CN111214651A

CN111214651A - 六型胶原蛋白在制备能提高再生神经有序性相关药物及移植物中的应用

Info

Publication number: CN111214651A
Application number: CN201911232782.0A
Authority: CN
Inventors: 邹剑龙; 孙佳慧; 朱庆棠; 邱帅; 何富林
Original assignee: First Affiliated Hospital of Sun Yat Sen University
Current assignee: First Affiliated Hospital of Sun Yat Sen University
Priority date: 2019-12-05
Filing date: 2019-12-05
Publication date: 2020-06-02

Abstract

本发明提供一种六型胶原蛋白在制备能提高再生神经有序性相关药物及神经移植物中的应用。所述六型胶原蛋白包括人源性六型胶原蛋白或动物源性同源六型胶原蛋白，所述动物源性同源六型胶原蛋白包括大鼠、小鼠或牛六型胶原蛋白。本发明将六型胶原蛋白COL6作为水凝胶填充于神经导管中，可促进再生神经纤维的集束化和有序性，使再生神经纤维在形态学上更加接近正常神经束结构,减少神经与靶器官的错配的概率,提高神经修复效果，且蛋白来源广泛。

Description

六型胶原蛋白在制备能提高再生神经有序性相关药物及移植物中的应用

技术领域

本发明涉及医药技术领域，具体涉及六型胶原蛋白在制备能提高再生神经有序性相关药物及移植物中的应用。

背景技术

目前治疗长段周围神经损伤的金标准依然是自体神经移植[1]，但不可避免会造成供体神经支配区域的损伤及取材区的手术瘢痕，因此迫切需求合适的人工神经替代品。目前包括神经导管和去细胞神经在内的多种人工神经移植物都有应用于临床，但修复效果还无法媲美自体神经移植[2-4]，相关形态学研究揭示出人工神经移植物普遍存在的问题，即神经干内原本密集的神经纤维束一旦长入移植材料中便会分散错长，只有少量神经纤维能支配到正确的靶器官[5,6]。如何促进再生神经纤维在移植物内正确、有序、快速生长一直是神经组织工程研究的热点和难点[7,8]。

在中枢和外周神经系统中，功能或起止点基本相同的神经纤维集合在一起形成神经束 [9]，神经束的存在使得原本错综复杂的神经网络在走形过程中按照功能和支配区域进行了天然的分类，为我们研究神经系统的结构和功能提供了方便，其形成机理与胚胎发育时期复杂的微环境诱导，尤其是以神经细胞粘附分子(NCAM)为代表的一系列细胞粘附分子(cell adhesion molecules,CAMs)的时空选择性表达有关，NCAM分子具有同源性结合能力，意味着同时表达NCAM的不同细胞之间能够相互贴合。抑制NCAM的功能会导致神经元轴突在发育过程中无法按照正常的途径集束生长，大量散乱的轴突无法支配正确的靶器官，从而造成相应的神经功能异常[10,11]。

另一方面，周围神经损伤通常会造成包括神经束在内的结构破坏，运用组织工程原理构建仿生性周围神经移植物是当今的研究热点，其中结构仿生和内环境仿生是该领域的两大课题。多通道导管及去细胞神经移植物在一定程度上实现了结构仿生[12]；而在微环境优化方面，已有不少研究证实，在移植物内添加胞外基质(extracellular matrix,ECM)、神经营养因子及支持细胞等均可促进神经再生，提升神经修复效果[2,13]。其中，ECM中的胶原和层粘连蛋白等成分能为神经细胞和非神经细胞的早期生长及与神经营养因子的结合提供合适的微环境[14]。目前已有相关研究通过利用胶原蛋白良好的促进神经再生活性来提高神经再生速度及数量[15]。多种生长因子NGF、NT-3和FGFs等能促进轴突的生长、提高神经元的存活率[16,17],并对感觉或运动神经纤维的生长发挥特异性导向作用[18]。除了引入上述促进性因素外，还可以采用消除神经生长抑制性因素的策略。研究证实硫酸软骨素蛋白多糖类(CSPGs)对轴突生长有强烈的抑制作用，清除损伤部位的CSPGs，抑制其生成或阻断CSPGs对生长锥微管构建的影响，可使再生轴突穿过损伤区[19-21]。CSPGs同样存在于周围神经ECM中，有学者用软骨素酶ABC来处理神经断端或分解移植物中的CSPGs 可增加再生轴突的数量，提高神经修复效果[22,23]。这些措施均属于周围神经再生微环境的调控。

然而，有研究表明，以上这些促神经再生手段虽能增加轴突再生数量及速度，但移植物内轴突生长散乱无序，失去了原有的集束特征，导致轴突错配率很高[5]。这种结果的产生可能会抵消部分促神经再生的效益。因此，如何控制再生神经轴突的生长行为，使轴突在神经移植物中保持神经束的形态变得尤其重要，也是未来改进周围神经移植物内环境所要达到的目标。

发明内容

有鉴于此，为了攻克神经再生无序的难题，本发明人通过实验研究发现了能够增加再生神经纤维有序性、减少神经纤维与靶器官错配率的六型胶原蛋白(Collagen VI,COL6)。

本发明提供该COL6在制备能提高再生神经有序性相关药物中的应用。

本发明还提供该COL6在制备能提高再生神经有序性的神经移植物中的应用。

本发明所述的六型胶原蛋白包括人源性六型胶原蛋白或动物源性同源六型胶原蛋白，所述动物源性同源六型胶原蛋白包括大鼠、小鼠或牛六型胶原蛋白。

本发明所述所述人源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列1所述的COL6A1蛋白单体、如蛋白质序列2所述的COL6A2蛋白单体以及如蛋白质序列3所述的COL6A3蛋白单体。

本发明所述大鼠源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列4所述的COL6A1蛋白单体、如蛋白质序列5所述的COL6A2蛋白单体、如蛋白质序列6所述的COL6A3蛋白单体。

本发明所述小鼠源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列7所述的COL6A1蛋白单体、如蛋白质序列8所述的COL6A2蛋白单体以及如蛋白质序列9所述的COL6A3蛋白单体。

本发明所述牛源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列10所述的COL6A1六型胶原蛋白单体、如蛋白质序列11所述的COL6A2六型胶原蛋白单体或如蛋白质序列12所述的COL6A3六型胶原蛋白单体。

本发明所述能提高再生神经有序性的药物为凝胶剂。

本发明所述制备能提高再生神经有序性的移植物，包括用凝胶灌注或溶液浸泡的方式将六型胶原蛋白负载到神经移植物中。

本发明所述以该六型胶原蛋白制备能提高再生神经有序性的移植物，包括将六型胶原蛋白作为成分之一与其他成分混合后共同作为制备神经移植物的原料。

本发明六型胶原蛋白发挥调控轴突有序化的有效浓度为0.1到1.0微克/毫升。

本发明在神经纤维再生微环境中加入一定量的六型胶原蛋白(COL6)分子，COL6作为一种细胞外基质蛋白分布于神经纤维的胞外空间，由于COL6能够与神经细胞粘附分子(NCAM1)的FNⅢ结构域发生结合，因此，在轴膜上一过性表达的NCAM1分子一旦与胞外 COL6分子结合便增加了在轴膜上的稳定性，随着NCAM在轴膜上富集度的增加，不同轴膜之间同源性结合的能力也随之增强，其结果便是引起不同轴突之间相互吸引，最终将大量散在分布的单根神经纤维汇集成神经束样结构。在此过程中，原本向着随机方向生长的神经纤维由于相互汇聚，其再生方向矢量也发生叠加，最终向着统一的方向有序生长。

本发明的有益效果在于：

1.为了克服现有神经损伤修复治疗过程中出现的神经再生散乱无序的缺陷，本发明人找到一种被称为六型胶原(COL6)的蛋白质，将COL6作为水凝胶填充于神经导管中，可促进再生神经纤维的集束化和有序性，使再生神经纤维在形态学上更加接近正常神经束结构, 减少神经与靶器官的错配的概率,提高神经修复效果。

2.本发明所述COL6可提取自人和其他哺乳动物(本发明已通过实验验证大鼠，小鼠和牛来源的COL6能够达到与人源性COL6同样的预期作用),因此蛋白来源广泛。

附图说明：

图1为六型胶原体外促进轴突集束及有序化效果图；

图2为负载六型胶原的神经导管修复大鼠坐骨神经缺损宏观效果图；

图3为负载六型胶原的神经导管修复大鼠坐骨神经缺损的纵切面神经镀银染色图。

具体实施方式：

实施例一：六型胶原蛋白提纯：

从新鲜人胎盘中分离羊膜，用0.5M的醋酸钠多次冲洗，以去除血清蛋白。清洗后的羊膜被切碎并匀浆。每80g(湿重)羊膜组织用8mg胃蛋白酶和0.5M甲酸(pH 2.1)处理24小时，整个过程在4摄氏度进行。离心后取上清液，向溶液中添加终浓度为1.2M的NaCl溶液，将胶原成份作为沉淀收集。将沉淀复溶于0.05m Tris-HCl缓冲液(pH 8.0，含1M NaCl)，并用含1.2M NaCl的0.5M乙酸溶液进行透析。除去沉淀物，然后用含1.7M NaCl的0.5M乙酸进一步对上清液进行透析。所得沉淀重悬于含有0.2％SDS、1mM EDTA、50mM Tris-HCl、100mMNaCl，pH 值为7.2的溶液中，并在95℃下加热3分钟。在同一缓冲液中，将可溶性蛋白质通过层析柱 (Sephacryl S-400，Pharmacia，1.6x 53cm)进行分离。收集接近孔隙体积(voidvolume) 的洗脱组分，用无菌超纯水进行透析后冻干保存。即可获得人源性六型胶原蛋白复合体 (COL6)。

此外也可购买商品化的六型胶原产品，如abcam公司，货号为ab7538的产品“Native Human Collagen VI”。

实施例二：

与实施例一基本相同，所不同之处在于新鲜大鼠胎盘中分离六型胶原蛋白复合体。

实施例三：

与实施例一基本相同，所不同之处在于新鲜小鼠胎盘中分离六型胶原蛋白复合体。

实施例四：

与实施例一基本相同，所不同之处在于新鲜牛胎盘中分离六型胶原蛋白复合体。

实施例五：COL6水凝胶的制备：

将实施例一、二、三或四获得的提纯COL6冻干粉末溶于3％醋酸中，配成浓度为1mg/ml 的原溶液，按照体积比1：50溶于生理盐水(或其他中性水溶液如PBS，或细胞培养液)中，至终浓度为20μg/ml即成为COL6预凝胶溶液。此时的COL6预凝胶溶液在室温放置2分钟左右即可自然凝固成胶。为了保持COL6预凝胶溶液的流动性，整个操作过程应在冰盒上进行。此外，也可将COL6原溶液按体积比1：50与其他预凝胶溶液(如Matrigel)混合，同样在室温下放置 2分钟作用即可成胶。为了保持其流动性，整个过程同样应在冰盒上进行。

实施例六：COL6水凝胶促进再生神经纤维集束及有序化的体外实验

将实施例五获得的COL6预凝胶溶液用培养液稀释到10μg/mL，涂布细胞培养皿，吸取多余液体后室温放置2分钟成胶，随后将大鼠背根神经节(DRG)组织块种植在包被有COL6水凝胶的培养皿中；单纯基质胶(Matrigel，10μg/mL)、以及基质胶(10μg/mL)与六型胶原(10μg/mL)混合物包被培养皿后分别与DRG组织块共同培养做平行对比实验。

