CN111944055B - 一种治疗代谢疾病的融合蛋白 - Google Patents

一种治疗代谢疾病的融合蛋白 Download PDF

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CN111944055B
CN111944055B CN201910407446.9A CN201910407446A CN111944055B CN 111944055 B CN111944055 B CN 111944055B CN 201910407446 A CN201910407446 A CN 201910407446A CN 111944055 B CN111944055 B CN 111944055B
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CN111944055A (zh
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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，特别是涉及一种治疗代谢疾病的融合蛋白及其制备方法和用途。本发明提供一种融合蛋白，包括Glucagon类似物片段和长效蛋白单元片段，所述Glucagon类似物片段包括：a）氨基酸序列如SEQ ID No.81所示的多肽片段：或，b）氨基酸序列与SEQ ID NO.81具有90%以上序列同一性且具有a）限定的多肽片段的功能的多肽片段。本发明所提供的融合蛋白具有良好的稳定性，且对于小鼠有良好的降糖和减重效果。

Description

一种治疗代谢疾病的融合蛋白
技术领域
本发明涉及生物技术领域，特别是涉及一种治疗代谢疾病的融合蛋白及其制备方法和用途。
背景技术
糖尿病按病理特征可分为一型糖尿病和二型糖尿病。一型糖尿病主要表现为胰岛素分泌不足，需要每天注射胰岛素；而二型糖尿病则是由于人体无法有效利用胰岛素造成。其中二型糖尿病患者占绝大多数。据估计大约80-90％二型糖尿病患者明显肥胖(Centerfor disease control and prevention(CDC)National Diabetes Fact Sheet,2014)。
用于治疗二型糖尿病的常规化药如磺酰脲类、噻唑烷二酮类等降糖效果明显，但主要缺点是会导致体重增加(N Engl J Med，355(23):2427-43，2006)。而用于二型糖尿病的蛋白类药物主要是GLP-1R(GLP-1受体)激动剂，如杜拉鲁肽(Dulaglutide，商品名：
Figure BDA0002061691890000011
)、阿必鲁肽(Albiglutide，商品名
Figure BDA0002061691890000012
)、利拉鲁肽(Liraglutide，商品名
Figure BDA0002061691890000013
及
Figure BDA0002061691890000014
分别用于治疗肥胖和糖尿病)、艾塞那肽(Exenatide，商品名
Figure BDA0002061691890000015
)、利西拉肽(Lixisenatide，商品名
Figure BDA0002061691890000016
)及索马鲁肽(Semaglutide)等。GLP-1R激动剂具有显著的降血糖效应，而且与胰岛素不同的是，GLP-1R激动剂的降糖作用是严格地血糖依赖性的，不容易造成低血糖，还有降体重的效果。但是这些药物在治疗中存在副作用，主要是胃肠道的影响，例如恶心，而且减重大部分都不超过平均体重的10％。减肥手术(Bariatric surgery)虽然可以显著改善肥胖症和治疗糖尿病，然而其应用并不广泛，因为大部分的患者出于手术风险及长期后遗症的考虑，并不愿意接受这种手术(Obesity and Diabetes，New Surgical and Nonsurgical Approaches，Springer出版社，2015)。
目前新一代的糖尿病药物主要集中于双效或多效肠降血糖素(Incretin)受体激动剂的研究，如GLP-1R/GCGR和GLP-1R/GIPR双效激动剂，甚至GLP-1R/GCGR/GIPR三效激动剂(Nature Medicine,22(7):694-695，2016)。其中，胰高血糖素(Glucagon，GCG)和GLP-1(Glucagon-like peptide-1)的受体在结构上相关，但是这两种激素在控制葡萄糖中表现出截然相反的作用。临床上，GLP-1及其类似物主要用于糖尿病人的血糖控制，而胰高血糖素(Glucagon，GCG)则用于急性低血糖症。近年来，越来越多的研究证明，胰高血糖素(Glucagon)尽管存在升血糖的风险，但是却能有效减少体重；更重要的是，GLP-1与Glucagon似乎有正向的附加或协同生理作用，例如Glucagon受体(GCGR)与GLP-1受体(GLP-1R)双激动剂比GLP-1R单激动剂能更有效地减重。虽然GCGR激动可能会导致血糖水平增加，但是这个风险可以通过GLP-1R激动和/或GIPR激动而适当地抵消。Matthias H.
Figure BDA0002061691890000021
等的综述文章里详尽地介绍了目前处于临床或临床前的各种杂合肽形式(Cell Metab，24(1):51-62，2016)。Alessandro Pocai等报道基于胃泌酸调节素(Oxyntomodulin，OXM)的双效GLP-1R/GCGR激动剂(Diabetes；58(10):2258-2266，2009)，或者Richard D.DiMarchi等报道的基于GCG的双效GLP-1R/GCGR激动剂(US9018164B2)，甚至三效的GLP-1R/GCGR/GIPR激动剂(US9150632B2)。这些多特异性的杂合肽大多基于GLP-1或GCG，通过序列突变来提高活性和抵抗蛋白酶水解，这些类似物大都将第二位的丝氨酸(Ser)突变成非天然氨基酸Aib来抵抗DPP-IV的酶解。罗氏与益普生合作研发的GLP-1R激动剂降糖药Taspoglutide(引入了非天然氨基酸Aib)，抗体生成率达到了49％，最终停止了所有Ⅲ期临床研究(DiabetesCare,36:498-504,2013)。也有少数报道第二位保持天然丝氨酸(Ser)的交联脂肪酸的Glucagon类似物(Diabetes Obes Metab，18(12):1176-1190，2016)。该类似物(MEDI0382)包括30个氨基酸，与天然Glucagon相比，突变了9个氨基酸。同时，虽然MEDI0382的第二位也保留了天然的Ser氨基酸，但是仅能支持一天一次的给药频率。为了减少给药频率，目前较常用的技术手段PEG交联或脂肪酸交联，例如索马鲁肽(Semaglutide)等，但其涉及化学合成及交联步骤，因此制备工序比较复杂。
FGF21作为一种重要的代谢调节剂已经在II型糖尿病临床前模型(T2DM)实验中被证明能够改善多种代谢异常。FGF21作为糖尿病患者的治疗药物在提高胰岛素敏感性，改善血糖控制，减轻体重，降低低密度脂蛋白胆固醇(LDL-C)和甘油三酯，同时增加高密度脂蛋白胆固醇水平(HDL-C)这些方面有潜在作用。在糖尿病鼠和猴子中，人FGF21能够降低空腹血清葡萄糖浓度，减少空腹血清甘油三酯，胰岛素和胰高血糖素的浓度。此外，在饮食诱导肥胖的啮齿动物模型中，FGF21给药导致剂量依赖的总体重减轻。因此，FGF21具有治疗糖尿病，肥胖，血脂异常和代谢综合征等疾病的潜力。
但是，FGF21具有非常短的血清半衰期：小鼠体内30分钟，猴子2小时。因此，为了维持体内生物活性需要每日注射或连续输注相应FGF21蛋白质。在人体研究中，在肥胖、血脂异常、TDM2及其他与胰岛素抵抗相关疾病的患者体内，循环FGF21水平往往升高，有研究表明FGF21浓度增加与CVD风险增加有关联，还会导致骨质疏松，影响生殖(促进新陈代谢进而导致能量不足)等(Proc Natl Acad Sci USA，109(8):3143–8，2012；Mol Metab，5(8):690-8，2016)。FGF家族序列的同源性以及FGFR1受体的广泛分布，也对临床大剂量使用FGF21所带来的潜在安全性问题带来关注(J Intern Med，281(3):233-246，2017)。
GCGR/GLP-1R双效激动剂、GLP-1R/GIPR双效激动剂、GLP-1R/GCGR/GIPR三效激动剂及FGF21类似物都分别用于治疗糖尿病及减重，另外还有将GLP-1类似物与FGF21通过Fc融合制备成双效活性蛋白的报道(The American Diabetes Association，2016)。如上所述，目前基于Glucagon或胃泌酸调节素改造而成的双效甚至三效多肽普遍需要将部分氨基酸取代非天然氨基酸来提高稳定性和活性，甚至还需要通过脂肪酸或PEG修饰，技术上极难与FGF21类似物融合表达制备成单一分子。目前也并无关于双效或者多效激动剂类多肽与FGF21类似物组合用药的报道。
