CN113493519A - 一种半衰期显著延长的治疗眼部血管新生疾病的融合蛋白 - Google Patents

一种半衰期显著延长的治疗眼部血管新生疾病的融合蛋白 Download PDF

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CN113493519A
CN113493519A CN202010197997.XA CN202010197997A CN113493519A CN 113493519 A CN113493519 A CN 113493519A CN 202010197997 A CN202010197997 A CN 202010197997A CN 113493519 A CN113493519 A CN 113493519A
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黄岩山
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Zhejiang Doer Biologics Co Ltd
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Abstract

本发明涉及生物技术领域，特别是涉及一种融合蛋白及其制备方法和用途。本发明提供一种融合蛋白，所述融合蛋白包括亲水性重复序列片段、拮抗VEGF片段、免疫球蛋白Fc片段。本发明所提供的融合蛋白在血清中具有更短的半衰期，而在玻璃体中则表现出良好的半衰期，从而使得融合蛋白具有更佳的靶向性，被证明相比目前现有技术中的药物具有更优越的半衰期和良好的药理学性质。此外，本发明所提供的融合蛋白还具有良好的稳定性、较低的粘度，从而具有良好的产业化前景。

Description

一种半衰期显著延长的治疗眼部血管新生疾病的融合蛋白
技术领域
本发明涉及生物技术领域，特别是涉及一种融合蛋白及其制备方法和用途，所述融合蛋白可以用于治疗眼部血管新生疾病，且具有显著延长的半衰期。
背景技术
血管新生，一种从原有血管组织中形成新血管组织的生理过程，在发育和疾病的过程中，起着重要的作用。一些严重的眼部病变，比如湿性老年性黄斑变性、视网膜静脉阻塞、增殖性的糖尿病引发的黄斑水肿，它们的发生机制与血管新生密切相关。以湿性的老年性黄斑变性(wet AMD)为例，随着年龄的增大，脉络膜清除衰老、死亡的细胞的能力减弱，残留的细胞碎片在黄斑附近的视网膜和脉络膜之间瘀集，形成玻璃疣，影响眼部供血，进而引起刺激产生炎症反应和血管新生。因为受到缺氧压力的影响，这种异常的血管新生产生的新的血管壁非常脆弱，且极易渗透，这会导致眼球体液流失和出血。
随着人口的老龄化，眼部抗血管新生的治疗需求非常迫切，但有效的治疗手段比较少。仍以湿性AMD为例，若3年内无法及时治疗，致盲率将从近20％升至75％。目前我国湿性AMD患者接近50万，每年新增患者约4万人。目前治疗湿性AMD，主要有激光凝固法、光动力学疗法、玻璃体切除手术、抗血管新生化药的注射、抗血管新生多肽或蛋白的注射以及干细胞/RNA干扰的注射。
新生血管抑制类产品，尤其是多靶点联合抑制剂是目前国内外眼科临床上的热点。
VEGF(血管内皮生长因子)，是一种在血管再生、血管新生、内皮细胞生长等过程中具有活性的生长因子。对于内皮细胞，它可以诱导增殖，促进迁移，抑制凋亡，以及增加血管通透性。VEGF有A、B、C、D四种亚型，它的受体VEGFR有3种，属于酪氨酸激酶。其中，A、B亚型可以结合VEGFR1(FLT1)，A、C、D亚型可以结合VEGFR2(KDR)，C、D亚型可以结合VEGFR3(FLT4)。VEGF结合受体后，受体通过同二聚或异二聚以激活下游信号通路，并实现上述的生理功能。VEGF-A是单抗类药物的主要靶点，在血管内皮细胞和外周血单核细胞中特异性表达。它有多种异构体：VEGF-A 121可自由分泌；VEGF-A 165可结合肝素，有相当一部分可结合细胞，不过大部分可自由分泌；VEGF-A 189分泌后可结合细胞，与肝素和细胞外基质的结合力强，它也可以通过肝素、肝素酶、纤溶酶，以可溶形式释放。另外，还有VEGF-A 206和VEGF-A145，表达比较少。
目前上市的用于治疗上述眼底疾病的重组融合蛋白或抗体类药物(Bevacizumab、Ranibizumab、Aflibercept、Conbercept(只在中国上市)和Brolucizumab)都是抗VEGF类药物，需要通过玻璃体直接注射给药，平均给药周期为1-3个月。玻璃体穿刺注射，不仅操作复杂，而且打破了眼球原来完全封闭的结构，每次注射都有一定的感染风险，因此这种给药方式给患者和医师带来了不小的挑战。同样的疗效下，怎样实现注射次数更少，使患者有更好的依从性是目前的研发关键，例如，如果将给药周期延长至4-6个月甚至更长，情况将会得到显著改善。
发明内容
鉴于以上所述现有技术的缺点，本发明的目的在于提供一种半衰期显著延长的治疗眼部血管新生疾病的融合蛋白及其制备方法和用途，用于解决现有技术中的问题。
为实现上述目的及其他相关目的，本发明一方面提供一种融合蛋白，所述融合蛋白包括亲水性重复序列片段、拮抗VEGF片段、免疫球蛋白Fc片段。
在本发明一些实施方式中，所述亲水性重复序列片段选自类明胶蛋白片段、或多肽复合单元片段。
在本发明一些实施方式中，所述亲水性重复序列片段包括：
a)氨基酸序列如SEQ ID No.28～29其中之一所示的多肽片段；
或，b)氨基酸序列与SEQ ID No.28～29其中之一具有90％以上序列一致性且具有a)限定的多肽片段的功能的多肽片段；或，
c)氨基酸序列如SEQ ID No.30所示的多肽片段；
或，d)氨基酸序列与SEQ ID No.30具有90％以上序列一致性且具有c)限定的多肽片段的功能的多肽片段。
在本发明一些实施方式中，所述拮抗VEGF片段包括：
e)氨基酸序列如SEQ ID No.1～7其中之一所示的多肽片段；或，
f)氨基酸序列与SEQ ID No.1～7其中之一具有90％以上序列一致性且具有e)限定的多肽片段的功能的多肽片段。
在本发明一些实施方式中，所述免疫球蛋白Fc片段包括：
g)氨基酸序列如SEQ ID No.33～41其中之一所示的多肽片段；或，
h)氨基酸序列与SEQ ID No.33～41其中之一具有90％以上序列一致性且具有g)限定的多肽片段的功能的多肽片段；
所述免疫球蛋白Fc片段为人源的。
在本发明一些实施方式中，所述融合蛋白还包括连接肽片段，优选的，所述连接肽片段富含G、S和/或A。
在本发明一些实施方式中，所述连接肽片段包括氨基酸序列如SEQ ID NO.42-43其中之一所示的多肽片段。
在本发明一些实施方式中，所述融合蛋白还包括拮抗Ang片段，所述拮抗Ang片段选自拮抗Ang-1片段、或拮抗Ang-2片段。
在本发明一些实施方式中，所述亲水性重复序列片段位于融合蛋白的N端和/或C端，所述拮抗VEGF片段位于免疫球蛋白Fc片段的N端或C端；
在本发明一些实施方式中，拮抗VEGF片段、或拮抗Ang片段独立地位于免疫球蛋白Fc片段的N端或C端，优选的，拮抗VEGF片段、拮抗Ang片段分别位于免疫球蛋白Fc片段的N端和C端。
在本发明一些实施方式中，所述融合蛋白的氨基酸序列包括SEQ ID NO.11-12、SEQ ID NO.15-16、SEQ ID NO.18-19其中之一所示的序列；
或，所述融合蛋白的氨基酸序列包括SEQ ID NO.20和SEQ ID NO.21所示的序列、SEQ ID NO.22和SEQ ID NO.24所示的序列、SEQ ID NO.23和SEQ ID NO.24所示的序列、SEQID NO.25和SEQ ID NO.7所示的序列、或SEQ ID NO.26和SEQ ID NO.27所示的序列。
本发明另一方面提供一种分离的多核苷酸，编码所述的融合蛋白。
本发明另一方面提供一种构建体，所述构建体含有所述的分离的多核苷酸。
本发明另一方面提供一种表达系统，所述表达系统含有所述的构建体或基因组中整合有外源的所述的多核苷酸。
本发明另一方面提供所述的融合蛋白的制备方法，包括：在合适的条件下培养所述的表达系统，使之表达所述融合蛋白，分离、纯化以提供所述融合蛋白。
本发明另一方面提供一种药物组合物，包括所述的融合蛋白或所述的表达系统的培养物。
本发明另一方面提供所述的融合蛋白、所述的药物组合物在制备药物中的用途。
在本发明一些实施方式中，所述药物选自用于眼部血管新生相关疾病的药物。
附图说明
图1A显示为本发明实施例6组别1在新西兰大白兔玻璃体内的药代动力学结果示意图。
图1B显示为本发明实施例6组别2在新西兰大白兔玻璃体内的药代动力学结果示意图。
图1C显示为本发明实施例6组别3在新西兰大白兔玻璃体内的药代动力学结果示意图。
图1D显示为本发明实施例6组别4在新西兰大白兔玻璃体内的药代动力学结果示意图。
图2显示为本发明实施例7中各组别4级光斑平均渗漏面积改善率示意图。
图3显示为本发明实施例7中各组别视网膜下高反射信号物质(SHRM)平均厚度改善率示意图。
图4显示为本发明实施例7中DR301AbB4对光斑率及渗漏面积改善情况示意图。
具体实施方式
本发明发明人经过大量探索研究，意外发现亲水性重复序列片段、拮抗VEGF片段、免疫球蛋白Fc片段所构成的融合蛋白，通过玻璃体注射给药，在血清中具有更短的半衰期，而在玻璃体中则表现出良好的半衰期，从而使得融合蛋白具有更佳的靶向性，具有良好的产业化前景，在此基础上完成了本发明。
本发明第一方面提供一种融合蛋白，所述融合蛋白包括亲水性重复序列片段、拮抗VEGF片段、免疫球蛋白Fc片段。本发明所提供的融合蛋白通常指通过DNA重组技术得到的多个基因重组后的表达产物。所述融合蛋白可以是线性的，其所包括的拮抗VEGF片段则可以是线性的结构域；所述融合蛋白也可以是单克隆抗体类似的结构，其所包括的拮抗VEGF片段也则可以来自单克隆抗体的Fab区域(由轻链和Fd链组成)。在本发明中，当拮抗VEGF片段为线性结构域时，所述融合蛋白也是线性的，从而可以包括多个结构域片段，并可以通过免疫球蛋白Fc片段形成二聚体，并可以在形成的二聚体的N或C端包括有亲水性重复序列片段，以形成包括亲水性重复序列片段、拮抗VEGF片段、免疫球蛋白Fc片段的融合蛋白。当所述的拮抗VEGF片段来自单克隆抗体的Fab区域时，即所述融合蛋白具有类似单克隆抗体的结构时，可以通过Fd链与免疫球蛋白Fc片段融合形成二聚体，即所述融合蛋白具有单克隆抗体类似的结构，并可以在该结构的基础上进一步融合亲水性重复序列片段，例如融合在单克隆抗体类似结构的轻链或重链两端(N或C端)，以形成包括亲水性重复序列片段、拮抗VEGF片段、免疫球蛋白Fc片段的融合蛋白。
本发明所提供的融合蛋白中，可以包括亲水性重复序列片段，所述亲水性重复序列片段通常不含丝氨酸(S)和苏氨酸(T)，在原核或真核表达系统的制备过程中，均不会出现糖基化的问题。另外，由于Asn(N)及Gln(Q)的脱酰胺化造成的不均一现象以及由于氨基酸种类较多导致的潜在蛋白酶位点增多而引起的产物不均一等问题，在本发明所提供的亲水性重复序列片段中均不会出现。
本发明所提供的融合蛋白中，所述亲水性重复序列可以为类明胶蛋白片段。所述类明胶蛋白片段通常主要由甘氨酸(G)、脯氨酸(P)、丙氨酸(A)和谷氨酸(E)组成，并具有明胶特征性的G-X-Y三元单体(Triplet)的结构，其中G代表甘氨酸(G)，X和Y分别独立地选自脯氨酸(P)、丙氨酸(A)或谷氨酸(E)。通常来说，所述类明胶蛋白片段如果分子量太大，重组表达制备困难，相反，分子量太小起不到显著延长半衰期的作用。优选的，所述类明胶蛋白片段的氨基酸长度可以为100-500；更优选的，所述类明胶蛋白片段的氨基酸长度可以为150-500；进一步优选的，所述类明胶蛋白片段的氨基酸长度可以为200-400。在本发明一具体实施例中，所述亲水性重复序列片段包括：
a)氨基酸序列如SEQ ID No.28～29其中之一所示的多肽片段；
b)氨基酸序列与SEQ ID No.28～29其中之一具有90％以上序列一致性且具有a)限定的多肽片段的功能的多肽片段。具体的，所述b)中的氨基酸序列具体指：如SEQ IDNo.28～29其中之一所示的氨基酸序列经过取代、缺失或者添加一个或多个(具体可以是1-50、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，或者在N-末端和/或C-末端添加一个或多个(具体可以是1-50个、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，且具有氨基酸如SEQ ID No.28～29其中之一所示的多肽片段的功能的多肽片段，例如，所述亲水性重复序列通常具有较高的高亲水性，可以显著增大蛋白水合半径及表观分子量，在玻璃体给药后，更大的表观分子量可以支持了更长的眼内半衰期，减少给药次数。所述b)中的氨基酸序列可与SEQ ID No.28～29其中之一具有90％、93％、95％、97％、或99％以上的一致性(Sequence identity)。
本文中，序列一致性(sequence identity)指参与对比的序列中相同残基的百分比。可采用本领域周知的计算软件计算两条或多条目的序列的序列一致性，这些软件可获自如NCBI。
本发明所提供的融合蛋白中，所述亲水性重复序列可以为多肽复合单元片段。所述多肽复合单元片段通常是一类由脯氨酸(P)、丙氨酸(A)和谷氨酸(E)三种氨基酸构成的柔性多肽或者蛋白，例如，可以是包括一个或多个氨基酸序列如SEQ ID No.31或SEQ IDNo.32所示的多肽单元的多肽片段。通常来说，所述多肽复合单元片段需要具有合适的分子量，如果分子量太大，重组表达制备困难，相反，分子量太小则无法显著增大表观分子量并延长半衰期。优选的，所述多肽复合单元片段的氨基酸长度可以为100-500；更优选的，所述多肽复合单元片段的氨基酸长度可以为150-500；进一步优选的，所述多肽复合单元片段的氨基酸长度可以为200-400。在本发明一具体实施例中，所述多肽复合单元片段包括：
c)氨基酸序列如SEQ ID No.30所示的多肽片段；
d)氨基酸序列与SEQ ID No.30具有90％以上序列一致性且具有c)限定的多肽片段的功能的多肽片段。具体的，所述d)中的氨基酸序列具体指：如SEQ ID No.30所示的氨基酸序列经过取代、缺失或者添加一个或多个(具体可以是1-50、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，或者在N-末端和/或C-末端添加一个或多个(具体可以是1-50个、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，且具有氨基酸如SEQ ID No.30所示的多肽片段的功能的多肽片段，例如，可以增大蛋白的水合半径。所述d)中的氨基酸序列可与SEQ ID No.30具有90％、93％、95％、97％、或99％以上的一致性(Sequence identity)。
本发明所提供的融合蛋白中，可以包括拮抗VEGF片段。所述拮抗VEGF片段通常可以是能够拮抗VEGF的多肽或蛋白片段，例如，所述拮抗VEGF片段可以是VEGFR的胞外区(例如，Aflibercept和Conbercept)；具有拮抗VEGF功能的结构域蛋白，包括但不限于：DARPin、Anticalin、scFv(例如，Brolucizumab等)、Fab(例如，Ranibizumab等)、单域抗体等。在本发明一具体实施例中，所述拮抗VEGF片段可以包括：
e)氨基酸序列如SEQ ID No.1～7其中之一所示的多肽片段；
f)氨基酸序列与SEQ ID No.1～7其中之一具有90％以上序列一致性且具有e)限定的多肽片段的功能的多肽片段。具体的，所述f)中的氨基酸序列具体指：如SEQ ID No.1～7其中之一所示的氨基酸序列经过取代、缺失或者添加一个或多个(具体可以是1-50、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，或者在N-末端和/或C-末端添加一个或多个(具体可以是1-50个、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，且具有氨基酸如SEQ ID No.1～7其中之一所示的多肽片段的功能的多肽片段，例如，可以拮抗VEGF。所述f)中的氨基酸序列可与SEQ ID No.1～7其中之一具有90％、93％、95％、97％、或99％以上的一致性(Sequence identity)。所述拮抗VEGF片段通常是人源的。
本发明所提供的融合蛋白中，可以包括免疫球蛋白Fc片段。所述免疫球蛋白Fc片段通常是免疫球蛋白的重链恒定区或其中的一部分，无抗原结合活性，是抗体分子与效应分子和细胞相互作用的部位。例如，所述免疫球蛋白Fc片段可以包括IgG1的一个CH2结构域、一个CH3结构域和一个免疫球蛋白铰链区，铰链区起始氨基酸位置对于本领域技术人员来说是可以调整的。在本发明一具体实施例中，所述免疫球蛋白Fc片段可以包括：
g)氨基酸序列如SEQ ID No.33～41其中之一所示的多肽片段；
h)氨基酸序列与SEQ ID No.33～41其中之一具有90％以上序列一致性且具有g)限定的多肽片段的功能的多肽片段。具体的，所述h)中的氨基酸序列具体指：如SEQ IDNo.33～41其中之一所示的氨基酸序列经过取代、缺失或者添加一个或多个(具体可以是1-50、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，或者在N-末端和/或C-末端添加一个或多个(具体可以是1-50个、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，且具有氨基酸如SEQ ID No.33～41其中之一所示的多肽片段的功能的多肽片段，例如，可以使得抗体天然会形成二聚体，从而可以形成二价以提高蛋白活性，并可以通过FC与通过FcRn结合的机制使得抗体的半衰期被有效提升。所述h)中的氨基酸序列可与SEQ ID No.33～41其中之一具有90％、93％、95％、97％、或99％以上的一致性(Sequence identity)。所述免疫球蛋白Fc片段通常是人源的。
本发明所提供的融合蛋白中，还可以包括连接肽片段。所述融合蛋白中，通常可以包括多个连接肽片段，例如，至少部分的结构域或各结构域之间均可以设有连接肽片段。所述连接肽片段通常可以为一段长度合适的由甘氨酸(G)、丝氨酸(S)和/或丙氨酸(A)构成的柔性多肽，从而使相邻的蛋白质结构域可相对于彼此自由移动，例如，所述连接肽片段的氨基酸序列可以包括如(GS)n、(GGS)n、(GGSG)n、(GGGS)nA、(GGGGS)nA、(GGGGA)nA、(GGGGG)nA等序列，其中，n选自1-10之间的整数。在本发明一具体实施例中，所述连接肽片段的氨基酸序列的长度可以为5-26。在本发明一更优选的具体实施例中，所述连接肽片段可以包括氨基酸序列如SEQ ID NO.42-43其中之一所示的多肽片段。
本发明所提供的融合蛋白中，当所述融合蛋白是线性的，所述亲水性重复序列片段可以独立或同时位于融合蛋白的N端和/或C端，所述拮抗VEGF片段可以位于免疫球蛋白Fc片段的N端或C端。当所述的拮抗VEGF片段来自单克隆抗体的Fab区域时，即所述融合蛋白具有单克隆抗体类似的结构时，所述亲水性重复序列片段可以融合于抗体的合适位置，例如，可以独立或同时位于Fab区轻链的N端和/或C端、Fab区Fd链的N端、或者位于免疫球蛋白Fc片段的C端。在本发明一具体实施例中，所述融合蛋白的氨基酸序列可以包括SEQ IDNO.11-12、SEQ ID NO.15-16、SEQ ID NO.18-19其中之一所示的序列；或，所述融合蛋白的氨基酸序列可以包括SEQ ID NO.20和SEQ ID NO.21所示的序列、SEQ ID NO.22和SEQ IDNO.24所示的序列、SEQ ID NO.23和SEQ ID NO.24所示的序列、SEQ ID NO.25和SEQ IDNO.7所示的序列、或SEQ ID NO.26和SEQ ID NO.27所示的序列。
本发明所提供的融合蛋白与未融合亲水性重复序列的蛋白相比，表观分子量显著增大，尤其是当亲水性重复序列分别与双价的拮抗VEGF的多肽或蛋白结构域融合时，形成的复合物表观分子量极大。在本发明一具体实施例中，通过DLS结果可知，包括亲水性重复序列片段的融合蛋白比未融合亲水性重复序列的融合蛋白表观分子量显著增大。理论上，包括亲水性重复序列片段的融合蛋白在血清中的半衰期应该具有叠加效应，例如，如果将Aflibercept和亲水性重复序列融合，Fc能通过结合外周单核细胞或内皮细胞表面的FcRn而减少降解，亲水性重复序列会引起水合半径增大(减少肾小球过滤)，应该会获得血清半衰期远比Aflibercept长的复合物。然而，本发明人意外发现，在Aflibercept的N端融合亲水性重复序列片段以后(SEQ ID No.16)，反而影响了Aflibercept的血清半衰期，说明亲水性重复序列片段与免疫球蛋白Fc片段的组合，并不会进一步延长Fc融合蛋白或抗体的半衰期，反而可能影响了Fc与FcRn的结合，加速代谢。但是，令人意想不到的是，当把包括亲水性重复序列片段和Aflibercept的融合蛋白(SEQ ID No.16)注射到动物玻璃体内时，半衰期却远比单独的Aflibercept长得多，而该融合蛋白在血清中半衰期缩短，则有利于在血清中的快速清除。
已有研究显示，抑制新生血管类药物用来治疗眼底新生血管增生类疾病，其作用部位在视网膜下的脉络膜血管层(choriocapillaris)和布鲁赫膜(Bruch’s membrane)，因此药物需要有效到达这些部位，才能发挥其药效。已有研究显示，跟分子量较小的Fab(约50KD)相比，分子量较大的完整抗体(约150KD)并不能有效穿过视网膜，到达起效部位(Mordenti,J.等，Toxicologic Pathology,1999，27(5),536–544.)。但是令人惊讶的是，按本发明所提供的融合蛋白，即使表观分子量高达500KD，玻璃体注射后仍然体现了很好的抑制新生血管的生长。
同样地，在本发明的另一具体实施例中，当拮抗VEGF片段为Ranibizumab时，在其轻链N端和C端分别融合所述亲水性重复序列，形成的融合蛋白在血清中的半衰期不但没有进一步延长，反而明显缩短，而在玻璃体中的半衰期却大大延长了。
本发明所提供的融合蛋白中，还可以包括拮抗Angiopoietin(血管生成素，Ang)片段，所述拮抗Ang片段可以与拮抗VEGF片段形成靶向VEGF/Ang-1/2的双特异性融合蛋白。所述拮抗Ang片段可以是拮抗Ang-1(血管生成素1)片段、或拮抗Ang-2(血管生成素2)片段。所述拮抗Ang-1片段可以是能够拮抗Ang-1的多肽或蛋白结构域，所述拮抗Ang-2片段可以是能够拮抗Ang-2的多肽或蛋白结构域。Ang-2可以在血管新生以及内皮细胞的生存、增殖、迁移、黏附、骨架重构等方面起到调节作用，同时能够维持血管稳定性。Ang-2结合受体TEK/TIE2，通过诱导同二聚化激活酪氨酸激酶活性。Ang-1在胚胎发育过程中，为血管新生和心脏发育所必须，在不同条件下，激活或抑制血管新生，调节血管的成熟度和稳定性，以及内皮细胞和基质、间质的相互作用。Ang-2与Ang-1可以竞争性结合TEK/TIE2，调节Ang-1的信号通路。同时，Ang-1/2能够与VEGF协同作用，促进内皮细胞的迁移和增殖，因此也是一种血管生成信号。在本发明一具体实施例中，所述拮抗Ang片段可以包括：
i)氨基酸序列如SEQ ID No.8-9其中之一所示的多肽片段；
j)氨基酸序列与SEQ ID No.8-9其中之一具有90％以上序列一致性且具有g)限定的多肽片段的功能的多肽片段。具体的，所述j)中的氨基酸序列具体指：如SEQ ID No.8-9其中之一所示的氨基酸序列经过取代、缺失或者添加一个或多个(具体可以是1-50、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，或者在N-末端和/或C-末端添加一个或多个(具体可以是1-50个、1-30个、1-20个、1-10个、1-5个、1-3个、1个、2个、或3个)氨基酸而得到的，且具有氨基酸如SEQ ID No.8-9其中之一所示的多肽片段的功能的多肽片段，例如，可以拮抗Ang-1和/或Ang-2。所述j)中的氨基酸序列可与SEQ ID No.8-9其中之一具有90％、93％、95％、97％、或99％以上的一致性。
本发明所提供的融合蛋白中，当融合蛋白为双特异性融合蛋白时，如果融合蛋白是线性的，拮抗VEGF片段和拮抗Ang片段可以独立地位于免疫球蛋白Fc片段的N端或C端。优选的，拮抗VEGF片段、拮抗Ang片段可以分别位于免疫球蛋白Fc片段的N端和C端。所述亲水性重复序列片段可以独立或同时位于融合蛋白的N端和/或C端。如果拮抗VEGF片段来自单克隆抗体的Fab区域，即所述融合蛋白具有类似单克隆抗体的结构时，则拮抗Ang片段可以位于免疫球蛋白Fc片段的C端，所述亲水性重复序列片段可以独立或同时位于融合蛋白的合适位置，例如，可以位于Fab区轻链的N端和/或C端、Fab区Fd链的N端、或者位于免疫球蛋白Fc片段的C端。
在本发明一具体实施例中，所述融合蛋白的氨基酸序列可以包括SEQ ID NO.15、SEQ ID NO.18、SEQ ID NO.19其中之一所示的序列；或，所述融合蛋白的氨基酸序列可以包括SEQ ID NO.22和SEQ ID NO.24所示的序列、SEQ ID NO.23和SEQ ID NO.24所示的序列、或SEQ ID NO.26和SEQ ID NO.27所示的序列。
本发明所提供的融合蛋白(双特异性融合蛋白)包括亲水性重复序列片段，所形成的融合蛋白同样在血清中的半衰期不但没有进一步延长，反而明显缩短，而在玻璃体中的半衰期却大大延长了。
本发明所提供的融合蛋白中，为了获得自动分泌到宿主细胞外的重组蛋白、或利于重组蛋白的纯化，还可以将一些氨基酸(例如，包括但不限于，适合的接头肽、信号肽、前导肽、末端延伸等)添加至重组蛋白的N-末端、C-末端和/或该蛋白内的其它合适区域内。例如，所述融合蛋白的N端和/或C端还可以包括一个或多个多肽片段，这些多肽片段可以是蛋白标签等。具体可以是例如FLAG、HA、Poly-His、GST、MBP、c-Myc等，这些标签可用于对蛋白进行纯化或检测。
本发明第二方面提供一种分离的多核苷酸，编码本发明第一方面所提供的融合蛋白。
本发明第三方面提供一种构建体，所述构建体含有本发明第二方面所提供的分离的多核苷酸。所述构建体通常可以通过将所述分离的多核苷酸插入合适的载体中构建获得，本领域技术人员可选择合适的表达载体。例如，所述载体的类型可以是包括但不限于质粒、噬菌粒、噬菌体衍生物、动物病毒和粘粒等。再例如，所述载体可以是表达载体，也可以是克隆载体。通常，合适的载体包含在至少一种有机体中起作用的复制起点、启动子序列、方便的限制酶位点和一个或多个可选择的标记。这些启动子的代表性例子有：大肠杆菌的lac或trp启动子；λ噬菌体PL启动子；真核启动子包括CMV立即早期启动子、HSV胸苷激酶启动子、早期和晚期SV40启动子、毕赤酵母的甲醇氧化酶启动子和其它一些已知的可控制基因在原核或真核细胞或其病毒中表达的启动子。标记基因可用于提供用于选择转化的宿主细胞的表型性状，包括但不限于真核细胞培养用的二氢叶酸还原酶、新霉素抗性以及绿色荧光蛋白(GFP)，或用于大肠杆菌的四环素或氨苄青霉素抗性。当本文所述的多核苷酸在高等真核细胞中表达时，如果在载体中插入增强子序列，则将会使转录得到增强，增强子是DNA的顺式作用因子，通常大约有10到300个碱基对，作用于启动子以增强基因的转录。
本发明第四方面提供一种表达系统，所述表达系统含有本发明第三方面所提供的构建体或基因组中整合有外源的本发明第二方面所提供的多核苷酸，从而可表达所述的融合蛋白。所述表达系统可以是宿主细胞，所述宿主细胞可以是原核细胞，如细菌细胞；或是低等真核细胞，如酵母细胞；丝状真菌细胞、或是高等真核细胞，如哺乳动物细胞。代表性例子有：大肠杆菌，链霉菌属；鼠伤寒沙门氏菌的细菌细胞；真菌细胞如酵母、丝状真菌、植物细胞；果蝇S2或Sf9的昆虫细胞；CHO、COS、293细胞、或Bowes黑素瘤细胞的动物细胞等。将构建体导入宿主细胞的方法对于本领域技术人员来说应该是已知的，例如，可以显微注射法、基因枪法、电穿孔法、病毒介导的转化法、电子轰击法、磷酸钙沉淀法等方法。
本发明第五方面提供本发明第一方面所提供的融合蛋白的制备方法，本领域技术人员可选择合适的方法以制备所述融合蛋白，例如，所述制备方法可以包括：在合适的条件下培养本发明第四方面所提供的表达系统，使之表达所述融合蛋白，收集含有所述融合蛋白的培养物，而后分离及纯化以提供所述融合蛋白。
本发明第六方面提供一种药物组合物，包括本发明第一方面所提供的融合蛋白或本发明第四方面所提供的表达系统的培养物。所述药物组合物中，所述融合蛋白或培养物的含量通常为治疗有效量的。本发明中，“治疗有效量”通常指一用量在经过适当的给药期间后，能够达到治疗如上所列出的疾病的效果。优选的治疗有效量的选择可以由本领域普通技术人员根据各种因素来确定(例如通过临床试验)。所述的因素包括但不限于：本发明融合蛋白的药代动力学参数例如生物利用率、代谢、半衰期等；患者所要治疗的疾病的严重程度、患者的体重、患者的免疫状况、给药的途径等。优选所述制剂具有从2.0至10.0的pH值。所述药物组合物还可以包括药学上可接受的载体。所述载体可以包括各种赋形剂和稀释剂，这些载体本身并不是必要的活性成分，且施用后没有过分的毒性。合适的载体对于本领域技术人员来说应该是熟知的，例如，在Remington's Pharmaceutical Sciences(MackPub.Co.，N.J.，1991)中可找到关于药学上可接受的载体的充分讨论。在本发明一优选具体实施例中，所述药物组合物可以通过注射途径来给药，尤其是玻璃体腔内注射，因此所述药物组合物优选是粉针剂(如冻干粉针剂)和液体制剂。
本发明第七方面提供本发明第一方面所提供的融合蛋白、本发明第六方面所提供的药物组合物在制备药物中的用途，所述药物可以选自用于治疗眼部血管新生相关疾病的药物。眼部血管新生相关疾病通常指由于在眼部的角膜、虹膜、脉络膜、视网膜、视盘等成熟组织中出现新生血管，从而导致眼部结构和功能的破坏的相关疾病。具体来说，眼部血管新生相关疾病可以是与角膜新生血管相关疾病、虹膜新生血管相关疾病、视网膜新生血管相关疾病、脉络膜新生血管相关疾病等，更具体可以是视网膜静脉阻塞、新生血管性青光眼、视网膜脱离、视网膜创伤、视网膜黄斑变性、黄斑水肿等。在本发明一具体实例中，本发明所提供的融合蛋白在血清中具有更短的半衰期，而在玻璃体中则表现出良好的半衰期，从而使得融合蛋白具有更佳的靶向性，安全性更高，可以被应用于眼部血管新生相关疾病的治疗。
本发明第八方面提供一种治疗方法包括：向个体施用治疗有效量的本发明第一方面所提供的融合蛋白、本发明第四方面所提供的表达系统的培养物、或本发明第六方面所提供的药物组合物。
本发明中，“治疗”一词包括可导致欲求的药学和/或生理效果的预防性、治愈性或缓和性处置。该效果较佳是指医疗上可减少疾病的一种或多种症状或者完全消除疾病，或阻滞、延迟疾病的发生和/或降低疾病发展或恶化的风险。
本发明中，“个体”通常包括人类、非人类的灵长类，或其他哺乳动物(如狗、猫、马、羊、猪、牛等)，其可因利用所述制剂、试剂盒或联合制剂进行治疗而获益。