如图1所示，自上而下分别是单纯COL6(10μg/mL)、单纯基质胶(10μg/mL)、以及基质胶(10μg/mL)与COL6(10μg/mL)混合铺板的培养皿，深色椭圆形结构为DRG组织块，深色线条样结构为再生的神经纤维。其中，COL6组的DRG其再生轴突聚集成束，且轴突再生路径呈放射状直线(上)。基质胶组可见再生轴突分支较多，密度较大，但轴突生长缺乏方向性(中)。当在基质胶中添加一定量的COL6混合铺板，可使原本杂乱无序的轴突再次变的有序(下)。

实施例七：将预凝胶灌注到神经导管中：

将实施例五获得的COL6预凝胶溶液通过注射器注入内径为1mm长8mm的医用硅胶管，在37 摄氏度培养箱中放置10min，待其完全成胶后，将导管放入无菌生理盐水中保存。

实施例八：动物手术：

常规麻醉成年SD大鼠，暴露坐骨神经，切除8mm神经缺损，用实施例七获得的负载COL6 水凝胶的神经导管桥接神经断端，分层缝合肌肉和皮肤，手术过程全程无菌操作。术后常规饲养，2周后灌注取材坐骨神经，切片染色观察。

如图2所示，显示硅胶导管内再生两周的坐骨神经。其中添加了Matrigel水凝胶以及 Matrigel+COL6混合水凝胶的导管内再生神经在直径上要明显大于空导管组。

如图3所示，再生神经组织纵切后行镀银染色，结果显示空导管组(左)的再生神经纤维多集中在外围，且神经散乱无序。Matrigel水凝胶组(中)的再生神经纤维向组织外围高度集中，靠近组织中央位置神经纤维数量极少。Matrigel+Collagen IV混合水凝胶组的再生神经纤维分布均匀，组织中央也有相对较多的神经纤维，且神经纤维走行相对有序(右)。

以上实施例仅用以说明本发明的技术方案而非对其限制，尽管参照上述实施例对本发明进行了详细的说明，所属领域的普通技术人员依然可以对本发明的具体实施方式进行修改或者等同替换，而这些未脱离本发明精神和范围的任何修改或者等同替换，其均在申请待批的本发明的权利要求保护范之内。

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[21].Bradbury EJ,Moon LD,Popat RJ,King VR,Bennett GS,Patel PN,FawcettJW,Mcmahon SB.Chondroitinase ABC promotes functional recovery after spinalcord injury[J]. Nature,2002,416(6881):636-640.

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序列表

<110> 中国

<120> 六型胶原蛋白在制备能提高再生神经有序性相关药物及移植物中的应用

<130> [1].Autologous transplantation with fewer fibers repairslargeperipheral nerve defects[J]. Neural Regeneration Research, 2017,12(12):2077-2083.