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治疗代谢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，本发明提供一方面提供一种治疗代谢疾病的融合蛋白，包括Glucagon类似物片段和长效蛋白单元片段，所述Glucagon类似物片段包括：
a)氨基酸序列如SEQ ID No.81所示的多肽片段：
X1SX3GTFTSDYSKYLDX16X17X18AQDFVQWLX27X28X29Xz(SEQ ID No.81)
X1选自H或Y；X3选自Q或E；X16选自除Y、N、W、和H以外的任一氨基酸；X17选自除P、L、T、F和H以外的任一氨基酸；X18选自除P、F、H和W以外的任一氨基酸；X17与X18不同时为R；X27选自M或L；X28选自D或A；X29为T或缺失；Xz选自GGPSSGAPPPS或GPSSGAPPPS；
或，b)氨基酸序列与SEQ ID NO.81具有90％以上序列同一性且具有a)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a)中的多肽片段选自氨基酸序列如SEQ IDNO.29、SEQ ID NO.32、SEQ ID NO.33、SEQ ID NO.35、SEQ ID NO.38、SEQ ID NO.42、SEQ IDNO.43、SEQ ID NO.44其中之一所示的多肽片段。
在本发明一些实施方式中，所述长效蛋白单元片段源自哺乳动物免疫球蛋白的FC部分。
在本发明一些实施方式中，所述长效蛋白单元片段包括：
c)氨基酸序列如SEQ ID NO.4～13其中之一所示的多肽片段；
或，d)氨基酸序列与SEQ ID NO.4～13其中之一具有90％以上序列同一性且具有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，所述融合蛋白还包括第一连接肽片段，所述第一连接肽片段位于Glucagon类似物片段和长效蛋白单元片段之间，优选的，所述第一连接肽片段富含G、S和/或A。
在本发明一些实施方式中，所述第一连接肽片段包括氨基酸序列如SEQ ID NO.14～23其中之一所示的多肽片段。
在本发明一些实施方式中，所述融合蛋白自N端至C端依次包括Glucagon类似物片段、第一连接肽片段和长效蛋白单元片段。
在本发明一些实施方式中，所述融合蛋白的氨基酸序列SEQ ID NO.56、SEQ IDNO.59、SEQ ID NO.60、SEQ ID NO.62、SEQ ID NO.65、SEQ ID NO.69、SEQ ID NO.70、SEQ IDNO.71其中之一所示。
在本发明一些实施方式中，所述融合蛋白还包括FGF21类似物片段。
在本发明一些实施方式中，所述FGF21类似物片段包括：
e)氨基酸序列如SEQ ID NO.119所示的多肽片段：
HPIPDSSPLLQFGGQVRQX 19YLYTDDAQQTEX 31HLEIX 36EDGTVGX 43AX 45DQSPESLL QLX 56ALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFREX 98LLEDGYNVYQSEAH GLPLHX 118PGNX 122SPHRDPAPRGPX 134RFLPLPGLPPALPEPPGILAPQPPDVGSSDPLX 167MV X 170 X 171SQX 174RSPSX 179 X 180b181；
N端HPIPDSS可缺失或部分缺失；X19选自R、Y、V、E或C；X31选自A或C；X36选自R或K；X43选自G或C；X45选自A、K、E或V；X56选自K、R、V或I；X98选自L、R或D；X118选自L或C；X122选自K或R；X134选自A或C；X167选自S、A或R；X170选自G或E；X171选自P或G；X174选自G、A或L；X179选自Y、A或F；X180选自A或E；X181选自S、K或缺失；
或，f)氨基酸序列与SEQ ID NO.119具有80％以上序列同一性且具有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e)中的多肽片段选自氨基酸序列如SEQ ID NO.87～90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第二连接肽片段，所述第二接肽片段位于长效蛋白单元片段和FGF21类似物片段之间，优选的，所述第二连接肽片段富含G、S和/或A。
在本发明一些实施方式中，所述第二连接肽片段包括氨基酸序列如SEQ ID NO.14～23其中之一所示的多肽片段。
在本发明一些实施方式中，所述融合蛋白自N端至C端依次包括Glucagon类似物片段、第一连接肽片段、长效蛋白单元片段和FGF21类似物片段；
或，所述融合蛋白自N端至C端依次包括Glucagon类似物片段、第一连接肽片段、长效蛋白单元片段、第二连接肽片段和FGF21类似物片段。
在本发明一些实施方式中，所述融合蛋白的氨基酸序列如SEQ ID NO.91～115其中之一所示。
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如权利要求17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。
本发明另一方面提供所述药物选自用于治疗代谢相关疾病的药物。
附图说明
图1A显示为血清稳定性随时间变化的结果示意图。
图1B显示为血清稳定性随时间变化的结果示意图。
图2A显示为实施例6中的融合蛋白在db/db小鼠的降糖效果示意图。
图2B显示为实施例6中的融合蛋白在db/db小鼠的降糖效果示意图。
图3显示为实施例7中的融合蛋白对DIO小鼠体重的影响作用示意图。
具体实施方式
本发明发明人经过大量探索研究，意外发现将GCG类似物与Fc融合以后，对GLP-1R与GCGR的活性影响完全是不一样的，从而提供了一种新的融合蛋白，所述融合蛋白具有良好的稳定性，且对于小鼠有良好的降糖和减重效果，从而具有良好的产业化前景，在此基础上完成了本发明。
本发明中，术语“糖尿病”通常包括一型糖尿病、二型糖尿病、妊娠糖尿病以及引起高血糖症的其他症状。该术语用于代谢紊乱，其中胰腺产生不了足够的胰岛素或身体的细胞未能适当响应胰岛素，因此组织细胞吸收葡萄糖效率下降导致葡萄糖在血液中积累。一型糖尿病也称为胰岛素依赖性糖尿病和幼年发病型糖尿病，通过β细胞破坏引起，通常导致绝对胰岛素缺乏。二型糖尿病也称为非胰岛素依赖性糖尿病和成年发病型糖尿病，普遍与胰岛素抗性相关。
本发明中，术语“肥胖”通常指脂肪组织的过量，当能量摄取超过能量消耗时，过量卡里路贮存于脂肪中，则导致肥胖。在本文中，肥胖最佳地被视为任何程度的危害健康的过量脂肪组织的形成。在本文中体重指数(BMI＝体重(千克)除以身高(米)的平方)超过25的个体视为肥胖。
本发明中，“肠降血糖素”(Incretin)通常是通过增强葡萄糖刺激的胰岛素分泌(亦称为葡萄糖依赖的胰岛素分泌，GSIS)来调控血糖的胃肠激素(Lancet，368:1696-705，2006)。肠降血糖素还可通过延缓胃排空的方式减慢营养吸收的速度并直接地减少食物吸收。同时，肠降血糖素还抑制肠道α细胞分泌胰高血糖素(Glucagon)。迄今为止有两种已知的肠降血糖素：胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素多肽(GIP)。
本发明中，“GIP”通常是由133个氨基酸的前体(pre-pro-GIP)通过蛋白水解加工得到的42个氨基酸的肽，这些分子参与多种生物功能，包括葡萄糖体内平衡、胰岛素分泌、胃排空和肠生长以及食物摄取调节。
本发明中，“胰高血糖素样肽”(GLP-1)：是从肠L-细胞分泌的30或31个氨基酸的多肽肠促胰岛素激素，有GLP-1(7-36)和GLP-1(7-37)两种活性形式。GLP-1在进餐后释放到循环中，并通过激活GLP-1受体发挥生物活性。GLP-1具有许多生物学作用，包括葡萄糖依赖性的促胰岛素分泌、抑制胰高血糖素生成、延缓胃排空和抑制食欲(Trends Pharmacol Sci，32(1):8-15，2011)等。天然GLP-1由于能够被二肽基肽酶-4(DPP-IV)、中性肽链内切酶(NEP)、血浆激肽释放酶或纤溶酶等快速降解因而限制了其治疗潜力。由于天然GLP-1在体内仅有大约2分钟的超短半衰期，因此，出现了通过利用化学修饰和/或制剂形式来改善功效以治疗糖尿病和肥胖症的方法(Bioorg Med Chem Lett，23(14)：4011-8，2013；ExpertOpin Investig Drugs，25(2):145-58，2016)。
