基酸序列之间的同源性程度是序列所共有的位置处相同或匹配的核苷酸或氨基酸的数目的函数。如本发明中所用的术语，如果两个序列基本上相同并且序列的功能活性是保守的，则核酸/多核苷酸序列与另一个序列“同源”(如本发明所使用的，术语“同源”不推断进化相关性)。如果在最佳比对(允许缺口)时，两个核酸序列共有至少约50％的序列相似性或同一性，或如果序列共有限定的功能基序，则认为两个核酸序列基本上相同。在可选的实施方案中，最佳比对的基本上相同序列中的序列相似性可以具有至少60％、70％、75％、80％、85％、90％、95％、98％或99％同一性。如本发明所用的，序列之间给定百分比的同源性表示最佳比对序列中的序列同一性程度。“不相关”或“非同源”序列与本发明公开的任何核酸和多肽共有小于40％的同一性，但优选小于约25％的同一性。
基本上互补的核酸是其中一个分子的互补物与另一个分子基本上相同的核酸。如果在最佳比对时，两个核酸或蛋白质序列共有至少约70％的序列同一性，则认为两个核酸或蛋白质序列基本上相同。在可选的实施方式中，序列同一性可以例如为至少75％、至少80％、至少85％、至少90％、至少95％、至少98％或至少99％。用于比较同一性的序列的最佳比对可以使用多种算法进行，如Smith和Waterman,1981,Adv.Appl.Math 2:482的局部同源性算法、Needleman和Wunsch,1970,J.Mol.Biol.48:443的同源性比对算法、Pearson和Lipman,1988,Proc.Natl.Acad.Sci.USA 85:2444的相似性搜索法、和这些算法的计算机化执行(如Wisconsin Genetics软件Package,Genetics Computer Group,Madison,WI,U.S.A.中的GAP、BESTFIT、FASTA和TFASTA)。也可使用Altschul等,1990,J.Mol.Biol.215:403-10中描述的BLAST算法(利用公开的默认设置)确定序列同一性。用于进行BLAST分析的软件可以通过国家生物技术信息中心(National Center for BiotechnologyInformation；网址为http://www.ncbi.nlm.nih.gov/)获得。BLAST算法包括首先通过鉴定查询序列中长度为W的短字来鉴定高分序列对(high scoring sequence pair，HSP)，当与数据库序列中相同长度的字比对时，所述短字匹配或满足一些正值阈值得分T。T被称为相邻字分数阈值(neighbourhood word scorethreshold)。初始相邻字命中(initialneighbourhood word hit)充当启动搜索以找到更长的HSP的起源(seeds，种子)。单词命中沿着每个序列在两个方向上延伸，只要可以增加累积比对得分。当满足以下参数时，停止在每个方向上的单词命中的延伸：累积比对得分从其最大实现值下降量X；由于一个或多个负得分残基比对的累积，累积分数变为零或以下；或达到任一序列的末端。BLAST算法参数W、T和X确定比对的灵敏度和速度。BLAST程序可以使用默认值：字长(W)为11、BLOSUM62评分矩阵(Henikoff和Henikoff,1992,Proc.Natl.Acad.Sci.USA 89:10915-10919)比对(B)为50、期望值(E)为10(或1或0.1或0.01或0.001或0.0001)、M＝5、N＝4、以及两条链的比较。使用BLAST算法的两个序列之间的统计相似性的一个量度是最小总和概率(P(N))，其提供了两个核苷酸或氨基酸序列之间的匹配偶然发生的概率的指示。在本发明的可选实施方案中，如果测试序列比较中的最小总和概率小于约1，优选小于约0.1，更优选小于约0.01，最优选小于约0.001，则核苷酸或氨基酸序列被认为是基本上相同的。
两个核酸序列基本上互补的可选指示是两个序列在中等严格条件或优选严格条件下彼此杂交。在中等严格条件下与过滤器结合序列的杂交可以例如于65℃下在0.5MNaHPO4、7％十二烷基硫酸钠(SDS)、1mM EDTA中进行，并于42℃在0.2×SSC/0.1％SDS中洗涤(参见Ausubel等(编辑),1989,Current Protocols in Molecular Biology,第1卷,Green Publishing Associates,Inc.和John Wiley&Sons,Inc.,New York,p.2.10.3处)。可选地，在严格条件下与过滤器结合序列的杂交可以例如于65℃下在0.5M NaHPO4、7％SDS、1mM EDTA中进行，并且于68℃下在0.1×SSC/0.1％SDS中洗涤(参见Ausubel等(编辑),1989,同上)。杂交条件可以根据已知方法根据感兴趣的序列进行修改(参见Tijssen,1993,Laboratory Techniques in Biochemistry and Molecular Biology--Hybridizationwith Nucleic Acid Probes,第I部分,第2章"Overview of principles ofhybridization and the strategy of nucleic acid probe assays",Elsevier,NewYork)。通常，将严格条件选择为在限定离子强度和pH下比特定序列的热熔点低约5℃。例如，在一个实施方式中，本发明的化合物是与NRP1或SEMA3A核酸序列(优选人序列)杂交的反义/RNAi或shRNA。
如本发明中所用的，关于炎性疾病或状况(例如，视网膜病变、脑缺血、中风、败血症等)的术语“治疗(treating)”或“治疗(treatment)”的意思是指与所述疾病或状况有关的一种或多种症状或病理生理反应的降低/改善。非限制性实例包括水肿、肿胀、瘙痒、疼痛、血管通透性过高；血液视网膜屏障完整性、SEMA3A、VEGF和/或TGF-β表达增加、单核吞噬细胞募集/趋化性、促炎性细胞因子的产生和/或分泌、血管或神经元退化等。
如本发明中所用的，关于炎性疾病或状况的术语“预防(preventing，阻止)”或“预防(prevention，阻止)”的意思是指与疾病或状况有关的至少一种症状的进展减少或延缓发生。
本发明中使用的冠词“一个或一种((a)，(an))”和“该”是指一个或多于一个(即至少一个)冠词语法对象
本发明中使用的术语“包含(including)”和“包括(comprising)”的意思是短语“包含但不限于”和“包括但不限于”，并且可与其互换使用。
本发明中使用的术语“如”是指短语“如但不限于”，并且可与其互换使用。
通过以下非限制性实施例进一步详细说明本发明。
实施例1
材料和方法(实施例2-9和12)
LyzM-cre/Nrpfl/fl小鼠的产生。从Jackson实验室(The Jackson Laboratory)购买C57Bl/6野生型(WT)。从Jackson实验室购买LyzM-Cre(Lyz2tm1(cre)Ifo/J；号码004781)和NRP1floxed小鼠(Nrp1tm2Ddg/J；号码005247)并且喂养以获得缺乏NRP1的骨髓细胞的LyzM-cre/Nrpfl/fl。
O2诱导的视网膜病变。从出生后7天(P7)至12天将小鼠幼崽(WT或LyzM-Cre(Jackson实验室)或LysM-Cre/Nrp1fl/fl)和其代孕母亲(CD1，Charles River)暴露于75％O2并且返回至室内空气(52)。该模型充当人眼新生血管性疾病如糖尿病性视网膜病变的代替物，其特征在于破坏性病理性血管生成的晚期阶段(53，54)。一经返回至室内空气，缺氧造成的新血管形成(NV)从P14向前发展(26)。在不同时间点摘除眼并且解剖视网膜用于如所述的FACS分析或mRNA分析。在其它实验中，将解剖的视网膜铺片(flatmount)并用荧光素化的(fluoresceinated)异凝集素B4(1：100)在1mM CaCl2中温育过夜，以利用ImageJ和SWIFT-NV方法在P17时确定无血管面积或新血管形成面积的程度(55)。
消化的视网膜和脾的FACS。将来自WT或LysM-Cre/Nrp1fl/fl小鼠的视网膜匀化并且于37℃在750U/mL脱氧核糖核酸酶I(Sigma)和0.5mg/mL的胶原酶D(Roche)的溶液中温育15min，并轻轻振动。随后用70μm细胞滤器过滤匀化物并且在PBS+3％胎牛血清中洗涤。将脾样本匀化并且在37℃用1mg/mL的胶原酶D温育10min。在PBS+3％胎牛血清中洗涤匀化物，将小球(pellet，沉淀)重悬并且于室温在裂解缓冲液(10mM KCHO3；150mM NH4Cl；0.1mM EDTA)中温育5min。在室温用LEAFTM纯化的抗小鼠CD16/32(Biolegend)温育细胞悬浮液(视网膜或脾)15min以阻断Fc受体。随后于室温用以下抗体温育细胞30min：FITC抗小鼠/人CD11b(Biolegend)、PE/CY7抗小鼠Ly-6G/Ly-6C(Gr-1；Biolegend)、Pacific blueTM抗小鼠F4/80(Biolegend)、7AAD(BD Biosciences)和抗m神经毡蛋白(mNeuropilin)-1别藻蓝蛋白结合的大鼠IgG2A(R&D Systems)或同型对照别藻蓝蛋白结合的大鼠IgG2A(R&DSystems)。
为了分析CX3CR1和CD45表达，使用补充有Alexa Fluor 700抗小鼠CD45.2(Biolegend)和抗小鼠CX3CR1藻红蛋白结合的山羊IgG(R&D Systems)或山羊IgG同型的上述抗体进行另外的胞外染色。在LSRII(BD Biosciences)装置上进行对照藻红蛋白结合的FACS并且使用FlowJoTM软件(7.6.5版)分析数据。
BrdU注射。经历OIR或保持在含氧量正常的条件下的野生型小鼠在P13时以1mg/小鼠的剂量被腹膜内地注射溶解于PBS中的5-溴-2-脱氧尿苷(BrdU；Sigma)。
BrdU掺入的分析。在来自P14WT小鼠的视网膜细胞上进行染色。如上所述获得样本。如上所述进行胞外染色(CD45.2(中/低)；Gr-1-；CD11b+，F4/80+；7AAD)。随后用Cytofix/CytopermTM缓冲液(BD Biosciences)将细胞固定30min并且用Perm/WashTM缓冲液(BD Biosciences)透化10min。接下来，于37℃用300ug/mL的脱氧核糖核酸酶处理细胞1h并且用Perm/WashTM洗涤。于4℃使用抗BrdU-PE抗体(Ebioscience)或同型对照PE结合的小鼠IgG1 κ(Ebioscience)进行BrdU胞内染色25min。细胞随后在Perm/WashTM中洗涤并且在LSRII(BD Biosciences)上的FACS分析之前在PBS+3％胎牛血清中重悬。
玻璃体切割术。先前诊断患有PDR的所有受试者被随访并且由一个玻璃体视网膜外科医生(FAR)进行手术。对照患者经历由相同的外科医生进行的非血管性病理(ERM(视网膜前膜)或MH(黄斑裂洞))的外科治疗。在手术室环境中，患者在局部眼球后/眼球周麻醉下经历外科手术。使用5％聚维酮碘溶液来清洁眼周皮肤，并且局部滴入眼并留在在陷凹内某个位置5分钟。通过25-gauge阀门插管(Alcon)进行三端口25-gauge结膜睫状环玻璃体切割术(three-port 25-gauge transconjunctival pars plana vitrectomy)。在使用广角观察系统(ResightTM，Zeiss)的显微镜可视化下，用25-gauge波切头(vitrector)收集未稀释的玻璃体。在玻璃体活检之后，打开注入管线并且以常规方式进行玻璃体切割术和膜剥离以治疗糖尿病性玻璃体出血和牵引性视网膜脱离。这之后是全视网膜眼内激光凝固(panretinal endolaser photocoagulation)、流体-空气交换和玻璃体内抗VEGF注射。
通过ELISA量化SEMA3A蛋白质。在活检后立即在干冰上冷冻玻璃体样本并且储存于-80°。在分析之前于4℃下以15000x g离心样本5分钟。根据制造商的说明书(USCN LifeScience Inc.)使用酶联免疫吸附测定(ELISA)量化上清液中SEMA3A水平。
通过蛋白质印迹评价SEMA3A蛋白质水平。来自PDR和对照患者的等体积玻璃体液体(20uL)通过标准SDS-PAGE技术评价SEMA3A的存在(Abcam)。
实时PCR分析。使用GenEluteTM哺乳动物总RNA小量提取试剂盒(Mammalian TotalRNA Miniprep Kit，Sigma)分离RNA并且用脱氧核糖核酸酶I(DNase I)消化以阻止基因组DNA的扩增。在ABIBiosystems实时PCR仪中使用M-MLV逆转录酶(Life Technologies)进行逆转录并且使用SybrTM Green (BioRad)分析基因表达。β-肌动蛋白用作参考基因(关于所使用的寡核苷酸的序列的细节参见实施例10中的表2)。
免疫组织化学。为了使全视网膜脉管系统可视化，使用用于视网膜脉管系统和抗大鼠神经毡蛋白-1抗体(山羊IgG；R&D Systems)和IBA1(兔多克隆的；Wako)的PBS中的1mMCaCl2中罗丹明标记的Griffonia(Bandeiraea)Simplicifolia凝集素I(VectorLaboratories，Inc.)将铺片视网膜染色。
原代腹膜巨噬细胞培养。用氧(2L/min)中2％异氟烷将成年WT或LyzMcre/NRP1fl/fl小鼠麻醉并且随后通过颈椎脱位进行安乐死。随后，产生小鼠腹部皮肤中的小切口。将皮肤拉至每个小鼠尺寸并且用5ml的PBS加3％FBS洗涤腹膜腔2min。随后，以1000rpm将收获的细胞离心5min，在培养基(DMEM F12加10％FBS和1％链霉素/青霉素)重悬并且铺板。在37℃，5％CO2气氛下培养1h后，更换培养基并且在相同条件下将细胞再培养24h，之后用于细胞因子或细胞迁移(transwell migration)测定。
细胞迁移测定。在具有8μm孔插入物的24孔板中进行迁移测定。将重悬浮于200μl培养基(DMEM F12加10％FBS和1％链霉素/青霉素)中的原代腹膜巨噬细胞(5×105细胞)添加至上室。将具有或不具有迁移因子：MCP-1(100ng/ml)、SEMA3A(100ng/ml)、和VEGF165(50ng/ml)的800μl培养基添加至下室。细胞被允许在5％CO2空气下于37℃过夜细胞迁移穿过插入膜。在一些实验中，首先在37℃用Y-27632(Sigma)——选择性ROCK(Rho相关卷曲螺旋形成蛋白质丝氨酸/苏氨酸激酶(Rho-associated coiled coil froming proteinserine/threonine kinase))抑制剂(100μg/ml)——预处理细胞1h。随后用PBS洗涤插入物，并且用棉签从插入膜的上表面擦拭未迁移细胞。随后用4％多聚甲醛(PFA)固定具有迁移细胞的膜20分钟，用PBS洗涤两次并且置于载玻片上。使用具有DAPI(VectorLaboratories，Inc.)的封固剂将细胞染色。随后，使用倒置荧光显微镜以20×放大率对每个膜拍摄9个随机视野，并使用ImageJ软件计数细胞
脉络膜外植体和微脉管萌芽检验。离体脉络膜外植体和微脉管萌芽的量化如之前所述(56)。简要地，在摘除眼之后立即将来自LysM-Cre/Nrp1+/+和LysM-Cre/Nrp1fl/fl小鼠(每个情况n＝6)的脉络膜解剖。在将分离的脉络膜铺至24孔组织培养板中并且覆盖MatrigelTM(BD Biosciences)后，用EGMTM-2培养基、具有填充PBS的脂质体(脂质体-PBS)的EGM-2培养基、或具有填充二氯亚甲基二膦酸二钠盐的脂质体(脂质体-氯膦酸盐)(Sigma)的EGMTM-2培养基处理样本。按照(57)进行脂质体的包装。十二小时后，包含乘客化合物(passenger compound)的脂质体被从孔中移除，随后用PBS洗涤。将来自原代腹膜巨噬细胞培养物(来自LysM-Cre/Nrp1+/+或LysM-Cre/Nrp1fl/fl小鼠)的巨噬细胞添加至脉络膜外植体培养物，以研究巨噬细胞对微脉管萌芽的影响。
可溶重组NRP1。经历OIR的野生型小鼠在P12时被玻璃体内地注射来自质粒(29)或R&D Systems的rmNRP1陷阱-1(图19C和20R，SEQ ID NO：25)。
使用的重组蛋白质。重组小鼠CCL2/JE/MCP-1(来自大肠杆菌)(R&D Systems)体外使用浓度100ng/ml。-重组人SEMA3A Fc嵌合体(来自小鼠骨髓瘤细胞系，NS0)(R&DSystems)体外使用浓度100ng/ml。-重组人VEGF165(PeproTech)体外使用浓度50ng/ml。
统计分析。数据表示为平均值±s.e.m。在合适的情况下，使用Student T检验和ANOVA来比较不同组；P<0.05被认为是统计学差异。对于ELISA，使用非参数Mann-Whitney检验(GraphPad Prism)进行统计学分析。
研究批准：人样本。我们获得Maisonneuve-Rosemont医院(HMR)伦理委员会(参考CER：10059)的人临床方案和知情同意书的批准，并且募集患者，从患有T1DM或T2DM的患者的局部核心玻璃体活检取样。整个过程作为门诊手术在Maisonneuve-Rosemont医院眼科系门诊室内的小手术室进行。打开所有仪器并以无菌方式处理。该研究符合赫尔辛基宣言(declaration Helsinki)的原则。
研究批准：动物。对于眼科和视觉研究(Ophthalmic and Vision Research)中使用的动物，所有研究根据视觉和眼科学研究协会(Association for Research in Visionand Ophthalmology，ARVO)声明进行，并由蒙特利尔大学的动物保护委员会(Animal CareCommittee of the University of Montreal)批准，符合加拿大动物保护协会(CanadianCouncil on Animal Care)所建立的指导原则。从Jackson实验室采购C57Bl/6野生型(WT)。were从Jackson实验室购买LyzM-Cre(Lyz2tm1(cre)Ifo/J；号码004781)和神经毡蛋白1floxed小鼠(Nrp1tm2Ddg/J；号码005247)。
表3：玻璃体切割术患者的特征
MH：黄斑裂洞(Macular hole)
MMD：近视性黄斑退化
ERM：视网膜前膜
PDR：增殖糖尿病性视网膜病变
Ret.Det.：视网膜脱离
实施例2
NRP1鉴定继发于血管损伤转移的单核吞噬细胞(MP)群
为了确定MP(单核吞噬细胞)如小胶质细胞或巨噬细胞是否参与与增殖性视网膜病变相关的血管发病机理，首先对整个小鼠视网膜进行FACS分析以通过评价氧诱导视网膜病变(OIR，图1A，P7–P12(出生后7–12天)的75％氧以诱导血管闭塞以及直到P17的室内空气以达到最大的视网膜前新血管形成(26,33))的演变阐明巨噬细胞/小胶质细胞积累的动力学(图1B、E、H)。结果表明在所有分析时间点OIR中的显著较高数量的视网膜巨噬细胞/小胶质细胞(Gr-1-，F4/80+，CD11b+，细胞，数据未显示)，其包括在P10的血管闭塞阶段期间36％增加(P＝0.0004)(图1C)、在P14的新生血管性阶段期间63％上升(P<0.0001)(图1F)和在P17的最大的新血管形成期间172％激增(P＝0.0006)(图1I)。
重要地是，在每个研究的时间点，我们观察到OIR中的NRP1阳性MP成比例的增加，其中在P10时上升37％(P＝0.0240)(图1D)、P14时上升61％(P＝0.0196)(图1G)和P17时上升155％(P＝0.0058)(图1J)，其表明NRP1阳性MP的此亚群在疾病发展期间被募集至神经视网膜。对于所有OIR实验，为了确定足够的代谢健康记录小鼠幼崽的重量(数据未显示)(35)。
为了确立MP驻留型NRP1在视网膜病变中的作用，通过使Nrp1floxed小鼠与LysM-Cre小鼠(36)杂交产出LysM-Cre/Nrp1fl/fl后代而产生骨髓特异性NRP1敲除。得到的小鼠在与LysM-Cre/Nrp1+/+同窝对照相比时显示视网膜MP中的NRP1表达减少～80％(P＝0.0004)(图1K)。值得注意的，测试小鼠对于Crb1基因的rd8突变为阴性(37)。LysM-Cre/Nrp1fl/fl小鼠在与同窝幼畜比较时在整个实验期间(P1-P17)没有显示体重、大小、或开阔场地活性上的任何不同(数据未显示)并且具有相似数目的驻留型视网膜小胶质细胞(数据未显示)。明显地，骨髓细胞上NRP1的缺失完全消除了在P10和P14OIR时巨噬细胞/小胶质细胞的进入(图1L-O)，表明在缺血性视网膜损伤早期期间此受体在MP趋化性中的关键作用。在P17时，在最大的病理新血管形成后，MP浸入发生很大程度上独立于NRP1(图1P、Q和R)。与潜在的小胶质细胞同一性一致，以上鉴定的表达NRP1的Gr1-/CD11b+/F4/80+细胞表达高水平的CX3CR1和中/低水平的CD45(图1S并且数据未显示)。如所预期的，在LysM-Cre/Nrp1fl/fl视网膜中，CD45低/CX3CR1高MP缺乏NRP1(图1T)。
实施例3
NRP1+骨髓细胞在视网膜中定位于病理新血管形成的部位
鉴于NRP1+巨噬细胞/小胶质细胞在OIR期间明显流入，接下来确定这些细胞在疾病发展期间的定位。视网膜铺片上的免疫荧光表明NRP1阳性巨噬细胞/小胶质细胞(用IBA1和NRP1共标记)与OIR的P14时的新生病理簇(图2A-C)以及OIR的P17时的成熟簇(图2D-F)密切相关。图2B和2E中的白色箭头指向与视网膜前簇有关的NRP1阳性MP。NRP1也如之前所报道的由新生血管簇内皮上的内皮细胞表达(21)。与图1中展示的数据一致，LysM-Cre/Nrp1fl/fl小鼠具有较低数目的巨噬细胞/小胶质细胞和较不明显的新血管形成(参见以下的全量化)(图2G-K)。
实施例4
SEMA3A在患有活性增殖糖尿病性视网膜病变的患者的玻璃体中升高
为了确立我们的发现对NRP1在视网膜病变中的MP趋化性中的专性(obligate)作用的临床相关性，确定SEMA3A直接在患有活性PDR的患者的玻璃体中的浓度。未稀释玻璃体的十七个样本获自患有PDR的患者并且17个获自非血管病理的对照患者。患者的详细特征包含在表1中(实施例1)。对照患者(20)呈现非血管病理，并且显示非糖尿病相关的视网膜损伤——如继发于纤维化组织和黄斑膨胀(图3C)的脉管系统上的牵引张力——的指征(图3A，B(白色箭头))。相比之下，来自PDR患者的所有视网膜显示具有高渗透性微血管(荧光染料的渗漏)(图3D，G插图)、微动脉瘤(图3D-G)和纤维性瘢痕组织——指示晚期视网膜病变(图3G)——的视盘(disc)(图3D)或视网膜前新血管形成(图3F)的指征。此外，由于血管屏障功能受损，患者显示一些黄斑水肿的证据，包括由于外渗液的焦点聚结而引起的囊样形成(白色箭头)(图3H)。
与在PDR中的作用一致，基于ELISA的SEMA3A检测揭示了当与来自对照患者的玻璃体比较时，具有PDR的患者的玻璃体液中的蛋白质浓度高5倍(P＝0.0132)(图3I)。以等体积的玻璃体通过蛋白质印迹分析确认结果，其中SEMA3A(125和95kDa同种型)(38，39)在具有PDR的患者中升高(图3J)。因此，SEMA3A在玻璃体中的上调在糖尿病眼部病理中被诱导。
实施例5
NRP1配体在OIR期间在视网膜神经节细胞层中被诱导
为了获得增殖性视网膜病变中NRP1的两个显著配体的表达的精确动力学曲线，确定OIR小鼠模型中的SEMA3A和VEGF信息的水平。对整个视网膜的实时定量PCR(RT-qPCR)表明在P10时的高氧(血管变性，vasodegenerative)阶段和从P12至P17的缺血/新生血管性阶段期间SEMA3A在OIR中被强烈地诱导(图4A)。在野生型和LysM-Cre/Nrp1fl/fl视网膜中发生了观察到的诱导。相反地，如所预期的，从P12至P17时在OIR的缺血性阶段中VEGF转录物唯一地上升(图4B)。重要的是，当与野生型视网膜比较时，VEGF在LysM-Cre/Nrp1fl/fl中被显著地较少诱导(当比较野生型OIR时在P12时最低程度增加(P＝0.0451)而在P14时低于～55％(P＝0.0003))(图4B)，指示更健康的视网膜。
接下来，对无血管区域中的视网膜层进行激光捕获显微切割(LCM)随后RT-qPCR以指出OIR中的SEMA3A和VEGF信息的源(图4C)。SEMA3A和VEGF两者在神经节细胞层中被强烈地诱导，而VEGF在内核层中也增加(图4D，E)。因此，两种配体的源地理上与视网膜MP的定位一致(图2)。
实施例6
血管损伤后单核吞噬细胞(MP)在视网膜中不增殖
为了确定NRP1+MP的显著上升是否由于从体循环流入或视网膜内MP增殖的增加，研究这些细胞的局部视网膜增殖。在P13时，将小鼠全身注射BrdU(处死前24小时)并且对视网膜(图5A)和脾(图5B)进行FACS分析。在视网膜内，Gr1-/CD11b+/F4/80+MP没有显示明显的增殖(P＝0.4708)。在脾中观察到相当多的增殖。在含氧量正常和OIR之间没有观察到明显不同(图5C)。视网膜中的MP的不增殖表明视网膜病变期间的显著堆积NRP1+MP具有全身起源。
实施例7
SEMA3A和VEGF165通过NRP1转移MP
鉴于NRP1对骨髓细胞转移到血管损伤部位(图1)以及NRP1在视网膜病变中的主要配体的诱导(图3-4)和这些细胞的可能的全身起源(图5)的要求，确定引起MP的趋化性的这些线索倾向。从野生型小鼠中分离原代巨噬细胞培养物，并使其经历Transwell Boyden室迁移测定。SEMA3A(100ng/ml)(P<0.0001)和VEGF165(50ng/ml)(P＝0.0027)两者以与阳性对照MCP-1(100ng/ml)相似的量级引起巨噬细胞趋化性(P<0.0001)(图6A，B)。通过证实Y-27632——选择性抑制剂ROCK(Rho相关卷曲螺旋形成蛋白质丝氨酸/苏氨酸激酶)——消除其趋化性质而证实这些数据。ROCK是NRP1信号传导的下游(40)并且已知介导单核细胞迁移(41)。VEGF迁移部分地尚未显著地减少，表明来自替代受体如最近报道的VEGFR1的贡献(33)。与NRP1在SEMA3A和VEGF介导的趋化性中的作用一致，来自LysM-Cre/Nrp1fl/fl小鼠的巨噬细胞独特地(uniquely，唯一的)响应MCP-1并且不由于SEMA3A或VEGF而转移(图6C)。
实施例8
NRP1+巨噬细胞使离体微脉管萌芽增强。
为了研究NRP1表达巨噬细胞对微脉管血管生成的影响，分离来自LysM-Cre/Nrp1+/+小鼠或LysM-Cre/Nrp1fl/fl小鼠的脉络膜组织并且在MatrigelTM中生长以评价微脉管萌芽。来自LysM-Cre/Nrp1fl/fl小鼠的脉络膜当与来自LysM-Cre/Nrp1+/+小鼠的脉络膜相比时萌芽少～20％的微血管(P＝0.018)(图7A)。为了研究NRP1+巨噬细胞在促进微脉管萌芽中的作用，使用氯膦酸盐-脂质体将内源性巨噬细胞从分离的脉络膜组织中消除。在来自LysM-Cre/Nrp1fl/fl和LysM-Cre/Nrp1+/+小鼠两者的外植体中，含有PBS的脂质体(即媒介物对照)对血管萌芽没有影响，但是氯膦酸盐-脂质体降低微脉管萌芽～60％(对于LysM-Cre/Nrp1+/+脉络膜P＝0.0114，对于LysM-Cre/Nrp1fl/fl脉络膜P＝0.0007)(图7B-E)。为了验证NRP1+巨噬细胞是否倾向于促进血管生成，从LysM-Cre/Nrp1+/+或LysM-Cre/Nrp1fl/fl小鼠提取腹膜巨噬细胞，并且引入至之前用氯膦酸盐脂质体处理并且洗涤的脉络膜外植体培养物中。当与来自LysM-Cre/Nrp1fl/fl小鼠的巨噬细胞相比时，LysM-Cre/Nrp1+/+巨噬细胞强烈地使微脉管萌芽增强50-100％(对于LysM-Cre/Nrp1+/+脉络膜P＝0.0068，对于LysM-Cre/Nrp1fl/fl脉络膜P＝0.0491)(图7D和E)并且独立于脉络膜外植体的基因型。
实施例9
骨髓驻留型NRP1的缺乏降低视网膜病变中的血管变性和病理新血管形成
鉴于在OIR的早期阶段期间MP渗入中的NRP1细胞信号传导的专性作用(图1)，接下来确定NRP1的骨髓细胞特异性消融对疾病发展的影响。在P12时在从75％O2中退出后，当与野生型(P＝0.0011)和LysM-Cre/Nrp1+l+(P<0.0001)对照相比时，LysM-Cre/Nrp1fl/fl小鼠显示显著较低水平的视网膜血管闭塞(图8A，B)。这可能归因于LysM-Cre/Nrp1fl/fl小鼠的视网膜中存在较低水平的IL-1β(数据未显示)。重要的是，在P17时，当病理新血管形成高峰时(26)，骨髓驻留型NRP1的缺失极度地降低无血管面积(当与野生型相比时为～35％(P<0.0001)以及相比于LysM-Cre/Nrp1+l+小鼠为～30％(P＝0.0008))(图8C，D)。反过来，观察到与缺血性视网膜病变有关的破坏性视网膜前新血管形成的明显降低(当与野生型相比时为～36％(P＝0.0008)以及相比于LysM-Cre/Nrp1+l+小鼠为～34％(P＝0.0013))(图8E，F)。
实施例10
可溶性SEMA3A中和陷阱的制备
产生抑制/中和SEMA3A的高亲合力陷阱。这些陷阱源自神经毡蛋白1(NRP1)并且任选地与6×-His标签或FC蛋白质结合(参见图19、20和27，和表1)。产生包含整个NRP1胞外结构域或能够保持SEMA3A结合的功能变体的各种变体。产生含有b1结构域(其与VEGF结合)和包含中和VEGF165突变的陷阱。显示陷阱在转化的人细胞中高度表达和分泌。开发了简单的纯化和制剂方案以产生SAR陷阱样本和随后的体内效力研究。
方法
细胞培养和材料。从Origene Inc获得人神经毡蛋白1(GenBankTM登录号_003873，SEQ ID NO：66)。Origen克隆在氨基酸140处包含保守突变，其将亮氨酸变为异亮氨酸。293T(ATCC)细胞在补充有10％胎牛血清的Dulbecco’s修饰Eagle’s培养基中生长。从InvivoGenInc购买pFUSE-hIgG1-Fc1载体。
克隆。利用PhusionTM高保真聚合酶(New England Biolabs)从Origene克隆RC217035PCR扩增神经毡蛋白-1的胞外结构域(残基1-856)或其部分并且在与人FC-1编码序列一致的框架内克隆在pFUSE-hIgG1-Fc1的EcoR1-BglII中。通过插入编码TEV蛋白酶切割位点的序列，然后插入6×His残基和对应FC构建体的FC编码部分上游的终止密码子来产生编码可溶性形式的陷阱的构建体。利用Q5定点突变试剂盒(NEB)引入额外的缺失(b1，b1b2)或VEGF165结合突变(例如，Y297A)。通过Sanger测序(Genome Quebec)验证所有构建体序列。组装的陷阱的核苷酸和氨基酸序列在附录1-21中描述。
在人细胞中评价陷阱表达。在293T细胞中转染编码小鼠和人陷阱的构建体。细胞转染后在FreeStyleTM 293培养基(Invitrogen)中生长48小时。转染后48小时，由293T细胞制备细胞裂解物。用PBS将细胞充分洗涤并且在补充有标准量的蛋白酶抑制剂(AEBSF、TPCK、TLCK、抗蛋白酶肽、亮肽酶素、胃酶抑素和E64，Sigma)的冰冷裂解缓冲液(50mM HEPESpH7.5、150mM NaCL、1.5mM MgCl2、1％曲拉通(Triton)X-100和10％甘油)中裂解。通过微型离心(12000g，20分钟)清除细胞裂解物。通过标准微型BCA(Sigma)确定裂解物浓度。将等量的蛋白质装载于5-20％PAGE-SDS梯度胶上并且转移至PVDF(Amersham)。来自转染细胞的清除条件培养基与用于FC或6xHis标签的蛋白质A琼脂糖(Pharmacia)或Talon树脂(Clontech)一起温育。用PBS洗涤树脂并在2×PAGE-SDS样本缓冲液中稀释，然后进行凝胶分离和转移。免疫印迹中使用的抗体是抗人神经毡蛋白-1(Cell Signaling)、小鼠单克隆抗6×-HIS(In Vitrogen)和报告基因HRP连接的抗人、小鼠和兔IgG(BioRAD)。所有抗体以1/2000稀释使用。在膜与ECL(Amersham)温育后利用Fuji成像系统捕获化学发光信号。
陷阱表达和纯化。通过聚乙烯亚胺(PEI)或磷酸钙沉淀标准转染法用编码各种陷阱的质粒转染293-T细胞。次日，用无血清培养基洗涤细胞两次并且用无血清完全培养基(自由式293培养基，InVitrogen)培养(fed)。在无血清培养基中生长60-72小时后收集条件培养基并通过摆动式离心(2000RPM，20分钟)清除细胞碎片。通过在蛋白A或G琼脂糖(Pharmacia)上传代随后用PBS充分洗涤和用0.1M甘氨酸pH 3.0洗脱，从转染的293T细胞的条件培养基中纯化FC陷阱。通过加入1/10体积的1M Tris pH 8和1/10体积的10×PBS pH7.4立即中和洗脱级分。通过在Talon琼脂糖(Clontech)上传代随后用PBS充分洗涤并且逐步咪唑洗脱(范围通常为10-150uM)，从转染的293T细胞的条件培养基中纯化可溶6×HIS标签陷阱。在5-15％或5-20％梯度PAGE-SDS凝胶上分析陷阱的纯化级分的样本。使用SafelyBlue染色试剂盒(InVitrogen)将凝胶染色。
用于体内注射的纯化陷阱的无菌制剂。合并来自40ml的条件培养基的纯化洗脱级分并在PBS中稀释至总体积为10ml。将稀释的陷阱蛋白通过0.2uM低蛋白结合过滤器(Progene)过滤灭菌。将蛋白质溶液浓缩，并用PBS在无菌PES浓缩装置(Pierce，标称MWCO30KD)上进行缓冲液交换。在如上所述，在PAGE-SDS上对无菌浓缩的陷阱样本(～30-50ul)分析和染色。
实施例11
陷阱对SEQMA3A和VEGF的亲和力
AP-VEGF165的产生。在pAPtag5载体(GenHunter)中在与碱性磷酸酶结构域(AP-VEGF165)一致的框架内亚克隆人VEGF165变体1(NM_001025366)的编码序列。利用聚乙烯亚胺(PEI)转染法用AP-VEGF165构建体转染HEK293T细胞。在过夜转染步骤后，在无血清培养基(In vitrogen)中培养细胞另外的60小时。收集细胞介质并且在PES装置(Pierce)上浓缩。在PAGE-SDS上分析浓缩的AP-VEGF165配体并且利用SimplyBlue安全染色(Lifetechnologies)定量。
Sema 3A和AP-VEGF165结合检验。用于确定结合SEMA 3A或VEGF 165的KD的饱和曲线如下获得。用在PBS中稀释的纯化陷阱包被高蛋白结合96孔板(Maxisorp，Nunc)的孔，然后用结合缓冲液(含有2％酪蛋白和0.05％吐温20的PBS)阻断。在广泛的浓度范围下在结合缓冲液中稀释SEMA3A-FC(R&Dsystems)或AP-VEGF165配体并加入孔中。过夜温育后，用含有0.05％吐温的PBS洗涤孔。使用HRP连接的抗人IgG(Biorad)和ECL底物(Pierce)检测结合的SEMA3a-FC。可选地，使用CPD星形底物(Roche)检测结合的AP-VEGF 165。在TECAN读数器上获得化学发光信号。使用Graph Pad prism软件通过非线性曲线拟合确定解离常数(KD)。
本发明的陷阱与SEMA3A和VEGF的相对亲和力已被评价。如实施例10中所述制备陷阱。在图19中也提供了陷阱检验的图示。
表4：各种陷阱的SEMA3A和VEGF解离常数
本发明的可溶性NRP1陷阱相比VEGF与SEMA3A更有效地结合。发现对SEMA3A的这种偏好是令人惊讶的，因为SEMA3A和VEGF被认为通常对NRP1具有相同的一般亲和力。在SEMA3A抑制优选高于VEGF抑制且可减少与VEGF抑制相关的副作用的情况下，对SEMA3A的增加的亲和力可能是有利的。
实施例12
治疗性玻璃体内施用可溶性NRP1降低视网膜病变中的MP渗入和病理新血管形成
为了确定以上发现的移动(translational)潜力，接下来将可溶重组小鼠(rm)NRP1mTrap 1多肽(图19C和20R，包含SEQ ID NO.25的结构域a1、a2、b1、b2和c)用作陷阱以隔离NRP1的OIR诱导配体。在P12时单一玻璃体内注射rmNRP1导致P14时在经历OIR的视网膜中存在的小胶质细胞数目降低30％(P＝0.0282)(图9A)。此发现证明可溶性NRP1(1μl，50μg/ml)损害小胶质细胞转移的效力。当与注射媒介物的对照相比时，玻璃体内施用可溶性NRP1引起病理性视网膜前血管生成明显减少～40％(P＝0.0025)(图9B，C)。总之，这些数据表明NRP1的配体的中和是减少视网膜病变中破坏性新血管形成的有效策略。
实施例13
用于败血症模型的材料和方法-实施例14至19
败血症的小鼠模型。研究根据加拿大委员会关于动物保护的加拿大动物在研究中的使用指南的规定进行。在6-8周龄的C57BL/6小鼠中腹膜内(i.p)递送LPS注射。
存活测定。为了产生存活数据，以25mg/kg的单次腹膜内注射LPS，以调整小鼠重量的接近100ul的体积来刺激(challenged)小鼠。然后监测小鼠，直到达到由加拿大动物保护委员会所定义的临界极限点。
促炎性细胞因子的测量。为了评估促炎性细胞因子，对小鼠进行腹膜内注射刺激——用15mg/kg的单次腹膜内注射LPS并在多个时间点处死，直到24小时。移除组织(脑、肝、肾)并使用GenEluteTM哺乳动物总RNA Miniprep试剂盒(Sigma)分离mRNA，并用脱氧核糖核酸酶I(DNase I)消化以阻止基因组DNA的扩增。使用M-MLV逆转录酶进行逆转录，并在ABIBiosystems实时PCR仪中使用SybrGreen分析基因表达。β-肌动蛋白用作参考基因。
原代腹膜巨噬细胞培养。将成年WT或LyzMcre/NRP1fl/fl小鼠用具有2％异氟烷的氧气(2L/min)麻醉，然后通过颈椎脱位实施安乐死。然后，在小鼠的腹部皮肤中产生小切口。将皮肤拉至每个小鼠尺寸并且腹膜腔用5ml的PBS加3％FBS洗涤2min。然后，将收获的细胞以1000rpm离心5min，重悬于培养基(DMEM F12加10％FBS和1％链霉素/青霉素)中并铺板。在37℃，5％CO2气氛下培养1小时后，更换培养基。
流式微珠阵列(Cytometric Bead Array，CBA)。根据制造商的指南(BDBioscience)进行CBA。从野生型或LyzMcre/NRP1fl/fl小鼠中分离巨噬细胞，并使其经历SEMA3A(100ng/ml)或媒介物12小时，并通过CBA处理。
陷阱和抗VEGF抗体施用。用人或小鼠NRP1陷阱-1(图19B，C和20A，20R，SEQ ID NO：25或SEQ ID NO：83)或VEGF中和抗体(R&D Systems，AF-493-NA)处理败血症的小鼠实验模型。
实验设计：每组3只小鼠。组：1-媒介物、2-LPS和3-LPS+NRP1Trap 1-媒介物：NaCl，2-LPS：15mg/kg；和3-LPS+NRP1-陷阱：在LPS注射后几分钟，小鼠接受静脉内单次注射4ug(体积为100uL)的重组小鼠NRP1陷阱，其对应于0.2mg/kg。
渗透性检验。对于渗透性测定，对小鼠进行腹膜内注射刺激——以15mg/kg单次腹膜内注射LPS，24小时后处死用于组织取样。通过量化组织中的伊文思蓝(Evans Blue，EB)外渗来评价肝、肾和脑血管通透性的变化。24小时后，静脉内注射10mg/ml的EB溶液(55mg/kg)。两小时后，处死小鼠，并用PBS灌注通过心脏。然后移除组织，使其在室温下干燥24小时，并确定干重。EB在甲酰胺中于65℃下提取过夜。然后在分光光度计中在620和740nm测量EB。
实时PCR分析。使用GenEluteTM哺乳动物总RNA Miniprep试剂盒(Sigma)分离RNA，并用脱氧核糖核酸酶I消化以阻止基因组DNA扩增。使用M-MLV逆转录酶(LifeTechnologies)进行逆转录，并在ABI Biosystems实时PCR仪中使用SybrGreen(BioRad)分析基因表达。β-肌动蛋白用作参考基因。关于所使用的寡核苷酸的序列的细节，参见下表3。
表3：用于RT-PCR分析的引物序列
实施例14
在感染性休克期间的若干器官中脑信号蛋白3A被上调
鉴于OIR中的SEMA3A，NRP1和先天免疫反应之间的关联(如上文实施例2-9所示)，接下来评价NRP1依赖性细胞反应在一般全身性炎症中的牵涉。这是首先通过确定感染性休克期间SEMA3A表达的动力学来探究。
向6至8周龄的C57BL/6小鼠(n＝5)施用LPS(15mg/kg)，并在LPS施用后0、4、8、12和24小时处死小鼠。收集关键器官例如脑、肾、肺和肝，并分离mRNA。在LPS注射后6小时，在分析的所有器官中强烈诱导SEMA3A mRNA的水平，并持续24小时(图11A-D)。类似地，另一种NRP1配体VEGF的表达水平在感染性休克的前6小时内在肾(图11B)、肺(图11C)和肝脏(图11D)中也显著增加。经典的促炎性细胞因子TNF-α和IL1-β的增加在LPS施用后6小时升高，并且与VEGF mRNA类似地减少(图12)。因此，在所有研究的炎症介导剂中，SEMA3A具有长效动力学特征并在诱导败血症后保持升高至少24小时。SEMA3A的这种特定的表达特征表明，与其他细胞因子相比，其对感染性休克的贡献可能是长效的。
实施例15
SEMA3A通过NRP1诱导骨髓细胞中的促炎性细胞因子的分泌
鉴于单核细胞和骨髓细胞对急性炎症反应和骨髓样细胞上的NRP1的存在的贡献，确定了SEMA3A和骨髓驻留型NRP1在炎性细胞因子产生中的贡献。
将分离的巨噬细胞暴露于SEMA3A(100ng/ml)或媒介物，并通过流式微珠阵列(CBA)分析细胞因子的产生。图13中呈现的结果表明，SEMA3A可以诱导已知促进感染性休克的促炎性细胞因子(例如IL-6(图13A)和TNF-α(图13B))的产生/分泌。特别重要的是，NRP1(LyzM/NRP1fl/fl)在骨髓细胞中的特异性敲除消除了SEMA3A诱导的IL-6和TNF-α的产生。值得注意的是，媒介物处理的对照LyzM/NRP1fl/fl巨噬细胞相比于野生型对照显示较少的IL-6、TNF-α和IL-1β的产生，突出了骨髓驻留型NRP1在败血症诱导的炎症中的作用。
实施例16
骨髓驻留型NRP1的缺乏降低败血症中的体内促炎性细胞因子的产生
因为骨髓驻留型NRP1对于促炎性细胞因子例如IL-6和TNF-α的体外释放是重要的，所以在体内探究了其贡献。向LyzM/NRP1fl/fl和对照野生型小鼠施用媒介物或LPS(15mg/kg)，并在LPS注射后6小时收集脑和肝。TNF-α(图14A，C)和IL-1b(图14B，D)水平的实时PCR分析表明了这些细胞因子在LyzM/NRP1f1/fl中的强烈下降。这些结果强调了NRP1及其配体对败血症体内发展的深远贡献。
实施例17
NRP1信号的抑制阻止败血症诱导的屏障功能损坏。
严重感染性休克的病理特征的一种——即便对器官衰竭有贡献——是血液屏障(肺中的血液和空气、肾中的血液和尿液、肝中的血液和胆汁以及脑中的体液分子)损害。鉴于SEMA3A在血液视网膜屏障的损坏中的作用(46)和关于败血症期间SEMA3A表达的此新颖数据，评价了用源自人NRP1的胞外结构域的陷阱中和SEMA3A的效果(陷阱-1，无FC，图19B，SEQ ID NO：83)。使用伊文思蓝渗透(Evans BluePermeation，EBP)检验，我们发现在所有被研究的器官即脑(图15A)、肾(图15B)和肝(图15C)中，当小鼠用4ug的NRP1衍生陷阱(0.2mg/kg，静脉注射)处理时，观察到LPS诱导的屏障功能损坏的显著降低。这些结果强烈表明可溶性NRP1的陷阱及其衍生物是有力抵抗败血症的治疗剂。
实施例18
NRP1衍生陷阱保护免于败血症
为了确定在败血症期间中和NRP1配体或NRP1抑制的治疗益处，进行存活研究。给小鼠施用高剂量的LPS(25mg/kg)。然后监测小鼠，并且当达到适当的终点时，进行人道处死。在第二组中，将小鼠静脉内注射不含FC(0.2mg/kg，图19B和20A，SEQ ID NO：83)的4ug重组陷阱-1，然后腹膜内注射LPS。在对照组中，在LPS注射后的前30小时内(图16A)，5/5小鼠(100％)死亡。相反，用陷阱处理的所有小鼠在30小时后仍然存活，并且在60小时后显示显著提高的存活率(3/5)。因此，死亡率从30小时后的100％(在对照组中)降低至60小时后的40％(图16A)。此外，40％的陷阱处理的小鼠在LPS注射后80小时保持存活。因此，当抑制通过NRP1的细胞信号传导时，在60％的情况中，存活时间至少两倍，而在40％的情况中存活时间几乎三倍。
使用在骨髓细胞中具有NPR1的特异性敲除的小鼠获得了类似的结果(图16B)。在骨髓样细胞中没有NRP1增加了存活时间，并且在30小时后将败血症诱导的死亡率从100％降低至40％(3/5)(图16B)，并且在60小时后从100％降低至40％。同样，40％的NRP1基因敲除小鼠在LPS注射后80小时仍存活。
总之，这些结果突出了在败血症治疗中抑制NRP1依赖性细胞信号传导的治疗价值。
实施例19
NRP1衍生的陷阱在感染性休克中降低炎性细胞因子的产生
鉴于NRP1陷阱对感染性休克中的存活率的治疗益处，接下来确定了感染性休克期间NRP1配体的中和对炎性细胞因子产生的影响。野生型小鼠被施用i)媒介物(n＝3)；ii)LPS(15mg/kg)(n＝3)或iii)LPS和NRP1小鼠陷阱1(无FC，图19C，SEQ ID NO：25，但无FC区)，并且在LPS注射后6小时收集脑。注射NRP1陷阱-1显著降低TNF-α(图17A)和IL-6(图17B)的产生。类似地，具有缺乏NRP1的骨髓细胞(LyzM-Cre/Nrpfl/fl)的小鼠(n＝3)产生相当少的TNF-α和IL-6，强调了该细胞途径对感染性休克进展的贡献。
实施例20
用于实施例21中描述的脑缺血/中风模型的材料和方法
此研究中使用的小鼠是2至3个月大的雄性C57Bl/6小鼠(22-28g)。
MCAO模型。使用Rousselet等描述的管腔内缝合技术产生MCAO小鼠模型(66)。简言之，将小鼠在具有3％异氟烷的氧气(1L/min)的室中麻醉，并用丁丙诺啡(0.1mg/kg体重，皮下)镇痛。在操作期间使用通过面罩提供的具有1.5％异氟烷的氧气维持麻醉。记录直肠温度并用加热垫保持稳定在37±0.5℃。在颈部中线切口后，暴露右颈动脉分叉并使用5-0丝缝线暂时阻断颈总动脉(CCA)。分离右内颈总动脉(ICA)和外颈总动脉(ECA)的分叉。将永久缝线尽可能远地放置在ECA周围，并将另一个稍微紧密的临时缝线放置在分叉远端的ECA上。右ICA暂时用5-0丝缝线闭塞，以避免出血。然后，在永久和临时缝线之间切割ECA中的小孔，通过该小孔引入12mm长的6-0硅涂覆(约9-10mm涂覆有硅)单丝缝线。将细丝从ECA推进到ICA腔中，直到它阻断Willis环中的大脑中动脉(MCA)的起点。通过将单丝插入至CCA，但不将其推进到MCA获得假手术(sham)动物。将ECA上的缝线紧系以将单丝固定在适当位置。MCAO后三十分钟，将单丝完全去除以允许再灌注。在CCA上的临时缝线也被移除以允许血液再循环。伤口闭合后，皮下注射1ml盐溶液以避免术后脱水。将小鼠置于笼中并保持在加热垫上1小时。同时，当小鼠完全从麻醉中苏醒时，检查一些基本的运动缺陷(行走同时绕弯和抓住尾巴同时弯曲；手术成功的指标)并且以125ul PBS中0.4ug的剂量将无FC的NRP1-陷阱-1(图19B SEQ IDNO:83)施用到尾静脉(在再灌注开始后约15分钟)。以与NRP1处理的动物相同的方式手术的对照动物在MCAO后接受媒介物(PBS)。因为通常观察到手术后体重减轻，将捣碎的食物放置在皮氏培养皿中以鼓励进食。
梗塞体积的确定。在MCAO后24小时进行神经学评价(参见以下部分)后，用具有3％异氟烷的氧气(1L/min)将动物深度麻醉，并断头。立即分离脑并转移到在干冰上冷却的异戊烷中，然后储存在-80℃。随后，将冷冻的脑在低温恒温器中于-22℃下冠状切成20μm切片，并将每第15个切片放置在带正电荷的玻璃载玻片上。将脑切片用甲酚紫染色15min。拍摄每个切片。基于缺血性区域中相对缺少染色来描绘梗塞面积，并通过使用NIH ImageJ软件测量。将每个切片中的梗塞面积确定为对侧半球的总面积减去同侧半球的非受影响区域。
神经学评价。手术后1小时，以及MCAO后24小时，动物经历一系列运动检测。检查和评分如下：0，正常；1，经由尾部提起整个动物的侧前或后肢弯曲；2，行走时向对侧转弯，以及抓住尾巴时C形侧弯；4行走时向对侧转弯，以及抓住尾巴时C形侧弯并屈肢；5，昏迷或濒死。所获得的神经学评分的大小与损伤的严重程度成正比。
实施例21
NRP1-陷阱保护免于脑缺血和中风
为了评价SEMA3A中和对脑缺血或中风的结果，成年(8-12周龄)小鼠经历短暂大脑中动脉闭塞(MCAO)模型。简单地说，在MCAO终止后，将125ul PBS中的0.4ug小鼠NRP1-陷阱(陷阱-1，无FC)(图19C，图20R SEQ ID NO：25)施用至尾静脉(再灌注开始后约15分钟)。为了可视化由MCAO诱导的脑损伤，冠状脑切片用甲酚紫染色。在每个切片上，未染色区域对应于脑的缺血性区域(图18A)。在系列冠状切片上的这些面积的测量表明，与大脑未受伤的假手术动物相比，在MCAO后24小时，梗塞区域构成闭塞小鼠的同侧半球的48％。NRP1治疗降低脑损伤；同侧半球的梗塞体积减少了80％(图18B，C)。
通过对屈肢、身体的C形侧弯和转弯运动的存在的神经学评分来评价神经损伤。将在手术后1小时未显示出转弯和弯曲行为的MCAO小鼠从进一步研究中排除(图18D)。与假手术动物相比，在经历MCAO的小鼠中观察到前肢或后肢屈曲、身体C形侧弯、转弯运动。当在手术后24小时评价时，与未处理的MCAO小鼠相比，NRP1治疗显著提高缺血性小鼠的神经学评分60％(图18E)。
总之，这些结果显示，NRP1途径的抑制保护免受脑缺血和中风，并降低与脑缺血和中风相关的神经损伤。
实施例22
在糖尿病性视网膜病变和早产儿视网膜病变的小鼠模型中，神经毡蛋白衍生陷阱增强血管再生并且阻止缺血性视网膜中的病理新血管形成。
使用充分建立的氧诱导增殖性视网膜病变(OIR)的小鼠模型(Smith等，1994)研究病理性血管变性以及视网膜前血管增殖。该模型基于早产儿视网膜病变(ROP)，并且经常用作糖尿病性视网膜病变和ROP的增殖(血管生成期)的替代物。
P7-P12时将哺乳母亲及其幼仔暴露于75％氧气。存在血管变性(在P12评价)和血管增殖(在P17评价)阶段，并且是高度可再现的，使得干预对疾病发展的评价准确而迅速。在P12时将陷阱G(SEQ ID NO：38)或陷阱M(缺少b2和c结构域，SEQ ID NO：42)注射到玻璃体中(1ul，0.5ug/ul)。将解剖的视网膜铺片，并在1mM CaCl2中用荧光素化的异凝集素B4(1:100)温育过夜，以确定P17时的无血管面积或新血管形成面积的程度。在凝集素染色的视网膜中无血管面积被确定为无染色区域。新血管形成被确定为界定视网膜前簇的饱和凝集素染色的面积(54,55)。