<160> 12

<170> SIPOSequenceListing 1.0

<210> 1

<211> 1028

<212> PRT

<213> Homo sapiens

<400> 1

Met Arg Ala Ala Arg Ala Leu Leu Pro Leu Leu Leu Gln Ala Cys Trp

1 5 10 15

Thr Ala Ala Gln Asp Glu Pro Glu Thr Pro Arg Ala Val Ala Phe Gln

20 25 30

Asp Cys Pro Val Asp Leu Phe Phe Val Leu Asp Thr Ser Glu Ser Val

35 40 45

Ala Leu Arg Leu Lys Pro Tyr Gly Ala Leu Val Asp Lys Val Lys Ser

50 55 60

Phe Thr Lys Arg Phe Ile Asp Asn Leu Arg Asp Arg Tyr Tyr Arg Cys

65 70 75 80

Asp Arg Asn Leu Val Trp Asn Ala Gly Ala Leu His Tyr Ser Asp Glu

85 90 95

Val Glu Ile Ile Gln Gly Leu Thr Arg Met Pro Gly Gly Arg Asp Ala

100 105 110

Leu Lys Ser Ser Val Asp Ala Val Lys Tyr Phe Gly Lys Gly Thr Tyr

115 120 125

Thr Asp Cys Ala Ile Lys Lys Gly Leu Glu Gln Leu Leu Val Gly Gly

130 135 140

Ser His Leu Lys Glu Asn Lys Tyr Leu Ile Val Val Thr Asp Gly His

145 150 155 160

Pro Leu Glu Gly Tyr Lys Glu Pro Cys Gly Gly Leu Glu Asp Ala Val

165 170 175

Asn Glu Ala Lys His Leu Gly Val Lys Val Phe Ser Val Ala Ile Thr

180 185 190

Pro Asp His Leu Glu Pro Arg Leu Ser Ile Ile Ala Thr Asp His Thr

195 200 205

Tyr Arg Arg Asn Phe Thr Ala Ala Asp Trp Gly Gln Ser Arg Asp Ala

210 215 220

Glu Glu Ala Ile Ser Gln Thr Ile Asp Thr Ile Val Asp Met Ile Lys

225 230 235 240

Asn Asn Val Glu Gln Val Cys Cys Ser Phe Glu Cys Gln Pro Ala Arg

245 250 255

Gly Pro Pro Gly Leu Arg Gly Asp Pro Gly Phe Glu Gly Glu Arg Gly

260 265 270

Lys Pro Gly Leu Pro Gly Glu Lys Gly Glu Ala Gly Asp Pro Gly Arg

275 280 285

Pro Gly Asp Leu Gly Pro Val Gly Tyr Gln Gly Met Lys Gly Glu Lys

290 295 300

Gly Ser Arg Gly Glu Lys Gly Ser Arg Gly Pro Lys Gly Tyr Lys Gly

305 310 315 320

Glu Lys Gly Lys Arg Gly Ile Asp Gly Val Asp Gly Val Lys Gly Glu

325 330 335

Met Gly Tyr Pro Gly Leu Pro Gly Cys Lys Gly Ser Pro Gly Phe Asp

340 345 350

Gly Ile Gln Gly Pro Pro Gly Pro Lys Gly Asp Pro Gly Ala Phe Gly

355 360 365

Leu Lys Gly Glu Lys Gly Glu Pro Gly Ala Asp Gly Glu Ala Gly Arg

370 375 380

Pro Gly Ser Ser Gly Pro Ser Gly Asp Glu Gly Gln Pro Gly Glu Pro

385 390 395 400

Gly Pro Pro Gly Glu Lys Gly Glu Ala Gly Asp Glu Gly Asn Pro Gly

405 410 415

Pro Asp Gly Ala Pro Gly Glu Arg Gly Gly Pro Gly Glu Arg Gly Pro

420 425 430

Arg Gly Thr Pro Gly Thr Arg Gly Pro Arg Gly Asp Pro Gly Glu Ala

435 440 445

Gly Pro Gln Gly Asp Gln Gly Arg Glu Gly Pro Val Gly Val Pro Gly

450 455 460

Asp Pro Gly Glu Ala Gly Pro Ile Gly Pro Lys Gly Tyr Arg Gly Asp

465 470 475 480

Glu Gly Pro Pro Gly Ser Glu Gly Ala Arg Gly Ala Pro Gly Pro Ala

485 490 495

Gly Pro Pro Gly Asp Pro Gly Leu Met Gly Glu Arg Gly Glu Asp Gly

500 505 510

Pro Ala Gly Asn Gly Thr Glu Gly Phe Pro Gly Phe Pro Gly Tyr Pro

515 520 525

Gly Asn Arg Gly Ala Pro Gly Ile Asn Gly Thr Lys Gly Tyr Pro Gly

530 535 540

Leu Lys Gly Asp Glu Gly Glu Ala Gly Asp Pro Gly Asp Asp Asn Asn

545 550 555 560

Asp Ile Ala Pro Arg Gly Val Lys Gly Ala Lys Gly Tyr Arg Gly Pro

565 570 575

Glu Gly Pro Gln Gly Pro Pro Gly His Gln Gly Pro Pro Gly Pro Asp

580 585 590

Glu Cys Glu Ile Leu Asp Ile Ile Met Lys Met Cys Ser Cys Cys Glu

595 600 605

Cys Lys Cys Gly Pro Ile Asp Leu Leu Phe Val Leu Asp Ser Ser Glu

610 615 620

Ser Ile Gly Leu Gln Asn Phe Glu Ile Ala Lys Asp Phe Val Val Lys

625 630 635 640

Val Ile Asp Arg Leu Ser Arg Asp Glu Leu Val Lys Phe Glu Pro Gly

645 650 655

Gln Ser Tyr Ala Gly Val Val Gln Tyr Ser His Ser Gln Met Gln Glu

660 665 670

His Val Ser Leu Arg Ser Pro Ser Ile Arg Asn Val Gln Glu Leu Lys

675 680 685

Glu Ala Ile Lys Ser Leu Gln Trp Met Ala Gly Gly Thr Phe Thr Gly

690 695 700

Glu Ala Leu Gln Tyr Thr Arg Asp Gln Leu Leu Pro Pro Ser Pro Asn

705 710 715 720

Asn Arg Ile Ala Leu Val Ile Thr Asp Gly Arg Ser Asp Thr Gln Arg

725 730 735

Asp Thr Thr Pro Leu Asn Val Leu Cys Ser Pro Gly Ile Gln Val Val

740 745 750

Ser Val Gly Ile Lys Asp Val Phe Asp Phe Ile Pro Gly Ser Asp Gln

755 760 765

Leu Asn Val Ile Ser Cys Gln Gly Leu Ala Pro Ser Gln Gly Arg Pro

770 775 780

Gly Leu Ser Leu Val Lys Glu Asn Tyr Ala Glu Leu Leu Glu Asp Ala

785 790 795 800

Phe Leu Lys Asn Val Thr Ala Gln Ile Cys Ile Asp Lys Lys Cys Pro

805 810 815

Asp Tyr Thr Cys Pro Ile Thr Phe Ser Ser Pro Ala Asp Ile Thr Ile

820 825 830

Leu Leu Asp Gly Ser Ala Ser Val Gly Ser His Asn Phe Asp Thr Thr

835 840 845

Lys Arg Phe Ala Lys Arg Leu Ala Glu Arg Phe Leu Thr Ala Gly Arg

850 855 860

Thr Asp Pro Ala His Asp Val Arg Val Ala Val Val Gln Tyr Ser Gly

865 870 875 880

Thr Gly Gln Gln Arg Pro Glu Arg Ala Ser Leu Gln Phe Leu Gln Asn

885 890 895

Tyr Thr Ala Leu Ala Ser Ala Val Asp Ala Met Asp Phe Ile Asn Asp

900 905 910

Ala Thr Asp Val Asn Asp Ala Leu Gly Tyr Val Thr Arg Phe Tyr Arg

915 920 925

Glu Ala Ser Ser Gly Ala Ala Lys Lys Arg Leu Leu Leu Phe Ser Asp

930 935 940

Gly Asn Ser Gln Gly Ala Thr Pro Ala Ala Ile Glu Lys Ala Val Gln

945 950 955 960

Glu Ala Gln Arg Ala Gly Ile Glu Ile Phe Val Val Val Val Gly Arg

965 970 975

Gln Val Asn Glu Pro His Ile Arg Val Leu Val Thr Gly Lys Thr Ala

980 985 990

Glu Tyr Asp Val Ala Tyr Gly Glu Ser His Leu Phe Arg Val Pro Ser

995 1000 1005

Tyr Gln Ala Leu Leu Arg Gly Val Phe His Gln Thr Val Ser Arg Lys

1010 1015 1020

Val Ala Leu Gly

1025

<210> 2

<211> 1019

<212> PRT

<213> Homo sapiens

<400> 2

Met Leu Gln Gly Thr Cys Ser Val Leu Leu Leu Trp Gly Ile Leu Gly

1 5 10 15

Ala Ile Gln Ala Gln Gln Gln Glu Val Ile Ser Pro Asp Thr Thr Glu

20 25 30

Arg Asn Asn Asn Cys Pro Glu Lys Thr Asp Cys Pro Ile His Val Tyr

35 40 45

Phe Val Leu Asp Thr Ser Glu Ser Val Thr Met Gln Ser Pro Thr Asp

50 55 60

Ile Leu Leu Phe His Met Lys Gln Phe Val Pro Gln Phe Ile Ser Gln

65 70 75 80

Leu Gln Asn Glu Phe Tyr Leu Asp Gln Val Ala Leu Ser Trp Arg Tyr

85 90 95

Gly Gly Leu His Phe Ser Asp Gln Val Glu Val Phe Ser Pro Pro Gly

100 105 110

Ser Asp Arg Ala Ser Phe Ile Lys Asn Leu Gln Gly Ile Ser Ser Phe

115 120 125

Arg Arg Gly Thr Phe Thr Asp Cys Ala Leu Ala Asn Met Thr Glu Gln

130 135 140

Ile Arg Gln Asp Arg Ser Lys Gly Thr Val His Phe Ala Val Val Ile

145 150 155 160

Thr Asp Gly His Val Thr Gly Ser Pro Cys Gly Gly Ile Lys Leu Gln

165 170 175

Ala Glu Arg Ala Arg Glu Glu Gly Ile Arg Leu Phe Ala Val Ala Pro

180 185 190

Asn Gln Asn Leu Lys Glu Gln Gly Leu Arg Asp Ile Ala Ser Thr Pro

195 200 205

His Glu Leu Tyr Arg Asn Asp Tyr Ala Thr Met Leu Pro Asp Ser Thr

210 215 220

Glu Ile Asp Gln Asp Thr Ile Asn Arg Ile Ile Lys Val Met Lys His

225 230 235 240

Glu Ala Tyr Gly Glu Cys Tyr Lys Val Ser Cys Leu Glu Ile Pro Gly

245 250 255

Pro Ser Gly Pro Lys Gly Tyr Arg Gly Gln Lys Gly Ala Lys Gly Asn

260 265 270

Met Gly Glu Pro Gly Glu Pro Gly Gln Lys Gly Arg Gln Gly Asp Pro

275 280 285

Gly Ile Glu Gly Pro Ile Gly Phe Pro Gly Pro Lys Gly Val Pro Gly

290 295 300

Phe Lys Gly Glu Lys Gly Glu Phe Gly Ala Asp Gly Arg Lys Gly Ala

305 310 315 320

Pro Gly Leu Ala Gly Lys Asn Gly Thr Asp Gly Gln Lys Gly Lys Leu

325 330 335

Gly Arg Ile Gly Pro Pro Gly Cys Lys Gly Asp Pro Gly Asn Arg Gly

340 345 350

Pro Asp Gly Tyr Pro Gly Glu Ala Gly Ser Pro Gly Glu Arg Gly Asp

355 360 365

Gln Gly Gly Lys Gly Asp Pro Gly Arg Pro Gly Arg Arg Gly Pro Pro

370 375 380

Gly Glu Ile Gly Ala Lys Gly Ser Lys Gly Tyr Gln Gly Asn Ser Gly

385 390 395 400

Ala Pro Gly Ser Pro Gly Val Lys Gly Ala Lys Gly Gly Pro Gly Pro

405 410 415

Arg Gly Pro Lys Gly Glu Pro Gly Arg Arg Gly Asp Pro Gly Thr Lys

420 425 430

Gly Ser Pro Gly Ser Asp Gly Pro Lys Gly Glu Lys Gly Asp Pro Gly

435 440 445

Pro Glu Gly Pro Arg Gly Leu Ala Gly Glu Val Gly Asn Lys Gly Ala

450 455 460