本发明中，“胰高血糖素”(Glucagon)通常是29个氨基酸的肽，其对应于前胰高血糖素原的53-81位氨基酸，序列如SEQ ID NO：24所示(Nutrition,Metabolism&Cardiovascular Diseases，16：S28-S34，2006)。胰高血糖素受体活化已显示在啮齿类动物和人两者中增加能量消耗且减少食物摄入(Nat.Rev.Endocrinol,6：689-697，2010)并且这些效应在啮齿类动物中是稳定和持续的。胰高血糖素具有许多生理效应，例如通过刺激糖原分解和糖异生，增加低血糖状况下的血糖水平，调节肝酮生成，调节胆汁酸代谢和通过迷走神经的饱腹效应。在治疗上，胰高血糖素已经用于急性低血糖症，胰高血糖素受体激活减少食物摄取并促进动物和人的脂肪分解和体重减轻。
本发明中，术语“受体激动剂”通常可以为与受体结合且引发天然配体的通常应答的多肽、蛋白或其他小分子。
本发明中，“GLP-1受体(GLP-1R)激动剂”通常可以为与GLP-1R结合且能够引发与天然GLP-1相同或类似的特征性反应的多肽、蛋白或其他小分子。GLP-1R激动剂通过完全或部分激活GLP-1R，继而引起一系列细胞内的下游信号通路反应，产生相应的细胞活性：如β细胞分泌胰岛素；典型的GLP-1R激动剂包括天然GLP-1及其突变体、类似物，如艾塞那肽、利拉鲁肽(Liraglutide)等。
本发明中，“GLP-1类似物”或“GLP-1突变体”皆意为GLP-1R激动剂，可互相通用。
本发明中，“胰高血糖素受体(GCGR)激动剂”即Glucagon受体激动剂，通常可以为与GCGR结合且能够引发与天然胰高血糖素(Glucagon)相同或类似特征性反应的多肽、蛋白或其他小分子。GCGR激动剂通过完全或部分激活GCGR，继而引起一系列细胞内的下游信号通路反应，产生相应的细胞活性：如肝细胞糖原分解、糖质新生、脂肪酸氧化及生酮作用等。
本发明中，“Glucagon类似物”、“GCG类似物”、“Glucagon突变体”和“GCG突变体”皆意为Glucagon受体激动剂，可互相通用。
本发明中，“FGF21”通常指成纤维细胞生长因子(fibroblast growth factor，FGF)，又叫肝素结合生长因子(heparin binding growth factor)，是主要由垂体和下丘脑分泌的一类多肽物质。FGF具有多种功效，如促进成纤维细胞有丝分裂、中胚层细胞的生长，刺激血管形成等。而FGF21是FGF家族中的重要一员，目前该激素被当作药物开发成减肥药以及治疗糖尿病药物，并且该药物已经进入了临床试验阶段。FGF21通过FGF21相关受体(如FGFR1c)及其共受体β-klotho(KLB)发挥生理作用。
本发明中，“二聚体”通常通过免疫球蛋白的恒定区(FC)天然的非共价及共价作用而形成。如果没有其他特别指出，FC形成的二聚体皆为同二聚体，如本发明提供的二聚体所述。
本发明中，“EC50”(concentration for 50％of maximal effect)通常是指某一药物或者物质在刺激其相应的生物学反应的50％时所需的浓度。EC50值越低，表明该药物或物质的刺激或激动能力越强，例如，更直观地可表现为引起的细胞内信号越强，从而诱导某激素产生的能力越佳。
本发明中，“低密度脂蛋白”(LDL)通常属于血浆脂蛋白的一种，是血液中胆固醇的主要载体,其倾向于将胆固醇沉积在动脉壁上。白细胞试图消化低密度脂蛋白，但在这个过程却将它们变成毒素。越来越多的白细胞被吸引到发生变化的区域，致使动脉壁可能发炎。随着时间的推移，随着该过程继续，这些斑块沉积物可以积聚在动脉壁上，使得通道变得非常窄和缺乏韧性。如果太多的斑块累积，则动脉可以完全阻塞。当LDL与胆固醇形成的复合物(LDL-C)在动脉壁上产生太多斑块时，血液将不能自由流过动脉。斑块随时可能会在动脉中突然塌陷，导致血管堵塞，最终引发心脏病。
本发明中，“高密度蛋白”(HDL)通常有助于清除动脉上的LDL，起到清道夫的作用，将LDL从动脉上清走并回到肝脏。
本发明中，“甘油三酯(TG)”通常是另一种类型的脂肪，用于储存饮食过多的能量。血液中高水平的甘油三酯与动脉粥样硬化有关。高甘油三酯可以由超重和肥胖、身体缺乏运动、吸烟、过量的酒精消耗和高碳水化合物(超过总卡路里的60％)摄入引起。有时基础疾病或遗传疾病是高甘油三酯的原因。具有高甘油三酯的人通常具有高的总胆固醇水平，包括高LDL胆固醇和低HDL胆固醇，许多患有心脏病或糖尿病的人也具有高甘油三酯水平。
本发明第一方面提供一种融合蛋白，包括Glucagon类似物片段和长效蛋白单元片段，所述Glucagon类似物片段包括：
a)氨基酸序列如SEQ ID No.81所示的多肽片段；
X1SX3GTFTSDYSKYLDX16X17X18AQDFVQWLX27X28X29Xz(SEQ ID No.81)
X1选自H或Y；X3选自Q或E；X16选自除Y、N、W、和H以外的任一氨基酸；X17选自除P、L、T、F和H以外的任一氨基酸；X18选自除P、F、H和W以外的任一氨基酸；X17与X18不同时为R；X27选自M或L；X28选自D或A；X29为T或缺失；Xz选自GGPSSGAPPPS(SEQ ID NO.2)或GPSSGAPPPS(SEQID NO.3)；
或，b)氨基酸序列与SEQ ID NO.81具有90％以上序列同一性且具有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 ID No.81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.81所示的多肽片段的功能的多肽片段，例如，可以同时具有GCGR/GLP-1R双重激动活性、GLP-1R/GIPR双重激动活性或GLP-1R/GCGR/GIPR三重激动活性，并且可以能抵御体内蛋白酶水解。所述b)中的氨基酸序列可与SEQ ID No.81具有90％、93％、95％、97％、或99％以上的一致性(Sequence identity)。在本发明一具体实施例中，所述a)中的片段可以是氨基酸序列如SEQ ID NO.29、SEQ ID NO.32、SEQ ID NO.33、SEQ IDNO.35、SEQ ID NO.38、SEQ ID NO.42、SEQ ID NO.43、SEQ ID NO.44其中之一所示的多肽片段。本发明人发现，本发明筛选获得的GCG类似物即使保留了天然第二位的Ser，在与FC融合后，稳定性也足以支持一周一次的给药频率，降低了免疫原性的潜在风险。而在16、17和18位上的改造，除了减弱内肽酶对GCG类似物的降解外，也能较好地保持GCGR激动活性。
本发明所提供的融合蛋白中，所述长效蛋白单元片段可以源自哺乳动物免疫球蛋白的FC部分，所述免疫球蛋白是含有二硫键的多肽链分子，一般具有两条轻链和两条重链。此处用到的免疫球蛋白的FC部分具有免疫学领域术语的常用含义。具体的，该术语是指通过从抗体中去除两个抗原结合区(Fab片段)而得到的抗体片段。FC部分可以包括铰链区并且延伸通过CH2和CH3结构域到达抗体C末端。FC部分可以进一步包括一个或多个糖基化位点。人体有5种具有不同效应特征和药代动力学特性的人免疫球蛋白：IgG、IgA、IgM、IgD和IgE。IgG是血清中含量最高的免疫球蛋白。IgG在所有的免疫球蛋白中也是血清半衰期最长的(约23天)。进一步地，所述长效蛋白单元片段可选自免疫球蛋白的完整FC部分、免疫球蛋白的FC部分的片段或免疫球蛋白的FC部分的突变体。用于本发明的免疫球蛋白FC部分可以来源于哺乳动物IgG1、IgG2或IgG4的FC区或其突变体；优选的，可以是来源自人的IgG1、IgG2或IgG4的FC区或其突变体；更优选的，可以来源自人IgG1或IgG4的FC区或其突变体。在一个优选的实施方案中，FC结构域的第297位被甘氨酸或丙氨酸替换。上述内容是依照kabat的EU索引编号(Sequences of proteins of immunological interest，第五版，public health service,National Institutes of Health,Bethesda,MD(1991))。
本发明所提供的融合蛋白中，所述长效蛋白单元片段可以包括：c)氨基酸序列如SEQ ID NO.4～13其中之一所示的多肽片段；或，d)氨基酸序列与SEQ ID NO.4～13其中之一具有90％以上序列同一性且具有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.4～13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SEQID No.4～13其中之一所示的多肽片段的功能的多肽片段，例如，可以提高融合蛋白整体上的DPP-IV抵抗力。所述d)中的氨基酸序列可与SEQ ID No.4～13其中之一具有90％、93％、95％、97％、或99％以上的相似性。在本发明一优选实施例中，FC结构域可以来自人IgG1，并如SEQ ID NO.12、SEQ ID NO.13所示。在本发明另一优选实施例中，所述FC结构域来自人IgG4，如SEQ ID NO.9所示。所述FC链末端的K可去除便于提高表达产物的均一性，如SEQ IDNO.5、SEQ ID NO.9。本发明提供的优选GCG类似物与FC融合后，获得了极高的DPP-IV抵抗能力，目前并无现有技术揭示可通过融合FC来增加GCG类似物的DPP-IV酶抵抗能力，而且药效学实验表明稳定性能支持一周一次的给药频率。通过融合的方式，达到这种效果，是目前未有所见的。保留第二位的Ser，一方面降低了免疫原性风险，另一方面则是最大程度地保留了GCGR的激动活性，能有效地达到减重效果。