本发明所提供的融合蛋白在血清中具有更短的半衰期，而在玻璃体中则表现出良好的半衰期，从而使得融合蛋白具有更佳的靶向性，被证明相比目前现有技术中的药物具有更优越的半衰期和良好的药理学性质。此外，本发明所提供的融合蛋白还具有良好的稳定性、较低的粘度，从而具有良好的产业化前景。
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前，应理解，本发明的保护范围不局限于下述特定的具体实施方案；还应当理解，本发明实施例中使用的术语是为了描述特定的具体实施方案，而不是为了限制本发明的保护范围。
当实施例给出数值范围时，应理解，除非本发明另有说明，每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义，本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外，根据本技术领域的技术人员对现有技术的掌握及本发明的记载，还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
除非另外说明，本发明中所公开的实验方法、检测方法、制备方法均采用本技术领域常规的分子生物学、生物化学、染色质结构和分析、分析化学、细胞培养、重组DNA技术及相关领域的常规技术。这些技术在现有文献中已有完善说明，具体可参见Sambrook等MOLECULAR CLONING：A LABORATORY MANUAL，Second edition，Cold Spring HarborLaboratory Press，1989and Third edition，2001；Ausubel等，CURRENT PROTOCOLS INMOLECULAR BIOLOGY，John Wiley&Sons，New York，1987and periodic updates；theseries METHODS IN ENZYMOLOGY，Academic Press，San Diego；Wolffe，CHROMATINSTRUCTURE AND FUNCTION，Third edition，Academic Press，San Diego，1998；METHODS INENZYMOLOGY，Vol.304，Chromatin(P.M.Wassarman and A.P.Wolffe，eds.)，AcademicPress，San Diego，1999；和METHODS IN MOLECULAR BIOLOGY，Vol.119，ChromatinProtocols(P.B.Becker，ed.)Humana Press，Totowa，1999等。
实施例1
融合蛋白的基因构建：
表1融合蛋白序列
Figure BDA0002418321550000121
Figure BDA0002418321550000131
注：表中括号内L代表轻链，H代表重链。
(1)根据融合蛋白序列及氨基酸密码子表，设计其DNA序列(表1)。分别制备对应的多核苷酸DNA片段，各DNA片段均可由常规的固相合成技术合成拼接；
(2)设计引物进行巢式PCR扩增，获得目的基因，PCR拼接技术(包括引物设计、PCR引入突变及酶切等)为本领域技术人员所熟知的公知技术。本领域技术人员应当知晓，本实施例的PCR拼接过程并非是唯一的方法，例如，通过基因合成也可以获得目的基因。成功获得目的基因后，将目的基因克隆至哺乳动物细胞表达载体pTT5(Yves Durocher)，转化大肠杆菌Top10F’；阳性克隆鉴定后，接种于500ml LB培养基中，过夜培养，离心收集菌体，使用Omega
Figure BDA0002418321550000132
Endo-Free Plasmid Maxi Kit或类似方法提取质粒。
(3)取1.0mg质粒，使用FreeStyleTM 293 Expression Medium(Thermofisher)稀释至25ml；取3.0mg PEI(线性,25KD,Polysciences)，使用FreeStyleTM 293 ExpressionMedium稀释至25ml，加入到质粒溶液中，混匀，室温孵育30分钟；与此同时，取2.5x 109个对数期生长的HEK293F细胞(活率>95％)，1200RPM离心10分钟，弃上清；使用50ml FreeStyleTM293 Expression Medium重悬细胞，PEI质粒混合液孵育结束后，加入到细胞悬液中，37℃,5％CO2,140RPM震荡培养过夜后，补加500ml CD02培养基(中山康天晟合生物技术有限公司)，继续培养7天。
(4)重组蛋白的纯化：将细胞培养液以8000rpm，高速离心10min，得到上清上样到预先用平衡液(20mM PB，0.5M NaCl，pH7.0)平衡好的Protein A柱(博格隆(上海)生物技术有限公司)，再次平衡后，100％洗脱(洗脱液为0.1M Gly-HCl，pH3.0)；收集管中预先加入中和液为(1M Tris-HCl，pH8.0)，收集洗脱样品；最后加中和液到洗脱样品体积的1/10，并采用常规Bradford法测定蛋白浓度。
实施例2
融合蛋白的纯化：
实施例1中制备的融合蛋白经过如下步骤进行纯化：
对于不含亲水性重复序列的融合蛋白：用0.1M NaOH以2ml/min流速处理50mlProtein A层析柱(耐碱Protein A，博格隆，AA0273)，以除去柱上残留的蛋白；100mMGlycine 20mM Cit pH3.2平衡至少2个柱体积，然后用150mM NaCl 20mM PB(pH6.7)平衡至少2个柱体积，直至pH达到6.7，电导在15mS/cm；同时，取培养基上清1L，5000rcf离心20分钟，分离沉淀，取上清；再用0.22μm微孔滤膜过滤除去细胞碎片，检测样品浊度在20NTU以下，留样1ml；将培养基滤液以10ml/min的流速经过Protein A层析柱，柱上停留时间约5min；150mM NaCl 20mM PB(pH6.7)平衡至少5个柱体积，直至280nm吸收到3mAU以下；用10mM PB(pH7.0)平衡至少2个柱体积，直至电导到2.5mS/cm以下；用100％的100mMGlycine0.02M Cit(pH3.2)洗脱，根据280nm吸收值收集洗脱峰；得到的样品，按10％的体积加入1.0M NaOAc/HOAc(pH5.3)，轻轻混匀后，室温静置15分钟；0.22μm无菌过滤，然后4℃或-20℃保存。
对于含亲水性重复序列的融合蛋白：在经过上述Protein A纯化后，再进一步经50ml阴离子层析纯化(Q Bestarose FF，博格隆，AI0024)。用500mM NaCl 20mM Cit pH6.0平衡至少2个柱体积，然后用20mM CitNa pH6.0平衡至少5个柱体积，直至pH达到6.0，电导在3mS/cm左右；将Protein A纯化样品，以10ml/min的流速经过Q Bestarose FF层析柱，柱上停留时间约5min；用20mM CitNa pH6.0平衡至少5个柱体积，直至280nm吸收到3mAU以下；用40％的500mM NaCl 20mM Cit pH6.0洗脱，即200mM NaCl，根据280nm吸收值收集洗脱峰；用100％的500mM NaCl 20mM Cit pH6.0洗脱，根据280nm吸收值收集洗脱峰，4℃或-20℃保存。
实施例3
融合蛋白的DLS测定：
使用马尔文Zetasizer Nano ZS检测分子的粒径，吸取1～1.5mg样品(约1～1.5ml体积，由实施例1和2制备获得)于比色皿中，参数设置为Material：Protein；扩散介质：水；检测温度25℃。用173度光散射检测器进行测定，每个样品重复检测三次。
表2融合蛋白的DLS测定结果
样品名称 PdI 体积分布，单体峰粒径(d.nm)
Bevacizumab 0.42±0.13 9.82±0.16
DR301DpB01 0.494±0.14 9.383±0.33
DR301DpB2 0.788±0.18 19.13±0.63
DR301DpM2 0.493±0.15 19.28±0.11
DR301DpM5 0.424±0.04 17.46±1.15
DR301LtB1 0.418±0.07 18.71±0.49
DR301AbB4 0.611±0.10 19.51±0.21
DR301AbB8 0.524±0.08 19.09±0.80
从DLS结果看，融合了亲水性重复序列后，表观分子量显著增大。
实施例4
融合蛋白的体外活性检测：
1.VEGF受体包被(竞争法)：
ELISA板中加入5μg/mL的人源VEGF受体KDR(Abcam，ab155628)，每孔50μL，在37℃中放置2h。用1％BSA/TBS封闭，37℃放置2h。将融合蛋白和对照品Bevacizumab(SEQ IDNO.6/7)分别用PBST作3倍梯度稀释，将稀释好的样品80μL与等体积的1μg/mL的VEGF混合，37℃放置1h。将包被KDR的ELISA板洗板两次，拍干后，将梯度稀释后的混合物样品依次转移至该ELISA板中，37℃放置1h，然后洗板5次。向ELISA板中各孔加入1:1000稀释的鼠抗人VEGF抗体(Sigma，V4758)，每孔50μL，37℃放置1h，然后洗板5次。再加入1:1000稀释的HRP标记的羊抗鼠二抗(Thermofisher，货号31432)，每孔50μL，37℃放置1h，然后洗板5次。反应完后加入显色液，37℃避光显色15min，加入终止液终止显色反应，在酶标仪中检测OD450，具体结果如表3所示。
2.Ang-2包被：
取Ang-2蛋白(10691-H08H，Sino Biological Inc)，用50mM NaHCO3 pH9.6缓冲液稀释到1ug/ml。取96孔高吸附ELISA检测板，每孔加入100ul稀释后的Ang-2蛋白，包被过夜。洗板5次，在25℃，用5％脱脂奶粉溶于PBS(含0.01％Tween-20)pH7.4封闭。加入梯度稀释(PBS含0.01％Tween-20和1％BSA)的融合蛋白，25℃孵育1小时。洗板5次，最后用0.1ug/ml的HRP标记羊抗人IgG抗体，25℃孵育1小时，洗板5次。反应完后加入显色液，37℃避光显色15min，加入终止液终止显色反应，在酶标仪中检测OD450，具体结果如表3所示。
3.HUVEC细胞增殖拮抗法检测：
160ng/ml VEGF-A165(终浓度为80ng/ml)与各指定浓度融合蛋白等比混合后，每孔50μl加入到96孔板中，放在37℃培养箱中拮抗1h；10-cm dish中的HUVEC细胞(ScienceCell,Cat#8000)用1.5ml胰酶消化2min后，弃去胰酶，加入4ml ECM+1％培养基(ScienceCell,Cat#1001，含FBS,100XPS和ECGS)吹打细胞，转移至离心管中，800rpm/5min后，弃去上清，用5mlECM+1％培养基重悬，细胞计数；取4000/50μ/孔l细胞加入到已经拮抗1h的96孔培养板中；刺激72h后，每孔中加入10μl 5mg/ml的CellTiter-
Figure BDA0002418321550000161
试剂(Promega,G7571)，酶标仪检测RLU值，具体结果如表3所示。
表3融合蛋白的活性
Figure BDA0002418321550000162
Figure BDA0002418321550000171
实施例5
融合蛋白静脉注射在SD大鼠中的药代动力学：
SD大鼠随机均分组，每组5只，分别皮下注射表4中融合蛋白，2mg/kg，融合蛋白给药组在注射前和注射后3h,8h,12h,24h,36h,48h,72h,96h,120h,144h,168h取血，分离获得血清。用夹心ELISA方法检测融合蛋白在大鼠体内的药代情况。100ng/孔的hArg1 VEGF包被过夜，PBST洗涤3次。5％脱脂奶粉封闭后，PBST洗涤3次，各时间点的血清稀释至指定的倍数，按100μl/孔加入到ELISA酶标板中，在37℃孵育2h后，PBST洗涤3次，加入anti-Ang-2兔多抗(自制)，37℃孵育2小时，PBST洗涤3次，最后HRP标记的链霉亲和素稀释5万倍后加入到ELISA板中，37℃孵育1小时后用常规TMB法检测，读取OD450值，具体结果如表4所示。
表4融合蛋白在大鼠体内的药代动力学
Figure BDA0002418321550000172
注：组别1、2、3和4为四次独立实验。
从表4中所给出的实验结果，可以惊讶地发现在融合蛋白与亲水性重复序列融合后明显降低了其血清半衰期。
实施例6
融合蛋白玻璃体注射在新西兰大白兔中的药代动力学：
选取健康新西兰大白兔，要求雌雄各半、体重3kg左右、检疫合格、体重相近、年龄与体重相仿。分组并进行编号，每组4只，动物分别单剂量双眼给药：Aflibercept、DR301AbB4，DR301AbB8、DR301LtB2、DR301BvM5、DR301BvB1，50ug/50ul/眼，玻璃体腔注射。在14天和28天分别取样测定玻璃体中药物浓度。
从图1A-图1D可以看到，与SD大鼠中的血清半衰期结果相反，融合了亲水性重复序列后显著延长融合蛋白在玻璃体中的半衰期，表现在14天和28天相对药物浓度都比未融合亲水性重复序列的融合蛋白高得多。
实施例7
模型药效学研究
筛选体重3-5kg，年龄3-5岁的食蟹猴，雌雄各半。DAY 0双眼眼底激光诱导构建CNV模型，每只眼激光灼烧数量为6-8个，激光参数：波长532nm；功率500mW；光斑直径50um；曝光时间100ms。DAY 15经FFA判定成模后，按性别及四级光斑的渗漏面积将食蟹猴均匀分组，每组6只动物，按照下表组别与剂量进行药物干预，注射方式：玻璃体腔注射，50μl/眼，给药前以及给药后一周、两周时对各组动物进行眼底照相(FP)、FFA及光相干断层成像(OCT)检测，测量4级光斑渗漏面积及视网膜下高反射信号物质(SHRM)平均厚度，计算平均渗漏改善率及视网膜下高反射信号物质(SHRM)平均厚度改善率，判断对食蟹猴CNV模型的药效改善情况。
表5激光光凝诱导食蟹猴脉络膜新生血管模型分组情况
Figure BDA0002418321550000181
各组别的4级光斑平均渗漏面积改善率的实验结果具体如图2所示，其中，(平均渗漏面积减少量＝给药前平均渗漏面积－给药后平均渗漏面积；平均渗漏面积改善率(％)＝平均渗漏面积减少量/给药前平均渗漏面积×100％)。由图2可知，各组别相对于对照组均获得了更好的4级光斑平均渗漏面积改善率，且基本达到或更加优于阳性对照组的水平，说明本申请所提供的各组别药物能够显著降低对食蟹猴CNV模型的渗漏。
各组别的视网膜下高反射信号物质(SHRM)平均厚度改善率如图3所示，其中，SHRM平均厚度减少量＝给药前SHRM平均厚度－给药后SHRM平均厚度，SHRM平均厚度改善率(％)＝SHRM平均厚度减少量/给药前SHRM平均厚度×100％。由图3可知，各组别相对于对照组均获得了更好的SHRM平均厚度改善率，且基本达到或更加优于阳性对照组的水平，说明本申请所提供的各组别药物对食蟹猴CNV模型具有良好的药效。
图4示例性地给出了DR301AbB4对光斑率及渗漏面积改善情况。由图4可知，DR301AbB4能够显著减少4级光斑的数量，并改善渗漏面积(随着时间延长，逐渐缩小)。
综上所述，本发明有效克服了现有技术中的种种缺点而具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效，而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下，对上述实施例进行修饰或改变。因此，举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变，仍应由本发明的权利要求所涵盖。
序列表
<110> 浙江道尔生物科技有限公司
<120> 一种半衰期显著延长的治疗眼部血管新生疾病的融合蛋白
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Arg Asp Ser Thr Gly Trp Thr Pro Leu His Leu Ala Ala Pro Trp Gly
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His Pro Glu Ile Val Glu Val Leu Leu Lys Asn Gly Ala Asp Val Asn
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Ala Ala Asp Phe Gln Gly Trp Thr Pro Leu His Leu Ala Ala Ala Val
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Gly His Leu Glu Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val
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Asn Gly Asn Glu Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala
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Ala Met Thr Val Asp Val Gly Ala Leu Arg Cys Leu Ala Gly Ser Val
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Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
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Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
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Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val
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Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
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Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
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Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
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Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
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Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
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Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
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210
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Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
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Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
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Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
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Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
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Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
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Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
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Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
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Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
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Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
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Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
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Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
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Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
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Leu Ser Pro Gly Lys
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Gly Ser Ala Thr His Gln Glu Glu Cys Glu Trp Asp Pro Trp Thr Cys
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Glu His Met Leu Glu
50
<210> 9
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<212> PRT
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Met Arg Glu Trp Thr Glu Glu Met Gln Val Ile Phe Asp Ala Met Met
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Gly Ser Thr Ala Ser Ser Gly Ser Gly Ser Ala Thr His Arg Glu Trp
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Asn Asp Arg Gly Gly Gly Gly Gly
65 70
<210> 10
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Gly Ser Asp Leu Asp Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln
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Asp Asp Glu Val Arg Ile Leu Met Ala Asn Gly Ala Asp Val Asn Ala
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Arg Asp Ser Thr Gly Trp Thr Pro Leu His Leu Ala Ala Pro Trp Gly
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Gly His Leu Glu Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val
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100 105 110
Asn Gly Asn Glu Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala Glu Pro
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Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu
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Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
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Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly
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Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala
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Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
290 295 300
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
305 310 315 320
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Ser Leu Ser Pro Gly
355
<210> 11
<211> 690
<212> PRT
<213> 人工序列(Artificial Sequence)
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Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
20 25 30
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
35 40 45
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
50 55 60
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
65 70 75 80
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
85 90 95
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
100 105 110
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
115 120 125
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
130 135 140
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
145 150 155 160
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
165 170 175
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
180 185 190
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
195 200 205
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
210 215 220
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
225 230 235 240
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
245 250 255
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
260 265 270
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
275 280 285
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
290 295 300
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
305 310 315 320
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Gly Ser Asp Leu
325 330 335
Asp Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln Asp Asp Glu Val
340 345 350
Arg Ile Leu Met Ala Asn Gly Ala Asp Val Asn Ala Arg Asp Ser Thr