Lys Gly Asp Arg Gly Leu Pro Gly Pro Arg Gly Pro Gln Gly Ala Leu

465 470 475 480

Gly Glu Pro Gly Lys Gln Gly Ser Arg Gly Asp Pro Gly Asp Ala Gly

485 490 495

Pro Arg Gly Asp Ser Gly Gln Pro Gly Pro Lys Gly Asp Pro Gly Arg

500 505 510

Pro Gly Phe Ser Tyr Pro Gly Pro Arg Gly Ala Pro Gly Glu Lys Gly

515 520 525

Glu Pro Gly Pro Arg Gly Pro Glu Gly Gly Arg Gly Asp Phe Gly Leu

530 535 540

Lys Gly Glu Pro Gly Arg Lys Gly Glu Lys Gly Glu Pro Ala Asp Pro

545 550 555 560

Gly Pro Pro Gly Glu Pro Gly Pro Arg Gly Pro Arg Gly Val Pro Gly

565 570 575

Pro Glu Gly Glu Pro Gly Pro Pro Gly Asp Pro Gly Leu Thr Glu Cys

580 585 590

Asp Val Met Thr Tyr Val Arg Glu Thr Cys Gly Cys Cys Asp Cys Glu

595 600 605

Lys Arg Cys Gly Ala Leu Asp Val Val Phe Val Ile Asp Ser Ser Glu

610 615 620

Ser Ile Gly Tyr Thr Asn Phe Thr Leu Glu Lys Asn Phe Val Ile Asn

625 630 635 640

Val Val Asn Arg Leu Gly Ala Ile Ala Lys Asp Pro Lys Ser Glu Thr

645 650 655

Gly Thr Arg Val Gly Val Val Gln Tyr Ser His Glu Gly Thr Phe Glu

660 665 670

Ala Ile Gln Leu Asp Asp Glu Arg Ile Asp Ser Leu Ser Ser Phe Lys

675 680 685

Glu Ala Val Lys Asn Leu Glu Trp Ile Ala Gly Gly Thr Trp Thr Pro

690 695 700

Ser Ala Leu Lys Phe Ala Tyr Asp Arg Leu Ile Lys Glu Ser Arg Arg

705 710 715 720

Gln Lys Thr Arg Val Phe Ala Val Val Ile Thr Asp Gly Arg His Asp

725 730 735

Pro Arg Asp Asp Asp Leu Asn Leu Arg Ala Leu Cys Asp Arg Asp Val

740 745 750

Thr Val Thr Ala Ile Gly Ile Gly Asp Met Phe His Glu Lys His Glu

755 760 765

Ser Glu Asn Leu Tyr Ser Ile Ala Cys Asp Lys Pro Gln Gln Val Arg

770 775 780

Asn Met Thr Leu Phe Ser Asp Leu Val Ala Glu Lys Phe Ile Asp Asp

785 790 795 800

Met Glu Asp Val Leu Cys Pro Asp Pro Gln Ile Val Cys Pro Asp Leu

805 810 815

Pro Cys Gln Thr Glu Leu Ser Val Ala Gln Cys Thr Gln Arg Pro Val

820 825 830

Asp Ile Val Phe Leu Leu Asp Gly Ser Glu Arg Leu Gly Glu Gln Asn

835 840 845

Phe His Lys Ala Arg Arg Phe Val Glu Gln Val Ala Arg Arg Leu Thr

850 855 860

Leu Ala Arg Arg Asp Asp Asp Pro Leu Asn Ala Arg Val Ala Leu Leu

865 870 875 880

Gln Phe Gly Gly Pro Gly Glu Gln Gln Val Ala Phe Pro Leu Ser His

885 890 895

Asn Leu Thr Ala Ile His Glu Ala Leu Glu Thr Thr Gln Tyr Leu Asn

900 905 910

Ser Phe Ser His Val Gly Ala Gly Val Val His Ala Ile Asn Ala Ile

915 920 925

Val Arg Ser Pro Arg Gly Gly Ala Arg Arg His Ala Glu Leu Ser Phe

930 935 940

Val Phe Leu Thr Asp Gly Val Thr Gly Asn Asp Ser Leu His Glu Ser

945 950 955 960

Ala His Ser Met Arg Lys Gln Asn Val Val Pro Thr Val Leu Ala Leu

965 970 975

Gly Ser Asp Val Asp Met Asp Val Leu Thr Thr Leu Ser Leu Gly Asp

980 985 990

Arg Ala Ala Val Phe His Glu Lys Asp Tyr Asp Ser Leu Ala Gln Pro

995 1000 1005

Gly Phe Phe Asp Arg Phe Ile Arg Trp Ile Cys

1010 1015

<210> 3

<211> 3177

<212> PRT

<213> Homo sapiens

<400> 3

Met Arg Lys His Arg His Leu Pro Leu Val Ala Val Phe Cys Leu Phe

1 5 10 15

Leu Ser Gly Phe Pro Thr Thr His Ala Gln Gln Gln Gln Ala Asp Val

20 25 30

Lys Asn Gly Ala Ala Ala Asp Ile Ile Phe Leu Val Asp Ser Ser Trp

35 40 45

Thr Ile Gly Glu Glu His Phe Gln Leu Val Arg Glu Phe Leu Tyr Asp

50 55 60

Val Val Lys Ser Leu Ala Val Gly Glu Asn Asp Phe His Phe Ala Leu

65 70 75 80

Val Gln Phe Asn Gly Asn Pro His Thr Glu Phe Leu Leu Asn Thr Tyr

85 90 95

Arg Thr Lys Gln Glu Val Leu Ser His Ile Ser Asn Met Ser Tyr Ile

100 105 110

Gly Gly Thr Asn Gln Thr Gly Lys Gly Leu Glu Tyr Ile Met Gln Ser

115 120 125

His Leu Thr Lys Ala Ala Gly Ser Arg Ala Gly Asp Gly Val Pro Gln

130 135 140

Val Ile Val Val Leu Thr Asp Gly His Ser Lys Asp Gly Leu Ala Leu

145 150 155 160

Pro Ser Ala Glu Leu Lys Ser Ala Asp Val Asn Val Phe Ala Ile Gly

165 170 175

Val Glu Asp Ala Asp Glu Gly Ala Leu Lys Glu Ile Ala Ser Glu Pro

180 185 190

Leu Asn Met His Met Phe Asn Leu Glu Asn Phe Thr Ser Leu His Asp

195 200 205

Ile Val Gly Asn Leu Val Ser Cys Val His Ser Ser Val Ser Pro Glu

210 215 220

Arg Ala Gly Asp Thr Glu Thr Leu Lys Asp Ile Thr Ala Gln Asp Ser

225 230 235 240

Ala Asp Ile Ile Phe Leu Ile Asp Gly Ser Asn Asn Thr Gly Ser Val

245 250 255

Asn Phe Ala Val Ile Leu Asp Phe Leu Val Asn Leu Leu Glu Lys Leu

260 265 270

Pro Ile Gly Thr Gln Gln Ile Arg Val Gly Val Val Gln Phe Ser Asp

275 280 285

Glu Pro Arg Thr Met Phe Ser Leu Asp Thr Tyr Ser Thr Lys Ala Gln

290 295 300

Val Leu Gly Ala Val Lys Ala Leu Gly Phe Ala Gly Gly Glu Leu Ala

305 310 315 320

Asn Ile Gly Leu Ala Leu Asp Phe Val Val Glu Asn His Phe Thr Arg

325 330 335

Ala Gly Gly Ser Arg Val Glu Glu Gly Val Pro Gln Val Leu Val Leu

340 345 350

Ile Ser Ala Gly Pro Ser Ser Asp Glu Ile Arg Tyr Gly Val Val Ala

355 360 365

Leu Lys Gln Ala Ser Val Phe Ser Phe Gly Leu Gly Ala Gln Ala Ala

370 375 380

Ser Arg Ala Glu Leu Gln His Ile Ala Thr Asp Asp Asn Leu Val Phe

385 390 395 400

Thr Val Pro Glu Phe Arg Ser Phe Gly Asp Leu Gln Glu Lys Leu Leu

405 410 415

Pro Tyr Ile Val Gly Val Ala Gln Arg His Ile Val Leu Lys Pro Pro

420 425 430

Thr Ile Val Thr Gln Val Ile Glu Val Asn Lys Arg Asp Ile Val Phe

435 440 445

Leu Val Asp Gly Ser Ser Ala Leu Gly Leu Ala Asn Phe Asn Ala Ile

450 455 460

Arg Asp Phe Ile Ala Lys Val Ile Gln Arg Leu Glu Ile Gly Gln Asp

465 470 475 480

Leu Ile Gln Val Ala Val Ala Gln Tyr Ala Asp Thr Val Arg Pro Glu

485 490 495

Phe Tyr Phe Asn Thr His Pro Thr Lys Arg Glu Val Ile Thr Ala Val

500 505 510

Arg Lys Met Lys Pro Leu Asp Gly Ser Ala Leu Tyr Thr Gly Ser Ala

515 520 525

Leu Asp Phe Val Arg Asn Asn Leu Phe Thr Ser Ser Ala Gly Tyr Arg

530 535 540

Ala Ala Glu Gly Ile Pro Lys Leu Leu Val Leu Ile Thr Gly Gly Lys

545 550 555 560

Ser Leu Asp Glu Ile Ser Gln Pro Ala Gln Glu Leu Lys Arg Ser Ser

565 570 575

Ile Met Ala Phe Ala Ile Gly Asn Lys Gly Ala Asp Gln Ala Glu Leu

580 585 590

Glu Glu Ile Ala Phe Asp Ser Ser Leu Val Phe Ile Pro Ala Glu Phe

595 600 605

Arg Ala Ala Pro Leu Gln Gly Met Leu Pro Gly Leu Leu Ala Pro Leu

610 615 620

Arg Thr Leu Ser Gly Thr Pro Glu Val His Ser Asn Lys Arg Asp Ile

625 630 635 640

Ile Phe Leu Leu Asp Gly Ser Ala Asn Val Gly Lys Thr Asn Phe Pro

645 650 655

Tyr Val Arg Asp Phe Val Met Asn Leu Val Asn Ser Leu Asp Ile Gly

660 665 670

Asn Asp Asn Ile Arg Val Gly Leu Val Gln Phe Ser Asp Thr Pro Val

675 680 685

Thr Glu Phe Ser Leu Asn Thr Tyr Gln Thr Lys Ser Asp Ile Leu Gly

690 695 700

His Leu Arg Gln Leu Gln Leu Gln Gly Gly Ser Gly Leu Asn Thr Gly

705 710 715 720

Ser Ala Leu Ser Tyr Val Tyr Ala Asn His Phe Thr Glu Ala Gly Gly

725 730 735

Ser Arg Ile Arg Glu His Val Pro Gln Leu Leu Leu Leu Leu Thr Ala

740 745 750

Gly Gln Ser Glu Asp Ser Tyr Leu Gln Ala Ala Asn Ala Leu Thr Arg

755 760 765

Ala Gly Ile Leu Thr Phe Cys Val Gly Ala Ser Gln Ala Asn Lys Ala

770 775 780

Glu Leu Glu Gln Ile Ala Phe Asn Pro Ser Leu Val Tyr Leu Met Asp

785 790 795 800

Asp Phe Ser Ser Leu Pro Ala Leu Pro Gln Gln Leu Ile Gln Pro Leu

805 810 815

Thr Thr Tyr Val Ser Gly Gly Val Glu Glu Val Pro Leu Ala Gln Pro

820 825 830

Glu Ser Lys Arg Asp Ile Leu Phe Leu Phe Asp Gly Ser Ala Asn Leu

835 840 845

Val Gly Gln Phe Pro Val Val Arg Asp Phe Leu Tyr Lys Ile Ile Asp

850 855 860

Glu Leu Asn Val Lys Pro Glu Gly Thr Arg Ile Ala Val Ala Gln Tyr

865 870 875 880

Ser Asp Asp Val Lys Val Glu Ser Arg Phe Asp Glu His Gln Ser Lys

885 890 895

Pro Glu Ile Leu Asn Leu Val Lys Arg Met Lys Ile Lys Thr Gly Lys

900 905 910

Ala Leu Asn Leu Gly Tyr Ala Leu Asp Tyr Ala Gln Arg Tyr Ile Phe

915 920 925

Val Lys Ser Ala Gly Ser Arg Ile Glu Asp Gly Val Leu Gln Phe Leu

930 935 940

Val Leu Leu Val Ala Gly Arg Ser Ser Asp Arg Val Asp Gly Pro Ala

945 950 955 960