与媒介物对照相比，显示陷阱G有效地增强血管再生超过40％(图23B)。类似地，显示陷阱G抑制病理性新生血管形成～45％(图23C)。与媒介物对照相比，陷阱-M增强血管再生～60％(图23B)并且抑制病理性新血管形成～60％(图23C)。因此，具有受损的VEGF结合的陷阱M更有效地阻止病理性血管生成，并更容易导致缺血性视网膜中的增强的血管再生。
实施例23
神经毡蛋白衍生陷阱减少糖尿病视网膜中的血管渗漏。
在1型糖尿病的链脲菌素(STZ)模型中也研究了陷阱对糖尿病性视网膜病变中血管渗漏/渗透性的影响。在连续5天期间将STZ(55mg/kg)施用至～6周龄C57BL/6J小鼠，并监测血糖。如果小鼠的非禁食血糖高于17mM(300mg/dL)，则认为其为糖尿病。在STZ施用后的6和7周，小鼠被玻璃体内施用0.5ug(0.5ug/ul)陷阱G(SEQ ID NO：38)或M(SEQ ID NO：42)或小鼠抗-VEGF抗体(AF-493-NA，来自R&D)。可选地，在STZ后的12和13周，玻璃体内注射小鼠，在14周时评价血管渗透性。在玻璃体内注射SEMA陷阱(参见图24A)或抗VEGF抗体前至少3周，小鼠是高血糖/糖尿病。在STZ注射后8周通过伊文思蓝检验法确定视网膜血管渗漏如下。每个读数使用3个视网膜进行视网膜伊文思蓝(EB)渗透。伊文思蓝以45mg/kg静脉内注射并允许在视网膜提取前循环2小时。用TECANM1000PRO通过荧光测定法(620nm最大吸光度-740nm最小吸光度(背景))将伊文思蓝渗透在视网膜中量化，如下计算伊文蓝渗透(EBP)[以uL/(克*小时)测量]：[EB(ug)/湿视网膜重量(g)]/[血浆EB(ug/uL)*循环时间(小时)]。伊文思蓝渗透相对于对照进行表示。
陷阱-G(SEQ ID NO：38)和陷阱-M(SEQ ID NO：42)都显著降低血管通透性超过40％(图24B)。小鼠抗VEGF抗体(AF-493-NA)在这个早期阶段没有阻止血管通透性。在P17时陷阱G有效降低血管渗漏，如同抗VEGF中和Ab(图24C)，*p<0.05，n＝4，来自12只动物。
实施例24
神经毡蛋白衍生陷阱减少年龄相关黄斑变性的模型中的脉络膜新血管形成
在年龄相关性黄斑变性(AMD)的小鼠模型中测定NRP1陷阱G(SEQ ID NO：38)对脉络膜新血管形成(CNV)的影响。为了诱导CNV并因此模拟小鼠中的湿性AMD，使用安装在相干裂隙灯(Coherent slit lamp，400mW，50ms和50μm)上的氩激光器(532nm)，从乳头在6-8周龄小鼠上进行激光凝结(1-2个视盘直径)(Combadiere等，2007)。在激光烧伤后，被处理的小鼠被玻璃体内注射0.5ug的陷阱G。十四天(P14)后，将脉络膜放射状切开，平铺并用内皮细胞标记物荧光素化异凝集素B4染色(动物也任选地用荧光素葡聚糖灌注以使腔血管可视)，并且通过扫描激光共焦显微镜测量CNV的体积(Takeda等人，2009)。
陷阱G显示在激光烧伤后14天时显著降低脉络膜新血管形成(图25B)。
权利要求的范围不应当受到在实施例中阐述的优选实施方案的限制，而应当施用与作为整体的描述一致的最宽泛的解释。
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gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagaccccag atctgacaaa 2580
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 2640
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 2700
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 2760
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 2820
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 2880
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 2940
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 3000
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 3060
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 3120
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 3180
ttctcatgct ccgtgatgca cgaggctctg cacaaccact acacgcagaa gagcctctcc 3240
ctgtctccgg gtaaa 3255
<210> 3
<211> 1064
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (563)..(837)
<223> Xaa可以是任意自然存在的氨基酸
<400> 3
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
835 840 845
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
850 855 860
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
865 870 875 880
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
885 890 895
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
900 905 910
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
915 920 925
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
930 935 940
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
945 950 955 960
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
965 970 975
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
980 985 990
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
995 1000 1005
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
1010 1015 1020
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
1025 1030 1035
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
1040 1045 1050
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
1055 1060
<210> 4
<211> 3255
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<220>
<221> misc_feature
<222> (1750)..(2574)
<223> n是a、c、g或t
<400> 4
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1800
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1860
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1920
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1980
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2040
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2100
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2160
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2220
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2280
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2340
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2400
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2460
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2520
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnngacaaa 2580
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 2640
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 2700
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 2760
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 2820
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 2880
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 2940
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 3000
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 3060
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 3120
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 3180
ttctcatgct ccgtgatgca cgaggctctg cacaaccact acacgcagaa gagcctctcc 3240
ctgtctccgg gtaaa 3255
<210> 5
<211> 1064
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (404)..(837)
<223> Xaa可以是任意自然存在的氨基酸
<400> 5
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
405 410 415
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
515 520 525
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
835 840 845
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
850 855 860
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
865 870 875 880
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
885 890 895
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
900 905 910
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
915 920 925
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
930 935 940
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
945 950 955 960
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
965 970 975
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
980 985 990
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
995 1000 1005
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
1010 1015 1020
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
1025 1030 1035
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
1040 1045 1050
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
1055 1060
<210> 6
<211> 3255
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<220>
<221> misc_feature
<222> (1273)..(2574)
<223> n是a、c、g或t
<400> 6
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1320
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1380
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1440
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1500
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1560
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1620
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1680
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1740
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1800
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1860
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1920
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1980
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2040
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2100
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2160
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2220
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2280
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2340
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2400
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2460
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2520
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnngacaaa 2580
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 2640
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 2700
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 2760
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 2820
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 2880
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 2940
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 3000
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 3060
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 3120
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 3180
ttctcatgct ccgtgatgca cgaggctctg cacaaccact acacgcagaa gagcctctcc 3240
ctgtctccgg gtaaa 3255
<210> 7
<211> 1064
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (245)..(837)
<223> Xaa可以是任意自然存在的氨基酸
<400> 7
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
245 250 255
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
370 375 380
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
385 390 395 400
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
405 410 415
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
515 520 525
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
835 840 845
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
850 855 860
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
865 870 875 880
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
885 890 895
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
900 905 910
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
915 920 925
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
930 935 940
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
945 950 955 960
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
965 970 975
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
980 985 990
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
995 1000 1005
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
1010 1015 1020
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
1025 1030 1035
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
1040 1045 1050
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
1055 1060
<210> 8
<211> 3255
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<220>
<221> misc_feature
<222> (796)..(2574)
<223> n是a、c、g或t
<400> 8
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 840
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 900
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 960
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1020
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1080
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1140
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1200
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1260
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1320
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1380
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1440
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1500
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1560
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1620
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1680
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1740
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1800
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1860
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1920
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1980
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2040
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2100
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2160
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2220
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2280
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2340
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2400
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2460
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2520
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnngacaaa 2580
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 2640
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 2700
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 2760
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 2820
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 2880
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 2940
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 3000
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 3060
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 3120
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 3180
ttctcatgct ccgtgatgca cgaggctctg cacaaccact acacgcagaa gagcctctcc 3240
ctgtctccgg gtaaa 3255
<210> 9
<211> 791
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 9
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
565 570 575
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
580 585 590
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
595 600 605
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
610 615 620
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
625 630 635 640
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
645 650 655
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
660 665 670
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
675 680 685
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
690 695 700
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
705 710 715 720
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
725 730 735
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
740 745 750
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
755 760 765
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
770 775 780
Leu Ser Leu Ser Pro Gly Lys
785 790
<210> 10
<211> 2436
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 10
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgta gatctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 1800
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 1860
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 1920
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1980
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 2040
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 2100
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 2160
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 2220
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 2280
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 2340
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc acgaggctct gcacaaccac 2400
tacacgcaga agagcctctc cctgtctccg ggtaaa 2436
<210> 11
<211> 632
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 11
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
405 410 415
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
420 425 430
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
435 440 445
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
450 455 460
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
465 470 475 480
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
485 490 495
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
500 505 510
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
515 520 525
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
530 535 540
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
545 550 555 560
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
565 570 575
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
580 585 590
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
595 600 605
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
610 615 620
Ser Leu Ser Leu Ser Pro Gly Lys
625 630
<210> 12
<211> 1959
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 12
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcagatctga caaaactcac acatgcccac cgtgcccagc acctgaactc 1320
ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 1380
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1440
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1500
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1560
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1620
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1680
cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1740
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1800
cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1860
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcacgaggc tctgcacaac 1920
cactacacgc agaagagcct ctccctgtct ccgggtaaa 1959
<210> 13
<211> 473
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 13
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro
245 250 255
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
260 265 270
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
275 280 285
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
290 295 300
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
305 310 315 320
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
325 330 335
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
340 345 350
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
355 360 365
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met
370 375 380
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
385 390 395 400
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
405 410 415
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
420 425 430
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
435 440 445
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
450 455 460
Lys Ser Leu Ser Leu Ser Pro Gly Lys
465 470
<210> 14
<211> 1482
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 14
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgagatc tgacaaaact cacacatgcc caccgtgccc agcacctgaa 840
ctcctggggg gaccgtcagt cttcctcttc cccccaaaac ccaaggacac cctcatgatc 900
tcccggaccc ctgaggtcac atgcgtggtg gtggacgtga gccacgaaga ccctgaggtc 960
aagttcaact ggtacgtgga cggcgtggag gtgcataatg ccaagacaaa gccgcgggag 1020
gagcagtaca acagcacgta ccgtgtggtc agcgtcctca ccgtcctgca ccaggactgg 1080
ctgaatggca aggagtacaa gtgcaaggtc tccaacaaag ccctcccagc ccccatcgag 1140
aaaaccatct ccaaagccaa agggcagccc cgagaaccac aggtgtacac cctgccccca 1200
tcccgggagg agatgaccaa gaaccaggtc agcctgacct gcctggtcaa aggcttctat 1260
cccagcgaca tcgccgtgga gtgggagagc aatgggcagc cggagaacaa ctacaagacc 1320
acgcctcccg tgctggactc cgacggctcc ttcttcctct acagcaagct caccgtggac 1380
aagagcaggt ggcagcaggg gaacgtcttc tcatgctccg tgatgcacga ggctctgcac 1440
aaccactaca cgcagaagag cctctccctg tctccgggta aa 1482
<210> 15
<211> 1064
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 15
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
565 570 575
Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
580 585 590
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
595 600 605
Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
610 615 620
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
625 630 635 640
His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr
645 650 655
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
660 665 670
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
675 680 685
Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp
690 695 700
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
705 710 715 720
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly
725 730 735
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
740 745 750
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
755 760 765
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
770 775 780
Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu
785 790 795 800
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
805 810 815
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
820 825 830
Leu Asp Pro Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
835 840 845
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
850 855 860
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
865 870 875 880
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
885 890 895
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
900 905 910
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
915 920 925
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
930 935 940
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
945 950 955 960
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
965 970 975
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
980 985 990
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
995 1000 1005
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
1010 1015 1020
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
1025 1030 1035
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
1040 1045 1050
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
1055 1060
<210> 16
<211> 3255
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 16
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagaccccag atctgacaaa 2580
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 2640
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 2700
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 2760
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 2820
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 2880
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 2940
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 3000
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 3060
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 3120
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 3180
ttctcatgct ccgtgatgca cgaggctctg cacaaccact acacgcagaa gagcctctcc 3240
ctgtctccgg gtaaa 3255
<210> 17
<211> 1064
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (563)..(837)
<223> Xaa可以是任意自然存在的氨基酸
<400> 17
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
835 840 845
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
850 855 860
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
865 870 875 880
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
885 890 895
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
900 905 910
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
915 920 925
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
930 935 940
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
945 950 955 960
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
965 970 975
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
980 985 990
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
995 1000 1005
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
1010 1015 1020
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
1025 1030 1035