355 360 365
Gly Trp Thr Pro Leu His Leu Ala Ala Pro Trp Gly His Pro Glu Ile
370 375 380
Val Glu Val Leu Leu Lys Asn Gly Ala Asp Val Asn Ala Ala Asp Phe
385 390 395 400
Gln Gly Trp Thr Pro Leu His Leu Ala Ala Ala Val Gly His Leu Glu
405 410 415
Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val Asn Ala Gln Asp
420 425 430
Lys Phe Gly Lys Thr Ala Phe Asp Ile Ser Ile Asp Asn Gly Asn Glu
435 440 445
Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala Gly Pro Pro Gly Glu Ala
450 455 460
Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala Gly Glu Pro Gly
465 470 475 480
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
485 490 495
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
500 505 510
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
515 520 525
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
530 535 540
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
545 550 555 560
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
565 570 575
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
580 585 590
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
595 600 605
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
610 615 620
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
625 630 635 640
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
645 650 655
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
660 665 670
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
675 680 685
Pro Gly
690
<210> 12
<211> 610
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 12
Gly Ser Asp Leu Asp Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln
1 5 10 15
Asp Asp Glu Val Arg Ile Leu Met Ala Asn Gly Ala Asp Val Asn Ala
20 25 30
Arg Asp Ser Thr Gly Trp Thr Pro Leu His Leu Ala Ala Pro Trp Gly
35 40 45
His Pro Glu Ile Val Glu Val Leu Leu Lys Asn Gly Ala Asp Val Asn
50 55 60
Ala Ala Asp Phe Gln Gly Trp Thr Pro Leu His Leu Ala Ala Ala Val
65 70 75 80
Gly His Leu Glu Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val
85 90 95
Asn Ala Gln Asp Lys Phe Gly Lys Thr Ala Phe Asp Ile Ser Ile Asp
100 105 110
Asn Gly Asn Glu Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala Gly Pro
115 120 125
Pro Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala
130 135 140
Gly Glu Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu
355 360 365
Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro
370 375 380
Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu
385 390 395 400
Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala
405 410 415
Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro
420 425 430
Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu
435 440 445
Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro
450 455 460
Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu
465 470 475 480
Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala
485 490 495
Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro
500 505 510
Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu
515 520 525
Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro
530 535 540
Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu
545 550 555 560
Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala
565 570 575
Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro
580 585 590
Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu
595 600 605
Pro Ala
610
<210> 13
<211> 412
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 13
Gly Ser Asp Leu Asp Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln
1 5 10 15
Asp Asp Glu Val Arg Ile Leu Met Ala Asn Gly Ala Asp Val Asn Ala
20 25 30
Arg Asp Ser Thr Gly Trp Thr Pro Leu His Leu Ala Ala Pro Trp Gly
35 40 45
His Pro Glu Ile Val Glu Val Leu Leu Lys Asn Gly Ala Asp Val Asn
50 55 60
Ala Ala Asp Phe Gln Gly Trp Thr Pro Leu His Leu Ala Ala Ala Val
65 70 75 80
Gly His Leu Glu Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val
85 90 95
Asn Ala Gln Asp Lys Phe Gly Lys Thr Ala Phe Asp Ile Ser Ile Asp
100 105 110
Asn Gly Asn Glu Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala Asp Lys
115 120 125
Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro
130 135 140
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
145 150 155 160
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
165 170 175
Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
180 185 190
Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val
195 200 205
Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
210 215 220
Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys
225 230 235 240
Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
245 250 255
Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr
260 265 270
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
275 280 285
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
290 295 300
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
305 310 315 320
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
325 330 335
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
340 345 350
Lys Gly Gly Gly Gly Gly Ala Gln Gln Glu Glu Cys Glu Trp Asp Pro
355 360 365
Trp Thr Cys Glu His Met Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly
370 375 380
Ser Thr Ala Ser Ser Gly Ser Gly Ser Ala Thr His Gln Glu Glu Cys
385 390 395 400
Glu Trp Asp Pro Trp Thr Cys Glu His Met Leu Glu
405 410
<210> 14
<211> 418
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 14
Gly Ser Asp Leu Asp Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln
1 5 10 15
Asp Asp Glu Val Arg Ile Leu Met Ala Asn Gly Ala Asp Val Asn Ala
20 25 30
Arg Asp Ser Thr Gly Trp Thr Pro Leu His Leu Ala Ala Pro Trp Gly
35 40 45
His Pro Glu Ile Val Glu Val Leu Leu Lys Asn Gly Ala Asp Val Asn
50 55 60
Ala Ala Asp Phe Gln Gly Trp Thr Pro Leu His Leu Ala Ala Ala Val
65 70 75 80
Gly His Leu Glu Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val
85 90 95
Asn Ala Gln Asp Lys Phe Gly Lys Thr Ala Phe Asp Ile Ser Ile Asp
100 105 110
Asn Gly Asn Glu Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala Gly Pro
115 120 125
Pro Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala
130 135 140
Gly Glu Pro Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
145 150 155 160
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
165 170 175
Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp
180 185 190
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr
195 200 205
Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
210 215 220
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu
225 230 235 240
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
245 250 255
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys
260 265 270
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
275 280 285
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
290 295 300
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
305 310 315 320
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
325 330 335
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
340 345 350
Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Gly Ala Gln Gln Glu
355 360 365
Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu His Met Gly Ser Gly Ser
370 375 380
Ala Thr Gly Gly Ser Gly Ser Thr Ala Ser Ser Gly Ser Gly Ser Ala
385 390 395 400
Thr His Gln Glu Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu His Met
405 410 415
Leu Glu
<210> 15
<211> 750
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 15
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
20 25 30
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
35 40 45
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
50 55 60
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
65 70 75 80
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
85 90 95
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
100 105 110
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
115 120 125
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
130 135 140
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
145 150 155 160
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
165 170 175
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
180 185 190
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
195 200 205
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
210 215 220
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
225 230 235 240
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
245 250 255
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
260 265 270
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
275 280 285
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
290 295 300
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
305 310 315 320
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Gly Ser Asp Leu
325 330 335
Asp Lys Lys Leu Leu Glu Ala Ala Arg Ala Gly Gln Asp Asp Glu Val
340 345 350
Arg Ile Leu Met Ala Asn Gly Ala Asp Val Asn Ala Arg Asp Ser Thr
355 360 365
Gly Trp Thr Pro Leu His Leu Ala Ala Pro Trp Gly His Pro Glu Ile
370 375 380
Val Glu Val Leu Leu Lys Asn Gly Ala Asp Val Asn Ala Ala Asp Phe
385 390 395 400
Gln Gly Trp Thr Pro Leu His Leu Ala Ala Ala Val Gly His Leu Glu
405 410 415
Ile Val Glu Val Leu Leu Lys Tyr Gly Ala Asp Val Asn Ala Gln Asp
420 425 430
Lys Phe Gly Lys Thr Ala Phe Asp Ile Ser Ile Asp Asn Gly Asn Glu
435 440 445
Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala Gly Pro Pro Gly Glu Ala
450 455 460
Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala Gly Glu Pro Gly
465 470 475 480
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
485 490 495
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
500 505 510
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
515 520 525
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr
530 535 540
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
545 550 555 560
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
565 570 575
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
580 585 590
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
595 600 605
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
610 615 620
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
625 630 635 640
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
645 650 655
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
660 665 670
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
675 680 685
Pro Gly Lys Gly Gly Gly Gly Gly Ala Gln Gln Glu Glu Cys Glu Trp
690 695 700
Asp Pro Trp Thr Cys Glu His Met Gly Ser Gly Ser Ala Thr Gly Gly
705 710 715 720
Ser Gly Ser Thr Ala Ser Ser Gly Ser Gly Ser Ala Thr His Gln Glu
725 730 735
Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu His Met Leu Glu
740 745 750
<210> 16
<211> 684
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
20 25 30
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
35 40 45
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
50 55 60
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
65 70 75 80
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
85 90 95
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
100 105 110
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
115 120 125
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
130 135 140
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
145 150 155 160
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
165 170 175
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
180 185 190
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
195 200 205
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
210 215 220
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
225 230 235 240
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ser Asp Thr Gly
245 250 255
Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met
260 265 270
Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn
275 280 285
Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp
290 295 300
Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn
305 310 315 320
Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn
325 330 335
Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr
340 345 350
Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val
355 360 365
Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val
370 375 380
Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys
385 390 395 400
Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys
405 410 415
Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln
420 425 430
Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn
435 440 445
Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr His Thr Cys Pro
450 455 460
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
465 470 475 480
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
485 490 495
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
500 505 510
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
515 520 525
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
530 535 540
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
545 550 555 560
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
565 570 575
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
580 585 590
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
595 600 605
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
610 615 620
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
625 630 635 640
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
645 650 655
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
660 665 670