Ser Asn Leu Lys Gln Ser Gly Val Val Pro Phe Ile Phe Gln Ala Lys

965 970 975

Asn Ala Asp Pro Ala Glu Leu Glu Gln Ile Val Leu Ser Pro Ala Phe

980 985 990

Ile Leu Ala Ala Glu Ser Leu Pro Lys Ile Gly Asp Leu His Pro Gln

995 1000 1005

Ile Val Asn Leu Leu Lys Ser Val His Asn Gly Ala Pro Ala Pro Val

1010 1015 1020

Ser Gly Glu Lys Asp Val Val Phe Leu Leu Asp Gly Ser Glu Gly Val

1025 1030 1035 1040

Arg Ser Gly Phe Pro Leu Leu Lys Glu Phe Val Gln Arg Val Val Glu

1045 1050 1055

Ser Leu Asp Val Gly Gln Asp Arg Val Arg Val Ala Val Val Gln Tyr

1060 1065 1070

Ser Asp Arg Thr Arg Pro Glu Phe Tyr Leu Asn Ser Tyr Met Asn Lys

1075 1080 1085

Gln Asp Val Val Asn Ala Val Arg Gln Leu Thr Leu Leu Gly Gly Pro

1090 1095 1100

Thr Pro Asn Thr Gly Ala Ala Leu Glu Phe Val Leu Arg Asn Ile Leu

1105 1110 1115 1120

Val Ser Ser Ala Gly Ser Arg Ile Thr Glu Gly Val Pro Gln Leu Leu

1125 1130 1135

Ile Val Leu Thr Ala Asp Arg Ser Gly Asp Asp Val Arg Asn Pro Ser

1140 1145 1150

Val Val Val Lys Arg Gly Gly Ala Val Pro Ile Gly Ile Gly Ile Gly

1155 1160 1165

Asn Ala Asp Ile Thr Glu Met Gln Thr Ile Ser Phe Ile Pro Asp Phe

1170 1175 1180

Ala Val Ala Ile Pro Thr Phe Arg Gln Leu Gly Thr Val Gln Gln Val

1185 1190 1195 1200

Ile Ser Glu Arg Val Thr Gln Leu Thr Arg Glu Glu Leu Ser Arg Leu

1205 1210 1215

Gln Pro Val Leu Gln Pro Leu Pro Ser Pro Gly Val Gly Gly Lys Arg

1220 1225 1230

Asp Val Val Phe Leu Ile Asp Gly Ser Gln Ser Ala Gly Pro Glu Phe

1235 1240 1245

Gln Tyr Val Arg Thr Leu Ile Glu Arg Leu Val Asp Tyr Leu Asp Val

1250 1255 1260

Gly Phe Asp Thr Thr Arg Val Ala Val Ile Gln Phe Ser Asp Asp Pro

1265 1270 1275 1280

Lys Val Glu Phe Leu Leu Asn Ala His Ser Ser Lys Asp Glu Val Gln

1285 1290 1295

Asn Ala Val Gln Arg Leu Arg Pro Lys Gly Gly Arg Gln Ile Asn Val

1300 1305 1310

Gly Asn Ala Leu Glu Tyr Val Ser Arg Asn Ile Phe Lys Arg Pro Leu

1315 1320 1325

Gly Ser Arg Ile Glu Glu Gly Val Pro Gln Phe Leu Val Leu Ile Ser

1330 1335 1340

Ser Gly Lys Ser Asp Asp Glu Val Asp Asp Pro Ala Val Glu Leu Lys

1345 1350 1355 1360

Gln Phe Gly Val Ala Pro Phe Thr Ile Ala Arg Asn Ala Asp Gln Glu

1365 1370 1375

Glu Leu Val Lys Ile Ser Leu Ser Pro Glu Tyr Val Phe Ser Val Ser

1380 1385 1390

Thr Phe Arg Glu Leu Pro Ser Leu Glu Gln Lys Leu Leu Thr Pro Ile

1395 1400 1405

Thr Thr Leu Thr Ser Glu Gln Ile Gln Lys Leu Leu Ala Ser Thr Arg

1410 1415 1420

Tyr Pro Pro Pro Ala Val Glu Ser Asp Ala Ala Asp Ile Val Phe Leu

1425 1430 1435 1440

Ile Asp Ser Ser Glu Gly Val Arg Pro Asp Gly Phe Ala His Ile Arg

1445 1450 1455

Asp Phe Val Ser Arg Ile Val Arg Arg Leu Asn Ile Gly Pro Ser Lys

1460 1465 1470

Val Arg Val Gly Val Val Gln Phe Ser Asn Asp Val Phe Pro Glu Phe

1475 1480 1485

Tyr Leu Lys Thr Tyr Arg Ser Gln Ala Pro Val Leu Asp Ala Ile Arg

1490 1495 1500

Arg Leu Arg Leu Arg Gly Gly Ser Pro Leu Asn Thr Gly Lys Ala Leu

1505 1510 1515 1520

Glu Phe Val Ala Arg Asn Leu Phe Val Lys Ser Ala Gly Ser Arg Ile

1525 1530 1535

Glu Asp Gly Val Pro Gln His Leu Val Leu Val Leu Gly Gly Lys Ser

1540 1545 1550

Gln Asp Asp Val Ser Arg Phe Ala Gln Val Ile Arg Ser Ser Gly Ile

1555 1560 1565

Val Ser Leu Gly Val Gly Asp Arg Asn Ile Asp Arg Thr Glu Leu Gln

1570 1575 1580

Thr Ile Thr Asn Asp Pro Arg Leu Val Phe Thr Val Arg Glu Phe Arg

1585 1590 1595 1600

Glu Leu Pro Asn Ile Glu Glu Arg Ile Met Asn Ser Phe Gly Pro Ser

1605 1610 1615

Ala Ala Thr Pro Ala Pro Pro Gly Val Asp Thr Pro Pro Pro Ser Arg

1620 1625 1630

Pro Glu Lys Lys Lys Ala Asp Ile Val Phe Leu Leu Asp Gly Ser Ile

1635 1640 1645

Asn Phe Arg Arg Asp Ser Phe Gln Glu Val Leu Arg Phe Val Ser Glu

1650 1655 1660

Ile Val Asp Thr Val Tyr Glu Asp Gly Asp Ser Ile Gln Val Gly Leu

1665 1670 1675 1680

Val Gln Tyr Asn Ser Asp Pro Thr Asp Glu Phe Phe Leu Lys Asp Phe

1685 1690 1695

Ser Thr Lys Arg Gln Ile Ile Asp Ala Ile Asn Lys Val Val Tyr Lys

1700 1705 1710

Gly Gly Arg His Ala Asn Thr Lys Val Gly Leu Glu His Leu Arg Val

1715 1720 1725

Asn His Phe Val Pro Glu Ala Gly Ser Arg Leu Asp Gln Arg Val Pro

1730 1735 1740

Gln Ile Ala Phe Val Ile Thr Gly Gly Lys Ser Val Glu Asp Ala Gln

1745 1750 1755 1760

Asp Val Ser Leu Ala Leu Thr Gln Arg Gly Val Lys Val Phe Ala Val

1765 1770 1775

Gly Val Arg Asn Ile Asp Ser Glu Glu Val Gly Lys Ile Ala Ser Asn

1780 1785 1790

Ser Ala Thr Ala Phe Arg Val Gly Asn Val Gln Glu Leu Ser Glu Leu

1795 1800 1805

Ser Glu Gln Val Leu Glu Thr Leu His Asp Ala Met His Glu Thr Leu

1810 1815 1820

Cys Pro Gly Val Thr Asp Ala Ala Lys Ala Cys Asn Leu Asp Val Ile

1825 1830 1835 1840

Leu Gly Phe Asp Gly Ser Arg Asp Gln Asn Val Phe Val Ala Gln Lys

1845 1850 1855

Gly Phe Glu Ser Lys Val Asp Ala Ile Leu Asn Arg Ile Ser Gln Met

1860 1865 1870

His Arg Val Ser Cys Ser Gly Gly Arg Ser Pro Thr Val Arg Val Ser

1875 1880 1885

Val Val Ala Asn Thr Pro Ser Gly Pro Val Glu Ala Phe Asp Phe Asp

1890 1895 1900

Glu Tyr Gln Pro Glu Met Leu Glu Lys Phe Arg Asn Met Arg Ser Gln

1905 1910 1915 1920

His Pro Tyr Val Leu Thr Glu Asp Thr Leu Lys Val Tyr Leu Asn Lys

1925 1930 1935

Phe Arg Gln Ser Ser Pro Asp Ser Val Lys Val Val Ile His Phe Thr

1940 1945 1950

Asp Gly Ala Asp Gly Asp Leu Ala Asp Leu His Arg Ala Ser Glu Asn

1955 1960 1965

Leu Arg Gln Glu Gly Val Arg Ala Leu Ile Leu Val Gly Leu Glu Arg

1970 1975 1980

Val Val Asn Leu Glu Arg Leu Met His Leu Glu Phe Gly Arg Gly Phe

1985 1990 1995 2000

Met Tyr Asp Arg Pro Leu Arg Leu Asn Leu Leu Asp Leu Asp Tyr Glu

2005 2010 2015

Leu Ala Glu Gln Leu Asp Asn Ile Ala Glu Lys Ala Cys Cys Gly Val

2020 2025 2030

Pro Cys Lys Cys Ser Gly Gln Arg Gly Asp Arg Gly Pro Ile Gly Ser

2035 2040 2045

Ile Gly Pro Lys Gly Ile Pro Gly Glu Asp Gly Tyr Arg Gly Tyr Pro

2050 2055 2060

Gly Asp Glu Gly Gly Pro Gly Glu Arg Gly Pro Pro Gly Val Asn Gly

2065 2070 2075 2080

Thr Gln Gly Phe Gln Gly Cys Pro Gly Gln Arg Gly Val Lys Gly Ser

2085 2090 2095

Arg Gly Phe Pro Gly Glu Lys Gly Glu Val Gly Glu Ile Gly Leu Asp

2100 2105 2110

Gly Leu Asp Gly Glu Asp Gly Asp Lys Gly Leu Pro Gly Ser Ser Gly

2115 2120 2125

Glu Lys Gly Asn Pro Gly Arg Arg Gly Asp Lys Gly Pro Arg Gly Glu

2130 2135 2140

Lys Gly Glu Arg Gly Asp Val Gly Ile Arg Gly Asp Pro Gly Asn Pro

2145 2150 2155 2160

Gly Gln Asp Ser Gln Glu Arg Gly Pro Lys Gly Glu Thr Gly Asp Leu

2165 2170 2175

Gly Pro Met Gly Val Pro Gly Arg Asp Gly Val Pro Gly Gly Pro Gly

2180 2185 2190

Glu Thr Gly Lys Asn Gly Gly Phe Gly Arg Arg Gly Pro Pro Gly Ala

2195 2200 2205

Lys Gly Asn Lys Gly Gly Pro Gly Gln Pro Gly Phe Glu Gly Glu Gln

2210 2215 2220

Gly Thr Arg Gly Ala Gln Gly Pro Ala Gly Pro Ala Gly Pro Pro Gly

2225 2230 2235 2240

Leu Ile Gly Glu Gln Gly Ile Ser Gly Pro Arg Gly Ser Gly Gly Ala

2245 2250 2255

Ala Gly Ala Pro Gly Glu Arg Gly Arg Thr Gly Pro Leu Gly Arg Lys

2260 2265 2270

Gly Glu Pro Gly Glu Pro Gly Pro Lys Gly Gly Ile Gly Asn Arg Gly

2275 2280 2285

Pro Arg Gly Glu Thr Gly Asp Asp Gly Arg Asp Gly Val Gly Ser Glu

2290 2295 2300

Gly Arg Arg Gly Lys Lys Gly Glu Arg Gly Phe Pro Gly Tyr Pro Gly

2305 2310 2315 2320

Pro Lys Gly Asn Pro Gly Glu Pro Gly Leu Asn Gly Thr Thr Gly Pro

2325 2330 2335

Lys Gly Ile Arg Gly Arg Arg Gly Asn Ser Gly Pro Pro Gly Ile Val

2340 2345 2350

Gly Gln Lys Gly Asp Pro Gly Tyr Pro Gly Pro Ala Gly Pro Lys Gly

2355 2360 2365

Asn Arg Gly Asp Ser Ile Asp Gln Cys Ala Leu Ile Gln Ser Ile Lys

2370 2375 2380

Asp Lys Cys Pro Cys Cys Tyr Gly Pro Leu Glu Cys Pro Val Phe Pro

2385 2390 2395 2400

Thr Glu Leu Ala Phe Ala Leu Asp Thr Ser Glu Gly Val Asn Gln Asp

2405 2410 2415

Thr Phe Gly Arg Met Arg Asp Val Val Leu Ser Ile Val Asn Asp Leu