本发明所提供的融合蛋白中，还可以包括第一连接肽片段，所述第一连接肽片段通常位于Glucagon类似物片段和长效蛋白单元片段之间。所述第一连接肽片段通常可以是富含G、S和/或A的片段，例如，所述第一连接肽片段可以由甘氨酸G、丝氨酸S和丙氨酸A组成，本领域技术人员可选取合适的G、S和A的含量比例，优选的为12：3：1，或12：1：3，或12：1：2；或12：2：1等，而且S或A可以缺失，如可使G与A比例为4：1或使G与S比例为4：1。在本发明一具体实施例中，所述第一连接肽片段包括氨基酸序列如SEQ ID NO.14～23其中之一所示的多肽片段。
本发明所提供的融合蛋白中，所述融合蛋白自N端至C端可以依次包括Glucagon类似物片段、第一连接肽片段和长效蛋白单元片段。在本发明一具体实施例中，所述融合蛋白的氨基酸序列如SEQ ID NO.56、SEQ ID NO.59、SEQ ID NO.60、SEQ ID NO.62、SEQ IDNO.65、SEQ ID NO.69、SEQ ID NO.70、SEQ ID NO.71其中之一所示。
本发明所提供的融合蛋白中，所述融合蛋白还包括FGF21类似物片段，所述FGF21类似物片段可以包括：
e)氨基酸序列如SEQ ID NO.119所示的多肽片段：
HPIPDSSPLLQFGGQVRQX 19YLYTDDAQQTEX 31HLEIX 36EDGTVGX 43AX 45DQSPESLL QLX 56ALKPGVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFREX 98LLEDGYNVYQSEAH GLPLHX 118PGNX 122SPHRDPAPRGPX 134RFLPLPGLPPALPEPPGILAPQPPDVGSSDPLX 167MV X 170 X 171SQX 174RSPSX 179 X 180 X 181；
N端HPIPDSS可缺失或部分缺失；X19选自R、Y、V、E或C；X31选自A或C；X36选自R或K；X43选自G或C；X45选自A、K、E或V；X56选自K、R、V或I；X98选自L、R或D；X118选自L或C；X122选自K或R；X134选自A或C；X167选自S、A或R；X170选自G或E；X171选自P或G；X174选自G、A或L；X179选自Y、A或F；X180选自A或E；X181选自S、K或缺失；或，f)氨基酸序列与SEQ ID NO.119具有90％以上序列同一性且具有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.119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.119所示的多肽片段的功能的多肽片段，例如，可以是与天然FGF21(SEQ ID NO.87)具有相同或相似生物学功能。所述f)中的氨基酸序列可与SEQ ID No.119具有80％、85％、90％、93％、95％、97％、或99％以上的序列一致性。所述FGF21类似物片段的氨基酸序列可选自如US20140213512、US8188040、US9493530、WO 2016114633、US 20150291677、US 9422353、US 8541369、US7622445、US7576190、US20070142278、US 9006400或US 20130252884等专利或专利申请中所描述的FGF21类似物或突变体的氨基酸序列。在本发明一具体实施例中，所述e)中的多肽片段选自氨基酸序列如SEQ ID NO.87～90其中之一所示的多肽片段。
本发明所提供的融合蛋白中，还可以包括第二连接肽片段，所述第二连接肽片段通常位于长效蛋白单元片段和FGF21类似物片段之间。所述第二连接肽片段通常可以是富含G、S和/或A的片段，例如，所述第二连接肽片段可以由甘氨酸G、丝氨酸S和丙氨酸A组成，本领域技术人员可选取合适的G、S和A的含量比例，优选的为12：3：1，或12：1：3，或12：1：2；或12：2：1等，而且S或A可以缺失，如可使G与A比例为4：1或使G与S比例为4：1。在本发明一具体实施例中，所述第二连接肽片段包括氨基酸序列如SEQ ID NO.14～23其中之一所示的多肽片段。
本发明所提供的融合蛋白中，所述融合蛋白自N端至C端可以依次包括Glucagon类似物片段、第一连接肽片段、长效蛋白单元片段和FGF21类似物片段，也可以依次包括Glucagon类似物片段、第一连接肽片段、长效蛋白单元片段、第二连接肽片段和FGF21类似物片段。在本发明一具体实施例中，所述融合蛋白的氨基酸序列如SEQ ID NO.91～115其中之一所示。在本发明的一个动物体内药效实施例中，式II所述的融合蛋白组(A352L1F6L5M2)与相同剂量的式I所述的融合蛋白(A352L1F6)+FGF21类似物(F6L5M2)联合给药组相比具有更显著的减重效果。证明该融合蛋白A352L1F6L5M2的副作用可能更低，安全性提高(实施例7)。
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表达载体中构建获得，本领域技术人员可选择合适的表达载体，例如，所述表达载体可以是包括但不限于pcDNA3.1、pBudCE4.1、pEE14.1、pPIC9等。
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。所述表达系统可以是宿主细胞，所述宿主细胞可以表达如上所述的融合蛋白，所述宿主细胞可以是真核细胞和/或原核细胞，更具体可以是哺乳动物细胞、大肠杆菌、酵母等，更具体可以是HEK293、CHO等。
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，可以采用固相合成法，再例如，所述融合蛋白的制备方法可以包括：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，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(Mack Pub.Co.，N.J.，1991)中可找到关于药学上可接受的载体的充分讨论。
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代谢相关疾病的药物。代谢相关疾病可以是代谢综合征，代谢综合征的特征通常可以包括以下风险因素(例如，可以是三种以上)：(1)腹部肥胖(腹部内或周围脂肪组织过多)，(2)致动脉粥样硬化血脂异常，血脂失调，包括高甘油三酯、低HDL胆固醇及高LDL胆固醇，其增强动脉壁中斑块的积累，(3)血压升高，(4)胰岛素抗性或葡萄糖耐受不良，(5)血栓样状态，例如血液中高纤维蛋白或纤溶酶原活化因子抑制剂-1，以及(6)促发炎状态，例如血液中C反应性蛋白升高。其他风险因素可包括老化、激素失衡及遗传因素。在本发明一具体实例中，本发明所提供的融合蛋白对于小鼠有良好的降糖和减重效果，从而被证实可以可用于治疗肥胖症或糖尿病，例如，本发明的融合蛋白通常可以通过降低食欲、减少食物摄取、降低患者体内脂肪水平、提高能量消耗等机制来进行治疗。
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。
本文中，序列同一性(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同一性，这些软件可获自如NCBI。
众所周知，肠降血糖素(Incretin)类激素蛋白如GLP-1类似物、Exendin-4等会让患者产生恶心、呕吐等副作用，而且是剂量相关的。因此在能维持理想的血糖水平的情况下，尽量减少给药剂量理论上会缓解患者的不适副作用。另外，FGF21对于骨质疏松及生殖影响方面的报道也时有报道(Scand J Clin Lab Invest，75(2):121-5，2015；Mol Metab，5(8):690-8，2016)。理论上，药物副作用产生的风险与给药剂量成正比，在糖尿病药物领域，对药物的安全性极高。发明人发现本发明所述融合蛋白在很低剂量下就有很好的控制血糖和体重的效果，并且对胃肠道影响小，大大地减少了给药剂量，因而显著降低起潜在副作用风险。