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
1040 1045 1050
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
1055 1060
<210> 18
<211> 3255
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<220>
<221> misc_feature
<222> (1750)..(2574)
<223> n是a、c、g或t
<400> 18
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1800
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1860
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1920
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1980
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2040
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2100
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2160
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2220
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2280
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2340
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2400
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2460
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2520
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnngacaaa 2580
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 2640
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 2700
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 2760
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 2820
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 2880
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 2940
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 3000
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 3060
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 3120
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 3180
ttctcatgct ccgtgatgca cgaggctctg cacaaccact acacgcagaa gagcctctcc 3240
ctgtctccgg gtaaa 3255
<210> 19
<211> 1064
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (404)..(837)
<223> Xaa可以是任意自然存在的氨基酸
<400> 19
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
405 410 415
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
515 520 525
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
835 840 845
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
850 855 860
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
865 870 875 880
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
885 890 895
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
900 905 910
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
915 920 925
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
930 935 940
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
945 950 955 960
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
965 970 975
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
980 985 990
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
995 1000 1005
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
1010 1015 1020
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
1025 1030 1035
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr
1040 1045 1050
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
1055 1060
<210> 20
<211> 3255
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<220>
<221> misc_feature
<222> (1273)..(2574)
<223> n是a、c、g或t
<400> 20
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1320
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1380
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1440
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1500
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1560
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1620
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1680
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1740
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1800
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1860
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1920
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 1980
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2040
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2100
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2160
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2220
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2280
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2340
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2400
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2460
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 2520
nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnngacaaa 2580
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 2640
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 2700
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 2760
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 2820
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 2880
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 2940
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 3000
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 3060
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 3120
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 3180
ttctcatgct ccgtgatgca cgaggctctg cacaaccact acacgcagaa gagcctctcc 3240
ctgtctccgg gtaaa 3255
<210> 21
<211> 791
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 21
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro
565 570 575
Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
580 585 590
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
595 600 605
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
610 615 620
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
625 630 635 640
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
645 650 655
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
660 665 670
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
675 680 685
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys
690 695 700
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
705 710 715 720
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
725 730 735
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
740 745 750
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
755 760 765
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
770 775 780
Leu Ser Leu Ser Pro Gly Lys
785 790
<210> 22
<211> 2436
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 22
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgta gatctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 1800
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 1860
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 1920
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 1980
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 2040
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 2100
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 2160
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 2220
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 2280
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 2340
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc acgaggctct gcacaaccac 2400
tacacgcaga agagcctctc cctgtctccg ggtaaa 2436
<210> 23
<211> 632
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 23
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Arg Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
405 410 415
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
420 425 430
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
435 440 445
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
450 455 460
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
465 470 475 480
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
485 490 495
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
500 505 510
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
515 520 525
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
530 535 540
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
545 550 555 560
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
565 570 575
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
580 585 590
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
595 600 605
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
610 615 620
Ser Leu Ser Leu Ser Pro Gly Lys
625 630
<210> 24
<211> 1962
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 24
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcagatctga caaaactcac acatgcccac cgtgcccagc acctgaactc 1320
ctggggggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 1380
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 1440
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 1500
cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1560
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1620
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1680
cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1740
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1800
cctcccgtgc tggactccga cggctccttc ttcctctaca gcaagctcac cgtggacaag 1860
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcacgaggc tctgcacaac 1920
cactacacgc agaagagcct ctccctgtct ccgggtaaat ga 1962
<210> 25
<211> 1065
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 25
Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys Ile Glu Asn Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly Gly Arg Leu Trp Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Ile Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Gln Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Val Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Lys Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp Trp Ile Ser Leu Lys
340 345 350
Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Leu Gly Val Phe Ser Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Val Ser Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ala Ser Asn Gln Ala
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Thr
435 440 445
Gly Trp Ala Leu Pro Pro Ser Pro His Pro Tyr Thr Asn Glu Trp Leu
450 455 460
Gln Val Asp Leu Gly Asp Glu Lys Ile Val Arg Gly Val Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Ala Tyr Ser Asn Asn Gly Ser Asp Trp Lys Thr Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Ser Pro Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Ser Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
565 570 575
Asn Pro Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
580 585 590
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
595 600 605
Glu Lys Pro Thr Ile Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
610 615 620
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
625 630 635 640
His Trp Glu His Asp Ser His Ala Gln Leu Arg Trp Ser Val Leu Thr
645 650 655
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
660 665 670
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
675 680 685
Ser Pro Val Val Tyr Ser Gln Ser Ser Ala His Cys Met Thr Phe Trp
690 695 700
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
705 710 715 720
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Val Val Gly
725 730 735
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
740 745 750
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
755 760 765
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
770 775 780
Gln Glu Asp Cys Ala Lys Pro Thr Asp Leu Asp Lys Lys Asn Thr Glu
785 790 795 800
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
805 810 815
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
820 825 830
Leu Asp Pro Val Ser Ser Thr Met Val Arg Ser Gly Cys Lys Pro Cys
835 840 845
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
850 855 860
Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val
865 870 875 880
Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe
885 890 895
Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu
900 905 910
Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His
915 920 925
Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala
930 935 940
Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg
945 950 955 960
Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met
965 970 975
Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro
980 985 990
Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn
995 1000 1005
Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
1010 1015 1020
Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly
1025 1030 1035
Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
1040 1045 1050
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
1055 1060 1065
<210> 26
<211> 3261
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 26
atggagaggg ggctgccgtt gctgtgcgcc acgctcgccc ttgccctcgc cctggcgggc 60
gctttccgca gcgacaaatg tggcgggacc ataaaaatcg aaaacccagg gtacctcaca 120
tctcccggtt accctcattc ttaccatcca agtgagaagt gtgaatggct aatccaagct 180
ccggaaccct accagagaat catgatcaac ttcaacccac atttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtaatc gatggggaga atgaaggcgg ccgcctgtgg 300
gggaagttct gtgggaagat tgcaccttct cctgtggtgt cttcagggcc ctttctcttc 360
atcaaatttg tctctgacta tgagacacat ggggcagggt tttccatccg ctatgaaatc 420
ttcaagagag ggcccgaatg ttctcagaac tatacagcac ctactggagt gataaagtcc 480
cctgggttcc ctgaaaaata ccccaacagc ttggagtgca cctacatcat ctttgcacca 540
aagatgtctg agataatcct ggagtttgaa agttttgacc tggagcaaga ctcgaatcct 600
cccggaggaa tgttctgtcg ctatgaccgg ctggagatct gggatggatt ccctgaagtt 660
ggccctcaca ttgggcgtta ttgtgggcag aaaactcctg gccggatccg ctcctcttca 720
ggcgttctat ccatggtctt ttacactgac agcgcaatag caaaagaagg tttctcagcc 780
aactacagtg tgctacagag cagcatctct gaagatttta agtgtatgga ggctctgggc 840
atggaatctg gagagatcca ttctgatcag atcactgcat cttcacagta tggtaccaac 900
tggtctgtag agcgctcccg cctgaactac cctgaaaatg ggtggactcc aggagaagac 960
tcctacaagg agtggatcca ggtggacttg ggcctcctgc gattcgttac tgctgtaggg 1020
acacagggtg ccatttccaa ggaaaccaag aagaaatatt atgtcaagac ttacagagta 1080
gacatcagct ccaacggaga ggactggatc tccctgaaag agggaaataa agccattatc 1140
tttcagggaa acaccaaccc cacagatgtt gtcttaggag ttttctccaa accactgata 1200
actcgatttg tccgaatcaa acctgtatcc tgggaaactg gtatatctat gagatttgaa 1260
gtttatggct gcaagataac agattatcct tgctctggaa tgttgggcat ggtgtctgga 1320
cttatttcag actcccagat tacagcatcc aatcaagccg acaggaattg gatgccagaa 1380
aacatccgtc tggtgaccag tcgtaccggc tgggcactgc caccctcacc ccacccatac 1440
accaatgaat ggctccaagt ggacctggga gatgagaaga tagtaagagg tgtcatcatt 1500
cagggtggga agcaccgaga aaacaaggtg ttcatgagga agttcaagat cgcctatagt 1560
aacaatggct ctgactggaa aactatcatg gatgacagca agcgcaaggc taagtcgttc 1620
gaaggcaaca acaactatga cacacctgag cttcggacgt tttcacctct ctccacaagg 1680
ttcatcagga tctaccctga gagagccaca cacagtgggc ttgggctgag gatggagcta 1740
ctgggctgtg aagtggaagc acctacagct ggaccaacca cacccaatgg gaacccagtg 1800
gatgagtgtg acgacgacca ggccaactgc cacagtggca caggtgatga cttccagctc 1860
acaggaggca ccactgtcct ggccacagag aagccaacca ttatagacag caccatccaa 1920
tcagagttcc cgacatacgg ttttaactgc gagtttggct ggggctctca caagacattc 1980
tgccactggg agcatgacag ccatgcacag ctcaggtgga gtgtgctgac cagcaagaca 2040
gggccgattc aggaccatac aggagatggc aacttcatct attcccaagc tgatgaaaat 2100
cagaaaggca aagtagcccg cctggtgagc cctgtggtct attcccagag ctctgcccac 2160
tgtatgacct tctggtatca catgtccggc tctcatgtgg gtacactgag ggtcaaacta 2220
cgctaccaga agccagagga atatgatcaa ctggtctgga tggtggttgg gcaccaagga 2280
gaccactgga aagaaggacg tgtcttgctg cacaaatctc tgaaactata tcaggttatt 2340
tttgaaggtg aaatcggaaa aggaaacctt ggtggaattg ctgtggatga tatcagtatt 2400
aacaaccata tttctcagga agactgtgca aaaccaacag acctagataa aaagaacaca 2460
gaaattaaaa ttgatgaaac agggagcact ccaggatatg aaggagaagg ggaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg cttaagaccc tggatcccgt ctcgagcacc 2580
atggttagat ctggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 2640
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 2700
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 2760
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 2820
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 2880
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 2940
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 3000
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 3060
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 3120
ggctcttact tcgtctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 3180
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 3240
tcccactctc ctggtaaatg a 3261
<210> 27
<211> 813
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 27
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Thr Leu Ala Leu Ala Leu
1 5 10 15
Ala Leu Ala Gly Ala Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys
20 25 30
Ile Glu Asn Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly
85 90 95
Gly Arg Leu Trp Gly Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Ile Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Gln Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Val Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Lys Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Ser Leu Lys Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Leu Gly Val Phe Ser Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Val Ser Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ala Ser Asn Gln Ala Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Thr Gly Trp Ala Leu Pro Pro Ser Pro His Pro Tyr
465 470 475 480
Thr Asn Glu Trp Leu Gln Val Asp Leu Gly Asp Glu Lys Ile Val Arg
485 490 495
Gly Val Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Ala Tyr Ser Asn Asn Gly Ser Asp Trp Lys Thr
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Ser Pro Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Ser Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Val Ser Ser Thr Met Val Arg Ser Gly
580 585 590
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
595 600 605
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
610 615 620
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
625 630 635 640
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
645 650 655
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
660 665 670
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
675 680 685
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
690 695 700
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
705 710 715 720
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
725 730 735
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
740 745 750
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
755 760 765
Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
770 775 780
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
785 790 795 800
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
805 810
<210> 28
<211> 2442
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 28
atggagaggg ggctgccgtt gctgtgcgcc acgctcgccc ttgccctcgc cctggcgggc 60
gctttccgca gcgacaaatg tggcgggacc ataaaaatcg aaaacccagg gtacctcaca 120
tctcccggtt accctcattc ttaccatcca agtgagaagt gtgaatggct aatccaagct 180
ccggaaccct accagagaat catgatcaac ttcaacccac atttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtaatc gatggggaga atgaaggcgg ccgcctgtgg 300
gggaagttct gtgggaagat tgcaccttct cctgtggtgt cttcagggcc ctttctcttc 360
atcaaatttg tctctgacta tgagacacat ggggcagggt tttccatccg ctatgaaatc 420
ttcaagagag ggcccgaatg ttctcagaac tatacagcac ctactggagt gataaagtcc 480
cctgggttcc ctgaaaaata ccccaacagc ttggagtgca cctacatcat ctttgcacca 540
aagatgtctg agataatcct ggagtttgaa agttttgacc tggagcaaga ctcgaatcct 600
cccggaggaa tgttctgtcg ctatgaccgg ctggagatct gggatggatt ccctgaagtt 660
ggccctcaca ttgggcgtta ttgtgggcag aaaactcctg gccggatccg ctcctcttca 720
ggcgttctat ccatggtctt ttacactgac agcgcaatag caaaagaagg tttctcagcc 780
aactacagtg tgctacagag cagcatctct gaagatttta agtgtatgga ggctctgggc 840
atggaatctg gagagatcca ttctgatcag atcactgcat cttcacagta tggtaccaac 900
tggtctgtag agcgctcccg cctgaactac cctgaaaatg ggtggactcc aggagaagac 960
tcctacaagg agtggatcca ggtggacttg ggcctcctgc gattcgttac tgctgtaggg 1020
acacagggtg ccatttccaa ggaaaccaag aagaaatatt atgtcaagac ttacagagta 1080
gacatcagct ccaacggaga ggactggatc tccctgaaag agggaaataa agccattatc 1140
tttcagggaa acaccaaccc cacagatgtt gtcttaggag ttttctccaa accactgata 1200
actcgatttg tccgaatcaa acctgtatcc tgggaaactg gtatatctat gagatttgaa 1260
gtttatggct gcaagataac agattatcct tgctctggaa tgttgggcat ggtgtctgga 1320
cttatttcag actcccagat tacagcatcc aatcaagccg acaggaattg gatgccagaa 1380
aacatccgtc tggtgaccag tcgtaccggc tgggcactgc caccctcacc ccacccatac 1440
accaatgaat ggctccaagt ggacctggga gatgagaaga tagtaagagg tgtcatcatt 1500
cagggtggga agcaccgaga aaacaaggtg ttcatgagga agttcaagat cgcctatagt 1560
aacaatggct ctgactggaa aactatcatg gatgacagca agcgcaaggc taagtcgttc 1620
gaaggcaaca acaactatga cacacctgag cttcggacgt tttcacctct ctccacaagg 1680
ttcatcagga tctaccctga gagagccaca cacagtgggc ttgggctgag gatggagcta 1740
ctgggctgtg tctcgagcac catggttaga tctggttgta agccttgcat atgtacagtc 1800
ccagaagtat catctgtctt catcttcccc ccaaagccca aggatgtgct caccattact 1860
ctgactccta aggtcacgtg tgttgtggta gacatcagca aggatgatcc cgaggtccag 1920
ttcagctggt ttgtagatga tgtggaggtg cacacagctc agacgcaacc ccgggaggag 1980
cagttcaaca gcactttccg ctcagtcagt gaacttccca tcatgcacca ggactggctc 2040
aatggcaagg agttcaaatg cagggtcaac agtgcagctt tccctgcccc catcgagaaa 2100
accatctcca aaaccaaagg cagaccgaag gctccacagg tgtacaccat tccacctccc 2160
aaggagcaga tggccaagga taaagtcagt ctgacctgca tgataacaga cttcttccct 2220
gaagacatta ctgtggagtg gcagtggaat gggcagccag cggagaacta caagaacact 2280
cagcccatca tggacacaga tggctcttac ttcgtctaca gcaagctcaa tgtgcagaag 2340
agcaactggg aggcaggaaa tactttcacc tgctctgtgt tacatgaggg cctgcacaac 2400
caccatactg agaagagcct ctcccactct cctggtaaat ga 2442
<210> 29
<211> 633
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 29
Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys Ile Glu Asn Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly Gly Arg Leu Trp Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Ile Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Gln Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Val Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Lys Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp Trp Ile Ser Leu Lys
340 345 350
Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Leu Gly Val Phe Ser Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Val Ser Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Val Ser Ser Thr Met Val Arg Ser Gly Cys Lys Pro Cys