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
675 680
<210> 17
<211> 491
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu
1 5 10 15
Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val
20 25 30
Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr
35 40 45
Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe
50 55 60
Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu
65 70 75 80
Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg
85 90 95
Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile
100 105 110
Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr
115 120 125
Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys
130 135 140
His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly
145 150 155 160
Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
165 170 175
Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met
180 185 190
Thr Lys Lys Asn Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr
195 200 205
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
210 215 220
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
225 230 235 240
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
245 250 255
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
260 265 270
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
275 280 285
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
290 295 300
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
305 310 315 320
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
325 330 335
Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys
340 345 350
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
355 360 365
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
370 375 380
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
385 390 395 400
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
405 410 415
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
420 425 430
Gly Gly Gly Gly Gly Ala Gln Gln Glu Glu Cys Glu Trp Asp Pro Trp
435 440 445
Thr Cys Glu His Met Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly Ser
450 455 460
Thr Ala Ser Ser Gly Ser Gly Ser Ala Thr His Gln Glu Glu Cys Glu
465 470 475 480
Trp Asp Pro Trp Thr Cys Glu His Met Leu Glu
485 490
<210> 18
<211> 743
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
20 25 30
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
35 40 45
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
50 55 60
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
65 70 75 80
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
85 90 95
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
100 105 110
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
115 120 125
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
130 135 140
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
145 150 155 160
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
165 170 175
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
180 185 190
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
195 200 205
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
210 215 220
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
225 230 235 240
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ser Asp Thr Gly
245 250 255
Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met
260 265 270
Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn
275 280 285
Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp
290 295 300
Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn
305 310 315 320
Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn
325 330 335
Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr
340 345 350
Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val
355 360 365
Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val
370 375 380
Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys
385 390 395 400
Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys
405 410 415
Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln
420 425 430
Gly Leu Tyr Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn
435 440 445
Ser Thr Phe Val Arg Val His Glu Lys Asp Lys Thr His Thr Cys Pro
450 455 460
Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
465 470 475 480
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
485 490 495
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
500 505 510
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
515 520 525
Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
530 535 540
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
545 550 555 560
Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala
565 570 575
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg
580 585 590
Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
595 600 605
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
610 615 620
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
625 630 635 640
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
645 650 655
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
660 665 670
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly
675 680 685
Gly Ala Gln Gln Glu Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu His
690 695 700
Met Gly Ser Gly Ser Ala Thr Gly Gly Ser Gly Ser Thr Ala Ser Ser
705 710 715 720
Gly Ser Gly Ser Ala Thr His Gln Glu Glu Cys Glu Trp Asp Pro Trp
725 730 735
Thr Cys Glu His Met Leu Glu
740
<210> 19
<211> 724
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly
1 5 10 15
Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala
20 25 30
Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro
35 40 45
Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly
50 55 60
Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala
65 70 75 80
Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro
85 90 95
Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly
100 105 110
Glu Pro Gly Pro Ala Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala
115 120 125
Glu Gly Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu
130 135 140
Gly Ala Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly
145 150 155 160
Ala Pro Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu
165 170 175
Ala Gly Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala
180 185 190
Gly Ala Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly
195 200 205
Ala Pro Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala
210 215 220
Pro Gly Glu Pro Gly Pro Ala Gly Gly Ser Asp Thr Gly Arg Pro Phe
225 230 235 240
Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly
245 250 255
Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val
260 265 270
Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg
275 280 285
Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr
290 295 300
Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu
305 310 315 320
Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp
325 330 335
Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys
340 345 350
Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp
355 360 365
Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val
370 375 380
Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu
385 390 395 400
Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr
405 410 415
Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe
420 425 430
Val Arg Val His Glu Lys Asp Lys Thr His Thr Cys Pro Pro Cys Pro
435 440 445
Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys
450 455 460
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val
465 470 475 480
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr
485 490 495
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu
500 505 510
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His
515 520 525
Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys
530 535 540
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln
545 550 555 560
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu
565 570 575
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro
580 585 590
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn
595 600 605
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu
610 615 620
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val
625 630 635 640
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln
645 650 655
Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Gly Ala Gln
660 665 670
Gln Glu Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu His Met Gly Ser
675 680 685
Gly Ser Ala Thr Gly Gly Ser Gly Ser Thr Ala Ser Ser Gly Ser Gly
690 695 700
Ser Ala Thr His Gln Glu Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu
705 710 715 720
His Met Leu Glu
<210> 20
<211> 453
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys
450
<210> 21
<211> 465
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
20 25 30
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
35 40 45
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
50 55 60
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
65 70 75 80
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
85 90 95
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
100 105 110
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
115 120 125
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
130 135 140
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
145 150 155 160
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
165 170 175
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
180 185 190
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
195 200 205
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
210 215 220
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
225 230 235 240
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Asp Ile Gln Leu
245 250 255
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
260 265 270
Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr
275 280 285
Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Phe Thr Ser
290 295 300
Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
305 310 315 320
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
325 330 335
Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp Thr Phe Gly Gln
340 345 350
Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe
355 360 365
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
370 375 380
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
385 390 395 400
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
405 410 415
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
420 425 430
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
435 440 445
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
450 455 460
Glu
465
<210> 22
<211> 452
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile
35 40 45
Tyr Phe Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Pro Pro Gly Glu
210 215 220
Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala Gly Glu Pro
225 230 235 240
Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala Pro Gly Pro Pro Gly
245 250 255
Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro Gly Pro Pro Gly Glu
260 265 270
Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly Pro Pro Gly Pro Ala
275 280 285
Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Pro Gly
290 295 300
Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Pro Gly Ala
305 310 315 320
Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly Glu Pro Gly Pro Ala
325 330 335
Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala Gly
340 345 350
Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala Pro Gly Pro
355 360 365
Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro Gly Pro Pro
370 375 380
Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly Pro Pro Gly
385 390 395 400
Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu
405 410 415
Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Pro
420 425 430
Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly Glu Pro Gly
435 440 445
Pro Ala Gly Gly
450
<210> 23
<211> 690
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly
1 5 10 15
Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala
20 25 30
Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro
35 40 45
Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly
50 55 60
Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala
65 70 75 80
Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro
85 90 95
Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly
100 105 110
Glu Pro Gly Pro Ala Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala
115 120 125
Glu Gly Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu
130 135 140
Gly Ala Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly
145 150 155 160
Ala Pro Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu
165 170 175
Ala Gly Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala
180 185 190
Gly Ala Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly
195 200 205
Ala Pro Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala
210 215 220
Pro Gly Glu Pro Gly Pro Ala Gly Gly Gly Gly Gly Gly Ser Asp Ile
225 230 235 240
Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
245 250 255
Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
260 265 270
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Phe
275 280 285
Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
290 295 300
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
305 310 315 320
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp Thr Phe
325 330 335
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser
340 345 350
Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
355 360 365
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val
370 375 380
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
385 390 395 400
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr
405 410 415
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
420 425 430
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn
435 440 445
Arg Gly Glu Cys Gly Gly Gly Gly Ser Gly Pro Pro Gly Glu Ala Gly
450 455 460
Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala Gly Glu Pro Gly Pro
465 470 475 480
Ala Gly Glu Pro Gly Pro Glu Gly Ala Pro Gly Pro Pro Gly Pro Ala
485 490 495
Gly Glu Pro Gly Pro Ala Gly Ala Pro Gly Pro Pro Gly Glu Ala Gly
500 505 510
Pro Ala Gly Ala Pro Gly Glu Ala Gly Pro Pro Gly Pro Ala Gly Ala
515 520 525
Glu Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Pro Gly Pro Glu
530 535 540
Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Pro Gly Ala Pro Gly
545 550 555 560
Ala Glu Gly Glu Pro Gly Ala Pro Gly Glu Pro Gly Pro Ala Gly Glu
565 570 575
Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly Glu Ala Gly Glu Pro
580 585 590
Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala Pro Gly Pro Pro Gly
595 600 605
Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro Gly Pro Pro Gly Glu
610 615 620
Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly Pro Pro Gly Pro Ala
625 630 635 640
Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Pro Gly
645 650 655
Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Pro Gly Ala
660 665 670
Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly Glu Pro Gly Pro Ala
675 680 685
Gly Gly
690
<210> 24
<211> 512
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asp Phe Thr His Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Pro Tyr Tyr Tyr Gly Thr Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys Gly Gly Gly Gly Gly Ala Gln Gln Glu Glu Cys
450 455 460
Glu Trp Asp Pro Trp Thr Cys Glu His Met Gly Ser Gly Ser Ala Thr
465 470 475 480
Gly Gly Ser Gly Ser Thr Ala Ser Ser Gly Ser Gly Ser Ala Thr His
485 490 495
Gln Glu Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu His Met Leu Glu
500 505 510
<210> 25
<211> 466
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
20 25 30
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
35 40 45
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
50 55 60
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
65 70 75 80
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
85 90 95
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
100 105 110
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
115 120 125
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
130 135 140
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
145 150 155 160
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
165 170 175
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
180 185 190
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
195 200 205
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
210 215 220
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
225 230 235 240
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Asp Ile Gln Met
245 250 255
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
260 265 270
Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr
275 280 285
Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Phe Thr Ser
290 295 300
Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
305 310 315 320
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
325 330 335
Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp Thr Phe Gly Gln
340 345 350
Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe
355 360 365
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
370 375 380
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
385 390 395 400
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
405 410 415
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
420 425 430
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
435 440 445
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
450 455 460
Glu Cys
465
<210> 26
<211> 452
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly
1 5 10 15
Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala
20 25 30
Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro
35 40 45
Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly
50 55 60
Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala
65 70 75 80
Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro
85 90 95
Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly
100 105 110
Glu Pro Gly Pro Ala Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala
115 120 125
Glu Gly Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu
130 135 140
Gly Ala Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly
145 150 155 160
Ala Pro Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu
165 170 175
Ala Gly Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala
180 185 190
Gly Ala Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly
195 200 205
Ala Pro Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala
210 215 220
Pro Gly Glu Pro Gly Pro Ala Gly Gly Gly Gly Gly Gly Ser Asp Ile
225 230 235 240
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
245 250 255
Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
260 265 270
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile Tyr Phe
275 280 285
Thr Ser Ser Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
290 295 300
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
305 310 315 320
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Thr Val Pro Trp Thr Phe
325 330 335
Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser
340 345 350
Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala
355 360 365
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val
370 375 380
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser
385 390 395 400
Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr
405 410 415
Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys
420 425 430
Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn
435 440 445
Arg Gly Glu Cys
450
<210> 27
<211> 512
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Thr Asn Tyr
20 25 30
Gly Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe
50 55 60
Lys Arg Arg Phe Thr Phe Ser Leu Asp Thr Ser Lys Ser Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val
195 200 205
Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys
210 215 220
Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
225 230 235 240
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
245 250 255
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
260 265 270
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
275 280 285
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
290 295 300
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
305 310 315 320
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
325 330 335
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
340 345 350
Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln
355 360 365
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
370 375 380
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
385 390 395 400
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
405 410 415
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
420 425 430
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
435 440 445
Leu Ser Pro Gly Lys Gly Gly Gly Gly Gly Ala Gln Gln Glu Glu Cys
450 455 460
Glu Trp Asp Pro Trp Thr Cys Glu His Met Gly Ser Gly Ser Ala Thr
465 470 475 480
Gly Gly Ser Gly Ser Thr Ala Ser Ser Gly Ser Gly Ser Ala Thr His
485 490 495
Gln Glu Glu Cys Glu Trp Asp Pro Trp Thr Cys Glu His Met Leu Glu
500 505 510
<210> 28
<211> 233
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly
1 5 10 15
Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala
20 25 30
Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro
35 40 45
Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly
50 55 60
Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala
65 70 75 80
Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro
85 90 95
Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly
100 105 110
Glu Pro Gly Pro Ala Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala
115 120 125
Glu Gly Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu
130 135 140
Gly Ala Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly
145 150 155 160
Ala Pro Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu
165 170 175
Ala Gly Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala
180 185 190
Gly Ala Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly
195 200 205
Ala Pro Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala
210 215 220
Pro Gly Glu Pro Gly Pro Ala Gly Gly
225 230
<210> 29
<211> 119
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Gly Pro Pro Gly Glu Ala Gly Ala Pro Gly Pro Glu Gly Ala Glu Gly
1 5 10 15
Glu Ala Gly Glu Pro Gly Pro Ala Gly Glu Pro Gly Pro Glu Gly Ala
20 25 30
Pro Gly Pro Pro Gly Pro Ala Gly Glu Pro Gly Pro Ala Gly Ala Pro
35 40 45
Gly Pro Pro Gly Glu Ala Gly Pro Ala Gly Ala Pro Gly Glu Ala Gly
50 55 60
Pro Pro Gly Pro Ala Gly Ala Glu Gly Glu Ala Gly Pro Ala Gly Ala
65 70 75 80
Pro Gly Glu Pro Gly Pro Glu Gly Pro Pro Gly Glu Ala Gly Ala Pro
85 90 95
Gly Pro Pro Gly Ala Pro Gly Ala Glu Gly Glu Pro Gly Ala Pro Gly
100 105 110
Glu Pro Gly Pro Ala Gly Gly
115
<210> 30
<211> 252
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
20 25 30
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
35 40 45
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
50 55 60
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
65 70 75 80
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
85 90 95
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
100 105 110
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
115 120 125
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
130 135 140
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
145 150 155 160
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
165 170 175
Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
180 185 190
Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala Ala Pro Ala Pro
195 200 205
Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala Ala Glu Pro Ala
210 215 220
Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro Glu Ala Pro Ala
225 230 235 240
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala
245 250
<210> 31
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Ala Pro Ala Pro
1 5 10 15
Glu Ala Pro Ala
20
<210> 32
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Ala Glu Ala Glu Pro Ala Ala Pro Ala Pro Ala Glu Pro Ala Glu Pro
1 5 10 15
Glu Ala Pro Ala
20
<210> 33
<211> 229
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Glu Lys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ala Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu Ala Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
100 105 110
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn Ala Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Pro Gly Lys
225
<210> 34
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 35
<211> 232
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala
1 5 10 15
Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
20 25 30
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val
35 40 45
Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val
50 55 60
Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln
65 70 75 80
Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln
85 90 95
Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala
100 105 110
Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
115 120 125
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr
130 135 140
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
145 150 155 160
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr
165 170 175
Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
180 185 190
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe
195 200 205
Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys
210 215 220
Ser Leu Ser Leu Ser Pro Gly Lys
225 230
<210> 36
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val
1 5 10 15
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
20 25 30
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
35 40 45
His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
50 55 60
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
65 70 75 80
Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn
85 90 95
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser
100 105 110
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln
115 120 125
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
130 135 140
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
145 150 155 160
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
165 170 175
Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
180 185 190
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
195 200 205
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
210 215 220
Ser Pro Gly
225
<210> 37
<211> 229
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly Lys
225
<210> 38
<211> 228
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Glu Lys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala
100 105 110
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Pro Gly