在本发明所提供的融合蛋白的细胞生物学活性实验中，GLP-1R和GCGR激动活性体外细胞活性测定都采用荧光素酶报告基因检测法。此法基于GLP-1R和GCGR激动后能激活下游cAMP途径的原理。FGF21及其类似物的活性测定则是通过将FGF21信号通路相关基因共转染至HEK293T细胞，检测信号引起的荧光变化而获得。Joseph R.Chabenne等和RichardD.DiMarchi等曾报道，在Glucagon的C末端增加一段Exendin-4的C末端小肽cex(SEQ IDNO.3)后，使得其GLP-1R激动活性从0.7％增至1.6％，提高了约2倍左右(J Diabetes SciTechnol.4(6):1322–1331，2010及专利US9018164B2)，但是GCGR激动活性与GLP-1R激动活性的比例仅达到35：1左右。另外，Evers A等报道(J Med Chem.；60(10):4293-4303，2017)在GCG类似物的C末端加上cex序列后，GLP-1R激动活性反而下降了3倍左右，GCGR激动活性下降了14倍左右(文章中表2，肽7和8)。就是说，仅简单在天然Glucagon的C末端增加Exendin-4的C末端肽cex序列GPSSGAPPPS(SEQ ID NO.3)并不会显著提高甚至会进一步减弱其GLP-1R的激动活性。另一方面，Glucagon、GLP-1这类小肽与Fc，白蛋白这类载体融合蛋白进行融合表达的时候，由于空间位阻效应，活性往往是显著下降的(J.Pept.Sci.，14:588–595，2008)，并且这种活性变化是不可预测的。
本发明人意外地发现，将不同序列的GCG类似物与Fc融合以后，对GLP-1R与GCGR的活性影响完全是不一样的。GCG类似物的C末端额外加入cex或类似序列(SEQ ID NO.2-3)再进一步融合至FC链时，与GCG类似物直接与FC链融合相比，含有cex序列的结构其GLP-1R激动活性保留率明显提高，最高提高了200倍以上(实施例表2)，但是GCGR激动活性保留率却是基本不变，甚至略有下降的。
对于蛋白的稳定性而言，天然Glucagon有多处敏感的降解位点，包括第二位的DPP-IV降解位点，以及16-18位的SRR位点。尽管有报道认为Fc能提高活性蛋白的化学稳定性及血清稳定性，然而对于N端必须暴露的GLP-1或Glucagon类似物，Fc的作用似乎是无法一概而论的。天然的GLP-1或Glucagon与Fc融合后，仍能观察到其在37℃血清条件下的明显降解。本发明在天然Glucagon的基础上引入抵抗16-18位蛋白酶水解的突变，以增加其稳定性；在27、28位上的改造，防止氨基酸的脱酰胺和氧化的发生。这些突变体与Fc融合后，稳定性进一步获得提高。在本发明所提供的融合蛋白的稳定性实验中，在72小时仍然能检测到60％左右的GCGR激动活性。而此时含cex序列的天然Glucagon与Fc融合形成的二聚体(SEQID NO.52)已几乎检测不到任何的活性。
目前几乎所有基于Oxyntomodulin和Glucagon设计开发的GCGR、GLP-1R、GIPR多效激动剂都在第二位上引入抵抗DPP-IV的突变，如L型突变为D型氨基酸(L-Ser突变为D-Ser)，或引入非天然氨基酸Aib等(Cell Metabolism，24:51–62,2016)。然而，在本发明的实施例中，第二位保存天然L-Ser的二聚体融合蛋白呈现出非常高的血清稳定性，在24小时仍并没有显著的DPP-IV降解的迹象，而没有融合FC的对应多肽则快速地被DPP-IV水解(表3)。本发明人制备了天然Glucagon与FC融合的活性蛋白A001L1F6(SEQ ID NO.51)以及JosephR.Chabenne等报道的Glucagon-cex与FC融合的活性蛋白A012L1F6(SEQ ID NO.52)作为对照验证是否FC融合提高了稳定性。然而，A001L1F6(SEQ ID NO.51)和A012L1F6(SEQ IDNO.52)均无呈现出明显的抵抗DPP-IV的迹象(实施例4)。同时，实施例4中还可见，虽然同样是16-18位突变的GCG类似物的FC融合蛋白，但稳定性差异却极大。蛋白的空间构象极其复杂，因此符合SEQ ID NO.81的突变不但提高了肽链内部的稳定性，更有可能是改变了GCG类似物与FC链间的相互作用构象，进一步地提高了融合蛋白N端的稳定性。虽然有报道指出结合在血清白蛋白(如HSA)上可能会有助于提高蛋白的稳定性(如利拉鲁肽)，然而如果第二位不进行突变，根本无法使半衰期持续12小时以上，即不可能支持一周一次的给药频率。而本发明提供的GCG类似物药代及药效试验显示足以支持一周一次的给药频率，而非普遍报道的一天一次(如结合白蛋白的利拉鲁肽)。天然氨基酸的保留进一步减低免疫原性的风险，避免了化学交联还使制备过程更简易方便。
本发明还进行了瘦素受体缺陷二型糖尿病(db/db)小鼠的随机血糖实验，在其中一个实施例中，进行了db/db随机血糖实验，施用了本发明的融合蛋白的小鼠呈现出比利拉鲁肽显著的降糖效果，同时还有更好的减重效果。
本发明还进行了DIO小鼠的减重实验，GCGR激动剂具有潜在的减重效果已有多篇报道。然而天然Glucagon由于易被降解且分子量小，因此成药的潜力不高。目前Glucagon类似物主要用于急性的低血糖症状。长效GCG类似物用于糖尿病患者减重的临床报道也不断涌现。众所周知，肥胖是导致糖尿病患者胰岛素抵抗的原因之一，而体重减轻量是评价一个降糖药物的重要指标。此外，本发明的融合蛋白在DIO小鼠施用后，导致了体重的显著降低。
本发明的融合蛋白具有潜在的适合每周或以上施用一次的药物代谢动力学特性。剂量取决于施用频率和模式，受治疗的受试者的年龄、性别、重量和一般状况，治疗的状况和严重性，待治疗的任何伴随性疾病以及对于本领域技术人员显而易见的其他因素。同时，根据受治疗者的情况和其他病理状况，本发明的融合蛋白可以与一种或多种其他的治疗活性化合物或物质组合施用或应用，例如可以选择的其他的治疗活性化合物包括但不限于抗糖尿病药、抗高血脂药、抗肥胖药，抗高血压药和用于治疗起因于糖尿病或与糖尿病有关的并发症的试剂。
代谢相关疾病(例如，代谢综合征)与冠心病和血管斑块积累相关的其他病症风险增加相关，例如中风和外周血管疾病，成为粥样动脉硬化心血管病(ASCVD)。患有代谢综合征的患者可自处于早期的胰岛素抗性状态发展成完全成熟的二型糖尿病，并且ASCVD的风险进一步增加。不旨在受限于任何特定理论，胰岛素抗性、代谢综合征及血管疾病之间的关系可以涉及一种或多种共同发病机制，包括胰岛素刺激的血管舒张障碍、由氧化应力增强所致的胰岛素抗性相关性可用性降低，以及脂肪细胞衍生激素(诸如脂联素)异常(Lteif,Mather,Can.J.Cardiol.20(增刊B)：66B-76B，2004)
本发明的融合蛋白还可用于治疗肥胖症。在一些方面中，本发明的融合蛋白通过降低食欲、减少食物摄取、降低患者体内脂肪水平、提高能量消耗等机制来治疗肥胖症。
在一些潜在的实施方案中，本发明的融合蛋白可用于治疗非酒精性脂肪肝病(NAFLD)。NAFLD是指广谱肝脏疾病，范围自单纯脂肪肝(脂肪变性)至非酒精性脂肪变性肝炎(NASH)至肝硬化(肝脏的不可逆晚期瘢痕形成)。NAFLD的所有病期均具有在肝脏细胞中的脂肪累积。单纯脂肪肝为某类型的脂肪、甘油三酯在肝脏细胞中异常积累，但无发炎或瘢痕形成。在NASH中，脂肪累积与不同程度的肝脏发炎(肝炎)和瘢痕形成(纤维化)相关。发炎性细胞可破坏肝脏细胞(肝细胞坏死)。在术语“脂肪变性肝炎”和“脂肪变性坏死”中，脂肪变性是指脂肪浸润，肝炎是指肝脏中的炎症，并且坏死是指经破坏的肝脏细胞。NASH可最终导致肝脏瘢痕形成(纤维化)且接着导致不可逆晚期瘢痕形成(肝硬化)，由NASH导致的肝硬化为NAFLD谱内的最后且最严重的病期。
综上所述，本发明所提供的融合蛋白具有半衰期长的优势，通常可以被认为能够支持一周一次或更长的给药频率，另外，所述融合蛋白具有显著的降糖和减重效果，且体内外稳定性好、免疫原性低。另外，所述融合蛋白由于不需要引入非天然氨基酸，无需涉及化学合成及交联步骤，因此可通过重组方法制备，极大地简化了制备工序。
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
式I所示融合蛋白的制备：
本实施例中所制备的融合蛋白通过式I表达，具体结构为：A-L-F(式I)，优选的由GCG类似物片段(对应式I中的A)、连接肽片段(对应式I中的L)及Fc(对应式I中的F)融合而获得的二聚体融合蛋白的氨基酸序列如下文的表1所示。
在知晓了二聚体融合蛋白的氨基酸序列的基础上，本领域技术人员能够采用现有技术对其进行制备：由于带有FC序列，因此可通过高亲和力和高特异性的Protein A树脂层析进行蛋白纯化，在这里仅示例性地给出一种可行的制备方法。
制备过程如下：
(1)根据蛋白序列及氨基酸密码子表，设计其DNA序列。分别制备重组蛋白中A、L、F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，拼接A、L、F分别对应的DNA片段，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 E.Z.N.A.