405 410 415
Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys
420 425 430
Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val
435 440 445
Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe
450 455 460
Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu
465 470 475 480
Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His
485 490 495
Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala
500 505 510
Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg
515 520 525
Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met
530 535 540
Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro
545 550 555 560
Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn
565 570 575
Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val
580 585 590
Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr
595 600 605
Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu
610 615 620
Lys Ser Leu Ser His Ser Pro Gly Lys
625 630
<210> 30
<211> 1965
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 30
atggagaggg ggctgccgtt gctgtgcgcc acgctcgccc ttgccctcgc cctggcgggc 60
gctttccgca gcgacaaatg tggcgggacc ataaaaatcg aaaacccagg gtacctcaca 120
tctcccggtt accctcattc ttaccatcca agtgagaagt gtgaatggct aatccaagct 180
ccggaaccct accagagaat catgatcaac ttcaacccac atttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtaatc gatggggaga atgaaggcgg ccgcctgtgg 300
gggaagttct gtgggaagat tgcaccttct cctgtggtgt cttcagggcc ctttctcttc 360
atcaaatttg tctctgacta tgagacacat ggggcagggt tttccatccg ctatgaaatc 420
ttcaagagag ggcccgaatg ttctcagaac tatacagcac ctactggagt gataaagtcc 480
cctgggttcc ctgaaaaata ccccaacagc ttggagtgca cctacatcat ctttgcacca 540
aagatgtctg agataatcct ggagtttgaa agttttgacc tggagcaaga ctcgaatcct 600
cccggaggaa tgttctgtcg ctatgaccgg ctggagatct gggatggatt ccctgaagtt 660
ggccctcaca ttgggcgtta ttgtgggcag aaaactcctg gccggatccg ctcctcttca 720
ggcgttctat ccatggtctt ttacactgac agcgcaatag caaaagaagg tttctcagcc 780
aactacagtg tgctacagag cagcatctct gaagatttta agtgtatgga ggctctgggc 840
atggaatctg gagagatcca ttctgatcag atcactgcat cttcacagta tggtaccaac 900
tggtctgtag agcgctcccg cctgaactac cctgaaaatg ggtggactcc aggagaagac 960
tcctacaagg agtggatcca ggtggacttg ggcctcctgc gattcgttac tgctgtaggg 1020
acacagggtg ccatttccaa ggaaaccaag aagaaatatt atgtcaagac ttacagagta 1080
gacatcagct ccaacggaga ggactggatc tccctgaaag agggaaataa agccattatc 1140
tttcagggaa acaccaaccc cacagatgtt gtcttaggag ttttctccaa accactgata 1200
actcgatttg tccgaatcaa acctgtatcc tgggaaactg gtatatctat gagatttgaa 1260
gtttatggct gcgtctcgag caccatggtt agatctggtt gtaagccttg catatgtaca 1320
gtcccagaag tatcatctgt cttcatcttc cccccaaagc ccaaggatgt gctcaccatt 1380
actctgactc ctaaggtcac gtgtgttgtg gtagacatca gcaaggatga tcccgaggtc 1440
cagttcagct ggtttgtaga tgatgtggag gtgcacacag ctcagacgca accccgggag 1500
gagcagttca acagcacttt ccgctcagtc agtgaacttc ccatcatgca ccaggactgg 1560
ctcaatggca aggagttcaa atgcagggtc aacagtgcag ctttccctgc ccccatcgag 1620
aaaaccatct ccaaaaccaa aggcagaccg aaggctccac aggtgtacac cattccacct 1680
cccaaggagc agatggccaa ggataaagtc agtctgacct gcatgataac agacttcttc 1740
cctgaagaca ttactgtgga gtggcagtgg aatgggcagc cagcggagaa ctacaagaac 1800
actcagccca tcatggacac agatggctct tacttcgtct acagcaagct caatgtgcag 1860
aagagcaact gggaggcagg aaatactttc acctgctctg tgttacatga gggcctgcac 1920
aaccaccata ctgagaagag cctctcccac tctcctggta aatga 1965
<210> 31
<211> 911
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 31
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Glu Val Glu Ala Pro Thr Ala
405 410 415
Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp
420 425 430
Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly
435 440 445
Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr
450 455 460
Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp
465 470 475 480
Gly Ser His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln
485 490 495
Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His
500 505 510
Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys
515 520 525
Gly Lys Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser
530 535 540
Ala His Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly
545 550 555 560
Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln
565 570 575
Leu Val Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly
580 585 590
Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu
595 600 605
Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile
610 615 620
Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp
625 630 635 640
Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr
645 650 655
Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys
660 665 670
Pro Gly Asn Val Leu Lys Thr Leu Asp Pro Arg Ser Asp Lys Thr His
675 680 685
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
690 695 700
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
705 710 715 720
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
725 730 735
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
740 745 750
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
755 760 765
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
770 775 780
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
785 790 795 800
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
805 810 815
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
820 825 830
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
835 840 845
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
850 855 860
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
865 870 875 880
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
885 890 895
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
900 905 910
<210> 32
<211> 2799
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 32
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct gaagtggaag cccctacagc tggaccgacc 1320
actcccaacg ggaacttggt ggatgaatgt gatgacgacc aggccaactg ccacagtgga 1380
acaggtgatg acttccagct cacaggtggc accactgtgc tggccacaga aaagcccacg 1440
gtcatagaca gcaccataca atcagagttt ccaacatatg gttttaactg tgaatttggc 1500
tggggctctc acaagacctt ctgccactgg gaacatgaca atcacgtgca gctcaagtgg 1560
agtgtgttga ccagcaagac gggacccatt caggatcaca caggagatgg caacttcatc 1620
tattcccaag ctgacgaaaa tcagaagggc aaagtggctc gcctggtgag ccctgtggtt 1680
tattcccaga actctgccca ctgcatgacc ttctggtatc acatgtctgg gtcccacgtc 1740
ggcacactca gggtcaaact gcgctaccag aagccagagg agtacgatca gctggtctgg 1800
atggccattg gacaccaagg tgaccactgg aaggaagggc gtgtcttgct ccacaagtct 1860
ctgaaacttt atcaggtgat tttcgagggc gaaatcggaa aaggaaacct tggtgggatt 1920
gctgtggatg acattagtat taataaccac atttcacaag aagattgtgc aaaaccagca 1980
gacctggata aaaagaaccc agaaattaaa attgatgaaa cagggagcac gccaggatac 2040
gaaggtgaag gagaaggtga caagaacatc tccaggaagc caggcaatgt gttgaagacc 2100
ttagacccca gatctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 2160
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 2220
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 2280
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 2340
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 2400
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 2460
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 2520
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 2580
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 2640
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 2700
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc acgaggctct gcacaaccac 2760
tacacgcaga agagcctctc cctgtctccg ggtaaatga 2799
<210> 33
<211> 911
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 33
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Glu Val Glu Ala Pro Thr Ala
405 410 415
Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp
420 425 430
Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly
435 440 445
Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr
450 455 460
Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp
465 470 475 480
Gly Ser His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln
485 490 495
Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His
500 505 510
Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys
515 520 525
Gly Lys Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser
530 535 540
Ala His Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly
545 550 555 560
Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln
565 570 575
Leu Val Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly
580 585 590
Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu
595 600 605
Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile
610 615 620
Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp
625 630 635 640
Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr
645 650 655
Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys
660 665 670
Pro Gly Asn Val Leu Lys Thr Leu Asp Pro Arg Ser Asp Lys Thr His
675 680 685
Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val
690 695 700
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
705 710 715 720
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
725 730 735
Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
740 745 750
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser
755 760 765
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
770 775 780
Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
785 790 795 800
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
805 810 815
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
820 825 830
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
835 840 845
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
850 855 860
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
865 870 875 880
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
885 890 895
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
900 905 910
<210> 34
<211> 2799
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 34
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct gaagtggaag cccctacagc tggaccgacc 1320
actcccaacg ggaacttggt ggatgaatgt gatgacgacc aggccaactg ccacagtgga 1380
acaggtgatg acttccagct cacaggtggc accactgtgc tggccacaga aaagcccacg 1440
gtcatagaca gcaccataca atcagagttt ccaacatatg gttttaactg tgaatttggc 1500
tggggctctc acaagacctt ctgccactgg gaacatgaca atcacgtgca gctcaagtgg 1560
agtgtgttga ccagcaagac gggacccatt caggatcaca caggagatgg caacttcatc 1620
tattcccaag ctgacgaaaa tcagaagggc aaagtggctc gcctggtgag ccctgtggtt 1680
tattcccaga actctgccca ctgcatgacc ttctggtatc acatgtctgg gtcccacgtc 1740
ggcacactca gggtcaaact gcgctaccag aagccagagg agtacgatca gctggtctgg 1800
atggccattg gacaccaagg tgaccactgg aaggaagggc gtgtcttgct ccacaagtct 1860
ctgaaacttt atcaggtgat tttcgagggc gaaatcggaa aaggaaacct tggtgggatt 1920
gctgtggatg acattagtat taataaccac atttcacaag aagattgtgc aaaaccagca 1980
gacctggata aaaagaaccc agaaattaaa attgatgaaa cagggagcac gccaggatac 2040
gaaggtgaag gagaaggtga caagaacatc tccaggaagc caggcaatgt gttgaagacc 2100
ttagacccca gatctgacaa aactcacaca tgcccaccgt gcccagcacc tgaactcctg 2160
gggggaccgt cagtcttcct cttcccccca aaacccaagg acaccctcat gatctcccgg 2220
acccctgagg tcacatgcgt ggtggtggac gtgagccacg aagaccctga ggtcaagttc 2280
aactggtacg tggacggcgt ggaggtgcat aatgccaaga caaagccgcg ggaggagcag 2340
tacaacagca cgtaccgtgt ggtcagcgtc ctcaccgtcc tgcaccagga ctggctgaat 2400
ggcaaggagt acaagtgcaa ggtctccaac aaagccctcc cagcccccat cgagaaaacc 2460
atctccaaag ccaaagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 2520
gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 2580
gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 2640
cccgtgctgg actccgacgg ctccttcttc ctctacagca agctcaccgt ggacaagagc 2700
aggtggcagc aggggaacgt cttctcatgc tccgtgatgc acgaggctct gcacaaccac 2760
tacacgcaga agagcctctc cctgtctccg ggtaaatga 2799
<210> 35
<211> 755
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 35
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Glu Val Glu
245 250 255
Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp Glu
260 265 270
Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp Phe
275 280 285
Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr Val
290 295 300
Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys
305 310 315 320
Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys His Trp Glu His Asp
325 330 335
Asn His Val Gln Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly Pro
340 345 350
Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp
355 360 365
Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val Ser Pro Val Val Tyr
370 375 380
Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp Tyr His Met Ser Gly
385 390 395 400
Ser His Val Gly Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu
405 410 415
Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly His Gln Gly Asp His
420 425 430
Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr Gln
435 440 445
Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala
450 455 460
Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys Ala
465 470 475 480
Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu
485 490 495
Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn
500 505 510
Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr Leu Asp Pro Arg Ser
515 520 525
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
530 535 540
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
545 550 555 560
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
565 570 575
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
580 585 590
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
595 600 605
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
610 615 620
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
625 630 635 640
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
645 650 655
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
660 665 670
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
675 680 685
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
690 695 700
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
705 710 715 720
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
725 730 735
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
740 745 750
Pro Gly Lys
755
<210> 36
<211> 2331
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 36
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aagaagtgga agcccctaca 840
gctggaccga ccactcccaa cgggaacttg gtggatgaat gtgatgacga ccaggccaac 900
tgccacagtg gaacaggtga tgacttccag ctcacaggtg gcaccactgt gctggccaca 960
gaaaagccca cggtcataga cagcaccata caatcagagt ttccaacata tggttttaac 1020
tgtgaatttg gctggggctc tcacaagacc ttctgccact gggaacatga caatcacgtg 1080
cagctcaagt ggagtgtgtt gaccagcaag acgggaccca ttcaggatca cacaggagat 1140
ggcaacttca tctattccca agctgacgaa aatcagaagg gcaaagtggc tcgcctggtg 1200
agccctgtgg tttattccca gaactctgcc cactgcatga ccttctggta tcacatgtct 1260
gggtcccacg tcggcacact cagggtcaaa ctgcgctacc agaagccaga ggagtacgat 1320
cagctggtct ggatggccat tggacaccaa ggtgaccact ggaaggaagg gcgtgtcttg 1380
ctccacaagt ctctgaaact ttatcaggtg attttcgagg gcgaaatcgg aaaaggaaac 1440
cttggtggga ttgctgtgga tgacattagt attaataacc acatttcaca agaagattgt 1500
gcaaaaccag cagacctgga taaaaagaac ccagaaatta aaattgatga aacagggagc 1560
acgccaggat acgaaggtga aggagaaggt gacaagaaca tctccaggaa gccaggcaat 1620
gtgttgaaga ccttagaccc cagatctgac aaaactcaca catgcccacc gtgcccagca 1680
cctgaactcc tggggggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 1740
atgatctccc ggacccctga ggtcacatgc gtggtggtgg acgtgagcca cgaagaccct 1800
gaggtcaagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagccg 1860
cgggaggagc agtacaacag cacgtaccgt gtggtcagcg tcctcaccgt cctgcaccag 1920
gactggctga atggcaagga gtacaagtgc aaggtctcca acaaagccct cccagccccc 1980
atcgagaaaa ccatctccaa agccaaaggg cagccccgag aaccacaggt gtacaccctg 2040
cccccatccc gggaggagat gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc 2100
ttctatccca gcgacatcgc cgtggagtgg gagagcaatg ggcagccgga gaacaactac 2160
aagaccacgc ctcccgtgct ggactccgac ggctccttct tcctctacag caagctcacc 2220
gtggacaaga gcaggtggca gcaggggaac gtcttctcat gctccgtgat gcacgaggct 2280
ctgcacaacc actacacgca gaagagcctc tccctgtctc cgggtaaatg a 2331
<210> 37
<211> 227
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 37
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
1 5 10 15
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
20 25 30
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
35 40 45
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
50 55 60
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
65 70 75 80
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
85 90 95
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
100 105 110
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
115 120 125
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
130 135 140
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
145 150 155 160
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
165 170 175
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
180 185 190
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
195 200 205
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
210 215 220
Pro Gly Lys
225
<210> 38
<211> 853
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 38
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
565 570 575
Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
580 585 590
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
595 600 605
Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
610 615 620
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
625 630 635 640
His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr
645 650 655
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
660 665 670
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
675 680 685
Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp
690 695 700
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
705 710 715 720
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly
725 730 735
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
740 745 750
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
755 760 765
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
770 775 780
Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu
785 790 795 800
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
805 810 815
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
820 825 830
Leu Asp Pro Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His
835 840 845
His His His His His
850
<210> 39
<211> 2625
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 39
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagaccccag atctggatcc 2580
aaggaaaact tgtatttcca gggccatcat catcatcatc attga 2625
<210> 40
<211> 580
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 40
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His His
565 570 575
His His His His
580
<210> 41
<211> 1806
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 41
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgta gatctggatc caaggaaaac ttgtatttcc agggccatca tcatcatcat 1800
cattga 1806
<210> 42
<211> 421
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 42
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His
405 410 415
His His His His His
420
<210> 43
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 43
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcagatctgg atccaaggaa aacttgtatt tccagggcca tcatcatcat 1320
catcattga 1329
<210> 44
<211> 262
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 44
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly
245 250 255
His His His His His His
260
<210> 45
<211> 852
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 45
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgagatc tggatccaag gaaaacttgt atttccaggg ccatcatcat 840
catcatcatt ga 852
<210> 46
<211> 853
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 46
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
565 570 575
Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
580 585 590
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
595 600 605
Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
610 615 620
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
625 630 635 640
His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr
645 650 655
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
660 665 670
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
675 680 685
Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp
690 695 700
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
705 710 715 720
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly
725 730 735
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
740 745 750
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
755 760 765
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
770 775 780
Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu
785 790 795 800
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
805 810 815
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
820 825 830
Leu Asp Pro Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His
835 840 845
His His His His His
850
<210> 47
<211> 2625
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 47
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagaccccag atctggatcc 2580
aaggaaaact tgtatttcca gggccatcat catcatcatc attga 2625
<210> 48
<211> 580
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 48
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His His
565 570 575
His His His His
580
<210> 49
<211> 1806
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 49
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgta gatctggatc caaggaaaac ttgtatttcc agggccatca tcatcatcat 1800
cattga 1806
<210> 50
<211> 421
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 50
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His
405 410 415
His His His His His
420
<210> 51
<211> 1329
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 51
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcagatctgg atccaaggaa aacttgtatt tccagggcca tcatcatcat 1320
catcattga 1329
<210> 52
<211> 700
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 52