2420 2425 2430

Thr Ile Ala Glu Ser Asn Cys Pro Arg Gly Ala Arg Val Ala Val Val

2435 2440 2445

Thr Tyr Asn Asn Glu Val Thr Thr Glu Ile Arg Phe Ala Asp Ser Lys

2450 2455 2460

Arg Lys Ser Val Leu Leu Asp Lys Ile Lys Asn Leu Gln Val Ala Leu

2465 2470 2475 2480

Thr Ser Lys Gln Gln Ser Leu Glu Thr Ala Met Ser Phe Val Ala Arg

2485 2490 2495

Asn Thr Phe Lys Arg Val Arg Asn Gly Phe Leu Met Arg Lys Val Ala

2500 2505 2510

Val Phe Phe Ser Asn Thr Pro Thr Arg Ala Ser Pro Gln Leu Arg Glu

2515 2520 2525

Ala Val Leu Lys Leu Ser Asp Ala Gly Ile Thr Pro Leu Phe Leu Thr

2530 2535 2540

Arg Gln Glu Asp Arg Gln Leu Ile Asn Ala Leu Gln Ile Asn Asn Thr

2545 2550 2555 2560

Ala Val Gly His Ala Leu Val Leu Pro Ala Gly Arg Asp Leu Thr Asp

2565 2570 2575

Phe Leu Glu Asn Val Leu Thr Cys His Val Cys Leu Asp Ile Cys Asn

2580 2585 2590

Ile Asp Pro Ser Cys Gly Phe Gly Ser Trp Arg Pro Ser Phe Arg Asp

2595 2600 2605

Arg Arg Ala Ala Gly Ser Asp Val Asp Ile Asp Met Ala Phe Ile Leu

2610 2615 2620

Asp Ser Ala Glu Thr Thr Thr Leu Phe Gln Phe Asn Glu Met Lys Lys

2625 2630 2635 2640

Tyr Ile Ala Tyr Leu Val Arg Gln Leu Asp Met Ser Pro Asp Pro Lys

2645 2650 2655

Ala Ser Gln His Phe Ala Arg Val Ala Val Val Gln His Ala Pro Ser

2660 2665 2670

Glu Ser Val Asp Asn Ala Ser Met Pro Pro Val Lys Val Glu Phe Ser

2675 2680 2685

Leu Thr Asp Tyr Gly Ser Lys Glu Lys Leu Val Asp Phe Leu Ser Arg

2690 2695 2700

Gly Met Thr Gln Leu Gln Gly Thr Arg Ala Leu Gly Ser Ala Ile Glu

2705 2710 2715 2720

Tyr Thr Ile Glu Asn Val Phe Glu Ser Ala Pro Asn Pro Arg Asp Leu

2725 2730 2735

Lys Ile Val Val Leu Met Leu Thr Gly Glu Val Pro Glu Gln Gln Leu

2740 2745 2750

Glu Glu Ala Gln Arg Val Ile Leu Gln Ala Lys Cys Lys Gly Tyr Phe

2755 2760 2765

Phe Val Val Leu Gly Ile Gly Arg Lys Val Asn Ile Lys Glu Val Tyr

2770 2775 2780

Thr Phe Ala Ser Glu Pro Asn Asp Val Phe Phe Lys Leu Val Asp Lys

2785 2790 2795 2800

Ser Thr Glu Leu Asn Glu Glu Pro Leu Met Arg Phe Gly Arg Leu Leu

2805 2810 2815

Pro Ser Phe Val Ser Ser Glu Asn Ala Phe Tyr Leu Ser Pro Asp Ile

2820 2825 2830

Arg Lys Gln Cys Asp Trp Phe Gln Gly Asp Gln Pro Thr Lys Asn Leu

2835 2840 2845

Val Lys Phe Gly His Lys Gln Val Asn Val Pro Asn Asn Val Thr Ser

2850 2855 2860

Ser Pro Thr Ser Asn Pro Val Thr Thr Thr Lys Pro Val Thr Thr Thr

2865 2870 2875 2880

Lys Pro Val Thr Thr Thr Thr Lys Pro Val Thr Thr Thr Thr Lys Pro

2885 2890 2895

Val Thr Ile Ile Asn Gln Pro Ser Val Lys Pro Ala Ala Ala Lys Pro

2900 2905 2910

Ala Pro Ala Lys Pro Val Ala Ala Lys Pro Val Ala Thr Lys Met Ala

2915 2920 2925

Thr Val Arg Pro Pro Val Ala Val Lys Pro Ala Thr Ala Ala Lys Pro

2930 2935 2940

Val Ala Ala Lys Pro Ala Ala Val Arg Pro Pro Ala Ala Ala Ala Ala

2945 2950 2955 2960

Lys Pro Val Ala Thr Lys Pro Glu Val Pro Arg Pro Gln Ala Ala Lys

2965 2970 2975

Pro Ala Ala Thr Lys Pro Ala Thr Thr Lys Pro Met Val Lys Met Ser

2980 2985 2990

Arg Glu Val Gln Val Phe Glu Ile Thr Glu Asn Ser Ala Lys Leu His

2995 3000 3005

Trp Glu Arg Ala Glu Pro Pro Gly Pro Tyr Phe Tyr Asp Leu Thr Val

3010 3015 3020

Thr Ser Ala His Asp Gln Ser Leu Val Leu Lys Gln Asn Leu Thr Val

3025 3030 3035 3040

Thr Asp Arg Val Ile Gly Gly Leu Leu Ala Gly Gln Thr Tyr His Val

3045 3050 3055

Ala Val Val Cys Tyr Leu Arg Ser Gln Val Arg Ala Thr Tyr His Gly

3060 3065 3070

Ser Phe Ser Thr Lys Lys Ser Gln Pro Pro Pro Pro Gln Pro Ala Arg

3075 3080 3085

Ser Ala Ser Ser Ser Thr Ile Asn Leu Met Val Ser Thr Glu Pro Leu

3090 3095 3100

Ala Leu Thr Glu Thr Asp Ile Cys Lys Leu Pro Lys Asp Glu Gly Thr

3105 3110 3115 3120

Cys Arg Asp Phe Ile Leu Lys Trp Tyr Tyr Asp Pro Asn Thr Lys Ser

3125 3130 3135

Cys Ala Arg Phe Trp Tyr Gly Gly Cys Gly Gly Asn Glu Asn Lys Phe

3140 3145 3150

Gly Ser Gln Lys Glu Cys Glu Lys Val Cys Ala Pro Val Leu Ala Lys

3155 3160 3165

Pro Gly Val Ile Ser Val Met Gly Thr

3170 3175

<210> 4

<211> 1025

<212> PRT

<213> Rattus norvegicus

<400> 4

Met Arg Leu Ala His Thr Leu Leu Pro Leu Leu Leu Gln Ala Cys Trp

1 5 10 15

Val Ala Ala Gln Asp Ile Gln Gly Ser Arg Ala Ile Ala Phe Gln Asp

20 25 30

Cys Pro Val Asp Leu Phe Phe Val Leu Asp Thr Ser Glu Ser Val Ala

35 40 45

Leu Arg Leu Lys Pro Tyr Gly Ala Leu Val Asp Lys Val Lys Ser Phe

50 55 60

Thr Lys Arg Phe Ile Asp Asn Leu Arg Asp Arg Tyr Tyr Arg Cys Asp

65 70 75 80

Arg Asn Leu Val Trp Asn Ala Gly Ala Leu His Tyr Ser Asp Glu Val

85 90 95

Glu Ile Ile Arg Gly Leu Met Arg Met Pro Ser Gly Arg Asp Glu Leu

100 105 110

Lys Ala Ser Ile Asp Ala Val Lys Tyr Phe Gly Lys Gly Thr Tyr Thr

115 120 125

Asp Cys Ala Ile Lys Lys Gly Leu Glu Glu Leu Leu Ile Gly Gly Ser

130 135 140

His Leu Lys Glu Asn Lys Tyr Leu Ile Val Val Thr Asp Gly His Pro

145 150 155 160

Leu Glu Gly Tyr Lys Glu Pro Cys Gly Gly Leu Glu Asp Ala Val Asn

165 170 175

Glu Ala Lys His Leu Gly Ile Lys Val Phe Ser Val Ala Ile Thr Pro

180 185 190

Asp His Leu Glu Pro Arg Leu Ser Ile Ile Ala Thr Asp His Thr Tyr

195 200 205

Arg Arg Asn Phe Thr Ala Ala Asp Trp Gly His Ser Arg Asp Ala Glu

210 215 220

Glu Thr Ile Ser Gln Thr Ile Asp Thr Ile Val Asp Met Ile Lys Asn

225 230 235 240

Asn Val Glu Gln Val Cys Cys Thr Phe Glu Cys Gln Ala Ala Arg Gly

245 250 255

Pro Pro Gly Pro Arg Gly Asp Pro Gly Tyr Glu Gly Glu Arg Gly Lys

260 265 270

Pro Gly Leu Pro Gly Glu Lys Gly Glu Ala Gly Asp Pro Gly Arg Pro

275 280 285

Gly Asp Leu Gly Pro Val Gly Tyr Gln Gly Met Lys Gly Glu Lys Gly

290 295 300

Ser Arg Gly Glu Lys Gly Ser Arg Gly Pro Lys Gly Tyr Lys Gly Glu

305 310 315 320

Lys Gly Lys Arg Gly Ile Asp Gly Val Asp Gly Met Lys Gly Glu Thr

325 330 335

Gly Tyr Pro Gly Leu Pro Gly Cys Lys Gly Ser Pro Gly Phe Asp Gly

340 345 350

Ile Gln Gly Pro Pro Gly Pro Lys Gly Asp Ala Gly Ala Phe Gly Leu

355 360 365

Lys Gly Glu Lys Gly Glu Ala Gly Ala Glu Gly Glu Ala Gly Arg Pro

370 375 380

Gly Asn Ser Gly Pro Pro Gly Asp Glu Gly Glu Pro Gly Glu Pro Gly

385 390 395 400

Pro Pro Gly Glu Lys Gly Glu Ala Gly Asp Glu Gly Asn Ala Gly Pro

405 410 415

Asp Gly Ala Pro Gly Glu Arg Gly Gly Pro Gly Glu Arg Gly Pro Arg

420 425 430

Gly Thr Pro Gly Val Arg Gly Pro Arg Gly Asp Pro Gly Glu Ala Gly

435 440 445

Pro Gln Gly Asp Gln Gly Arg Glu Gly Pro Val Gly Ile Pro Gly Asp

450 455 460

Pro Gly Glu Ser Gly Pro Ile Gly Pro Lys Gly Tyr Arg Gly Asp Glu

465 470 475 480

Gly Pro Pro Gly Pro Glu Gly Leu Arg Gly Ala Pro Gly Pro Val Gly

485 490 495

Pro Pro Gly Asp Pro Gly Leu Met Gly Glu Arg Gly Glu Asp Gly Pro

500 505 510

Pro Gly Asn Gly Thr Glu Gly Phe Pro Gly Phe Pro Gly Tyr Pro Gly

515 520 525

Asn Arg Gly Pro Pro Gly Ile Asn Gly Thr Lys Gly Tyr Pro Gly Leu

530 535 540

Lys Gly Asp Glu Gly Glu Ala Gly Asp Pro Gly Glu Asp Asn Asn Asp

545 550 555 560

Val Ser Pro Arg Gly Val Lys Gly Ala Lys Gly Tyr Arg Gly Pro Glu

565 570 575

Gly Pro Gln Gly Pro Pro Gly His Val Gly Pro Pro Gly Pro Asp Glu

580 585 590

Cys Glu Ile Leu Asp Ile Ile Met Lys Met Cys Ser Cys Cys Glu Cys

595 600 605

Thr Cys Gly Pro Ile Asp Ile Leu Phe Val Leu Asp Ser Ser Glu Ser

610 615 620

Ile Gly Leu Gln Asn Phe Glu Ile Ala Lys Asp Phe Ile Ile Lys Val

625 630 635 640

Ile Asp Arg Leu Ser Lys Asp Glu Leu Val Lys Phe Glu Pro Gly Gln

645 650 655

Ser His Ala Gly Val Val Gln Tyr Ser His Asn Gln Met Gln Glu His

660 665 670

Val Asp Met Arg Ser Pro Asn Val Arg Asn Ala Gln Asp Phe Lys Glu

675 680 685

Ala Val Lys Lys Leu Gln Trp Met Ala Gly Gly Thr Phe Thr Gly Glu

690 695 700

Ala Leu Gln Tyr Thr Arg Asp Arg Leu Leu Pro Pro Thr Gln Asn Asn

705 710 715 720

Arg Ile Ala Leu Val Ile Thr Asp Gly Arg Ser Asp Thr Gln Arg Asp