225
<210> 39
<211> 228
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
1 5 10 15
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
20 25 30
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
35 40 45
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
50 55 60
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser
65 70 75 80
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
85 90 95
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
100 105 110
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
115 120 125
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
130 135 140
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
145 150 155 160
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
165 170 175
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
180 185 190
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
195 200 205
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
210 215 220
Leu Ser Leu Gly
225
<210> 40
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
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 Ala 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 Asp Glu Leu 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> 41
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
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 Ala 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 Asp Glu Leu 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 Ala
225
<210> 42
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Gly Gly Gly Gly Ser
1 5
<210> 43
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Gly Gly Gly Gly Gly Ala
1 5
<210> 44
<211> 2070
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 44
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 60
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 120
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 180
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 240
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 300
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 360
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 420
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 480
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 540
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 600
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 660
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 720
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 780
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 840
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 900
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 960
gccgaaccgg ccgcaccagc tcctgctgag ccggccggat ccgacctgga taagaaactg 1020
ctggaagctg ctcgtgctgg tcaggacgac gaagttcgta tcctgatggc taacggtgct 1080
gacgttaacg ctagagactc tactggttgg actccgctgc acctggctgc tccatggggt 1140
cacccagaaa tcgttgaagt tctgctgaag aacggtgctg acgttaacgc tgctgacttt 1200
cagggttgga ctccgctgca cctggctgct gctgttggtc acctggaaat cgttgaagtt 1260
ctgctgaagt acggtgctga cgttaacgct caggacaaat tcggtaagac cgctttcgac 1320
atctccatcg acaacggtaa cgaagacctg gctgaaatcc tgcaaaaagc tgccggtcca 1380
cccggtgagg ctggagctcc aggacccgaa ggtgccgaag gagaggctgg tgaacctggt 1440
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 1500
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1560
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1620
gctagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1680
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1740
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1800
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1860
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1920
gtgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1980
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 2040
acgcagaaga gcctctccct gtctccgggt 2070
<210> 45
<211> 1830
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 45
ggatccgacc tggataagaa actgctggaa gctgctcgtg ctggtcagga cgacgaagtt 60
cgtatcctga tggctaacgg tgctgacgtt aacgctagag actctactgg ttggactccg 120
ctgcacctgg ctgctccatg gggtcaccca gaaatcgttg aagttctgct gaagaacggt 180
gctgacgtta acgctgctga ctttcagggt tggactccgc tgcacctggc tgctgctgtt 240
ggtcacctgg aaatcgttga agttctgctg aagtacggtg ctgacgttaa cgctcaggac 300
aaattcggta agaccgcttt cgacatctcc atcgacaacg gtaacgaaga cctggctgaa 360
atcctgcaaa aagctgccgg tccacccggt gaggctggag ctccaggacc cgaaggtgcc 420
gaaggagagg ctggtgaacc tggtggaccg tcagtcttcc tcttcccccc aaaacccaag 480
gacaccctca tgatctcccg gacccctgag gtcacatgcg tggtggtgga cgtgagccac 540
gaagaccctg aggtcaagtt caactggtac gtggacggcg tggaggtgca taatgccaag 600
acaaagccgc gggaggagca gtacgctagc acgtaccgtg tggtcagcgt cctcaccgtc 660
ctgcaccagg actggctgaa tggcaaggag tacaagtgca aggtctccaa caaagccctc 720
ccagccccca tcgagaaaac catctccaaa gccaaagggc agccccgaga accacaggtg 780
tacaccctgc ccccatcccg ggatgagctg accaagaacc aggtcagcct gacctgcctg 840
gtcaaaggct tctatcccag cgacatcgcc gtggagtggg agagcaatgg gcagccggag 900
aacaactaca agaccacgcc tcccgtgctg gactccgacg gctccttctt cctctacagc 960
aagctcaccg tggacaagag caggtggcag caggggaacg tcttctcatg ctccgtgatg 1020
catgaggctc tgcacaacca ctacacgcag aagagcctct ccctgtctcc gggtgccgaa 1080
ccggccgctc cagctcctgc agaacctgcc gctccagcac ctgaggctcc agccgctgaa 1140
cctgccgcac cagctccagc cgagcctgct gccccagctc cagaagcacc tgctgctgag 1200
cctgcagccc ctgctcctgc tgaaccagct gcacctgccc ctgaagctcc tgccgcagaa 1260
ccagccgctc ctgcccctgc tgagccagcc gctccagctc cagaagcccc agctgccgaa 1320
ccggccgctc cagctcctgc agaacctgcc gctccagcac ctgaggctcc agccgctgaa 1380
cctgccgcac cagctccagc cgagcctgct gccccagctc cagaagcacc tgctgctgag 1440
cctgcagccc ctgctcctgc tgaaccagct gcacctgccc ctgaagctcc tgccgcagaa 1500
ccagccgctc ctgcccctgc tgagccagcc gctccagctc cagaagcccc agctgccgaa 1560
ccggccgctc cagctcctgc agaacctgcc gctccagcac ctgaggctcc agccgctgaa 1620
cctgccgcac cagctccagc cgagcctgct gccccagctc cagaagcacc tgctgctgag 1680
cctgcagccc ctgctcctgc tgaaccagct gcacctgccc ctgaagctcc tgccgcagaa 1740
ccagccgctc ctgcccctgc tgagccagcc gctccagctc cagaagcccc agctgccgaa 1800
ccggccgcac cagctcctgc tgagccggcc 1830
<210> 46
<211> 2250
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 46
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 60
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 120
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 180
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 240
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 300
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 360
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 420
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 480
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 540
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 600
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 660
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 720
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 780
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 840
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 900
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 960
gccgaaccgg ccgcaccagc tcctgctgag ccggccggat ccgacctgga taagaaactg 1020
ctggaagctg ctcgtgctgg tcaggacgac gaagttcgta tcctgatggc taacggtgct 1080
gacgttaacg ctagagactc tactggttgg actccgctgc acctggctgc tccatggggt 1140
cacccagaaa tcgttgaagt tctgctgaag aacggtgctg acgttaacgc tgctgacttt 1200
cagggttgga ctccgctgca cctggctgct gctgttggtc acctggaaat cgttgaagtt 1260
ctgctgaagt acggtgctga cgttaacgct caggacaaat tcggtaagac cgctttcgac 1320
atctccatcg acaacggtaa cgaagacctg gctgaaatcc tgcaaaaagc tgccggtcca 1380
cccggtgagg ctggagctcc aggacccgaa ggtgccgaag gagaggctgg tgaacctggt 1440
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 1500
cctgaggtca catgcgtggt ggtggacgtg agccacgaag accctgaggt caagttcaac 1560
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccgcggga ggagcagtac 1620
gctagcacgt accgtgtggt cagcgtcctc accgtcctgc accaggactg gctgaatggc 1680
aaggagtaca agtgcaaggt ctccaacaaa gccctcccag cccccatcga gaaaaccatc 1740
tccaaagcca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggat 1800
gagctgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta tcccagcgac 1860
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacgcctccc 1920
gtgctggact ccgacggctc cttcttcctc tatagcaagc tcaccgtgga caagagcagg 1980
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 2040
acgcagaaga gcctctccct gtctccgggt aaaggtggag gtggcggtgc acaacaggaa 2100
gagtgtgaat gggacccttg gacttgtgaa cacatgggtt ctggttctgc cactggaggc 2160
tctggttcta cagcttcttc tggatctggt tctgctactc atcaagaaga gtgcgaatgg 2220
gacccttgga cttgtgagca catgttggaa 2250
<210> 47
<211> 2052
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 47
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 60
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 120
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 180
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 240
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 300
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 360
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 420
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 480
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 540
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 600
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 660
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 720
gccgaaccgg ccgcaccagc tcctgctgag ccggcctccg ataccggtag accatttgtg 780
gaaatgtact cagagatccc cgaaattatt cacatgactg agggacgcga gcttgtgatc 840
ccatgccgcg tcacatcccc taatattact gtcactttga aaaagttccc tctggacacc 900
ctgattccag atgggaagcg gatcatttgg gatagccgca agggctttat catttctaac 960
gctacctaca aggaaattgg cctgctgact tgcgaagcaa ccgtcaacgg ccatctgtat 1020
aagaccaatt acctcaccca tagacagact aatactatta tcgacgtcgt gttgtctcct 1080
agccacggta tcgaactcag tgtcggagaa aagctcgtgt tgaattgcac agcccgcacc 1140
gagcttaacg tcggcatcga ctttaactgg gagtatccta gttcaaagca ccagcataag 1200
aagctggtca atcgggacct gaaaacacag tccggctctg agatgaagaa gtttcttagt 1260
acccttacaa tcgacggggt cacacgctcc gatcagggtc tctatacatg cgctgccagt 1320
agcggtttga tgaccaagaa gaactccact ttcgtgcgcg tgcacgaaaa ggacaaaact 1380
cacacatgcc caccgtgccc agcacctgaa ctcctgggtg gaccgtcagt cttcctcttc 1440
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1500
gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1560
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca atagcacgta ccgtgtggtc 1620
agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1680
tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc 1740
cgagaaccac aggtgtacac cctgccccca tcccgggatg agctgaccaa gaaccaggtc 1800
agcctgacct gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1860
aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1920
ttcttcctct atagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1980
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 2040
tctccgggta aa 2052
<210> 48
<211> 2229
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 48
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 60
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 120
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 180
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 240
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 300
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 360
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 420
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 480
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 540
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 600
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 660
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 720
gccgaaccgg ccgcaccagc tcctgctgag ccggcctccg ataccggtag accatttgtg 780
gaaatgtact cagagatccc cgaaattatt cacatgactg agggacgcga gcttgtgatc 840
ccatgccgcg tcacatcccc taatattact gtcactttga aaaagttccc tctggacacc 900
ctgattccag atgggaagcg gatcatttgg gatagccgca agggctttat catttctaac 960
gctacctaca aggaaattgg cctgctgact tgcgaagcaa ccgtcaacgg ccatctgtat 1020
aagaccaatt acctcaccca tagacagact aatactatta tcgacgtcgt gttgtctcct 1080
agccacggta tcgaactcag tgtcggagaa aagctcgtgt tgaattgcac agcccgcacc 1140
gagcttaacg tcggcatcga ctttaactgg gagtatccta gttcaaagca ccagcataag 1200
aagctggtca atcgggacct gaaaacacag tccggctctg agatgaagaa gtttcttagt 1260
acccttacaa tcgacggggt cacacgctcc gatcagggtc tctatacatg cgctgccagt 1320
agcggtttga tgaccaagaa gaactccact ttcgtgcgcg tgcacgaaaa ggacaaaact 1380
cacacatgcc caccgtgccc agcacctgaa ctcctgggtg gaccgtcagt cttcctcttc 1440
cccccaaaac ccaaggacac cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 1500
gtggacgtga gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 1560
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca atagcacgta ccgtgtggtc 1620
agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1680
tccaacaaag ccctcccagc ccccatcgag aaaaccatct ccaaagccaa agggcagccc 1740
cgagaaccac aggtgtacac cctgccccca tcccgggatg agctgaccaa gaaccaggtc 1800
agcctgacct gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1860
aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1920
ttcttcctct atagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 1980
tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 2040
tctccgggta aaggtggagg tggcggtgca caacaggaag agtgtgaatg ggacccttgg 2100
acttgtgaac acatgggttc tggttctgcc actggaggct ctggttctac agcttcttct 2160
ggatctggtt ctgctactca tcaagaagag tgcgaatggg acccttggac ttgtgagcac 2220
atgttggaa 2229
<210> 49
<211> 2172
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 49