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Glu Val Glu Ala Pro Thr Ala
405 410 415
Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp
420 425 430
Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly
435 440 445
Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr
450 455 460
Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp
465 470 475 480
Gly Ser His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln
485 490 495
Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His
500 505 510
Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys
515 520 525
Gly Lys Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser
530 535 540
Ala His Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly
545 550 555 560
Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln
565 570 575
Leu Val Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly
580 585 590
Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu
595 600 605
Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile
610 615 620
Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp
625 630 635 640
Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr
645 650 655
Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys
660 665 670
Pro Gly Asn Val Leu Lys Thr Leu Asp Pro Arg Ser Gly Ser Lys Glu
675 680 685
Asn Leu Tyr Phe Gln Gly His His His His His His
690 695 700
<210> 53
<211> 2166
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 53
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct gaagtggaag cccctacagc tggaccgacc 1320
actcccaacg ggaacttggt ggatgaatgt gatgacgacc aggccaactg ccacagtgga 1380
acaggtgatg acttccagct cacaggtggc accactgtgc tggccacaga aaagcccacg 1440
gtcatagaca gcaccataca atcagagttt ccaacatatg gttttaactg tgaatttggc 1500
tggggctctc acaagacctt ctgccactgg gaacatgaca atcacgtgca gctcaagtgg 1560
agtgtgttga ccagcaagac gggacccatt caggatcaca caggagatgg caacttcatc 1620
tattcccaag ctgacgaaaa tcagaagggc aaagtggctc gcctggtgag ccctgtggtt 1680
tattcccaga actctgccca ctgcatgacc ttctggtatc acatgtctgg gtcccacgtc 1740
ggcacactca gggtcaaact gcgctaccag aagccagagg agtacgatca gctggtctgg 1800
atggccattg gacaccaagg tgaccactgg aaggaagggc gtgtcttgct ccacaagtct 1860
ctgaaacttt atcaggtgat tttcgagggc gaaatcggaa aaggaaacct tggtgggatt 1920
gctgtggatg acattagtat taataaccac atttcacaag aagattgtgc aaaaccagca 1980
gacctggata aaaagaaccc agaaattaaa attgatgaaa cagggagcac gccaggatac 2040
gaaggtgaag gagaaggtga caagaacatc tccaggaagc caggcaatgt gttgaagacc 2100
ttagacccca gatctggatc caaggaaaac ttgtatttcc agggccatca tcatcatcat 2160
cattga 2166
<210> 54
<211> 700
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 54
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Glu Val Glu Ala Pro Thr Ala
405 410 415
Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp
420 425 430
Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly
435 440 445
Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr
450 455 460
Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp
465 470 475 480
Gly Ser His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln
485 490 495
Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His
500 505 510
Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys
515 520 525
Gly Lys Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser
530 535 540
Ala His Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly
545 550 555 560
Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln
565 570 575
Leu Val Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly
580 585 590
Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu
595 600 605
Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile
610 615 620
Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp
625 630 635 640
Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr
645 650 655
Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys
660 665 670
Pro Gly Asn Val Leu Lys Thr Leu Asp Pro Arg Ser Gly Ser Lys Glu
675 680 685
Asn Leu Tyr Phe Gln Gly His His His His His His
690 695 700
<210> 55
<211> 2166
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 55
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccaggc tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct gaagtggaag cccctacagc tggaccgacc 1320
actcccaacg ggaacttggt ggatgaatgt gatgacgacc aggccaactg ccacagtgga 1380
acaggtgatg acttccagct cacaggtggc accactgtgc tggccacaga aaagcccacg 1440
gtcatagaca gcaccataca atcagagttt ccaacatatg gttttaactg tgaatttggc 1500
tggggctctc acaagacctt ctgccactgg gaacatgaca atcacgtgca gctcaagtgg 1560
agtgtgttga ccagcaagac gggacccatt caggatcaca caggagatgg caacttcatc 1620
tattcccaag ctgacgaaaa tcagaagggc aaagtggctc gcctggtgag ccctgtggtt 1680
tattcccaga actctgccca ctgcatgacc ttctggtatc acatgtctgg gtcccacgtc 1740
ggcacactca gggtcaaact gcgctaccag aagccagagg agtacgatca gctggtctgg 1800
atggccattg gacaccaagg tgaccactgg aaggaagggc gtgtcttgct ccacaagtct 1860
ctgaaacttt atcaggtgat tttcgagggc gaaatcggaa aaggaaacct tggtgggatt 1920
gctgtggatg acattagtat taataaccac atttcacaag aagattgtgc aaaaccagca 1980
gacctggata aaaagaaccc agaaattaaa attgatgaaa cagggagcac gccaggatac 2040
gaaggtgaag gagaaggtga caagaacatc tccaggaagc caggcaatgt gttgaagacc 2100
ttagacccca gatctggatc caaggaaaac ttgtatttcc agggccatca tcatcatcat 2160
cattga 2166
<210> 56
<211> 544
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 56
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Glu Val Glu
245 250 255
Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp Glu
260 265 270
Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp Phe
275 280 285
Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr Val
290 295 300
Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys
305 310 315 320
Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys His Trp Glu His Asp
325 330 335
Asn His Val Gln Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly Pro
340 345 350
Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp
355 360 365
Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val Ser Pro Val Val Tyr
370 375 380
Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp Tyr His Met Ser Gly
385 390 395 400
Ser His Val Gly Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu
405 410 415
Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly His Gln Gly Asp His
420 425 430
Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr Gln
435 440 445
Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala
450 455 460
Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys Ala
465 470 475 480
Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu
485 490 495
Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn
500 505 510
Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr Leu Asp Pro Arg Ser
515 520 525
Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His His His His His His
530 535 540
<210> 57
<211> 1698
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 57
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aagaagtgga agcccctaca 840
gctggaccga ccactcccaa cgggaacttg gtggatgaat gtgatgacga ccaggccaac 900
tgccacagtg gaacaggtga tgacttccag ctcacaggtg gcaccactgt gctggccaca 960
gaaaagccca cggtcataga cagcaccata caatcagagt ttccaacata tggttttaac 1020
tgtgaatttg gctggggctc tcacaagacc ttctgccact gggaacatga caatcacgtg 1080
cagctcaagt ggagtgtgtt gaccagcaag acgggaccca ttcaggatca cacaggagat 1140
ggcaacttca tctattccca agctgacgaa aatcagaagg gcaaagtggc tcgcctggtg 1200
agccctgtgg tttattccca gaactctgcc cactgcatga ccttctggta tcacatgtct 1260
gggtcccacg tcggcacact cagggtcaaa ctgcgctacc agaagccaga ggagtacgat 1320
cagctggtct ggatggccat tggacaccaa ggtgaccact ggaaggaagg gcgtgtcttg 1380
ctccacaagt ctctgaaact ttatcaggtg attttcgagg gcgaaatcgg aaaaggaaac 1440
cttggtggga ttgctgtgga tgacattagt attaataacc acatttcaca agaagattgt 1500
gcaaaaccag cagacctgga taaaaagaac ccagaaatta aaattgatga aacagggagc 1560
acgccaggat acgaaggtga aggagaaggt gacaagaaca tctccaggaa gccaggcaat 1620
gtgttgaaga ccttagaccc cagatctgga tccaaggaaa acttgtattt ccagggccat 1680
catcatcatc atcattga 1698
<210> 58
<211> 853
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 58
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ala Lys Lys Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
565 570 575
Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
580 585 590
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
595 600 605
Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
610 615 620
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
625 630 635 640
His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr
645 650 655
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
660 665 670
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
675 680 685
Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp
690 695 700
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
705 710 715 720
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly
725 730 735
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
740 745 750
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
755 760 765
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
770 775 780
Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu
785 790 795 800
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
805 810 815
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
820 825 830
Leu Asp Pro Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His
835 840 845
His His His His His
850
<210> 59
<211> 2625
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 59
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccattgccaa aaagaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagaccccag atctggatcc 2580
aaggaaaact tgtatttcca gggccatcat catcatcatc attga 2625
<210> 60
<211> 853
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 60
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Lys Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
565 570 575
Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
580 585 590
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
595 600 605
Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
610 615 620
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
625 630 635 640
His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr
645 650 655
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
660 665 670
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
675 680 685
Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp
690 695 700
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
705 710 715 720
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly
725 730 735
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
740 745 750
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
755 760 765
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
770 775 780
Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu
785 790 795 800
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
805 810 815
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
820 825 830
Leu Asp Pro Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His
835 840 845
His His His His His
850
<210> 61
<211> 2625
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 61
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagagaag 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagaccccag atctggatcc 2580
aaggaaaact tgtatttcca gggccatcat catcatcatc attga 2625
<210> 62
<211> 853
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 62
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln
115 120 125
Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu
130 135 140
Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys
145 150 155 160
Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp
165 170 175
Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile
180 185 190
Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly
195 200 205
Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met
210 215 220
Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn
225 230 235 240
Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu
245 250 255
Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala
260 265 270
Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn
275 280 285
Tyr Pro Glu Asn Gly Trp Thr Pro Gly Lys Lys Ser Tyr Arg Glu Trp
290 295 300
Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr
305 310 315 320
Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr
325 330 335
Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys
340 345 350
Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp
355 360 365
Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg
370 375 380
Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val
385 390 395 400
Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met
405 410 415
Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly
420 425 430
Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser
435 440 445
Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu
450 455 460
Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln
465 470 475 480
Gly Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile
485 490 495
Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser
500 505 510
Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro
515 520 525
Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr
530 535 540
Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu
545 550 555 560
Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
565 570 575
Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
580 585 590
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
595 600 605
Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
610 615 620
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
625 630 635 640
His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr
645 650 655
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
660 665 670
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
675 680 685
Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp
690 695 700
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
705 710 715 720
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly
725 730 735
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
740 745 750
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
755 760 765
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
770 775 780
Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu
785 790 795 800
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
805 810 815
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
820 825 830
Leu Asp Pro Arg Ser Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly His
835 840 845
His His His His His
850
<210> 63
<211> 2625
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 63
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggaaagaag 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagaccccag atctggatcc 2580
aaggaaaact tgtatttcca gggccatcat catcatcatc attga 2625
<210> 64
<211> 771
<212> PRT
<213> 人
<400> 64
Met Gly Trp Leu Thr Arg Ile Val Cys Leu Phe Trp Gly Val Leu Leu
1 5 10 15
Thr Ala Arg Ala Asn Tyr Gln Asn Gly Lys Asn Asn Val Pro Arg Leu
20 25 30
Lys Leu Ser Tyr Lys Glu Met Leu Glu Ser Asn Asn Val Ile Thr Phe
35 40 45
Asn Gly Leu Ala Asn Ser Ser Ser Tyr His Thr Phe Leu Leu Asp Glu
50 55 60
Glu Arg Ser Arg Leu Tyr Val Gly Ala Lys Asp His Ile Phe Ser Phe
65 70 75 80
Asp Leu Val Asn Ile Lys Asp Phe Gln Lys Ile Val Trp Pro Val Ser
85 90 95
Tyr Thr Arg Arg Asp Glu Cys Lys Trp Ala Gly Lys Asp Ile Leu Lys
100 105 110
Glu Cys Ala Asn Phe Ile Lys Val Leu Lys Ala Tyr Asn Gln Thr His
115 120 125
Leu Tyr Ala Cys Gly Thr Gly Ala Phe His Pro Ile Cys Thr Tyr Ile
130 135 140
Glu Ile Gly His His Pro Glu Asp Asn Ile Phe Lys Leu Glu Asn Ser
145 150 155 160
His Phe Glu Asn Gly Arg Gly Lys Ser Pro Tyr Asp Pro Lys Leu Leu
165 170 175
Thr Ala Ser Leu Leu Ile Asp Gly Glu Leu Tyr Ser Gly Thr Ala Ala
180 185 190
Asp Phe Met Gly Arg Asp Phe Ala Ile Phe Arg Thr Leu Gly His His
195 200 205
His Pro Ile Arg Thr Glu Gln His Asp Ser Arg Trp Leu Asn Asp Pro
210 215 220
Lys Phe Ile Ser Ala His Leu Ile Ser Glu Ser Asp Asn Pro Glu Asp
225 230 235 240
Asp Lys Val Tyr Phe Phe Phe Arg Glu Asn Ala Ile Asp Gly Glu His
245 250 255
Ser Gly Lys Ala Thr His Ala Arg Ile Gly Gln Ile Cys Lys Asn Asp
260 265 270
Phe Gly Gly His Arg Ser Leu Val Asn Lys Trp Thr Thr Phe Leu Lys
275 280 285
Ala Arg Leu Ile Cys Ser Val Pro Gly Pro Asn Gly Ile Asp Thr His
290 295 300
Phe Asp Glu Leu Gln Asp Val Phe Leu Met Asn Phe Lys Asp Pro Lys
305 310 315 320
Asn Pro Val Val Tyr Gly Val Phe Thr Thr Ser Ser Asn Ile Phe Lys
325 330 335
Gly Ser Ala Val Cys Met Tyr Ser Met Ser Asp Val Arg Arg Val Phe
340 345 350
Leu Gly Pro Tyr Ala His Arg Asp Gly Pro Asn Tyr Gln Trp Val Pro
355 360 365
Tyr Gln Gly Arg Val Pro Tyr Pro Arg Pro Gly Thr Cys Pro Ser Lys
370 375 380
Thr Phe Gly Gly Phe Asp Ser Thr Lys Asp Leu Pro Asp Asp Val Ile
385 390 395 400
Thr Phe Ala Arg Ser His Pro Ala Met Tyr Asn Pro Val Phe Pro Met
405 410 415
Asn Asn Arg Pro Ile Val Ile Lys Thr Asp Val Asn Tyr Gln Phe Thr
420 425 430
Gln Ile Val Val Asp Arg Val Asp Ala Glu Asp Gly Gln Tyr Asp Val
435 440 445
Met Phe Ile Gly Thr Asp Val Gly Thr Val Leu Lys Val Val Ser Ile
450 455 460
Pro Lys Glu Thr Trp Tyr Asp Leu Glu Glu Val Leu Leu Glu Glu Met
465 470 475 480
Thr Val Phe Arg Glu Pro Thr Ala Ile Ser Ala Met Glu Leu Ser Thr
485 490 495
Lys Gln Gln Gln Leu Tyr Ile Gly Ser Thr Ala Gly Val Ala Gln Leu
500 505 510
Pro Leu His Arg Cys Asp Ile Tyr Gly Lys Ala Cys Ala Glu Cys Cys
515 520 525
Leu Ala Arg Asp Pro Tyr Cys Ala Trp Asp Gly Ser Ala Cys Ser Arg
530 535 540
Tyr Phe Pro Thr Ala Lys Arg Arg Thr Arg Arg Gln Asp Ile Arg Asn
545 550 555 560
Gly Asp Pro Leu Thr His Cys Ser Asp Leu His His Asp Asn His His
565 570 575
Gly His Ser Pro Glu Glu Arg Ile Ile Tyr Gly Val Glu Asn Ser Ser
580 585 590
Thr Phe Leu Glu Cys Ser Pro Lys Ser Gln Arg Ala Leu Val Tyr Trp
595 600 605
Gln Phe Gln Arg Arg Asn Glu Glu Arg Lys Glu Glu Ile Arg Val Asp
610 615 620
Asp His Ile Ile Arg Thr Asp Gln Gly Leu Leu Leu Arg Ser Leu Gln
625 630 635 640
Gln Lys Asp Ser Gly Asn Tyr Leu Cys His Ala Val Glu His Gly Phe
645 650 655
Ile Gln Thr Leu Leu Lys Val Thr Leu Glu Val Ile Asp Thr Glu His
660 665 670
Leu Glu Glu Leu Leu His Lys Asp Asp Asp Gly Asp Gly Ser Lys Thr
675 680 685
Lys Glu Met Ser Asn Ser Met Thr Pro Ser Gln Lys Val Trp Tyr Arg
690 695 700
Asp Phe Met Gln Leu Ile Asn His Pro Asn Leu Asn Thr Met Asp Glu
705 710 715 720
Phe Cys Glu Gln Val Trp Lys Arg Asp Arg Lys Gln Arg Arg Gln Arg
725 730 735
Pro Gly His Thr Pro Gly Asn Ser Asn Lys Trp Lys His Leu Gln Glu
740 745 750
Asn Lys Lys Gly Arg Asn Arg Arg Thr His Glu Phe Glu Arg Ala Pro
755 760 765
Arg Ser Val
770
<210> 65
<211> 609
<212> PRT
<213> 人
<400> 65
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Gly Gly Thr Thr Val Leu
580 585 590
Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Gly Ile
595 600 605
Lys
<210> 66
<211> 923
<212> PRT
<213> 人
<400> 66
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro Ile Leu Ile Thr Ile Ile Ala Met
850 855 860
Ser Ala Leu Gly Val Leu Leu Gly Ala Val Cys Gly Val Val Leu Tyr
865 870 875 880
Cys Ala Cys Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu
885 890 895
Glu Asn Tyr Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp
900 905 910
Lys Leu Asn Thr Gln Ser Thr Tyr Ser Glu Ala
915 920
<210> 67
<211> 923
<212> PRT
<213> 小鼠
<400> 67
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Thr Leu Ala Leu Ala Leu
1 5 10 15
Ala Leu Ala Gly Ala Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys
20 25 30
Ile Glu Asn Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly
85 90 95
Gly Arg Leu Trp Gly Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Ile Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Gln Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Val Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Lys Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Ser Leu Lys Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Leu Gly Val Phe Ser Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Val Ser Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ala Ser Asn Gln Ala Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Thr Gly Trp Ala Leu Pro Pro Ser Pro His Pro Tyr
465 470 475 480
Thr Asn Glu Trp Leu Gln Val Asp Leu Gly Asp Glu Lys Ile Val Arg
485 490 495
Gly Val Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Ala Tyr Ser Asn Asn Gly Ser Asp Trp Lys Thr
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Ser Pro Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Ser Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Pro Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Ile Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Ser His Ala Gln Leu Arg
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Ser Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Val Val Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Thr Asp Leu Asp
805 810 815
Lys Lys Asn Thr Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro Ile Leu Ile Thr Ile Ile Ala Met
850 855 860
Ser Ala Leu Gly Val Leu Leu Gly Ala Val Cys Gly Val Val Leu Tyr
865 870 875 880
Cys Ala Cys Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu
885 890 895
Glu Asn Tyr Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp
900 905 910
Lys Leu Asn Pro Gln Ser Asn Tyr Ser Glu Ala
915 920
<210> 68
<211> 923
<212> PRT
<213> 褐鼠（ratus norvegicus）
<400> 68
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Thr Leu Ala Leu Ala Leu
1 5 10 15
Ala Leu Ala Gly Ala Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys
20 25 30
Ile Glu Asn Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly
85 90 95
Gly Arg Leu Trp Gly Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Ile Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Gln Asp Ser Asn Pro Pro Gly Gly Val Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Leu Lys Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Phe Gly Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Ser Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ala Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Thr Gly Trp Ala Leu Pro Pro Ser Pro His Pro Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Val Asp Leu Gly Asp Glu Lys Ile Val Arg
485 490 495