Figure BDA0002061691890000171
Endo-Free Plasmid Maxi Kit或类似方法提取质粒。
(3)转染HEK293F细胞及细胞表达：取1.0mg质粒，使用Freestyle 293表达培养基(Thermofisher)稀释至25ml；取3.0mg PEI(线性，25KD)，使用Freestyle 293表达培养基稀释至25ml，加入到质粒溶液中，混匀，室温孵育30分钟；与此同时，取对数期生长的HEK293F细胞(活率>95％)，计数；1100rpm，离心10分钟，弃上清；使用450ml Freestyle293表达培养基重悬细胞；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；7小时后，使用1000ml 293SFM II培养基(Thermofisher)置换Freestyle 293表达培养基，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)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。
(5)重组蛋白的理化性质鉴定：对纯化获得的重组蛋白进行HPLC分析，纯度大于95％以上。
实施例2
式I所示融合蛋白的体外细胞活性检测：
将实施例1中获得的融合蛋白进行体外活性测定，包括GLP-1R激动活性检测和GCGR激动活性检测。
GLP-1R激动活性检测：
GLP-1R激动活性检测采用荧光素酶报告基因检测法。将人源GLP-1R基因克隆至哺乳动物细胞表达质粒pCDNA3.1中，构建成重组表达质粒pCDNA3.1-GLP-1R，同时荧光素酶(luciferase)全长基因克隆至pCRE-EGFP质粒上，替换EGFP基因，得到pCRE-Luc重组质粒。pCDNA3.1-GLP-1R和pCRE-Luc质粒按摩尔比1:10的比例转染CHO细胞，筛选稳转表达株，获得重组CHO/GLP-1R稳转细胞株。
在9-cm细胞培养皿中用含10％FBS和300μg/ml G418的DMEM/F12培养基培养细胞，等汇合度至90％左右时，弃去培养上清，加入2ml胰酶消化3min后，加入2ml DMEM/F12培养基中和，转移至15ml离心管中，1000rpm离心5min后，弃去上清，加入2ml含10％FBS和300μg/ml G418的DMEM/F12培养基重悬，计数。用含10％FBS的DMEM/F12培养基稀释细胞至5×105细胞/ml，96孔板中每孔铺100μl，即5×104/孔，贴壁后换成含0.2％FBS的DMEM/F12培养基培养。铺在96孔板的细胞弃去上清后，将纯化的重组蛋白(表1和2)或天然Glucagon(杭州中肽生化有限公司，GLUC-004)与天然GLP-1(杭州中肽生化有限公司，GLUC-016B)作为对照，用含0.2％FBS的DMEM/F12培养基稀释至一系列指定浓度，加入到细胞培养孔中，100μl/孔，刺激6h后检测。根据荧光素酶报告检测试剂盒(Lucifersae reporter kit，Ray Biotech,Cat:68-LuciR-S200)说明书进行检测。
GCGR激动活性检测方法：
GCGR激动活性检测同样也采用荧光素酶报告基因检测法。将GCGR基因克隆至哺乳动物细胞表达质粒pCDNA3.1中，构建成重组表达质粒pCDNA3.1-GCGR，转染CHO细胞及稳转细胞株CHO/GCGR的构建同上。
结果如表1所示：
表1
Figure BDA0002061691890000191
表1中蛋白编号按照如下规则：GCG类似物多肽代号+连接肽代号+FC代号，如A382L1F6，表示GCG类似物多肽A382与代号为F6的IgG Fc通过代号为L1的连接肽融合获得。
此外，还对其他不带有Exendin-4C末端序列的二聚体融合蛋白：G232L1F6(SEQ IDNO.82)、G352L1F6(SEQ ID NO.83)、G382L1F6(SEQ ID NO.84)、G395L1F6(SEQ ID NO.85)、G402L1F6(SEQ ID NO.86)进行体外活性测定(制备和纯化方式同实施例1)，包括GLP-1R激动活性检测和GCGR激动活性检测。
测定结果与本发明的重组蛋白进行比较，结果如表2所示：
表2
Figure BDA0002061691890000201
说明：a.为加上Exendin-4的C末端延伸肽Cex(在本发明中为SEQ ID NO.2-3之任一)前后的GLP-1R激动活性比例。
b.为根据US9018164B2表2中披露的天然Glucagon与Glucagon Cex的GLP-1R激动活性数据计算获得的比例。
c.为根据Joseph R.Chabenne等(Joseph R.Chabenne等，J Diabetes SciTechnol.4(6):1322–1331，2010)文章中表1披露的天然Glucagon与Glucagon Cex的GLP-1R激动活性数据计算获得的比例。
如表2所示，当把本发明中含Exendin-4C末端序列的GCG类似物多肽通过连接肽与Fc融合制备成二聚体后，对GLP-1R的激动活性提高了200倍以上，而对GCGR的激动活性则无明显差异。相反，A001L1F6与A012L1F6的比例却只有21左右。
实施例3
式I所示融合蛋白的DPP-IV耐酶稳定性：
将纯化的融合蛋白溶解于10mM的HEPES缓冲液(含0.05mg/ml BSA)中，使其终浓度为5μM，加入终浓度为10nM的重组DPP-IV酶，于37℃温浴24小时后，检测体外GCGR细胞活性检测。活性保留率＝(DPP-IV酶处理后活性/处理前活性)×100％。
本实施例中采用了第二位引入非天然氨基酸Aib或D-Ser的GCG类似物作为对照：
GDSerGS：H-D-Ser-QGTFTSDYSKYLDSQAAQDFVQWLMNGGPSSGAPPPS(SEQ ID NO.79)；
GAibGS：H-Aib-QGTFTSDYSKYLDSQAAQDFVQWLMNGGPSSGAPPPS(SEQ ID NO.80)；
A123(SEQ ID NO.30)、A137(SEQ ID NO.32)、A175(SEQ ID NO.33)、A352(SEQ IDNO.42)、A382(SEQ ID NO.43)及A395(SEQ ID NO.44)作为本实施例中稳定性实验的对照。
结果如表3所示：
表3
Figure BDA0002061691890000211
Figure BDA0002061691890000221
实施例4
式I所示融合蛋白的血清稳定性试验：
体外细胞检测法：
(1)取融合蛋白，先超滤浓缩，再用20mM PB pH7.4稀释到1.6mg/ml，除菌过滤后，血清(FBS，GEMINI 900-108，A97E00G)稀释10倍，混匀，分装到无菌离心管中；
(2)另外取Glucagon(SEQ ID NO：24，杭州中肽生化有限公司，GLUC-004)，稀释到0.2mg/ml，除菌过滤后，血清稀释10倍，混匀，分装到无菌离心管中；
(3)上述样品1-2管于-20℃冻存作为对照，另几管置37℃培养箱，于不同时间点取样检测GCGR激动活性；
(4)CHO/GCGR细胞传代两次后铺96孔板，检测样品活性。相对活性随着时间的变化如图1A-B所示。从图1结果可见A073L1F6、A089L1F6、A123L1F6、A135L1F6、A137L1F6、A175L1F6、A187L1F6、A209L1F6、A232L1F6、A266L1F6、A271L1F6、A307L1F6、A352L1F6、A382L1F6、A395L1F6在血清中的稳定性相对其他融合蛋白明显较高。
残留活性：以0小时的活性值为100％，后续时间点测得的值与之相比而获得。
实施例5
式II所示融合蛋白的构建及活性测定：
本实施例中所制备的融合蛋白通过式II表达，具体结构为：A-L1-F-L2-B(式II)，其中，A为GCG类似物片段，F为长效蛋白单元片段，B为FGF21类似物片段，可以是天然FGF21(SEQ ID NO.87)或其衍生物，L1为连接肽片段，序列选自SEQ ID NO.14-23之任一；L2为连接肽片段，可以是不存在或选自SEQ ID NO.14-23之任一。制备成氨基酸如SEQ ID NO.91-115所示，对应的代号在表4中显示。
在知晓了A-L1-F-L2-B(式II)的氨基酸序列的基础上，本领域技术人员能够采用现有技术对其进行制备。由于带有FC序列，因此可通过高亲和力和高特异性的Protein A树脂层析进行蛋白纯化。具体方法可参照实施例1中的制备方法。对纯化获得的重组蛋白进行SDS-PAGE电泳或氨基酸序列验证，均与预期一致。天然FGF21、FGF21类似物的制备参考Xu J等的报道(Bioconjug Chem.；24(6):915-25，2013)并作如下修改：表达载体为PET30，宿主菌为BL21(DE3)(默克中国)。包涵体用洗涤液(50mM Tris,150mM NaCl,2M尿素，pH 8.0)洗涤四次，称重；按照(1:10的质量体积比)每0.1g包涵体加入1ml变性液(50mM Tris,150mMNaCl,8M urea,10mM DTT，pH 8.5)，室温摇床轻轻混合溶解5h以上；按照1:100-200的比例稀释复性。将变性液缓慢滴加到复性液中，过程中不断搅拌；滴加完成之后，将含有蛋白的复性液放于4℃、24h；结束后用0.45μm滤膜抽滤用于层析纯化。对照品F9L5W和F9L5M2具体方法可参照实施例1中的制备方法。
测活细胞的构建：
PCR扩增嘌呤霉素抗性基因pac，克隆到pcDNA3.1(+)，替换原有的G418抗性基因。PCR扩增GAL4DBD-ELK1、IRES、KLB(β-klotho)基因，依次克隆到pcDNA-Puro质粒上，构建质粒pcDNA-GAL4DBD-ELK1-IRES-KLB-Puro用于细胞转染筛选。构建好的重组质粒与pFR-Luc质粒(Agilent)采用Omega
Figure BDA0002061691890000232
Endo-Free Plasmid Midi Kit提取备用。细胞转染过程如下：HEK293T细胞铺6孔板，每孔3×105个细胞，培养过夜。
Opti-MEM培养基洗涤细胞两次后，加入2ml Opti-MEM培养基。按照如下比例配制细胞转染试剂：Lipofectamine 2000(6μl)：pFR-Luc(4.6μg)：
pcDNA-GAL4DBD-ELK1-IRES-KLB-Puro(1μg)。静置20min后，缓慢加入到6孔板中，边加边混匀。培养6h后换DMEM+10％FBS培养基，37℃，5％CO2继续培养。筛选获得具有FGF21活性响应的稳转细胞株。
细胞测活：
细胞长满培养皿后，胰酶消化，制备细胞悬液(1×105细胞/ml,DMEM+5％FBS+1μg/ml puromycin)，铺96孔板，每孔100μl，过夜培养。添加梯度浓度的待测样品，作用6h，使用Luciferase Reporter Assay Kit(Lucifersae reporter kit，Ray Biotech,Cat:68-LuciR-S200)进行荧光检测。结果如表4所示：
表4
Figure BDA0002061691890000231
Figure BDA0002061691890000241
表中蛋白编号按照如下规则：GCG类似物多肽代号+连接肽代号+FC代号+连接肽代号+FGF21类似物代号，如A382L1F6L5M2，表示GCG类似物多肽A382与代号为F6的IgG FC通过代号为L1的连接肽连接，再进一步与代号为M2的FGF21类似物通过代号为L5的连接肽连接，构建成一个融合蛋白。
实施例6
融合蛋白连续给药在db/db小鼠给药后随机血糖检测
瘦素受体缺陷二型糖尿病(db/db)小鼠中的降糖实验。db/db小鼠主要按照体重、非空腹血糖，药前OGTT反应三个指标进行筛选并均衡分组，每组10只，尽量排除过大或者过小的个体。根据表5所示剂量皮下注射，每4天给药一次，第一次为第0天，最后一次为第16天；阴性对照组生理盐水(PBS)(5μl/克体重)、阳性对照组利拉鲁肽(10nmol/千克体重)皮下注射方式每天给药一次，连续给药18天。在第一次注射前及第2d、6d、10d、14d、18d早上9点测定随机血糖值。随机血糖变化结果如图2所示。
图2A和图2B显示表5中的融合蛋白在db/db小鼠中降糖效果明显优于阳性对照利拉鲁肽。
表5
样品 SEQ ID NO. 剂量(nmol/kg)
A137L1F6 59 30
A175L1F6 60 30
A352L1F6 69 30
A382L1F6 70 30
A232L1F9L5M2 98 6
A089L1F9L5M2 100 6
A352L1F10L5M2 106 6
A175L1F2L5M2 109 6
实施例7
连续给药在诱导肥胖(DIO)小鼠中的药效研究：
本实施例的目的是研究不同的双效融合蛋白对DIO小鼠体重的影响作用。7周龄雄性C57BL/6J雄性小鼠给予高脂饲料(60％kcal from fat)继续饲养16周(共23周)，到体重约为55g时进行试验。饲养条件：12h光照/12h黑暗，自由采食，单笼饲养，给药前一天根据体重和体重生长曲线对小鼠进行分组(8只/组)，第二天皮下给药处理。按照20nmol/千克体重的剂量给药，4天一次，其他日期予以PBS假注射，连续给药28天；阴性对照组按5μl/克体重注射生理盐水(PBS)；阳性对照组注射利拉鲁肽(40nmol/千克体重)，每天一次给药，每天测量小鼠体重，并记录饮食量。最后一次给药后的第5天处死。眼眶取血。将血浆标本储存在-80℃。计算每组动物给药前及处死时的平均体重变化。结果如图3所示。
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
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Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
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225
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Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala
1 5 10 15
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<211> 12
<212> PRT
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Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10
<210> 16
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Gly Gly Ser Gly Gly Gly Ala Gly Gly Gly Gly Ser
1 5 10
<210> 17
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 18
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 18
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala
1 5 10 15
<210> 19
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Ala
1 5 10 15
<210> 20
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Ala
1 5 10 15
<210> 21
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Gly Gly Gly Gly Ser
1 5
<210> 22
<211> 16
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Ser
1 5 10 15
<210> 23
<211> 17
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
1 5 10 15
Ser
<210> 24
<211> 29
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr
20 25
<210> 25
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 26
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 27
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 28
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 29
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 30
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 31
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 32
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 33
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 34
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 35
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 36
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 37
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 38
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 39
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 40
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 41
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 42
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 43
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 44
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 45
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 46
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Arg Ala Gln Asp Phe Val Gln Trp Leu Met Ala Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 47
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 48
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Gly
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 49
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 50
<211> 39
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Gly
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<210> 51
<211> 273
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Gly Gly
20 25 30
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
35 40 45
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
50 55 60
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
65 70 75 80
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
85 90 95
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
100 105 110
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg
115 120 125
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
130 135 140
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
145 150 155 160
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
165 170 175
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
180 185 190
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
195 200 205
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
210 215 220
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
225 230 235 240
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
245 250 255
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
260 265 270
Gly
<210> 52
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 53
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 54
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 55
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 56
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 57
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 58
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 59
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 60
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 61
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 61
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 62
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 62
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 63
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 63
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 64
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 64
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 65
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 65
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 66
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 66
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 67
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 67
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 68
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 68
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 69
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 69
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 70
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 70
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 71
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 71