725 730 735

Thr Thr Pro Leu Ser Val Leu Cys Gly Ser Asp Ile Gln Val Val Ser

740 745 750

Val Gly Ile Lys Asp Val Phe Gly Phe Val Ala Gly Ser Asp Gln Leu

755 760 765

Asn Val Ile Ser Cys Gln Gly Leu Ser Gln Ser Arg Pro Gly Ile Ser

770 775 780

Leu Val Lys Glu Asn Tyr Ala Glu Leu Leu Asp Asp Gly Phe Leu Lys

785 790 795 800

Asn Ile Thr Ala Gln Ile Cys Ile Asp Lys Lys Cys Pro Asp Tyr Thr

805 810 815

Cys Pro Ile Thr Phe Ser Ser Pro Thr Asp Ile Thr Ile Leu Leu Asp

820 825 830

Ser Ser Ala Ser Val Gly Ser His Asn Phe Glu Thr Thr Lys Val Phe

835 840 845

Ala Lys Arg Leu Ala Glu Arg Phe Leu Ser Ala Gly Arg Glu Asp Pro

850 855 860

Thr Gln Val Val Arg Val Ala Val Val Gln Tyr Ser Gly Gln Gly Gln

865 870 875 880

Gln Gln Pro Gly Arg Ala Ser Leu Gln Phe Gln Gln Asn Tyr Thr Val

885 890 895

Leu Ala Ser Ser Val Asp Ser Met Asp Phe Ile Asn Asp Ala Thr Asp

900 905 910

Val Asn Asp Ala Leu Ser Tyr Val Thr Arg Phe Tyr Arg Glu Asn Ser

915 920 925

Ser Gly Ala Thr Lys Lys Arg Val Leu Leu Phe Ser Asp Gly Asn Ser

930 935 940

Gln Gly Ala Thr Ala Glu Ala Ile Glu Lys Ala Val Gln Glu Ala Gln

945 950 955 960

Arg Gly Gly Ile Glu Ile Phe Val Met Val Val Gly Pro Gln Val Asn

965 970 975

Glu Pro His Ile Arg Val Leu Val Thr Gly Lys Thr Ala Glu Tyr Asp

980 985 990

Val Ala Phe Gly Glu Arg His Leu Phe Arg Val Pro Asn Tyr Gln Ala

995 1000 1005

Leu Leu Arg Gly Val Leu Tyr Gln Thr Val Ser Arg Lys Val Ala Leu

1010 1015 1020

Gly

1025

<210> 5

<211> 1027

<212> PRT

<213> Rattus norvegicus

<400> 5

Met Thr Thr Thr Thr Lys Met Leu Gln Gly Ser Phe Ser Val Leu Leu

1 5 10 15

Leu Gly Gly Leu Leu Gly Val Leu His Ala Gln Gln Gln Glu Ala Ile

20 25 30

Ser Pro Asp Ile Ser Thr Thr Asp Arg Asn Asn Asn Cys Pro Glu Lys

35 40 45

Ala Asp Cys Pro Val Asn Val Tyr Phe Val Leu Asp Thr Ser Glu Ser

50 55 60

Val Ala Met Gln Ser Pro Thr Asp Ser Leu Leu Tyr His Met Gln Gln

65 70 75 80

Phe Val Pro Gln Phe Ile Ser Gln Leu Gln Asn Glu Phe Tyr Leu Glu

85 90 95

Gln Val Ala Leu Ser Trp Arg Tyr Gly Gly Leu His Phe Ser Asp Gln

100 105 110

Val Glu Val Phe Ser Pro Pro Gly Ser Asp Arg Ala Ser Phe Thr Lys

115 120 125

Ser Leu Gln Gly Ile Arg Ser Phe Arg Arg Gly Thr Phe Thr Asp Cys

130 135 140

Ala Leu Ala Asn Met Thr Gln Gln Ile Arg Gln His Val Gly Arg Gly

145 150 155 160

Val Val Asn Phe Ala Val Val Ile Thr Asp Gly His Val Thr Gly Asn

165 170 175

Pro Cys Gly Gly Ile Lys Met Gln Ala Glu Arg Ala Arg Glu Glu Gly

180 185 190

Ile Arg Leu Phe Ala Val Ala Pro Asn Arg Asn Leu Asn Glu Gln Gly

195 200 205

Leu Arg Asp Ile Ala Asn Thr Pro His Glu Leu Tyr Arg Asn Asn Tyr

210 215 220

Ala Thr Met Arg Pro Asp Ser Thr Glu Ile Asp Gln Asp Thr Ile Asn

225 230 235 240

Arg Ile Ile Lys Val Met Lys His Glu Ala Tyr Gly Glu Cys Tyr Lys

245 250 255

Val Ser Cys Leu Glu Ile Pro Gly Pro His Gly Pro Lys Gly Tyr Arg

260 265 270

Gly Gln Lys Gly Ala Lys Gly Asn Met Gly Glu Pro Gly Glu Pro Gly

275 280 285

Gln Lys Gly Arg Gln Gly Asp Pro Gly Ile Glu Gly Pro Ile Gly Phe

290 295 300

Pro Gly Pro Lys Gly Val Pro Gly Phe Lys Gly Glu Lys Gly Glu Phe

305 310 315 320

Gly Ser Asp Gly Arg Lys Gly Ala Pro Gly Leu Ala Gly Lys Asn Gly

325 330 335

Thr Asp Gly Gln Lys Gly Lys Leu Gly Arg Ile Gly Pro Pro Gly Cys

340 345 350

Lys Gly Asp Pro Gly Ser Arg Gly Pro Asp Gly Tyr Pro Gly Glu Ala

355 360 365

Gly Ser Pro Gly Glu Gln Gly Asp Gln Gly Ala Lys Gly Asp Ser Gly

370 375 380

Arg Pro Gly Arg Arg Gly Pro Pro Gly Asn Pro Gly Asp Lys Gly Ser

385 390 395 400

Lys Gly Tyr Arg Gly Asn Ser Gly Ala Pro Gly Ser Pro Gly Val Lys

405 410 415

Gly Gly Lys Gly Gly Pro Gly Pro Arg Gly Pro Lys Gly Glu Pro Gly

420 425 430

Arg Arg Gly Asp Pro Gly Thr Lys Gly Gly Pro Gly Ser Asp Gly Pro

435 440 445

Lys Gly Glu Lys Gly Asp Pro Gly Pro Glu Gly Pro Arg Gly Leu Ala

450 455 460

Gly Glu Ile Gly Ser Lys Gly Ala Lys Gly Asp Arg Gly Leu Pro Gly

465 470 475 480

Pro Arg Gly Pro Gln Gly Ala Leu Gly Glu Pro Gly Lys Gln Gly Ser

485 490 495

Arg Gly Asp Pro Gly Asp Ala Gly Pro Arg Gly Asp Ser Gly Gln Pro

500 505 510

Gly Pro Lys Gly Asp Pro Gly Arg Pro Gly Phe Ser Tyr Pro Gly Pro

515 520 525

Arg Gly Thr Pro Gly Glu Lys Gly Glu Pro Gly Pro Pro Gly Pro Glu

530 535 540

Gly Gly Arg Gly Asp Phe Gly Leu Lys Gly Ala Pro Gly Arg Lys Gly

545 550 555 560

Glu Lys Gly Glu Pro Ala Asp Pro Gly Pro Pro Gly Glu Pro Gly Pro

565 570 575

Arg Gly Pro Arg Gly Ile Pro Gly Pro Glu Gly Glu Pro Gly Pro Pro

580 585 590

Gly Asp Pro Gly Leu Thr Glu Cys Asp Val Met Thr Tyr Val Arg Glu

595 600 605

Thr Cys Gly Cys Cys Asp Cys Glu Lys Arg Cys Gly Ala Leu Asp Val

610 615 620

Val Phe Val Ile Asp Ser Ser Glu Ser Ile Gly Tyr Thr Asn Phe Thr

625 630 635 640

Leu Glu Lys Asn Phe Val Ile Asn Val Val Asn Arg Leu Gly Ala Ile

645 650 655

Ala Lys Asp Pro Lys Ser Glu Thr Gly Thr Arg Val Gly Val Val Gln

660 665 670

Tyr Ser His Glu Gly Thr Phe Glu Ala Ile Arg Leu Asp Asp Glu Arg

675 680 685

Val Asn Ser Leu Ser Ser Phe Lys Glu Ala Val Lys Asn Leu Glu Trp

690 695 700

Ile Ala Gly Gly Thr Trp Thr Pro Ser Ala Leu Lys Phe Ala Tyr Asn

705 710 715 720

Gln Leu Ile Lys Glu Ser Arg Arg Gln Lys Thr Arg Val Phe Ala Val

725 730 735

Val Ile Thr Asp Gly Arg His Asp Pro Arg Asp Asp Asp Leu Asn Leu

740 745 750

Arg Ala Leu Cys Asp Arg Asp Val Thr Val Thr Ala Ile Gly Ile Gly

755 760 765

Asp Met Phe His Glu Thr His Glu Ser Glu Asn Leu Tyr Ser Ile Ala

770 775 780

Cys Asp Lys Pro Gln Gln Val Arg Asn Met Thr Leu Phe Ser Asp Leu

785 790 795 800

Val Ala Glu Lys Phe Ile Asp Asp Met Glu Asp Val Leu Cys Pro Asp

805 810 815

Pro Gln Ile Val Cys Pro Glu Leu Pro Cys Gln Thr Glu Leu Tyr Val

820 825 830

Ala Gln Cys Thr Gln Arg Pro Val Asp Ile Val Phe Leu Leu Asp Gly

835 840 845

Ser Glu Arg Leu Gly Glu Gln Asn Phe Tyr Lys Ala Arg Arg Phe Val

850 855 860

Glu Glu Val Ser Arg Arg Leu Thr Leu Ala Arg Arg Asp Asp Asp Pro

865 870 875 880

Leu Asn Ala Arg Met Ala Leu Leu Gln Tyr Gly Ser Gln Asn Gln Gln

885 890 895

Gln Val Ala Phe Pro Leu Thr Tyr Asn Val Thr Thr Ile His Glu Ala

900 905 910

Leu Glu Arg Thr Thr Tyr Leu Asn Ser Phe Ser His Val Gly Thr Gly

915 920 925

Ile Val His Ala Ile Asn Asn Val Val Arg Gly Ala Arg Gly Gly Ala

930 935 940

Arg Arg His Ala Glu Leu Ser Phe Val Phe Leu Thr Asp Gly Val Thr

945 950 955 960

Gly Asn Asp Ser Leu Glu Glu Ser Val His Ser Met Arg Lys Gln Asn

965 970 975

Val Val Pro Thr Val Val Ala Val Gly Gly Asp Val Asp Met Asp Val

980 985 990

Leu Thr Lys Ile Ser Leu Gly Asp Arg Ala Ala Ile Phe Arg Glu Lys

995 1000 1005

Asp Phe Asp Ser Leu Ala Gln Pro Ser Phe Phe Asp Arg Phe Ile Arg

1010 1015 1020

Trp Ile Cys

1025

<210> 6

<211> 3237

<212> PRT

<213> Rattus norvegicus

<400> 6

Met Arg Lys His Arg His Leu Pro Leu Val Ala Val Phe Ser Leu Leu

1 5 10 15

Leu Ser Gly Ile Thr Met Thr His Ala Gln Gln Gln Ser Asp Val Lys

20 25 30

Asn Gly Ala Ala Ala Asp Ile Leu Phe Leu Val Asp Ser Ser Trp Ser

35 40 45

Ala Gly Lys Asp Arg Phe Leu Leu Val Gln Glu Phe Leu Ser Asp Val

50 55 60

Val Glu Ser Leu Ser Val Gly Asp Asn Asp Phe His Phe Ala Leu Val

65 70 75 80

Arg Leu Asn Gly Asn Pro His Thr Glu Phe Leu Leu Asn Ala Tyr His

85 90 95

Ser Lys Gln Glu Val Leu Ser His Ile Leu Asn Met Ser Tyr Ile Gly

100 105 110

Glu Ser Asn Gln Thr Gly Lys Gly Leu Glu Tyr Ile Ile His Ser His

115 120 125

Leu Thr Glu Ala Ser Gly Ser Arg Ala Ala Asp Gly Val Pro Gln Val

130 135 140

Ile Val Val Leu Thr Asp Gly Gln Ser Glu Glu Asp Gly Phe Ala Leu

145 150 155 160

Pro Ser Ala Glu Leu Lys Ser Ala Asp Val Asn Val Phe Ala Val Gly

165 170 175