Gly Val Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Ala Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Ala Phe Thr Pro Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Ser Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Val Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Pro Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Ile Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Ser His Ala Gln Leu Arg
660 665 670
Trp Arg Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Ser Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu His Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Val Val Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Pro Gln Glu Asp Cys Ala Lys Pro Thr Asp Leu Asp
805 810 815
Lys Lys Asn Thr Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Glu Glu Gly Lys Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro Ile Leu Ile Thr Ile Ile Ala Met
850 855 860
Ser Ala Leu Gly Val Leu Leu Gly Ala Val Cys Gly Val Val Leu Tyr
865 870 875 880
Cys Ala Cys Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu
885 890 895
Glu Asn Tyr Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp
900 905 910
Lys Leu Asn Pro Gln Ser Asn Tyr Ser Glu Ala
915 920
<210> 69
<211> 923
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (11)..(11)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (15)..(15)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (18)..(18)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (24)..(24)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (29)..(29)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (35)..(35)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (62)..(62)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (90)..(90)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (96)..(96)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (98)..(100)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (110)..(110)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (140)..(140)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (153)..(153)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (155)..(155)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (177)..(177)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (196)..(196)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (204)..(204)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (219)..(219)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (242)..(242)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (269)..(269)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (298)..(298)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (303)..(303)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (323)..(323)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (359)..(360)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (362)..(362)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (371)..(372)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (378)..(380)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (392)..(393)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (396)..(396)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (409)..(410)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (449)..(449)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (453)..(453)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (469)..(469)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (476)..(476)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (479)..(479)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (481)..(481)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (487)..(487)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (491)..(491)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (498)..(498)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (518)..(518)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (528)..(528)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (553)..(553)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (555)..(556)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (572)..(572)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (587)..(587)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (599)..(599)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (634)..(634)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (667)..(667)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (669)..(669)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (672)..(672)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (674)..(674)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (717)..(717)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (741)..(741)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (755)..(756)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (805)..(805)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (812)..(812)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (819)..(820)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (835)..(835)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (838)..(838)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (916)..(916)
<223> Xaa可以是任意自然存在的氨基酸
<220>
<221> misc_feature
<222> (919)..(919)
<223> Xaa可以是任意自然存在的氨基酸
<400> 69
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Xaa Leu Ala Leu Xaa Leu
1 5 10 15
Ala Xaa Ala Gly Ala Phe Arg Xaa Asp Lys Cys Gly Xaa Thr Ile Lys
20 25 30
Ile Glu Xaa Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Xaa Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Xaa Asp Gly Glu Asn Glu Xaa
85 90 95
Gly Xaa Xaa Xaa Gly Lys Phe Cys Gly Lys Ile Ala Pro Xaa Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Xaa Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Xaa Pro Xaa Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Xaa Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Xaa Asp Ser Asn Pro Pro Gly Gly Xaa Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Xaa Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Xaa Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Xaa Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Xaa Thr Asn Trp Ser Xaa Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Xaa Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Xaa Xaa Asp Xaa Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Xaa Xaa Lys Glu Gly Asn Lys Xaa Xaa Xaa Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Xaa Xaa Val Phe Xaa Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Xaa Xaa Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Xaa Ser Asn Gln Xaa Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Xaa Gly Trp Ala Leu Pro Pro Xaa Pro His Xaa Tyr
465 470 475 480
Xaa Asn Glu Trp Leu Gln Xaa Asp Leu Gly Xaa Glu Lys Ile Val Arg
485 490 495
Gly Xaa Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Xaa Tyr Ser Asn Asn Gly Ser Asp Trp Lys Xaa
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Xaa Phe Xaa Xaa Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Xaa Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Xaa Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Xaa Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Xaa Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Xaa His Xaa Gln Leu Xaa
660 665 670
Trp Xaa Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Xaa Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Xaa Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Xaa Xaa Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Xaa Gln Glu Asp Cys Ala Lys Xaa Asp Leu Asp Lys
805 810 815
Lys Asn Xaa Xaa Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Xaa Glu Gly Xaa Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro Ile Leu Ile Thr Ile Ile Ala Met
850 855 860
Ser Ala Leu Gly Val Leu Leu Gly Ala Val Cys Gly Val Val Leu Tyr
865 870 875 880
Cys Ala Cys Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu
885 890 895
Glu Asn Tyr Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp
900 905 910
Lys Leu Asn Xaa Gln Ser Xaa Tyr Ser Glu Ala
915 920
<210> 70
<211> 21
<212> PRT
<213> 人
<400> 70
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala
20
<210> 71
<211> 115
<212> PRT
<213> 人
<400> 71
Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro
1 5 10 15
Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys Cys Glu Trp Leu Ile
20 25 30
Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile Asn Phe Asn Pro His
35 40 45
Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe
50 55 60
Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly Lys Phe Cys Gly Lys
65 70 75 80
Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro Phe Leu Phe Ile Lys
85 90 95
Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly Phe Ser Ile Arg Tyr
100 105 110
Glu Leu Phe
115
<210> 72
<211> 119
<212> PRT
<213> 人
<400> 72
Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly
1 5 10 15
Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe
20 25 30
Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu
35 40 45
Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg
50 55 60
Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg
65 70 75 80
Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile
85 90 95
Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe
100 105 110
Ser Ala Asn Tyr Ser Val Leu
115
<210> 73
<211> 150
<212> PRT
<213> 人
<400> 73
Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln
1 5 10 15
Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser
20 25 30
Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr
35 40 45
Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala
50 55 60
Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr
65 70 75 80
Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile
85 90 95
Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn
100 105 110
Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg
115 120 125
Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg
130 135 140
Phe Glu Val Tyr Gly Cys
145 150
<210> 74
<211> 153
<212> PRT
<213> 人
<400> 74
Cys Ser Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln
1 5 10 15
Ile Thr Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile
20 25 30
Arg Leu Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His
35 40 45
Ser Tyr Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile
50 55 60
Val Arg Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val
65 70 75 80
Phe Met Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp
85 90 95
Lys Met Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly
100 105 110
Asn Asn Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser
115 120 125
Thr Arg Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu
130 135 140
Gly Leu Arg Met Glu Leu Leu Gly Cys
145 150
<210> 75
<211> 167
<212> PRT
<213> 人
<400> 75
Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe
1 5 10 15
Cys His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu
20 25 30
Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe
35 40 45
Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu
50 55 60
Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe
65 70 75 80
Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu
85 90 95
Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile
100 105 110
Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys
115 120 125
Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly
130 135 140
Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile
145 150 155 160
Ser Gln Glu Asp Cys Ala Lys
165
<210> 76
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 76
Gly Ser Lys Glu Asn Leu Tyr Phe Gln Gly
1 5 10
<210> 77
<211> 40
<212> PRT
<213> 人
<400> 77
Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu Glu Asn Tyr
1 5 10 15
Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp Lys Leu Asn
20 25 30
Thr Gln Ser Thr Tyr Ser Glu Ala
35 40
<210> 78
<211> 127
<212> PRT
<213> 人
<400> 78
Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly
1 5 10 15
Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys
20 25 30
Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile
35 40 45
Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp
50 55 60
Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly
65 70 75 80
Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro
85 90 95
Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly
100 105 110
Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser
115 120 125
<210> 79
<211> 127
<212> PRT
<213> 人
<400> 79
Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro
1 5 10 15
Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro
20 25 30
Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro
35 40 45
Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu
50 55 60
Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys
65 70 75 80
Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser
85 90 95
Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala
100 105 110
Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys
115 120 125
<210> 80
<211> 153
<212> PRT
<213> 人
<400> 80
Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile
1 5 10 15
Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg
20 25 30
Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg
35 40 45
Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val
50 55 60
Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val
65 70 75 80
Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr
85 90 95
Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro
100 105 110
Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe
115 120 125
Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe
130 135 140
Glu Val Tyr Gly Cys Lys Ile Thr Asp
145 150
<210> 81
<211> 161
<212> PRT
<213> 人
<400> 81
Tyr Pro Cys Ser Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp
1 5 10 15
Ser Gln Ile Thr Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu
20 25 30
Asn Ile Arg Leu Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala
35 40 45
Pro His Ser Tyr Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu
50 55 60
Lys Ile Val Arg Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn
65 70 75 80
Lys Val Phe Met Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser
85 90 95
Asp Trp Lys Met Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe
100 105 110
Glu Gly Asn Asn Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala
115 120 125
Leu Ser Thr Arg Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly
130 135 140
Gly Leu Gly Leu Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro
145 150 155 160
Thr
<210> 82
<211> 270
<212> PRT
<213> 人
<400> 82
Ala Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp
1 5 10 15
Asp Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr
20 25 30
Gly Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser
35 40 45
Thr Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly
50 55 60
Trp Gly Ser His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val
65 70 75 80
Gln Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp
85 90 95
His Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln
100 105 110
Lys Gly Lys Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn
115 120 125
Ser Ala His Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val
130 135 140
Gly Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp
145 150 155 160
Gln Leu Val Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu
165 170 175
Gly Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe
180 185 190
Glu Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp
195 200 205
Ile Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala
210 215 220
Asp Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser
225 230 235 240
Thr Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg
245 250 255
Lys Pro Gly Asn Val Leu Lys Thr Leu Asp Pro Ile Leu Ile
260 265 270
<210> 83
<211> 834
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 83
Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys Ile Glu Ser Pro Gly Tyr
1 5 10 15
Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr His Pro Ser Glu Lys Cys
20 25 30
Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr Gln Arg Ile Met Ile Asn
35 40 45
Phe Asn Pro His Phe Asp Leu Glu Asp Arg Asp Cys Lys Tyr Asp Tyr
50 55 60
Val Glu Val Phe Asp Gly Glu Asn Glu Asn Gly His Phe Arg Gly Lys
65 70 75 80
Phe Cys Gly Lys Ile Ala Pro Pro Pro Val Val Ser Ser Gly Pro Phe
85 90 95
Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu Thr His Gly Ala Gly Phe
100 105 110
Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly Pro Glu Cys Ser Gln Asn
115 120 125
Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser Pro Gly Phe Pro Glu Lys
130 135 140
Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile Val Phe Ala Pro Lys Met
145 150 155 160
Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe Asp Leu Glu Pro Asp Ser
165 170 175
Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr Asp Arg Leu Glu Ile Trp
180 185 190
Asp Gly Phe Pro Asp Val Gly Pro His Ile Gly Arg Tyr Cys Gly Gln
195 200 205
Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser Gly Ile Leu Ser Met Val
210 215 220
Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu Gly Phe Ser Ala Asn Tyr
225 230 235 240
Ser Val Leu Gln Ser Ser Val Ser Glu Asp Phe Lys Cys Met Glu Ala
245 250 255
Leu Gly Met Glu Ser Gly Glu Ile His Ser Asp Gln Ile Thr Ala Ser
260 265 270
Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu Arg Ser Arg Leu Asn Tyr
275 280 285
Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp Ser Tyr Arg Glu Trp Ile
290 295 300
Gln Val Asp Leu Gly Leu Leu Arg Phe Val Thr Ala Val Gly Thr Gln
305 310 315 320
Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys Tyr Tyr Val Lys Thr Tyr
325 330 335
Lys Ile Asp Val Ser Ser Asn Gly Glu Asp Trp Ile Thr Ile Lys Glu
340 345 350
Gly Asn Lys Pro Val Leu Phe Gln Gly Asn Thr Asn Pro Thr Asp Val
355 360 365
Val Val Ala Val Phe Pro Lys Pro Leu Ile Thr Arg Phe Val Arg Ile
370 375 380
Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser Met Arg Phe Glu Val Tyr
385 390 395 400
Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser Gly Met Leu Gly Met Val
405 410 415
Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr Ser Ser Asn Gln Gly Asp
420 425 430
Arg Asn Trp Met Pro Glu Asn Ile Arg Leu Val Thr Ser Arg Ser Gly
435 440 445
Trp Ala Leu Pro Pro Ala Pro His Ser Tyr Ile Asn Glu Trp Leu Gln
450 455 460
Ile Asp Leu Gly Glu Glu Lys Ile Val Arg Gly Ile Ile Ile Gln Gly
465 470 475 480
Gly Lys His Arg Glu Asn Lys Val Phe Met Arg Lys Phe Lys Ile Gly
485 490 495
Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met Ile Met Asp Asp Ser Lys
500 505 510
Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn Asn Tyr Asp Thr Pro Glu
515 520 525
Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg Phe Ile Arg Ile Tyr Pro
530 535 540
Glu Arg Ala Thr His Gly Gly Leu Gly Leu Arg Met Glu Leu Leu Gly
545 550 555 560
Cys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly Asn
565 570 575
Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly Thr
580 585 590
Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr Glu
595 600 605
Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr Tyr
610 615 620
Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys His
625 630 635 640
Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr Ser
645 650 655
Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile Tyr
660 665 670
Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val Ser
675 680 685
Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp Tyr
690 695 700
His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg Tyr
705 710 715 720
Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly His
725 730 735
Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser Leu
740 745 750
Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn Leu
755 760 765
Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser Gln
770 775 780
Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu Ile
785 790 795 800
Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly Glu
805 810 815
Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr Leu
820 825 830
Asp Pro
<210> 84
<211> 2571
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 84
atggagaggg ggctgccgct cctctgcgcc gtgctcgccc tcgtcctcgc cccggccggc 60
gcttttcgca acgataaatg tggcgatact ataaaaattg aaagccccgg gtaccttaca 120
tctcctggtt atcctcattc ttatcaccca agtgaaaaat gcgaatggct gattcaggct 180
ccggacccat accagagaat tatgatcaac ttcaaccctc acttcgattt ggaggacaga 240
gactgcaagt atgactacgt ggaagtcttc gatggagaaa atgaaaatgg acattttagg 300
ggaaagttct gtggaaagat agcccctcct cctgttgtgt cttcagggcc atttcttttt 360
atcaaatttg tctctgacta cgaaacacat ggtgcaggat tttccatacg ttatgaactt 420
ttcaagagag gtcctgaatg ttcccagaac tacacaacac ctagtggagt gataaagtcc 480
cccggattcc ctgaaaaata tcccaacagc cttgaatgca cttatattgt ctttgcgcca 540
aagatgtcag agattatcct ggaatttgaa agctttgacc tggagcctga ctcaaatcct 600
ccagggggga tgttctgtcg ctacgaccgg ctagaaatct gggatggatt ccctgatgtt 660
ggccctcaca ttgggcgtta ctgtggacag aaaacaccag gtcgaatccg atcctcatcg 720
ggcattctct ccatggtttt ttacaccgac agcgcgatag caaaagaagg tttctcagca 780
aactacagtg tcttgcagag cagtgtctca gaagatttca aatgtatgga agctctgggc 840
atggaatcag gagaaattca ttctgaccag atcacagctt cttcccagta tagcaccaac 900
tggtctgcag agcgctcccg cctgaactac cctgagaatg ggtggactcc cggagaggat 960
tcctaccgag agtggataca ggtagacttg ggccttctgc gctttgtcac ggctgtcggg 1020
acacagggcg ccatttcaaa agaaaccaag aagaaatatt atgtcaagac ttacaagatc 1080
gacgttagct ccaacgggga agactggatc accataaaag aaggaaacaa acctgttctc 1140
tttcagggaa acaccaaccc tacagatgtt gtggttgcag tattccccaa accactgata 1200
actcgatttg tccgaatcaa gcctgcaact tgggaaactg gcatatctat gagatttgaa 1260
gtatatggtt gcaagataac agattatcct tgctctggaa tgttgggtat ggtgtctgga 1320
cttatttctg actcccagat cacatcatcc aaccaagggg acagaaactg gatgcctgaa 1380
aacatccgcc tggtaaccag tcgctctggc tgggcacttc cacccgcacc tcattcctac 1440
atcaatgagt ggctccaaat agacctgggg gaggagaaga tcgtgagggg catcatcatt 1500
cagggtggga agcaccgaga gaacaaggtg ttcatgagga agttcaagat cgggtacagc 1560
aacaacggct cggactggaa gatgatcatg gatgacagca aacgcaaggc gaagtctttt 1620
gagggcaaca acaactatga tacacctgag ctgcggactt ttccagctct ctccacgcga 1680
ttcatcagga tctaccccga gagagccact catggcggac tggggctcag aatggagctg 1740
ctgggctgtg aagtggaagc ccctacagct ggaccgacca ctcccaacgg gaacttggtg 1800
gatgaatgtg atgacgacca ggccaactgc cacagtggaa caggtgatga cttccagctc 1860