ggtccacctg gtgaagctgg tgcacccgga cccgaaggtg ccgaaggaga ggctggtgaa 60
cctggacccg ccggtgaacc aggacctgaa ggagctccag gtcctcctgg acccgcagga 120
gagcccggtc ctgccggtgc tcctggtcca cccggagaag caggtccagc cggagctcct 180
ggtgaggctg gtcccccagg acccgctgga gctgaaggtg aggcaggtcc agccggcgct 240
ccaggtgagc caggaccaga aggtccacca ggagaagctg gagcacccgg tcctccagga 300
gcacccggcg ctgaaggaga acccggtgct cctggagaac ccggtccagc tggtgaagct 360
ggtgcacccg gacccgaagg tgccgaagga gaggctggtg aacctggacc cgccggtgaa 420
ccaggacctg aaggagctcc aggtcctcct ggacccgcag gagagcccgg tcctgccggt 480
gctcctggtc cacccggaga agcaggtcca gccggagctc ctggtgaggc tggtccccca 540
ggacccgctg gagctgaagg tgaggcaggt ccagccggcg ctccaggtga gccaggacca 600
gaaggtccac caggagaagc tggagcaccc ggtcctccag gagcacccgg cgctgaagga 660
gaacccggtg ctcctggaga acccggtcca gctggtggat ccgataccgg tagaccattt 720
gtggaaatgt actcagagat ccccgaaatt attcacatga ctgagggacg cgagcttgtg 780
atcccatgcc gcgtcacatc ccctaatatt actgtcactt tgaaaaagtt ccctctggac 840
accctgattc cagatgggaa gcggatcatt tgggatagcc gcaagggctt tatcatttct 900
aacgctacct acaaggaaat tggcctgctg acttgcgaag caaccgtcaa cggccatctg 960
tataagacca attacctcac ccatagacag actaatacta ttatcgacgt cgtgttgtct 1020
cctagccacg gtatcgaact cagtgtcgga gaaaagctcg tgttgaattg cacagcccgc 1080
accgagctta acgtcggcat cgactttaac tgggagtatc ctagttcaaa gcaccagcat 1140
aagaagctgg tcaatcggga cctgaaaaca cagtccggct ctgagatgaa gaagtttctt 1200
agtaccctta caatcgacgg ggtcacacgc tccgatcagg gtctctatac atgcgctgcc 1260
agtagcggtt tgatgaccaa gaagaactcc actttcgtgc gcgtgcacga aaaggacaaa 1320
actcacacat gcccaccgtg cccagcacct gaactcctgg gtggaccgtc agtcttcctc 1380
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 1440
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 1500
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaatagcac gtaccgtgtg 1560
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 1620
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1680
ccccgagaac cacaggtgta caccctgccc ccatcccggg atgagctgac caagaaccag 1740
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1800
agcaatgggc agccggagaa caactacaag accacgcctc ccgtgctgga ctccgacggc 1860
tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1920
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagtctctcc 1980
ctgtctccgg gtaaaggtgg aggtggcggt gcacaacagg aagagtgtga atgggaccct 2040
tggacttgtg aacacatggg ttctggttct gccactggag gctctggttc tacagcttct 2100
tctggatctg gttctgctac tcatcaagaa gagtgcgaat gggacccttg gacttgtgag 2160
cacatgttgg aa 2172
<210> 50
<211> 1395
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 50
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 60
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 120
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 180
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 240
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 300
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 360
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 420
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 480
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 540
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 600
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 660
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 720
gccgaaccgg ccgcaccagc tcctgctgag ccggccgaca tccagctgac ccagagcccc 780
tccagcctgt ccgcctccgt gggagaccgg gtgaccatca cctgttccgc tagccaggac 840
atctccaact acctgaactg gtatcagcag aagcctggca aggcccctaa ggtgctgatc 900
tacttcacct ccagcctgca ctccggcgtg cctagcaggt ttagcggcag cggctccggc 960
accgatttca ccctgaccat cagctccctg caacctgagg actttgccac ctactactgt 1020
cagcagtaca gcaccgtgcc ttggaccttt ggccagggca ccaaggtgga gatcaagcgg 1080
accgtggctg ctccctccgt gttcatcttt cccccctccg acgagcagct gaaaagcggc 1140
accgcctccg tggtgtgcct gctgaacaat ttttaccccc gggaggccaa ggtgcagtgg 1200
aaggtggaca acgccctcca gagcggcaat agccaggagt ccgtgaccga gcaggatagc 1260
aaggactcca cctacagcct gtcctccacc ctgaccctga gcaaggctga ttatgagaag 1320
cataaggtgt atgcttgtga ggtgacccac cagggcctgt cctcccccgt gaccaagagc 1380
ttcaaccggg gcgag 1395
<210> 51
<211> 1356
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 51
gacatccagc tgacccagag cccctccagc ctgtccgcct ccgtgggaga ccgggtgacc 60
atcacctgtt ccgctagcca ggacatctcc aactacctga actggtatca gcagaagcct 120
ggcaaggccc ctaaggtgct gatctacttc acctccagcc tgcactccgg cgtgcctagc 180
aggtttagcg gcagcggctc cggcaccgat ttcaccctga ccatcagctc cctgcaacct 240
gaggactttg ccacctacta ctgtcagcag tacagcaccg tgccttggac ctttggccag 300
ggcaccaagg tggagatcaa gcggaccgtg gctgctccct ccgtgttcat ctttcccccc 360
tccgacgagc agctgaaaag cggcaccgcc tccgtggtgt gcctgctgaa caatttttac 420
ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tccagagcgg caatagccag 480
gagtccgtga ccgagcagga tagcaaggac tccacctaca gcctgtcctc caccctgacc 540
ctgagcaagg ctgattatga gaagcataag gtgtatgctt gtgaggtgac ccaccagggc 600
ctgtcctccc ccgtgaccaa gagcttcaac cggggcgagt gcggtggtgg tggttctggt 660
ccacctggtg aagctggtgc acccggaccc gaaggtgccg aaggagaggc tggtgaacct 720
ggacccgccg gtgaaccagg acctgaagga gctccaggtc ctcctggacc cgcaggagag 780
cccggtcctg ccggtgctcc tggtccaccc ggagaagcag gtccagccgg agctcctggt 840
gaggctggtc ccccaggacc cgctggagct gaaggtgagg caggtccagc cggcgctcca 900
ggtgagccag gaccagaagg tccaccagga gaagctggag cacccggtcc tccaggagca 960
cccggcgctg aaggagaacc cggtgctcct ggagaacccg gtccagctgg tgaagctggt 1020
gcacccggac ccgaaggtgc cgaaggagag gctggtgaac ctggacccgc cggtgaacca 1080
ggacctgaag gagctccagg tcctcctgga cccgcaggag agcccggtcc tgccggtgct 1140
cctggtccac ccggagaagc aggtccagcc ggagctcctg gtgaggctgg tcccccagga 1200
cccgctggag ctgaaggtga ggcaggtcca gccggcgctc caggtgagcc aggaccagaa 1260
ggtccaccag gagaagctgg agcacccggt cctccaggag cacccggcgc tgaaggagaa 1320
cccggtgctc ctggagaacc cggtccagct ggtgga 1356
<210> 52
<211> 2070
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 52
ggtccacctg gtgaagctgg tgcacccgga cccgaaggtg ccgaaggaga ggctggtgaa 60
cctggacccg ccggtgaacc aggacctgaa ggagctccag gtcctcctgg acccgcagga 120
gagcccggtc ctgccggtgc tcctggtcca cccggagaag caggtccagc cggagctcct 180
ggtgaggctg gtcccccagg acccgctgga gctgaaggtg aggcaggtcc agccggcgct 240
ccaggtgagc caggaccaga aggtccacca ggagaagctg gagcacccgg tcctccagga 300
gcacccggcg ctgaaggaga acccggtgct cctggagaac ccggtccagc tggtgaagct 360
ggtgcacccg gacccgaagg tgccgaagga gaggctggtg aacctggacc cgccggtgaa 420
ccaggacctg aaggagctcc aggtcctcct ggacccgcag gagagcccgg tcctgccggt 480
gctcctggtc cacccggaga agcaggtcca gccggagctc ctggtgaggc tggtccccca 540
ggacccgctg gagctgaagg tgaggcaggt ccagccggcg ctccaggtga gccaggacca 600
gaaggtccac caggagaagc tggagcaccc ggtcctccag gagcacccgg cgctgaagga 660
gaacccggtg ctcctggaga acccggtcca gctggtggtg gcggtggcgg atcagacatc 720
cagctgaccc agagcccctc cagcctgtcc gcctccgtgg gagaccgggt gaccatcacc 780
tgttccgcta gccaggacat ctccaactac ctgaactggt atcagcagaa gcctggcaag 840
gcccctaagg tgctgatcta cttcacctcc agcctgcact ccggcgtgcc tagcaggttt 900
agcggcagcg gctccggcac cgatttcacc ctgaccatca gctccctgca acctgaggac 960
tttgccacct actactgtca gcagtacagc accgtgcctt ggacctttgg ccagggcacc 1020
aaggtggaga tcaagcggac cgtggctgct ccctccgtgt tcatctttcc cccctccgac 1080
gagcagctga aaagcggcac cgcctccgtg gtgtgcctgc tgaacaattt ttacccccgg 1140
gaggccaagg tgcagtggaa ggtggacaac gccctccaga gcggcaatag ccaggagtcc 1200
gtgaccgagc aggatagcaa ggactccacc tacagcctgt cctccaccct gaccctgagc 1260
aaggctgatt atgagaagca taaggtgtat gcttgtgagg tgacccacca gggcctgtcc 1320
tcccccgtga ccaagagctt caaccggggc gagtgcggtg gtggcggctc tggtccacct 1380
ggtgaagctg gtgcacccgg acccgaaggt gccgaaggag aggctggtga acctggaccc 1440
gccggtgaac caggacctga aggagctcca ggtcctcctg gacccgcagg agagcccggt 1500
cctgccggtg ctcctggtcc acccggagaa gcaggtccag ccggagctcc tggtgaggct 1560
ggtcccccag gacccgctgg agctgaaggt gaggcaggtc cagccggcgc tccaggtgag 1620
ccaggaccag aaggtccacc aggagaagct ggagcacccg gtcctccagg agcacccggc 1680
gctgaaggag aacccggtgc tcctggagaa cccggtccag ctggtgaagc tggtgcaccc 1740
ggacccgaag gtgccgaagg agaggctggt gaacctggac ccgccggtga accaggacct 1800
gaaggagctc caggtcctcc tggacccgca ggagagcccg gtcctgccgg tgctcctggt 1860
ccacccggag aagcaggtcc agccggagct cctggtgagg ctggtccccc aggacccgct 1920
ggagctgaag gtgaggcagg tccagccggc gctccaggtg agccaggacc agaaggtcca 1980
ccaggagaag ctggagcacc cggtcctcca ggagcacccg gcgctgaagg agaacccggt 2040
gctcctggag aacccggtcc agctggtgga 2070
<210> 53
<211> 1536
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 53
gaggtgcagc tggtggagtc cggcggcgga ctggtgcagc ctggaggaag cctgcggctg 60
agctgcgctg ccagcggata cgatttcacc cactacggca tgaattgggt gaggcaggct 120
cccggcaagg gcctggagtg ggtgggatgg atcaacacct acaccggcga gcccacctat 180
gccgccgatt tcaagcggag gttcaccttc agcctggata cctccaagtc caccgcctat 240
ctccagatga acagcctgag ggccgaggac accgctgtgt attactgcgc caagtatcct 300
tactactacg gcacctccca ctggtacttt gacgtgtggg gccagggcac cctggtgacc 360
gtgtcttccg ccagcaccaa gggaccttcc gtgttccccc tggctccttc cagcaagtcc 420
accagcggcg gcaccgctgc tctgggatgt ctggtgaagg actacttccc cgagcccgtg 480
accgtgtctt ggaatagcgg cgccctgacc tccggcgtgc acacattccc cgccgtgctg 540
caatccagcg gcctgtatag cctgtcctcc gtggtgaccg tgcccagctc cagcctgggc 600
acccagacct acatctgcaa tgtgaaccac aagcccagca acaccaaggt ggacaagaag 660
gtggagccca agtcctgcga caaaactcac acatgcccac cgtgcccagc acctgaactc 720
ctgggtggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 780
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 840
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagtacaata gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1080
cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1260
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacgc agaagagcct ctccctgtct ccgggtaaag gtggaggtgg cggtgcacaa 1380
caggaagagt gtgaatggga cccttggact tgtgaacaca tgggttctgg ttctgccact 1440
ggaggctctg gttctacagc ttcttctgga tctggttctg ctactcatca agaagagtgc 1500
gaatgggacc cttggacttg tgagcacatg ttggaa 1536
<210> 54
<211> 1398
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 54
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 60
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 120
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 180
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 240
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 300
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 360
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 420
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 480
gccgaaccgg ccgctccagc tcctgcagaa cctgccgctc cagcacctga ggctccagcc 540
gctgaacctg ccgcaccagc tccagccgag cctgctgccc cagctccaga agcacctgct 600
gctgagcctg cagcccctgc tcctgctgaa ccagctgcac ctgcccctga agctcctgcc 660
gcagaaccag ccgctcctgc ccctgctgag ccagccgctc cagctccaga agccccagct 720
gccgaaccgg ccgcaccagc tcctgctgag ccggccgaca tccagatgac ccagagccct 780
agctctctgt ccgcctctgt gggcgacaga gtgaccatca catgttccgc cagccaggat 840
atctctaact acctgaattg gtatcagcag aagccaggca aggctcccaa ggtgctgatc 900
tactttacat ccagcctgca ctctggagtg ccatcccgct tctctggttc cggaagcgga 960
accgacttta ccctgacaat ctcttccctg caacctgagg atttcgccac atactattgc 1020
cagcagtatt ccaccgtgcc ttggacattt ggccagggca ccaaggtgga gatcaagagg 1080
acagtggccg ctccatccgt gttcatcttt ccccctagcg acgagcagct gaagagcggc 1140
accgcctctg tggtgtgcct gctgaacaat ttctaccccc gggaggctaa ggtgcagtgg 1200
aaggtggata acgccctgca atctggcaat tcccaggaga gcgtgaccga gcaggactct 1260
aaggattcca catatagcct gagttctacc ctgacactgt ccaaggctga ctacgagaag 1320
cataaggtgt atgcctgcga ggtgacccat cagggcctgt ccagccccgt gacaaagagc 1380
tttaaccggg gcgagtgt 1398
<210> 55
<211> 1356
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 55
ggtccacctg gtgaagctgg tgcacccgga cccgaaggtg ccgaaggaga ggctggtgaa 60
cctggacccg ccggtgaacc aggacctgaa ggagctccag gtcctcctgg acccgcagga 120
gagcccggtc ctgccggtgc tcctggtcca cccggagaag caggtccagc cggagctcct 180
ggtgaggctg gtcccccagg acccgctgga gctgaaggtg aggcaggtcc agccggcgct 240
ccaggtgagc caggaccaga aggtccacca ggagaagctg gagcacccgg tcctccagga 300
gcacccggcg ctgaaggaga acccggtgct cctggagaac ccggtccagc tggtgaagct 360
ggtgcacccg gacccgaagg tgccgaagga gaggctggtg aacctggacc cgccggtgaa 420
ccaggacctg aaggagctcc aggtcctcct ggacccgcag gagagcccgg tcctgccggt 480
gctcctggtc cacccggaga agcaggtcca gccggagctc ctggtgaggc tggtccccca 540
ggacccgctg gagctgaagg tgaggcaggt ccagccggcg ctccaggtga gccaggacca 600
gaaggtccac caggagaagc tggagcaccc ggtcctccag gagcacccgg cgctgaagga 660
gaacccggtg ctcctggaga acccggtcca gctggtggtg gcggtggcgg atcagacatc 720
cagatgaccc agagccctag ctctctgtcc gcctctgtgg gcgacagagt gaccatcaca 780
tgttccgcca gccaggatat ctctaactac ctgaattggt atcagcagaa gccaggcaag 840
gctcccaagg tgctgatcta ctttacatcc agcctgcact ctggagtgcc atcccgcttc 900
tctggttccg gaagcggaac cgactttacc ctgacaatct cttccctgca acctgaggat 960
ttcgccacat actattgcca gcagtattcc accgtgcctt ggacatttgg ccagggcacc 1020
aaggtggaga tcaagaggac agtggccgct ccatccgtgt tcatctttcc ccctagcgac 1080
gagcagctga agagcggcac cgcctctgtg gtgtgcctgc tgaacaattt ctacccccgg 1140
gaggctaagg tgcagtggaa ggtggataac gccctgcaat ctggcaattc ccaggagagc 1200
gtgaccgagc aggactctaa ggattccaca tatagcctga gttctaccct gacactgtcc 1260
aaggctgact acgagaagca taaggtgtat gcctgcgagg tgacccatca gggcctgtcc 1320
agccccgtga caaagagctt taaccggggc gagtgt 1356
<210> 56
<211> 1596
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 56
atggagaccg atacactgct cctgtgggtc ctgctgctgt gggtgccagg ttccaccggg 60
gaggtgcagc tggtggagtc tggaggagga ctggtgcagc caggaggctc tctgagactg 120
tcctgcgccg ctagcggcta caccttcaca aactatggca tgaattgggt gcgccaggct 180
ccaggcaagg gcctggagtg ggtgggctgg atcaacacct acacaggcga gcccacctat 240
gccgctgact ttaagaggag gttcaccttc tccctggaca cctccaagag cacagcctac 300