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 72
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 72
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 73
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 73
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Arg Ala Gln Asp Phe Val Gln Trp Leu Met Ala Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 74
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 74
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 75
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 75
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Gly
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 76
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 76
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 77
<211> 283
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 77
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Gly
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly
275 280
<210> 78
<211> 274
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 78
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Glu Tyr Leu Asp Ser
1 5 10 15
Glu Arg Ala Arg Asp Phe Val Ala Trp Leu Glu Ala Gly Gly Gly Gly
20 25 30
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser
35 40 45
Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly
50 55 60
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
65 70 75 80
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln
85 90 95
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
100 105 110
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr
115 120 125
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
130 135 140
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
145 150 155 160
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
165 170 175
Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser
180 185 190
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
195 200 205
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
210 215 220
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
225 230 235 240
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met
245 250 255
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
260 265 270
Leu Gly
<210> 79
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 79
Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Gln Ala
1 5 10 15
Ala Gln Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Ser Gly
20 25 30
Ala Pro Pro Pro Ser
35
<210> 80
<211> 36
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 80
Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Gln Ala
1 5 10 15
Ala Gln Asp Phe Val Gln Trp Leu Met Asn Gly Gly Pro Ser Ser Gly
20 25 30
Ala Pro Pro Pro
35
<210> 81
<211> 30
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 81
Xaa Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa
1 5 10 15
Xaa Xaa Ala Gln Asp Phe Val Gln Trp Leu Xaa Xaa Xaa Xaa
20 25 30
<210> 82
<211> 273
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 82
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Gly Gly
20 25 30
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
35 40 45
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
50 55 60
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
65 70 75 80
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
85 90 95
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
100 105 110
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg
115 120 125
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
130 135 140
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
145 150 155 160
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
165 170 175
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
180 185 190
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
195 200 205
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
210 215 220
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
225 230 235 240
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
245 250 255
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
260 265 270
Gly
<210> 83
<211> 273
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 83
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Gly Gly
20 25 30
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
35 40 45
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
50 55 60
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
65 70 75 80
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
85 90 95
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
100 105 110
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg
115 120 125
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
130 135 140
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
145 150 155 160
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
165 170 175
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
180 185 190
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
195 200 205
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
210 215 220
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
225 230 235 240
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
245 250 255
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
260 265 270
Gly
<210> 84
<211> 273
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 84
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Gly Gly
20 25 30
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
35 40 45
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
50 55 60
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
65 70 75 80
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
85 90 95
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
100 105 110
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg
115 120 125
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
130 135 140
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
145 150 155 160
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
165 170 175
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
180 185 190
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
195 200 205
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
210 215 220
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
225 230 235 240
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
245 250 255
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
260 265 270
Gly
<210> 85
<211> 273
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 85
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Gly Gly
20 25 30
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
35 40 45
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
50 55 60
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
65 70 75 80
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
85 90 95
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
100 105 110
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg
115 120 125
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
130 135 140
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
145 150 155 160
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
165 170 175
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
180 185 190
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
195 200 205
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
210 215 220
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
225 230 235 240
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
245 250 255
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
260 265 270
Gly
<210> 86
<211> 273
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 86
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Gly Gly
20 25 30
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys
35 40 45
Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly
50 55 60
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
65 70 75 80
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu
85 90 95
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
100 105 110
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg
115 120 125
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
130 135 140
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
145 150 155 160
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
165 170 175
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu
180 185 190
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
195 200 205
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
210 215 220
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
225 230 235 240
Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His
245 250 255
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu
260 265 270
Gly
<210> 87
<211> 181
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 87
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Ala Ser
180
<210> 88
<211> 181
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 88
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Gly Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Glu Ser
180
<210> 89
<211> 181
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 89
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His
20 25 30
Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Cys Pro Gly Asn Lys Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Cys Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Ser Met Val Gly Gly Ser Gln Gly Arg Ser
165 170 175
Pro Ser Tyr Glu Ser
180
<210> 90
<211> 177
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 90
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
1 5 10 15
Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
20 25 30
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
35 40 45
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
50 55 60
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
65 70 75 80
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
85 90 95
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
100 105 110
His Cys Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
115 120 125
Pro Cys Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu
130 135 140
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
145 150 155 160
Pro Leu Ala Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
165 170 175
Ser
<210> 91
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 91
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470 475
<210> 92
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 92
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 93
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 93
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Ala
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 94
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 94
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 95
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 95
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 96
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 96
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 97
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 97
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 98
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 98
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 99
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 99
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 100
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 100
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 101
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 101
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Glu Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 102
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 102
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 103
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 103