acaggtggca ccactgtgct ggccacagaa aagcccacgg tcatagacag caccatacaa 1920
tcagagtttc caacatatgg ttttaactgt gaatttggct ggggctctca caagaccttc 1980
tgccactggg aacatgacaa tcacgtgcag ctcaagtgga gtgtgttgac cagcaagacg 2040
ggacccattc aggatcacac aggagatggc aacttcatct attcccaagc tgacgaaaat 2100
cagaagggca aagtggctcg cctggtgagc cctgtggttt attcccagaa ctctgcccac 2160
tgcatgacct tctggtatca catgtctggg tcccacgtcg gcacactcag ggtcaaactg 2220
cgctaccaga agccagagga gtacgatcag ctggtctgga tggccattgg acaccaaggt 2280
gaccactgga aggaagggcg tgtcttgctc cacaagtctc tgaaacttta tcaggtgatt 2340
ttcgagggcg aaatcggaaa aggaaacctt ggtgggattg ctgtggatga cattagtatt 2400
aataaccaca tttcacaaga agattgtgca aaaccagcag acctggataa aaagaaccca 2460
gaaattaaaa ttgatgaaac agggagcacg ccaggatacg aaggtgaagg agaaggtgac 2520
aagaacatct ccaggaagcc aggcaatgtg ttgaagacct tagacccctg a 2571
<210> 85
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 85
gacggccagg tcatcactat tg 22
<210> 86
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 86
ccacaggatt ccatacccaa ga 22
<210> 87
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 87
gctcctgctc cgtagcctgc 20
<210> 88
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 88
tcggcgttgc tttcggtccc 20
<210> 89
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 89
gccctgagtc aagaggacag 20
<210> 90
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 90
ctcctaggcc cctcagaagt 20
<210> 91
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 91
ccctcacact cagatcatct tct 23
<210> 92
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 92
gctacgacgt gggctacag 19
<210> 93
<211> 21
<212> DNA
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 93
ctggtacatc aggacctcac a 21
<210> 94
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 94
gagctcctta acatgccctg 20
<210> 95
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 95
agacaaagcc agagtccttc agaga 25
<210> 96
<211> 23
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 96
gccactcctt ctgtgactcg agc 23
<210> 97
<211> 40
<212> PRT
<213> 人
<400> 97
Trp His Asn Gly Met Ser Glu Arg Asn Leu Ser Ala Leu Glu Asn Tyr
1 5 10 15
Asn Phe Glu Leu Val Asp Gly Val Lys Leu Lys Lys Asp Lys Leu Asn
20 25 30
Thr Gln Ser Thr Tyr Ser Glu Ala
35 40
<210> 98
<211> 64
<212> PRT
<213> 人
<400> 98
Thr Ile Ile Ala Met Ser Ala Leu Gly Val Leu Leu Gly Ala Val Cys
1 5 10 15
Gly Val Val Leu Tyr Cys Ala Cys Trp His Asn Gly Met Ser Glu Arg
20 25 30
Asn Leu Ser Ala Leu Glu Asn Tyr Asn Phe Glu Leu Val Asp Gly Val
35 40 45
Lys Leu Lys Lys Asp Lys Leu Asn Thr Gln Ser Thr Tyr Ser Glu Ala
50 55 60
<210> 99
<211> 19
<212> PRT
<213> 人
<400> 99
Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser
1 5 10 15
Gly Ile Lys
<210> 100
<211> 856
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 100
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro
850 855
<210> 101
<211> 856
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 101
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro
850 855
<210> 102
<211> 856
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 102
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Lys Lys
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro
850 855
<210> 103
<211> 856
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 103
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ala Lys Lys Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro
850 855
<210> 104
<211> 856
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 104
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Lys
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro
850 855
<210> 105
<211> 583
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 105
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys
580
<210> 106
<211> 583
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 106
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys
580
<210> 107
<211> 424
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 107
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys
420
<210> 108
<211> 424
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 108
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys
420
<210> 109
<211> 265
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 109
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu
260 265
<210> 110
<211> 642
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 110
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Glu Val
420 425 430
Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp
435 440 445
Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp
450 455 460
Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr
465 470 475 480
Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn
485 490 495
Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys His Trp Glu His
500 505 510
Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly
515 520 525
Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala
530 535 540
Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val Ser Pro Val Val
545 550 555 560
Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp Tyr His Met Ser
565 570 575
Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro
580 585 590
Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly His Gln Gly Asp
595 600 605
His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr
610 615 620
Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile
625 630 635 640
Ala Val
<210> 111
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 111
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Glu Val
420 425 430
Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp
435 440 445
Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp
450 455 460
Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr
465 470 475 480
Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn
485 490 495
Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys His Trp Glu His
500 505 510
Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly
515 520 525
Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala
530 535 540
Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val Ser Pro Val Val
545 550 555 560
Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp Tyr His Met Ser
565 570 575
Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro
580 585 590
Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly His Gln Gly Asp
595 600 605
His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr
610 615 620
Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile
625 630 635 640
Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys
645 650 655
Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp
660 665 670
Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys
675 680 685
Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr Leu Asp Pro
690 695 700
<210> 112
<211> 547
<212> PRT
<213> 人工序列
<220>
<223> 合成多核苷酸
<400> 112
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Glu Val Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly
275 280 285
Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly
290 295 300
Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr
305 310 315 320
Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr
325 330 335
Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys
340 345 350
His Trp Glu His Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr
355 360 365
Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile
370 375 380
Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val
385 390 395 400
Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp
405 410 415
Tyr His Met Ser Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg
420 425 430
Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly
435 440 445
His Gln Gly Asp His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser
450 455 460
Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn
465 470 475 480
Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser
485 490 495
Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu
500 505 510
Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly
515 520 525
Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr
530 535 540
Leu Asp Pro
545
<210> 113
<211> 703
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 113
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Glu Val
420 425 430
Glu Ala Pro Thr Ala Gly Pro Thr Thr Pro Asn Gly Asn Leu Val Asp
435 440 445
Glu Cys Asp Asp Asp Gln Ala Asn Cys His Ser Gly Thr Gly Asp Asp
450 455 460
Phe Gln Leu Thr Gly Gly Thr Thr Val Leu Ala Thr Glu Lys Pro Thr
465 470 475 480
Val Ile Asp Ser Thr Ile Gln Ser Glu Phe Pro Thr Tyr Gly Phe Asn
485 490 495
Cys Glu Phe Gly Trp Gly Ser His Lys Thr Phe Cys His Trp Glu His
500 505 510
Asp Asn His Val Gln Leu Lys Trp Ser Val Leu Thr Ser Lys Thr Gly
515 520 525
Pro Ile Gln Asp His Thr Gly Asp Gly Asn Phe Ile Tyr Ser Gln Ala
530 535 540
Asp Glu Asn Gln Lys Gly Lys Val Ala Arg Leu Val Ser Pro Val Val
545 550 555 560
Tyr Ser Gln Asn Ser Ala His Cys Met Thr Phe Trp Tyr His Met Ser
565 570 575
Gly Ser His Val Gly Thr Leu Arg Val Lys Leu Arg Tyr Gln Lys Pro
580 585 590
Glu Glu Tyr Asp Gln Leu Val Trp Met Ala Ile Gly His Gln Gly Asp
595 600 605
His Trp Lys Glu Gly Arg Val Leu Leu His Lys Ser Leu Lys Leu Tyr
610 615 620
Gln Val Ile Phe Glu Gly Glu Ile Gly Lys Gly Asn Leu Gly Gly Ile
625 630 635 640
Ala Val Asp Asp Ile Ser Ile Asn Asn His Ile Ser Gln Glu Asp Cys
645 650 655
Ala Lys Pro Ala Asp Leu Asp Lys Lys Asn Pro Glu Ile Lys Ile Asp
660 665 670
Glu Thr Gly Ser Thr Pro Gly Tyr Glu Gly Glu Gly Glu Gly Asp Lys
675 680 685
Asn Ile Ser Arg Lys Pro Gly Asn Val Leu Lys Thr Leu Asp Pro
690 695 700
<210> 114
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 114
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro Arg Ser Asp Lys Thr His Thr Cys
850 855 860
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
865 870 875 880
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
885 890 895
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
900 905 910
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
915 920 925
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
930 935 940
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
945 950 955 960
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
965 970 975
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
980 985 990
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
995 1000 1005
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1010 1015 1020
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1025 1030 1035
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
1040 1045 1050
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1055 1060 1065
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
1070 1075 1080
Gly Lys
1085
<210> 115
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (584)..(858)
<223> Xaa可以是任意自然存在的氨基酸
<400> 115
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
835 840 845
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys
850 855 860
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
865 870 875 880
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
885 890 895
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
900 905 910
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
915 920 925
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
930 935 940
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
945 950 955 960
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
965 970 975
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
980 985 990
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
995 1000 1005
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1010 1015 1020
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1025 1030 1035
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
1040 1045 1050
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1055 1060 1065
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
1070 1075 1080
Gly Lys
1085
<210> 116
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (425)..(858)
<223> Xaa可以是任意自然存在的氨基酸
<400> 116
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
515 520 525
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
835 840 845
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys
850 855 860
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
865 870 875 880
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
885 890 895
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
900 905 910
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
915 920 925
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
930 935 940
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
945 950 955 960
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
965 970 975
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
980 985 990
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
995 1000 1005
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1010 1015 1020
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1025 1030 1035
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
1040 1045 1050
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1055 1060 1065
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
1070 1075 1080
Gly Lys
1085
<210> 117
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (266)..(858)
<223> Xaa可以是任意自然存在的氨基酸
<400> 117
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Xaa Xaa Xaa Xaa Xaa Xaa Xaa
260 265 270
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
275 280 285
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
290 295 300
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
305 310 315 320
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
325 330 335
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
340 345 350
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
355 360 365
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
370 375 380
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
385 390 395 400
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
405 410 415
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
515 520 525
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
835 840 845
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys
850 855 860
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
865 870 875 880
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
885 890 895
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
900 905 910
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
915 920 925
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
930 935 940
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
945 950 955 960
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
965 970 975
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
980 985 990
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
995 1000 1005
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1010 1015 1020
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1025 1030 1035
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
1040 1045 1050
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1055 1060 1065
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
1070 1075 1080
Gly Lys
1085
<210> 118
<211> 812
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 118
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Arg Ser Asp Lys Thr His Thr Cys Pro
580 585 590
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
595 600 605
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
610 615 620
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
625 630 635 640
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
645 650 655
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
660 665 670
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
675 680 685
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
690 695 700
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
705 710 715 720
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
725 730 735
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
740 745 750
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
755 760 765
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
770 775 780
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
785 790 795 800
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
805 810
<210> 119
<211> 653
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 119
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Arg Ser Asp Lys Thr His Thr Cys
420 425 430
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
435 440 445
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
450 455 460
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
465 470 475 480
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
485 490 495
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
500 505 510
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
515 520 525
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
530 535 540
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
545 550 555 560
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
565 570 575
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
580 585 590
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
595 600 605
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
610 615 620
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
625 630 635 640
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
645 650
<210> 120
<211> 494
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 120
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Arg Ser Asp Lys Thr His Thr
260 265 270
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
275 280 285
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
290 295 300
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
305 310 315 320
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
325 330 335
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
340 345 350
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
355 360 365
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
370 375 380
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
385 390 395 400
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
405 410 415
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
420 425 430
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
435 440 445
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
450 455 460
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
465 470 475 480
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
485 490
<210> 121
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 121
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Leu Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Val Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Asn His Val Gln Leu Lys
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Asn Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Ala Ile Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Ala Asp Leu Asp
805 810 815
Lys Lys Asn Pro Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro Arg Ser Asp Lys Thr His Thr Cys
850 855 860
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
865 870 875 880
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
885 890 895
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
900 905 910
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
915 920 925
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
930 935 940
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
945 950 955 960
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
965 970 975
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
980 985 990
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
995 1000 1005
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1010 1015 1020
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1025 1030 1035
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
1040 1045 1050
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1055 1060 1065
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
1070 1075 1080
Gly Lys
1085
<210> 122
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (584)..(858)
<223> Xaa可以是任意自然存在的氨基酸
<400> 122
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
835 840 845
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys
850 855 860
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
865 870 875 880
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
885 890 895
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
900 905 910
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
915 920 925
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
930 935 940
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
945 950 955 960
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
965 970 975
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
980 985 990
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
995 1000 1005
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1010 1015 1020
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1025 1030 1035
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
1040 1045 1050
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1055 1060 1065
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
1070 1075 1080
Gly Lys
1085
<210> 123
<211> 1085
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<220>
<221> misc_feature
<222> (425)..(858)
<223> Xaa可以是任意自然存在的氨基酸
<400> 123
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
420 425 430
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
435 440 445
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
450 455 460
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
465 470 475 480
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
485 490 495
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
500 505 510
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
515 520 525
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
530 535 540
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
545 550 555 560
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
565 570 575
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
580 585 590
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
595 600 605
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