ctccagatga actccctgag ggccgaggac accgccgtgt actattgcgc taagtacccc 360
cactactatg gctccagcca ttggtatttc gacgtgtggg gacagggcac cctggtgaca 420
gtgtcttccg cctctaccaa gggaccttcc gtgtttcctc tggctccaag ctctaagtct 480
acctccggag gaacagccgc tctgggatgt ctggtgaagg actatttccc tgagccagtg 540
accgtgtcct ggaacagcgg cgccctgacc tccggagtgc acacatttcc tgctgtgctc 600
cagtccagcg gcctgtacag cctgtcttcc gtggtgaccg tgccaagctc ttccctgggc 660
acccagacat atatctgcaa cgtgaatcac aagccatcca acacaaaggt ggacaagaag 720
gtggagccca agtcctgcga caaaactcac acatgcccac cgtgcccagc acctgaactc 780
ctgggtggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 840
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 900
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 960
cagtacaata gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1020
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1080
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1140
cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1200
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1260
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1320
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1380
cactacacgc agaagagcct ctccctgtct ccgggtaaag gtggaggtgg cggtgcacaa 1440
caggaagagt gtgaatggga cccttggact tgtgaacaca tgggttctgg ttctgccact 1500
ggaggctctg gttctacagc ttcttctgga tctggttctg ctactcatca agaagagtgc 1560
gaatgggacc cttggacttg tgagcacatg ttggaa 1596
<210> 57
<211> 1359
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 57
gaggtgcagc tggtggagtc cggcggcgga ctggtgcagc ctggaggaag cctgcggctg 60
agctgcgctg ccagcggata cgatttcacc cactacggca tgaattgggt gaggcaggct 120
cccggcaagg gcctggagtg ggtgggatgg atcaacacct acaccggcga gcccacctat 180
gccgccgatt tcaagcggag gttcaccttc agcctggata cctccaagtc caccgcctat 240
ctccagatga acagcctgag ggccgaggac accgctgtgt attactgcgc caagtatcct 300
tactactacg gcacctccca ctggtacttt gacgtgtggg gccagggcac cctggtgacc 360
gtgtcttccg ccagcaccaa gggaccttcc gtgttccccc tggctccttc cagcaagtcc 420
accagcggcg gcaccgctgc tctgggatgt ctggtgaagg actacttccc cgagcccgtg 480
accgtgtctt ggaatagcgg cgccctgacc tccggcgtgc acacattccc cgccgtgctg 540
caatccagcg gcctgtatag cctgtcctcc gtggtgaccg tgcccagctc cagcctgggc 600
acccagacct acatctgcaa tgtgaaccac aagcccagca acaccaaggt ggacaagaag 660
gtggagccca agtcctgcga caaaactcac acatgcccac cgtgcccagc acctgaactc 720
ctgggtggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 780
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 840
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 900
cagtacaata gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 960
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1020
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1080
cgggatgagc tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1140
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1200
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1260
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1320
cactacacgc agaagagcct ctccctgtct ccgggtaaa 1359
<210> 58
<211> 639
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 58
gacatccagc tgacccagag cccctccagc ctgtccgcct ccgtgggaga ccgggtgacc 60
atcacctgtt ccgctagcca ggacatctcc aactacctga actggtatca gcagaagcct 120
ggcaaggccc ctaaggtgct gatctacttc acctccagcc tgcactccgg cgtgcctagc 180
aggtttagcg gcagcggctc cggcaccgat ttcaccctga ccatcagctc cctgcaacct 240
gaggactttg ccacctacta ctgtcagcag tacagcaccg tgccttggac ctttggccag 300
ggcaccaagg tggagatcaa gcggaccgtg gctgctccct ccgtgttcat ctttcccccc 360
tccgacgagc agctgaaaag cggcaccgcc tccgtggtgt gcctgctgaa caatttttac 420
ccccgggagg ccaaggtgca gtggaaggtg gacaacgccc tccagagcgg caatagccag 480
gagtccgtga ccgagcagga tagcaaggac tccacctaca gcctgtcctc caccctgacc 540
ctgagcaagg ctgattatga gaagcataag gtgtatgctt gtgaggtgac ccaccagggc 600
ctgtcctccc ccgtgaccaa gagcttcaac cggggcgag 639
<210> 59
<211> 1419
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 59
atggagaccg atacactgct cctgtgggtc ctgctgctgt gggtgccagg ttccaccggg 60
gaggtgcagc tggtggagtc tggaggagga ctggtgcagc caggaggctc tctgagactg 120
tcctgcgccg ctagcggcta caccttcaca aactatggca tgaattgggt gcgccaggct 180
ccaggcaagg gcctggagtg ggtgggctgg atcaacacct acacaggcga gcccacctat 240
gccgctgact ttaagaggag gttcaccttc tccctggaca cctccaagag cacagcctac 300
ctccagatga actccctgag ggccgaggac accgccgtgt actattgcgc taagtacccc 360
cactactatg gctccagcca ttggtatttc gacgtgtggg gacagggcac cctggtgaca 420
gtgtcttccg cctctaccaa gggaccttcc gtgtttcctc tggctccaag ctctaagtct 480
acctccggag gaacagccgc tctgggatgt ctggtgaagg actatttccc tgagccagtg 540
accgtgtcct ggaacagcgg cgccctgacc tccggagtgc acacatttcc tgctgtgctc 600
cagtccagcg gcctgtacag cctgtcttcc gtggtgaccg tgccaagctc ttccctgggc 660
acccagacat atatctgcaa cgtgaatcac aagccatcca acacaaaggt ggacaagaag 720
gtggagccca agtcctgcga caaaactcac acatgcccac cgtgcccagc acctgaactc 780
ctgggtggac cgtcagtctt cctcttcccc ccaaaaccca aggacaccct catgatctcc 840
cggacccctg aggtcacatg cgtggtggtg gacgtgagcc acgaagaccc tgaggtcaag 900
ttcaactggt acgtggacgg cgtggaggtg cataatgcca agacaaagcc gcgggaggag 960
cagtacaata gcacgtaccg tgtggtcagc gtcctcaccg tcctgcacca ggactggctg 1020
aatggcaagg agtacaagtg caaggtctcc aacaaagccc tcccagcccc catcgagaaa 1080
accatctcca aagccaaagg gcagccccga gaaccacagg tgtacaccct gcccccatcc 1140
cgggaggaga tgaccaagaa ccaggtcagc ctgacctgcc tggtcaaagg cttctatccc 1200
agcgacatcg ccgtggagtg ggagagcaat gggcagccgg agaacaacta caagaccacg 1260
cctcccgtgc tggactccga cggctccttc ttcctctata gcaagctcac cgtggacaag 1320
agcaggtggc agcaggggaa cgtcttctca tgctccgtga tgcatgaggc tctgcacaac 1380
cactacacgc agaagagcct ctccctgtct ccgggtaaa 1419
<210> 60
<211> 1071
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 60
ggtagcgatc tagataaaaa gctcctagag gccgcacgtg caggccagga tgatgaagta 60
aggatactta tggctaacgg tgctgatgtt aacgcgcggg atagtaccgg gtggacccca 120
ttgcacttgg cggcgccttg gggccacccc gaaatagtag aagttctgtt aaaaaatggt 180
gcggacgtaa atgctgccga cttccagggt tggacaccac tacacttggc agcagctgta 240
ggtcacctcg aaatagtgga ggtcttgttg aaatacggtg ccgacgttaa cgcgcaagac 300
aagttcggaa agacggcttt cgatatcagc atagataatg gcaatgaaga cctcgcggaa 360
atcctccaga aggccgccga gcccaaaagc tgcgacaaaa ctcatacctg cccaccatgc 420
ccggcgcctg agttattggg cggtccaagt gtatttctgt ttccacctaa gcctaaagac 480
acccttatga taagtagaac accagaggtt acctgcgtcg tggtggatgt ttcgcacgaa 540
gatcccgaag tgaaattcaa ttggtacgtg gacggagtag aggttcataa cgcaaaaact 600
aaaccacgcg aggagcagta cgcaagcacc taccgcgtag tgagtgttct cactgtgttg 660
caccaagact ggctcaacgg taaagaatat aaatgtaaag taagtaataa ggccctccct 720
gcgccaattg agaagaccat aagcaaggcg aagggacagc caagagagcc acaagtttac 780
actttgcccc ctagtagaga tgagcttacc aagaatcagg tttcacttac atgtctcgtc 840
aaggggtttt acccgtcaga tatagcggtc gaatgggagt ctaatggaca gccggagaac 900
aattataaaa ccacccctcc ggtattggac tcggacggat cttttttctt atactctaag 960
ctgactgtgg ataaatcacg ctggcaacaa ggcaatgtgt tttcctgctc tgtcatgcac 1020
gaagctttgc ataaccatta cactcaaaaa tcgctgagtc tgtctcctgg a 1071
<210> 61
<211> 1236
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 61
gggtctgatt tagataagaa gcttctcgaa gcagcacggg caggtcaaga tgatgaagtg 60
agaattctga tggcgaacgg ggcagacgta aatgctcgtg attccaccgg ttggactcca 120
ctgcacttgg cggccccatg ggggcatccg gagattgtcg aagttttgct gaagaatgga 180
gcagacgtaa acgccgcgga tttccagggt tggacgccgc ttcacttagc cgctgctgta 240
ggacatctcg aaattgtaga agttcttttg aagtatggag ctgacgttaa cgcccaggac 300
aaatttggaa agaccgcttt tgacatttcc atcgataatg gtaatgaaga tctggccgaa 360
atccttcaaa aggccgcgga taagacccac acgtgcccgc cttgtccggc gccagaactt 420
ctagggggtc cgagcgtgtt cctatttcct ccaaagccaa aagacactct tatgatatcg 480
cgaacacccg aagtaacttg cgttgttgtg gacgtatcgc acgaagatcc ggaggttaag 540
ttcaactggt atgtcgacgg tgtggaggtc cataatgcga aaacgaagcc ccgggaggaa 600
caatatgcat ccacatatcg cgtagtatcg gttttaaccg tcctacatca ggactggctc 660
aatgggaaag aatacaaatg taaagtatcc aacaaggcac tacccgctcc gatagaaaag 720
acaatctcga aagcaaaggg tcaacctcgc gagccccaag tttacacact tccaccttct 780
cgagatgagc tgaccaagaa ccaagtttct ttgacgtgtc ttgtgaaagg tttttatcct 840
tcagatatag ccgtagaatg ggaaagtaat gggcagcctg aaaacaatta caaaaccacg 900
ccaccagtcc tggactctga tggttctttt tttctatata gtaagttgac agttgacaaa 960
tcacggtggc aacaaggcaa tgtcttctcg tgttctgtga tgcatgaagc actgcataac 1020
cattatacgc aaaagagtct gagcctatcc ccagggaagg ggggaggagg gggtgctcag 1080
caagaagagt gcgagtggga tccatggacc tgcgaacata tgggttccgg gagcgctacc 1140
gggggatcag gcagtaccgc atcctccggg agtgggtcgg cgacccatca agaggagtgc 1200
gaatgggacc cttggacgtg cgagcacatg cttgag 1236
<210> 62
<211> 1254
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 62
ggctcggatc tggacaagaa attattagag gccgctcgag ccggccaaga cgatgaagtg 60
cgaatcctaa tggcaaacgg ggccgacgtg aatgctcgag attcgacggg atggaccccc 120
ttgcacttag cagctccttg ggggcacccg gaaattgtcg aagtattgtt gaagaatggg 180
gcggacgtaa acgctgcaga cttccaggga tggacaccat tacacctagc ggccgccgtc 240
gggcacctcg agatcgttga ggtcttattg aagtacggtg cagatgttaa cgcacaagat 300
aagttcggca aaaccgcttt tgacattagt atcgacaatg gtaatgagga cctcgcagag 360
atcctacaga aggccgcggg tcccccagga gaagcgggtg caccgggacc ggagggtgca 420
gagggcgagg cgggagaacc cggaggtcca tccgtgtttt tattcccccc gaaacctaag 480
gatacactaa tgatctcacg gacacccgaa gtgacatgcg tagtggtcga cgtgtcccac 540
gaggatcccg aagtaaaatt caactggtat gtagacgggg tagaggtgca caacgcaaaa 600
acgaaaccgc gtgaagagca gtacgctagc acctaccgag tggtttcggt gctcactgtc 660
ttacaccagg attggctaaa tggaaaggag tataagtgta aggtctcaaa taaagcgttg 720
cctgcaccta tcgaaaagac catcagcaaa gcgaaaggcc aaccccgcga accgcaggta 780
tacacgctcc ccccctcgcg agacgagctg acaaaaaacc aggttagtct gacttgcctc 840
gtgaaggggt tttacccgag cgacatagcc gtagaatggg aaagcaacgg tcaaccagaa 900
aacaactata agacgactcc tccggttttg gactcagacg gttcgttctt cctatacagc 960
aaactgacag tcgataaatc caggtggcaa cagggaaacg tattctcgtg cagtgtcatg 1020
cacgaagccc tacataacca ctatactcag aagtcgctat cattatcgcc gggcaagggt 1080
ggcgggggag gcgcgcagca agaggagtgc gagtgggatc catggacttg cgagcacatg 1140
gggtccggaa gtgccacggg aggctctggg agcactgcgt cgtcaggttc aggaagtgct 1200
acccaccagg aggaatgcga atgggatccc tggacttgtg aacacatgtt agag 1254
<210> 63
<211> 1473
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 63
agcgatacgg ggaggccatt cgtagagatg tactctgaga ttcctgaaat aatacacatg 60
accgaaggac gtgaattagt tatcccgtgt agagtgacta gcccgaacat cacagtcaca 120
ctaaaaaagt tccctctcga tacgttgatt cccgatggca agcgcataat atgggattct 180
cggaagggct ttattatctc aaatgcaaca tataaggaga ttgggttatt aacatgtgaa 240
gctaccgtaa acggacattt atataagaca aattatttga cgcatcgtca aaccaacact 300
attattgatg tagtattgtc gccgtcgcat gggatagaac taagtgtggg tgaaaagctc 360
gttctaaatt gcacggcgcg gacagaactt aatgtcggga tagattttaa ttgggagtac 420
cctagttcga agcaccagca taagaaacta gtaaaccgtg acctgaagac acaaagtggt 480
agcgagatga agaaattcct ttctacccta acaatcgacg gtgtcactcg ttctgaccaa 540
ggtctttaca catgcgctgc atcgtctggg cttatgacta aaaaaaatag cacttttgtc 600
cgggtacacg agaaggataa gacccacacg tgtcctccat gtcccgcccc cgagttacta 660
ggcggaccgt cagtgttcct ctttccgccc aaaccgaaag acactctcat gatatcacgt 720
acaccagaag tcacctgtgt ggttgtagat gtttctcacg aagaccccga ggttaaattc 780
aattggtacg tcgacggtgt cgaggtccat aatgcgaaga ctaagccaag agaggaacag 840
tataactcca cataccgtgt ggtttcagtg ttgaccgttc tgcatcagga ctggttgaat 900
ggtaaagagt ataaatgtaa agtgtcaaat aaagcgcttc cagctccaat tgagaaaacg 960
attagcaagg ccaaaggcca accacgggag ccccaggtat acacacttcc acccagccgc 1020
gatgagttga cgaaaaacca ggtgtcacta acgtgcctcg tcaaaggctt ttacccttcc 1080
gatatcgcag tcgaatggga atccaatggg caacccgaaa ataattacaa gaccacacca 1140
cctgtcctag actccgacgg tagtttcttt ctctatagca agttaaccgt agataagagc 1200
cgttggcaac agggtaatgt tttttcgtgc tccgtaatgc atgaggctct tcacaaccat 1260
tatacacaaa agtctttgtc tctctcacca ggcaaggggg gaggaggagg tgcgcagcag 1320
gaggagtgcg aatgggatcc gtggacatgc gagcatatgg gtagtggaag tgcgacgggt 1380
ggatctggtt ccacagcttc ctctgggtcc ggtagtgcaa cgcaccagga ggagtgtgag 1440
tgggacccat ggacgtgtga acatatgcta gaa 1473

Claims (17)

1.一种融合蛋白，所述融合蛋白包括亲水性重复序列片段、拮抗VEGF片段、免疫球蛋白Fc片段。
2.如权利要求1所述的融合蛋白，其特征在于，所述亲水性重复序列片段选自类明胶蛋白片段、或多肽复合单元片段。
3.如权利要求2所述的融合蛋白，其特征在于，所述亲水性重复序列片段包括：
a)氨基酸序列如SEQ ID No.28～29其中之一所示的多肽片段；
或，b)氨基酸序列与SEQ ID No.28～29其中之一具有90％以上序列一致性且具有a)限定的多肽片段的功能的多肽片段；或，
c)氨基酸序列如SEQ ID No.30所示的多肽片段；
或，d)氨基酸序列与SEQ ID No.30具有90％以上序列一致性且具有c)限定的多肽片段的功能的多肽片段。
4.如权利要求1所述的融合蛋白，其特征在于，所述拮抗VEGF片段包括：
e)氨基酸序列如SEQ ID No.1～7其中之一所示的多肽片段；或，
f)氨基酸序列与SEQ ID No.1～7其中之一具有90％以上序列一致性且具有e)限定的多肽片段的功能的多肽片段。
5.如权利要求1所述的融合蛋白，其特征在于，所述免疫球蛋白Fc片段包括：
g)氨基酸序列如SEQ ID No.33～41其中之一所示的多肽片段；或，
h)氨基酸序列与SEQ ID No.33～41其中之一具有90％以上序列一致性且具有g)限定的多肽片段的功能的多肽片段；
所述免疫球蛋白Fc片段为人源的。
6.如权利要求1所述的融合蛋白，其特征在于，所述融合蛋白还包括连接肽片段，优选的，所述连接肽片段富含G、S和/或A。
7.如权利要求6所述的融合蛋白，其特征在于，所述连接肽片段包括氨基酸序列如SEQID NO.42-43其中之一所示的多肽片段。
8.如权利要求1所述的融合蛋白，其特征在于，所述融合蛋白还包括拮抗Ang片段，所述拮抗Ang片段选自拮抗Ang-1片段、或拮抗Ang-2片段。
9.如权利要求1或8任一权利要求所述的融合蛋白，其特征在于，所述亲水性重复序列片段位于融合蛋白的N端和/或C端，所述拮抗VEGF片段位于免疫球蛋白Fc片段的N端或C端；
和/或，拮抗VEGF片段、或拮抗Ang片段独立地位于免疫球蛋白Fc片段的N端或C端，优选的，拮抗VEGF片段、拮抗Ang片段分别位于免疫球蛋白Fc片段的N端和C端。
10.如权利要求1所述的融合蛋白，其特征在于，所述融合蛋白的氨基酸序列包括SEQID NO.11-12、SEQ ID NO.15-16、SEQ ID NO.18-19其中之一所示的序列；
或，所述融合蛋白的氨基酸序列包括SEQ ID NO.20和SEQ ID NO.21所示的序列、SEQID NO.22和SEQ ID NO.24所示的序列、SEQ ID NO.23和SEQ ID NO.24所示的序列、SEQ IDNO.25和SEQ ID NO.7所示的序列、或SEQ ID NO.26和SEQ ID NO.27所示的序列。
11.一种分离的多核苷酸，编码如权利要求1～10任一权利要求所述的融合蛋白。
12.一种构建体，所述构建体含有如权利要求11所述的分离的多核苷酸。
13.一种表达系统，所述表达系统含有如权利要求12所述的构建体或基因组中整合有外源的如权利要求11所述的多核苷酸。
14.如权利要求1-10任一权利要求所述的融合蛋白的制备方法，包括：在合适的条件下培养如权利要求13所述的表达系统，使之表达所述融合蛋白，分离、纯化以提供所述融合蛋白。
15.一种药物组合物，包括如权利要求1-10之任一权利要求所述的融合蛋白或如权利要求13所述的表达系统的培养物。
16.如权利要求1-10任一权利要求所述的融合蛋白、如权利要求15所述的药物组合物在制备药物中的用途。
17.如权利要求16所述的用途，其特征在于，所述药物选自用于眼部血管新生相关疾病的药物。
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