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 104
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 104
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 105
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 105
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 106
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 106
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Ala Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 107
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 107
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 108
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 108
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 109
<211> 477
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 109
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Gly Gly Gly Gly Ala Gly Gly
275 280 285
Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser Pro
290 295 300
Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp
305 310 315 320
Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr
325 330 335
Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys
340 345 350
Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg
355 360 365
Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe
370 375 380
Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly Tyr
385 390 395 400
Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro Gly
405 410 415
Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe
420 425 430
Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile
435 440 445
Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met
450 455 460
Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 110
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 110
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 111
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 111
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 112
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 112
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 113
<211> 479
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 113
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser
290 295 300
Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr
305 310 315 320
Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp
325 330 335
Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln
340 345 350
Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr
355 360 365
Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu
370 375 380
His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp
385 390 395 400
Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys
405 410 415
Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys
420 425 430
Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro
435 440 445
Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu
450 455 460
Ser Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 114
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 114
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Asp Ser Ser Pro Leu Leu
290 295 300
Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala
305 310 315 320
Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly
325 330 335
Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu
340 345 350
Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu
355 360 365
Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro
370 375 380
Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val
385 390 395 400
Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro Gly Asn Lys
405 410 415
Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe Leu Pro
420 425 430
Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala
435 440 445
Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ala Met Val Gly
450 455 460
Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470 475
<210> 115
<211> 475
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 115
Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Gln Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Ala Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro
50 55 60
Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe
65 70 75 80
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
85 90 95
Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe
100 105 110
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro
115 120 125
Arg Glu Glu Gln Phe Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr
130 135 140
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val
145 150 155 160
Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala
165 170 175
Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln
180 185 190
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
195 200 205
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
210 215 220
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser
225 230 235 240
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu
245 250 255
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His
260 265 270
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Gly Gly Gly Gly Ala
275 280 285
Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Asp Ser Ser Pro Leu Leu
290 295 300
Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala
305 310 315 320
Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly
325 330 335
Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu
340 345 350
Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu
355 360 365
Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro
370 375 380
Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val
385 390 395 400
Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro Gly Asn Lys
405 410 415
Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe Leu Pro
420 425 430
Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala
435 440 445
Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ala Met Val Gly
450 455 460
Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser
465 470 475
<210> 116
<211> 423
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 116
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 Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly Gly Gly
225 230 235 240
Gly Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly
245 250 255
Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu
260 265 270
Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala Asp
275 280 285
Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val
290 295 300
Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro
305 310 315 320
Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser
325 330 335
Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu
340 345 350
Ala His Gly Leu Pro Leu His Leu Pro Gly Asn Lys Ser Pro His Arg
355 360 365
Asp Pro Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu
370 375 380
Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro
385 390 395 400
Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly
405 410 415
Arg Ser Pro Ser Tyr Ala Ser
420
<210> 117
<211> 424
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 117
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 Gly Gly Gly Gly Ala Gly Gly Gly Gly Ala Gly Gly
225 230 235 240
Gly Gly Ala His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly
245 250 255
Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr
260 265 270
Glu Ala His Leu Glu Ile Arg Glu Asp Gly Thr Val Gly Gly Ala Ala
275 280 285
Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly
290 295 300
Val Ile Gln Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg
305 310 315 320
Pro Asp Gly Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys
325 330 335
Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser
340 345 350
Glu Ala His Gly Leu Pro Leu His Cys Pro Gly Asn Lys Ser Pro His
355 360 365
Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg Phe Leu Pro Leu Pro Gly
370 375 380
Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro
385 390 395 400
Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Gly Ser Gln
405 410 415
Gly Arg Ser Pro Ser Tyr Glu Ser
420
<210> 118
<211> 478
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 118
His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser
1 5 10 15
Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
35 40 45
Ser Gly Gly Gly Gly Ser Ala Asp Lys Thr His Thr Cys Pro Pro Cys
50 55 60
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
65 70 75 80
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
85 90 95
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
100 105 110
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
115 120 125
Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
130 135 140
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
145 150 155 160
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
165 170 175
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
180 185 190
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
195 200 205
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
210 215 220
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
225 230 235 240
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
245 250 255
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
260 265 270
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Gly Gly Gly Ala Gly
275 280 285
Gly Gly Gly Ala Gly Gly Gly Gly Ala His Pro Ile Pro Asp Ser Ser
290 295 300
Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu Tyr Thr
305 310 315 320
Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg Glu Asp Gly
325 330 335
Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu Leu Gln Leu
340 345 350
Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys Thr Ser
355 360 365
Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly Ser Leu His
370 375 380
Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Arg Leu Leu Glu Asp Gly
385 390 395 400
Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Cys Pro
405 410 415
Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly Pro Cys Arg
420 425 430
Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly
435 440 445
Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser
450 455 460
Met Val Gly Gly Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser
465 470 475
<210> 119
<211> 181
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 119
His Pro Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val
1 5 10 15
Arg Gln Xaa Tyr Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Xaa His
20 25 30
Leu Glu Ile Xaa Glu Asp Gly Thr Val Gly Xaa Ala Xaa Asp Gln Ser
35 40 45
Pro Glu Ser Leu Leu Gln Leu Xaa Ala Leu Lys Pro Gly Val Ile Gln
50 55 60
Ile Leu Gly Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly
65 70 75 80
Ala Leu Tyr Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg
85 90 95
Glu Xaa Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His
100 105 110
Gly Leu Pro Leu His Xaa Pro Gly Asn Xaa Ser Pro His Arg Asp Pro
115 120 125
Ala Pro Arg Gly Pro Xaa Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro
130 135 140
Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val
145 150 155 160
Gly Ser Ser Asp Pro Leu Xaa Met Val Xaa Xaa Ser Gln Xaa Arg Ser
165 170 175
Pro Ser Xaa Xaa Xaa
180

Claims (7)

1.一种融合蛋白，其特征在于，所述融合蛋白的氨基酸序列如SEQ ID NO.106、SEQ IDNO.109其中之一所示。
2.一种分离的多核苷酸，编码如权利要求1所述的融合蛋白。
3.一种构建体，所述构建体含有如权利要求2所述的分离的多核苷酸。
4.一种表达系统，所述表达系统含有如权利要求3所述的构建体或基因组中整合有外源的如权利要求2所述的多核苷酸。
5.如权利要求1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4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。
6.一种药物组合物，包括如权利要求1所述的融合蛋白或如权利要求5所述的表达系统的培养物。
7.如权利要求1所述的融合蛋白或如权利要求6所述的药物组合物在制备药物中的用途；所述药物选自用于治疗代谢相关疾病的药物，所述代谢相关疾病选自糖尿病、肥胖、非酒精性脂肪肝、高血脂中的至少一种。
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