610 615 620
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
625 630 635 640
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
645 650 655
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
660 665 670
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
675 680 685
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
690 695 700
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
705 710 715 720
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
725 730 735
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
740 745 750
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
755 760 765
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
770 775 780
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
785 790 795 800
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
805 810 815
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
820 825 830
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
835 840 845
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Asp Lys Thr His Thr Cys
850 855 860
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
865 870 875 880
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
885 890 895
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
900 905 910
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
915 920 925
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
930 935 940
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
945 950 955 960
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
965 970 975
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
980 985 990
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
995 1000 1005
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
1010 1015 1020
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
1025 1030 1035
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
1040 1045 1050
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
1055 1060 1065
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
1070 1075 1080
Gly Lys
1085
<210> 124
<211> 812
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 124
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ser Ser Asn Gln Gly Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Ser Gly Trp Ala Leu Pro Pro Ala Pro His Ser Tyr
465 470 475 480
Ile Asn Glu Trp Leu Gln Ile Asp Leu Gly Glu Glu Lys Ile Val Arg
485 490 495
Gly Ile Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Gly Tyr Ser Asn Asn Gly Ser Asp Trp Lys Met
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Pro Ala Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Gly Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Arg Ser Asp Lys Thr His Thr Cys Pro
580 585 590
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
595 600 605
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
610 615 620
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
625 630 635 640
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
645 650 655
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
660 665 670
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
675 680 685
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
690 695 700
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
705 710 715 720
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
725 730 735
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
740 745 750
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
755 760 765
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
770 775 780
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
785 790 795 800
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
805 810
<210> 125
<211> 653
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 125
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Asn Asp Lys Cys Gly Asp Thr Ile Lys
20 25 30
Ile Glu Ser Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Asp Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Phe Asp Gly Glu Asn Glu Asn
85 90 95
Gly His Phe Arg Gly Lys Phe Cys Gly Lys Ile Ala Pro Pro Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Leu Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Thr Pro Ser Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Val Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Pro Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Asp Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Ile Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Val Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Ala Ser Thr Asn Trp Ser Ala Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Arg Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Lys Ile Asp Val Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Thr Ile Lys Glu Gly Asn Lys Pro Val Leu Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Val Ala Val Phe Pro Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Ala Thr Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Arg Ser Asp Lys Thr His Thr Cys
420 425 430
Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu
435 440 445
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu
450 455 460
Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys
465 470 475 480
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
485 490 495
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
500 505 510
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
515 520 525
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
530 535 540
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
545 550 555 560
Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
565 570 575
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
580 585 590
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
595 600 605
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
610 615 620
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
625 630 635 640
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
645 650
<210> 126
<211> 1086
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 126
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys
20 25 30
Ile Glu Asn Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly
85 90 95
Gly Arg Leu Trp Gly Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Ile Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Gln Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Val Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Lys Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Ser Leu Lys Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Leu Gly Val Phe Ser Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Val Ser Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ala Ser Asn Gln Ala Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Thr Gly Trp Ala Leu Pro Pro Ser Pro His Pro Tyr
465 470 475 480
Thr Asn Glu Trp Leu Gln Val Asp Leu Gly Asp Glu Lys Ile Val Arg
485 490 495
Gly Val Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Ala Tyr Ser Asn Asn Gly Ser Asp Trp Lys Thr
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Ser Pro Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Ser Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Glu Val Glu Ala Pro Thr Ala Gly Pro
580 585 590
Thr Thr Pro Asn Gly Asn Pro Val Asp Glu Cys Asp Asp Asp Gln Ala
595 600 605
Asn Cys His Ser Gly Thr Gly Asp Asp Phe Gln Leu Thr Gly Gly Thr
610 615 620
Thr Val Leu Ala Thr Glu Lys Pro Thr Ile Ile Asp Ser Thr Ile Gln
625 630 635 640
Ser Glu Phe Pro Thr Tyr Gly Phe Asn Cys Glu Phe Gly Trp Gly Ser
645 650 655
His Lys Thr Phe Cys His Trp Glu His Asp Ser His Ala Gln Leu Arg
660 665 670
Trp Ser Val Leu Thr Ser Lys Thr Gly Pro Ile Gln Asp His Thr Gly
675 680 685
Asp Gly Asn Phe Ile Tyr Ser Gln Ala Asp Glu Asn Gln Lys Gly Lys
690 695 700
Val Ala Arg Leu Val Ser Pro Val Val Tyr Ser Gln Ser Ser Ala His
705 710 715 720
Cys Met Thr Phe Trp Tyr His Met Ser Gly Ser His Val Gly Thr Leu
725 730 735
Arg Val Lys Leu Arg Tyr Gln Lys Pro Glu Glu Tyr Asp Gln Leu Val
740 745 750
Trp Met Val Val Gly His Gln Gly Asp His Trp Lys Glu Gly Arg Val
755 760 765
Leu Leu His Lys Ser Leu Lys Leu Tyr Gln Val Ile Phe Glu Gly Glu
770 775 780
Ile Gly Lys Gly Asn Leu Gly Gly Ile Ala Val Asp Asp Ile Ser Ile
785 790 795 800
Asn Asn His Ile Ser Gln Glu Asp Cys Ala Lys Pro Thr Asp Leu Asp
805 810 815
Lys Lys Asn Thr Glu Ile Lys Ile Asp Glu Thr Gly Ser Thr Pro Gly
820 825 830
Tyr Glu Gly Glu Gly Glu Gly Asp Lys Asn Ile Ser Arg Lys Pro Gly
835 840 845
Asn Val Leu Lys Thr Leu Asp Pro Val Ser Ser Thr Met Val Arg Ser
850 855 860
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
865 870 875 880
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
885 890 895
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
900 905 910
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
915 920 925
Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
930 935 940
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
945 950 955 960
Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
965 970 975
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
980 985 990
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
995 1000 1005
Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
1010 1015 1020
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp
1025 1030 1035
Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys
1040 1045 1050
Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
1055 1060 1065
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser
1070 1075 1080
Pro Gly Lys
1085
<210> 127
<211> 813
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 127
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys
20 25 30
Ile Glu Asn Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly
85 90 95
Gly Arg Leu Trp Gly Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Ile Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Gln Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Val Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Lys Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Ser Leu Lys Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Leu Gly Val Phe Ser Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Val Ser Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Lys Ile Thr Asp Tyr Pro Cys Ser
420 425 430
Gly Met Leu Gly Met Val Ser Gly Leu Ile Ser Asp Ser Gln Ile Thr
435 440 445
Ala Ser Asn Gln Ala Asp Arg Asn Trp Met Pro Glu Asn Ile Arg Leu
450 455 460
Val Thr Ser Arg Thr Gly Trp Ala Leu Pro Pro Ser Pro His Pro Tyr
465 470 475 480
Thr Asn Glu Trp Leu Gln Val Asp Leu Gly Asp Glu Lys Ile Val Arg
485 490 495
Gly Val Ile Ile Gln Gly Gly Lys His Arg Glu Asn Lys Val Phe Met
500 505 510
Arg Lys Phe Lys Ile Ala Tyr Ser Asn Asn Gly Ser Asp Trp Lys Thr
515 520 525
Ile Met Asp Asp Ser Lys Arg Lys Ala Lys Ser Phe Glu Gly Asn Asn
530 535 540
Asn Tyr Asp Thr Pro Glu Leu Arg Thr Phe Ser Pro Leu Ser Thr Arg
545 550 555 560
Phe Ile Arg Ile Tyr Pro Glu Arg Ala Thr His Ser Gly Leu Gly Leu
565 570 575
Arg Met Glu Leu Leu Gly Cys Val Ser Ser Thr Met Val Arg Ser Gly
580 585 590
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
595 600 605
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
610 615 620
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
625 630 635 640
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
645 650 655
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
660 665 670
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
675 680 685
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
690 695 700
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
705 710 715 720
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
725 730 735
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
740 745 750
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
755 760 765
Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
770 775 780
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
785 790 795 800
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
805 810
<210> 128
<211> 654
<212> PRT
<213> 人工序列
<220>
<223> 合成多肽
<400> 128
Met Glu Arg Gly Leu Pro Leu Leu Cys Ala Val Leu Ala Leu Val Leu
1 5 10 15
Ala Pro Ala Gly Ala Phe Arg Ser Asp Lys Cys Gly Gly Thr Ile Lys
20 25 30
Ile Glu Asn Pro Gly Tyr Leu Thr Ser Pro Gly Tyr Pro His Ser Tyr
35 40 45
His Pro Ser Glu Lys Cys Glu Trp Leu Ile Gln Ala Pro Glu Pro Tyr
50 55 60
Gln Arg Ile Met Ile Asn Phe Asn Pro His Phe Asp Leu Glu Asp Arg
65 70 75 80
Asp Cys Lys Tyr Asp Tyr Val Glu Val Ile Asp Gly Glu Asn Glu Gly
85 90 95
Gly Arg Leu Trp Gly Lys Phe Cys Gly Lys Ile Ala Pro Ser Pro Val
100 105 110
Val Ser Ser Gly Pro Phe Leu Phe Ile Lys Phe Val Ser Asp Tyr Glu
115 120 125
Thr His Gly Ala Gly Phe Ser Ile Arg Tyr Glu Ile Phe Lys Arg Gly
130 135 140
Pro Glu Cys Ser Gln Asn Tyr Thr Ala Pro Thr Gly Val Ile Lys Ser
145 150 155 160
Pro Gly Phe Pro Glu Lys Tyr Pro Asn Ser Leu Glu Cys Thr Tyr Ile
165 170 175
Ile Phe Ala Pro Lys Met Ser Glu Ile Ile Leu Glu Phe Glu Ser Phe
180 185 190
Asp Leu Glu Gln Asp Ser Asn Pro Pro Gly Gly Met Phe Cys Arg Tyr
195 200 205
Asp Arg Leu Glu Ile Trp Asp Gly Phe Pro Glu Val Gly Pro His Ile
210 215 220
Gly Arg Tyr Cys Gly Gln Lys Thr Pro Gly Arg Ile Arg Ser Ser Ser
225 230 235 240
Gly Val Leu Ser Met Val Phe Tyr Thr Asp Ser Ala Ile Ala Lys Glu
245 250 255
Gly Phe Ser Ala Asn Tyr Ser Val Leu Gln Ser Ser Ile Ser Glu Asp
260 265 270
Phe Lys Cys Met Glu Ala Leu Gly Met Glu Ser Gly Glu Ile His Ser
275 280 285
Asp Gln Ile Thr Ala Ser Ser Gln Tyr Gly Thr Asn Trp Ser Val Glu
290 295 300
Arg Ser Arg Leu Asn Tyr Pro Glu Asn Gly Trp Thr Pro Gly Glu Asp
305 310 315 320
Ser Tyr Lys Glu Trp Ile Gln Val Asp Leu Gly Leu Leu Arg Phe Val
325 330 335
Thr Ala Val Gly Thr Gln Gly Ala Ile Ser Lys Glu Thr Lys Lys Lys
340 345 350
Tyr Tyr Val Lys Thr Tyr Arg Val Asp Ile Ser Ser Asn Gly Glu Asp
355 360 365
Trp Ile Ser Leu Lys Glu Gly Asn Lys Ala Ile Ile Phe Gln Gly Asn
370 375 380
Thr Asn Pro Thr Asp Val Val Leu Gly Val Phe Ser Lys Pro Leu Ile
385 390 395 400
Thr Arg Phe Val Arg Ile Lys Pro Val Ser Trp Glu Thr Gly Ile Ser
405 410 415
Met Arg Phe Glu Val Tyr Gly Cys Val Ser Ser Thr Met Val Arg Ser
420 425 430
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
435 440 445
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
450 455 460
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
465 470 475 480
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
485 490 495
Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
500 505 510
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
515 520 525
Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
530 535 540
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
545 550 555 560
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
565 570 575
Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly
580 585 590
Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp
595 600 605
Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp
610 615 620
Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His
625 630 635 640
Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
645 650

Claims (69)

1.治疗或预防炎症的方法，其包括在受试者中抑制NRP1依赖性细胞信号传导。
2.预防或降低先天免疫反应超活化的方法，其包括在受试者中抑制NRP1依赖性细胞信号传导。
3.权利要求2所述的方法，其中所述先天免疫反应超活化包括i)IL-6、IL-1β和TNFα的分泌和/或单核吞噬细胞(MP)的募集。
4.权利要求1-3中任一项所述的方法，其中抑制NRP1依赖性细胞信号传导包括：
(a)降低NRP1表达或活性；和/或
(b)降低NRP1配体表达或活性；
其中所述NRP1配体是SEMA3A、VEGF和/或TGF-β。
5.权利要求4所述的方法，其中所述方法包括(i)通过抑制NRP1与至少一种NRP1配体的结合降低NRP1活性。
6.权利要求5所述的方法，其中所述NRP1配体是SEMA3A、VEGF或TGF-β。
7.权利要求5或6所述的方法，其中抑制NRP1与至少一种NRP1配体的结合包括施用抗NRP1抗体或NRP1陷阱，其中所述陷阱包含NRP1多肽或其功能片段或变体。
8.权利要求7所述的方法，其中所述NRP1多肽对应于可溶性NRP1同种型2。
9.权利要求8所述的方法，其中所述可溶性NRP1同种型2包括具有如图22中所示的氨基酸序列的多肽或基本上由具有如图22中所示的氨基酸序列的多肽组成，而无信号肽。
10.权利要求7所述的方法，其中所述NRP1多肽对应于所述NRP1同种型1多肽的胞外结构域。
11.权利要求10所述的方法，其中所述NRP1同种型1多肽如图26中所示并且其中所述胞外结构域包含图26中显示的所述NRP1多肽的氨基酸22至859(SEQ ID NO：66的残基22至859)。
12.权利要求7至11中任一项所述的方法，其中所述NRP1陷阱包括NRP1多肽，其包括(i)如SEQ ID NO：65中所示的NRP1多肽的氨基酸22至609；(ii)如SEQ ID NO：66中所示的NRP1多肽的氨基酸22至859；(iii)如SEQ ID NO：69中所示的NRP1多肽的氨基酸22至859(iv)或(i)、(ii)或(iii)的功能片段或功能变体。
13.权利要求7至12中任一项所述的方法，其中所述抗NRP1抗体抑制SEMA3A与NPR-1的结合但基本上不抑制VEGF与NRP1的结合，并且其中所述NRP1陷阱与SEMA3A结合但基本上不与VEGF165结合或具有与SEMA3A结合亲和力相比降低的对VEGF165的结合亲和力。
14.权利要求13所述的方法，其中所述NRP1陷阱(i)完全或部分地缺少NRP1的结构域b1和/或b2；或(ii)包括抑制VEGF与NRP1结合的至少一个氨基酸点突变。
15.权利要求13所述的方法，其中所述抗NRP1抗体不与NRP1的结构域b1和/或b2结合。
16.权利要求14所述的方法，其中所述点突变包括(a)在对应于图22或图26中所示的NRP1氨基酸序列的酪氨酸297的氨基酸残基处的结构域b1的氨基酸取代或缺失；(b)在对应于图22或图26中所示的NRP1氨基酸序列的天冬氨酸320的氨基酸残基处的结构域b1中的氨基酸取代或缺失；和/或(c)在对应于图22或图26中所示的NRP1氨基酸序列的谷氨酸319的氨基酸残基处的结构域b1中的氨基酸取代或缺失。
17.权利要求16所述的方法，其中所述点突变是Y297A取代；D320K取代和/或E319K取代。
18.权利要求7至12中任一项所述的方法，其中所述NRP1陷阱：
(a)包含所述NRP1多肽的结构域a1、a2、b1、b2、和c；
(b)包含所述NRP1多肽的结构域a1、a2、b1和b2；
(c)包含所述NRP1多肽的结构域a1、a2、和b1；
(d)包含所述NRP1多肽的结构域a1和a2；
(e)包含所述NRP1多肽的结构域b1，其中所述结构域b1包括在对应于包含如图26中所示的氨基酸序列的NRP1多肽的(i)酪氨酸297；(ii)天冬氨酸320和/或(iii)谷氨酸319的氨基酸残基处的至少一个点突变，其中所述至少一个突变降低或消除与VEGF165的结合；
(f)完全或部分地缺少所述NRP1多肽的结构域c；
(g)完全或部分地缺少所述NRP1多肽的结构域b1；
(h)完全或部分地缺少所述NRP1多肽的结构域b2；
(i)缺少所述NRP1多肽的结构域b1和b2；或
(j)缺少所述NRP1多肽的结构域b1、b2和c。
19.权利要求18所述的方法，其中(i)所述结构域a1包括对应于如图26中所示的NRP1多肽的氨基酸27至141的氨基酸序列或基本上由对应于如图26中所示的NRP1多肽的氨基酸27至141的氨基酸序列组成；(ii)所述结构域a2包括对应于如图26中所示的NRP1多肽的氨基酸147至265的氨基酸序列；(iii)所述结构域b1包括对应于如图26中所示的NRP1多肽的氨基酸275至424的氨基酸序列；(iv)所述结构域b2包括对应于如图26中所示的NRP1多肽的氨基酸431至583的氨基酸序列；和/或(v)所述结构域c结构域包括对应于如图26中所示的NRP1多肽的氨基酸645至811的氨基酸序列。
20.权利要求18所述的方法，其中(i)所述结构域a1包括对应于如图26中所示的NRP1多肽的氨基酸22至148的氨基酸序列或基本上由对应于如图26中所示的NRP1多肽的氨基酸22至148的氨基酸序列组成；(ii)所述结构域a2包括对应于如图26中所示的NRP1多肽的氨基酸149至275的氨基酸序列；(iii)所述结构域b1包含对应于如图26中所示的NRP1多肽的氨基酸276至428的氨基酸序列；(iv)所述结构域b2包含对应于如图26中所示的NRP1多肽的氨基酸429至589的氨基酸序列；和/或(v)所述结构域c结构域包含对应于如图26中所示的NRP1多肽的氨基酸590至859的氨基酸序列。
21.权利要求7所述的方法，其中所述方法包括通过施用基本上由如表1中所示的陷阱或其功能变体组成的NRP1陷阱来抑制所述NRP1与至少一种NRP1配体的结合。
22.权利要求7至20中任一项所述的方法，其中所述NRP1陷阱进一步包括蛋白质纯化结构域。
23.权利要求22所述的方法，其中所述纯化结构域是聚组氨酸标签。
24.权利要求7至20中任一项所述的方法，其中所述NRP1陷阱进一步包括FC结构域。
25.权利要求22至24中任一项所述的方法，其中所述NRP1陷阱包括能够使所述蛋白质纯化结构域或FC结构域从所述NRP1陷阱移除的蛋白酶或肽酶切割位点。
26.权利要求25所述的方法，其中所述蛋白酶或肽酶是TEV蛋白酶切割位点。
27.权利要求26所述的方法，其中所述TEV蛋白酶切割位点包括氨基酸序列GSKENLYFQG。
28.权利要求4所述的方法，其中所述方法包括降低NRP1配体表达或活性，和其中所述NRP1配体是SEMA3A。
29.权利要求28所述的方法，包括通过施用抗SEMA3A抗体来抑制SEMA3A与NRP1的结合而降低SEMA3A活性，所述抗SEMA3A抗体与SEMA3A的SEMA结构域结合。
30.权利要求4所述的方法，其中所述方法包括通过施用NRP1反义、shRNA或siRNA降低NRP1表达。
31.权利要求4所述的方法，其中所述方法包括通过施用SEMA3A反义、shRNA或siRNA降低SEMA3A表达。
32.NRP1多肽陷阱，其包含与SEMA3A、VEGF165和/或TGF-β结合的NRP1多肽或其功能片段或变体。
33.权利要求32所述的NRP1多肽陷阱，其中所述NRP1多肽对应于可溶性NRP1同种型2。
34.权利要求33所述的NRP1多肽陷阱，其中所述可溶性NRP1同种型2包含具有如图22中所示的氨基酸序列的多肽或基本上由具有如图22中所示的氨基酸序列的多肽组成，无信号肽。
35.权利要求34所述的NRP1多肽陷阱，其中所述NRP1多肽对应于所述NRP1同种型1多肽的胞外结构域。
36.权利要求35所述的NRP1多肽陷阱，其中所述NRP1同种型1多肽如图26中所示并且其中所述胞外结构域对应于图26中显示的所述NPR1多肽的氨基酸22至859(SEQ ID NO：66的残基22至859)。
37.权利要求32至36中任一项所述的NRP1多肽陷阱，其中所述NRP1陷阱包括NRP1多肽，其包含(i)如SEQ ID NO：65中所示的NRP1多肽的氨基酸22至609；(ii)如SEQ ID NO：66中所示的NRP1多肽的氨基酸22至859；(iii)如SEQ ID NO：69中所示的NRP1多肽的氨基酸22至859(iv)或(i)、(ii)或(iii)的功能片段或功能变体。
38.权利要求32至37中任一项所述的NRP1多肽陷阱，其中NRP1陷阱与SEMA3A结合但基本上不与VEGF165结合或具有与SEMA3A结合亲和力相比降低的VEGF165结合亲和力。
39.权利要求38所述的NRP1多肽陷阱，其中所述NRP1陷阱(i)完全或部分地缺少NRP1的结构域b1和/或b2；或(ii)包含抑制VEGF与NRP1结合的至少一个氨基酸点突变。
40.权利要求39所述的NRP1多肽陷阱，其中所述点突变包含(a)在对应于图22或图26中所示的NRP1氨基酸序列的酪氨酸297的氨基酸残基处的结构域b1中的氨基酸取代或缺失；(b)在对应于图22或图26中所示的NRP1氨基酸序列的天冬氨酸320的氨基酸残基处的结构域b1中的氨基酸取代或缺失；和/或(c)在对应于图22或图26中所示的NRP1氨基酸序列的谷氨酸319的氨基酸残基处的结构域b1中的氨基酸取代或缺失。
41.权利要求40所述的NRP1多肽陷阱，其中所述突变点是Y297A取代；D320K取代和/或E319K取代。
42.权利要求32至38中任一项所述的NRP1多肽陷阱，其中所述陷阱：
(a)包含所述NRP1多肽的结构域a1、a2、b1、b2、和c；
(b)包含所述NRP1多肽的结构域a1、a2、b1和b2；
(c)包含所述NRP1多肽的结构域a1、a2、和b1；
(d)包含所述NRP1多肽的结构域a1和a2；
(e)包含所述NRP1多肽的结构域b1，其中所述结构域b1包括在对应于包含如图26中所示的氨基酸序列的NRP1多肽的(i)酪氨酸297；(ii)天冬氨酸320和/或(iii)谷氨酸319的氨基酸残基处的至少一个点突变，其中所述至少一个突变降低或消除与VEGF165的结合；
(f)完全或部分地缺少所述NRP1多肽的结构域c；
(g)完全或部分地缺少所述NRP1多肽的结构域b1；
(h)完全或部分地缺少所述NRP1多肽的结构域b2；
(i)缺少所述NRP1多肽的结构域b1和b2；或
(j)缺少所述NRP1多肽的结构域b1、b2和c。
43.权利要求42所述的NRP1多肽陷阱，其中(i)所述结构域a1包含或基本上由对应于如图26中所示的NRP1多肽的氨基酸27至141的氨基酸序列组成；(ii)所述结构域a2包含对应于如图26中所示的NRP1多肽的氨基酸147至265的氨基酸序列；(iii)所述结构域b1包含对应于如图26中所示的NRP1多肽的氨基酸275至424的氨基酸序列；(iv)所述结构域b2包含对应于如图26中所示的NRP1多肽的氨基酸431至583的氨基酸序列；和/或(v)所述结构域c结构域包含对应于如图26中所示的NRP1多肽的氨基酸645至811的氨基酸序列。
44.权利要求42所述的NRP1多肽陷阱，其中(i)所述结构域a1包含或基本上由对应于如图26中所示的NRP1多肽的氨基酸22至148的氨基酸序列组成；(ii)所述结构域a2包含对应于如图26中所示的NRP1多肽的氨基酸149至275的氨基酸序列；(iii)所述结构域b1包含对应于如图26中所示的NRP1多肽的氨基酸276至428的氨基酸序列；(iv)所述结构域b2包含对应于如图26中所示的NRP1多肽的氨基酸429至589的氨基酸序列；和/或(v)所述结构域c结构域包含对应于如图26中所示的NRP1多肽的氨基酸590至859的氨基酸序列。
45.权利要求32所述的NRP1多肽陷阱，其中所述陷阱基本上由如表1中所示的陷阱或其功能变体组成。
46.权利要求32至44中任一项所述的NRP1多肽陷阱，其中所述陷阱进一步包含蛋白质纯化结构域。
47.权利要求46所述的NRP1多肽陷阱，其中所述纯化结构域是聚组氨酸标签。
48.权利要求32至47中任一项所述的NRP1多肽陷阱，其中所述NRP1陷阱进一步包含FC结构域。
49.权利要求46至48中任一项所述的NRP1多肽陷阱，其中所述NRP1陷阱包含能够使所述蛋白质纯化结构域或FC结构域从所述NRP1陷阱移除的蛋白酶或肽酶切割位点。
50.权利要求49所述的NRP1多肽陷阱，其中所述蛋白酶或肽酶切割位点是TEV蛋白酶切割位点。
51.权利要求50所述的NRP1多肽陷阱，其中所述TEV蛋白酶切割位点包含氨基酸序列GSKENLYFQG。
52.核酸，其编码权利要求32-51中任一项所述的NRP1多肽陷阱。
53.表达载体，其包含权利要求52所述的核酸。
54.宿主细胞，其包含权利要求53所述的载体。
55.组合物，其包含权利要求32至51中任一项所述的NRP1多肽陷阱、权利要求52所述的核酸、权利要求53所述的载体或权利要求54所述的宿主细胞和适合的载体。
56.权利要求55所述的组合物用于(ii)预防或治疗炎症，或(ii)预防或降低先天免疫反应超活化。
57.用于预防或治疗炎症的化合物，其中所述化合物：
(a)降低NRP1表达或活性；和/或
(b)降低NRP1配体表达或活性。
58.用于预防或降低先天免疫反应超活化的化合物，其中所述化合物：
(a)降低NRP1表达或活性；和/或
(b)降低NRP1配体表达或活性。
59.权利要求57或58所述的化合物，其中所述化合物是：
(i)抗SEMA3A抗体；
(ii)抗VEGF165抗体
(iii)抗NRP1抗体；
(iv)NRP1陷阱；
(v)SEMA3A反义、shRNA或siRNA；
(vi)NRP1反义、shRNA或siRNA；或
(vii)VEGF反义、shRNA或siRNA。
60.权利要求59所述的化合物，其中所述化合物是NRP1多肽陷阱。
61.用于治疗或预防炎症的组合物，其包含权利要求57-60中任一项所限定的化合物和适合的载体。
62.用于预防或降低先天免疫反应超活化的组合物，其包含权利要求57-60中任一项所限定的化合物和适合的载体。
63.权利要求32-51中任一项所述的NRP1多肽陷阱、权利要求52所述的核酸、权利要求53所述的载体、权利要求54所述的宿主细胞、权利要求57-60中任一项所述的化合物或权利要求55、61和62中任一项所述的组合物在制备用于预防或治疗炎症的药物中的应用。
64.权利要求32-51中任一项所述的NRP1多肽陷阱、权利要求52所述的核酸、权利要求53所述的载体、权利要求54所述的宿主细胞、权利要求57-60中任一项所述的化合物或权利要求55、61和62中任一项所述的组合物在制备用于预防或治疗炎症的药物中的应用。
65.权利要求32-51中任一项所述的NRP1多肽陷阱、权利要求52所述的核酸、权利要求53所述的载体、权利要求54所述的宿主细胞、权利要求57-60中任一项所限定的所述化合物或权利要求55、61和62中任一项所限定的所述组合物用于预防或治疗先天免疫反应超活化的应用。
66.权利要求32-51中任一项所述的NRP1多肽陷阱、权利要求52所述的核酸、权利要求53所述的载体、权利要求54所述的宿主细胞、权利要求57-60中任一项所限定的所述化合物或权利要求55、61和62中任一项所限定的所述组合物用于预防或降低先天免疫反应超活化的应用。
67.权利要求1-31中任一项所述的方法，其中所述受试者患有或可能患有感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症、糖尿病、葡萄膜炎、糖尿病性视网膜病变、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病或中风。
68.权利要求1-31中任一项所述的方法、权利要求32-51中任一项所述的NRP1多肽陷阱、权利要求52所述的核酸、权利要求53所述的载体、权利要求54所述的宿主细胞、权利要求57-60中任一项所限定的化合物或权利要求55、61和62中任一项所限定的组合物，其中所述方法、NRP1多肽陷阱、核酸、载体、宿主细胞、化合物、组合物或应用是用于治疗或预防感染性休克、关节炎、炎性肠病(IBD)、皮肤炎症、糖尿病、葡萄膜炎、糖尿病性视网膜病变、年龄相关的黄斑变性(AMD)、早产儿视网膜病变、多发性硬化、肌萎缩性侧索硬化症(ALS)、年龄相关的认知衰退/阿尔兹海默病或中风。
69.权利要求1-31中任一项所述的方法、权利要求32-51中任一项所述的NRP1多肽陷阱、权利要求52所述的核酸、权利要求53所述的载体、权利要求54所述的宿主细胞、权利要求57-60中任一项所限定的化合物或权利要求55、61和62中任一项所限定的组合物，其中所述方法、NRP1多肽陷阱、核酸、载体、宿主细胞、化合物、组合物或应用是用于治疗或预防感染性休克或中风。
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