Val Glu Asp Ala Asp Glu Arg Thr Leu Arg Glu Ile Ala Ser Glu Pro

180 185 190

Leu Ser Met His Val Phe Asn Leu Glu Asn Val Thr Ser Leu His Asp

195 200 205

Met Val Gly Asn Leu Val Ser Cys Ile His Ser Ser Val Asn Pro Glu

210 215 220

Arg Ala Gly Asp Lys Glu Ser Leu Lys Asp Ile Thr Ala Gln Asp Ser

225 230 235 240

Ala Asp Ile Ile Phe Leu Ile Asp Gly Ser Gln Asn Thr Gly Lys Ala

245 250 255

Asn Phe Asp Val Ile Arg Asp Phe Leu Val Asn Val Leu Glu Arg Leu

260 265 270

Ser Val Gly Asn Gln Gln Val Arg Val Gly Val Val Gln Tyr Ser Asp

275 280 285

Glu Pro Arg Thr Met Phe Ser Leu Asp Ser Tyr Pro Ser Lys Ala Ala

290 295 300

Val Leu Asp Ala Val Lys Arg Leu Ser Phe Ala Gly Gly Glu Leu Ala

305 310 315 320

Asn Ile Gly Gln Ala Leu Asp Phe Val Val Glu Asn His Phe Thr Arg

325 330 335

Thr Gly Gly Ser Arg Val Glu Glu Gly Val Pro Gln Val Leu Val Leu

340 345 350

Ile Ser Ala Gly Pro Ser Ser Asp Glu Ile Arg Asp Ala Val Val Ala

355 360 365

Leu Lys Gln Gly Ser Val Phe Ser Phe Gly Leu Gly Ala Gln Ala Ala

370 375 380

Ser Arg Val Glu Leu Gln His Ile Ala Thr Asp Asp Asn Leu Val Phe

385 390 395 400

Thr Val Pro Glu Phe Arg Ser Phe Gly Asp Leu Gln Glu Gln Leu Leu

405 410 415

Pro Tyr Leu Val Gly Val Ala Gln Arg His Phe Val Leu Gln Pro Pro

420 425 430

Ala Ile Val Thr Gln Val Met Glu Val Asn Lys Arg Asp Ile Val Phe

435 440 445

Leu Val Asp Gly Ser Ser Ser Leu Gly Gln Ala Asn Phe Asn Ala Ile

450 455 460

Arg Asp Phe Ile Ser Arg Val Ile Gln Arg Leu Glu Ile Gly Gln Asp

465 470 475 480

Leu Val Gln Val Ser Val Ala Gln Tyr Ala Asp Thr Val Lys Pro Glu

485 490 495

Phe Tyr Leu Asn Thr Tyr Ser Thr Lys Lys Asp Ala Ile Thr Thr Val

500 505 510

Arg Lys Met Lys Ala Leu Glu Gly Ser Ala Leu Tyr Thr Gly Ser Ala

515 520 525

Leu Asp Phe Val Arg Asn Asn Leu Phe Thr Ser Ser Ala Gly His Arg

530 535 540

Ala Ala Glu Gly Val Pro Lys Leu Leu Val Leu Ile Thr Gly Gly Lys

545 550 555 560

Ser Leu Asp Asp Val Ser Gln Ala Ala Gln Glu Leu Gln Lys Gly Ser

565 570 575

Ile Met Ala Leu Val Ile Gly Ser Arg Ala Ala Asp Glu Asp Glu Leu

580 585 590

Lys Glu Ile Ala Phe Asp Ser Ser Leu Val Phe Ile Pro Ala Glu Phe

595 600 605

Arg Pro Ala Pro Leu Gln Ser Met Leu Pro Ser Leu Met Ala Pro Leu

610 615 620

Arg Thr Leu Thr Gly Thr Thr Glu Val His Val Asn Lys Arg Asp Ile

625 630 635 640

Ile Phe Leu Leu Asp Gly Ser Asp Asn Val Gly Lys Asn Asn Phe Pro

645 650 655

Tyr Val Arg Asp Phe Val Thr Asn Leu Val Asn Ser Leu Asp Val Gly

660 665 670

Ser Asp Asn Ile Arg Val Gly Leu Val Gln Phe Ser Asp Thr Pro Val

675 680 685

Thr Glu Phe Ser Leu Asp Thr Tyr Gln Thr Lys Ser Glu Leu Leu Ala

690 695 700

His Leu Arg Arg Leu Gln Leu Lys Gly Gly Thr Gly Leu Asn Ala Gly

705 710 715 720

Ser Ala Leu Ser Tyr Val His Ala Asn His Phe Thr Glu Ala Gly Gly

725 730 735

Ser Arg Ile Arg Glu His Val Pro Gln Leu Leu Leu Leu Leu Met Ala

740 745 750

Gly Pro Ser Glu Asp Val Tyr Leu Gln Ala Ala Asn Ala Leu Val Arg

755 760 765

Ser Gly Val Leu Thr Phe Cys Val Gly Thr Asn Gln Ala Asp Lys Ala

770 775 780

Glu Leu Glu Arg Ile Ala Phe Asn Pro Ser Leu Val Tyr Leu Met Asp

785 790 795 800

Asp Phe Ser Ala Leu Pro Ala Leu Pro Gln Gln Leu Ile Gln Pro Leu

805 810 815

Thr Thr Tyr Val Ser Gly Gly Val Gln Glu Val Pro Leu Ser Gln Pro

820 825 830

Glu Val Lys Arg Asp Ile Leu Phe Leu Phe Asp Gly Ser Val Asn Val

835 840 845

Met Gly Gln Phe Pro Ala Val Arg Asp Phe Leu Tyr Arg Ile Ile Glu

850 855 860

Glu Leu Asp Val Lys Pro Asp Gly Thr Arg Val Ala Ile Ala Gln Phe

865 870 875 880

Ser Asp Asp Val Arg Val Glu Ser Arg Phe Asn Glu His Gln Thr Lys

885 890 895

Ala Glu Ile Leu Asn Leu Val Lys Lys Met Lys Leu Lys Thr Gly Lys

900 905 910

Gly Leu Asn Leu Gly Leu Ala Leu Asp His Ala Leu Arg Thr Ile Phe

915 920 925

Val Arg Ser Ala Gly Ser Arg Ile Glu Asp Asn Val Gln Gln Phe Leu

930 935 940

Val Leu Leu Val Ala Gly Arg Ser Thr Asp Ala Val Ala Gly Pro Ala

945 950 955 960

Ser Ser Leu Lys Gln Arg Gly Val Ile Pro Phe Ile Phe Gln Ala Lys

965 970 975

Asn Ala Asn Pro Ser Glu Leu Glu Gln Ile Val Pro Ser Pro Ala Phe

980 985 990

Ile Leu Ala Ala Glu Ser Leu Pro Lys Ile Gly Asp Leu Gln Ser Glu

995 1000 1005

Ile Val Gly Leu Leu Lys Ala Lys Gln Thr Ser Asp Thr Val Ser Gly

1010 1015 1020

Glu Lys Asp Val Val Phe Leu Ile Asp Gly Ser Glu Gly Val Arg Ser

1025 1030 1035 1040

Gly Phe Pro Leu Leu Lys Glu Phe Val Gln Arg Val Val Glu Ser Leu

1045 1050 1055

Asp Val Gly Pro Asn Gln Val Arg Val Ala Leu Val Gln Tyr Ser Asp

1060 1065 1070

Arg Thr Arg Pro Glu Phe Tyr Leu Asn Ser His Met Asp Gln Gln Gly

1075 1080 1085

Val Ile Ser Ala Ile Arg Arg Leu Thr Leu Leu Gly Gly Pro Thr Pro

1090 1095 1100

Asn Thr Gly Ala Ala Leu Asp Phe Val Leu Arg Asn Ile Leu Thr Ser

1105 1110 1115 1120

Ser Thr Gly Ser Arg Ile Glu Glu Gly Val Pro Gln Leu Leu Ile Val

1125 1130 1135

Leu Thr Ala Glu Arg Ser Gly Asp Asp Val Arg Gly Pro Ser Val Val

1140 1145 1150

Leu Lys Gln Gly Gly Ala Val Pro Ile Gly Ile Gly Ile Gly Asn Ala

1155 1160 1165

Asp Ile Ser Glu Met Gln Thr Ile Ser Phe Ile Pro Asp Phe Ala Val

1170 1175 1180

Ala Ile Pro Thr Phe Arg Glu Leu Gly Thr Ile Gln Gln Val Ile Ser

1185 1190 1195 1200

Glu Arg Val Ile Gln Leu Asn Arg Glu Gln Leu Ser Ser Leu Thr Pro

1205 1210 1215

Val Leu Met Pro Ser Pro Ser Ala Gly Pro Gly Asn Lys Lys Asp Val

1220 1225 1230

Val Phe Leu Ile Asp Gly Ser Gln Asn Ala Gly Ala Glu Phe Gln His

1235 1240 1245

Ile Arg Thr Leu Ile Glu Arg Leu Val Glu Tyr Leu Asp Ile Gly Phe

1250 1255 1260

Asp Thr Thr Arg Val Ala Val Ile Gln Phe Ser Glu Asp Thr Lys Met

1265 1270 1275 1280

Glu Phe Pro Leu Asn Ala His Phe Ser Lys Asp Glu Val Gln Asn Ala

1285 1290 1295

Val Arg Arg Leu Arg Pro Lys Gly Gly Arg Gln Val Tyr Ile Gly Asn

1300 1305 1310

Ala Leu Glu Tyr Val Leu Lys Asn Ile Phe Gln Arg Pro Leu Gly Ser

1315 1320 1325

Arg Ile Glu Glu Gly Val Pro Gln Phe Leu Val Leu Ile Ser Ser Gly

1330 1335 1340

Lys Ser Ala Asp Glu Val Asp Asp Ser Ala Val Glu Leu Lys Gln Phe

1345 1350 1355 1360

Gly Val Ala Pro Leu Thr Val Ala Arg His Thr Asp Gln Glu Glu Leu

1365 1370 1375

Val Lys Ile Ser Leu Ser Pro Glu Tyr Val Phe Ser Val Ser Thr Phe

1380 1385 1390

Arg Glu Leu Pro Arg Leu Glu Gln Arg Leu Leu Thr Pro Ile Thr Thr

1395 1400 1405

Leu Thr Ser Gln Gln Ile Gln Gln Ile Leu Ala Ser Thr Arg Tyr Pro

1410 1415 1420

Pro Ser Val Ala Glu Ser Asp Ala Ala Asp Ile Val Phe Leu Ile Asp

1425 1430 1435 1440

Ser Ser Asp Ala Met Lys Pro Asp Gly Ile Ala His Ile Arg Asp Phe

1445 1450 1455

Val Ser Arg Ile Val Arg Arg Leu Asn Ile Gly Pro Asn Lys Val Arg

1460 1465 1470

Ile Gly Val Val Gln Phe Ser Asn Asp Val Phe Pro Glu Phe Tyr Leu

1475 1480 1485

Lys Thr His Lys Ser Gln Asn Ser Val Leu Glu Ala Ile Arg Arg Leu

1490 1495 1500

Arg Phe Lys Gly Gly Ser Pro Leu Asn Thr Gly Arg Ala Leu Glu Phe

1505 1510 1515 1520

Val Ala Arg Asn Leu Phe Val Lys Ser Ala Gly Ser Arg Ile Glu Asp

1525 1530 1535

Gly Val Pro Gln His Leu Val Leu Phe Leu Gly Gly Lys Ser Gln Asp

1540 1545 1550

Asp Val Ser Arg His Ala Gln Val Ile Ser Ser Ser Gly Ile Met Ser

1555 1560 1565

Leu Gly Ile Gly Asp Arg Asn Ile Asp Arg Thr Asp Leu Gln Thr Ile

1570 1575 1580

Thr Asn Asp Pro Arg Leu Val Phe Thr Val Arg Glu Phe Arg Glu Leu

1585 1590 1595 1600

Pro Asn Ile Glu Glu Arg Val Met Leu Ser Phe Gly Pro Ser Gly Pro

1605 1610 1615

Thr Pro Gln Pro Pro Glu Val Glu Phe Pro Ser Ser Arg Pro Glu Lys

1620 1625 1630

Lys Lys Ala Asp Ile Val Phe Leu Leu Asp Gly Ser Ile Asn Phe Arg

1635 1640 1645

Arg Asp Ser Phe Gln Glu Val Leu Arg Phe Ala Ser Glu Ile Val Asp

1650 1655 1660

Thr Val Tyr Glu Asp Gly Asp Ser Ile Arg Val Gly Leu Val Gln Tyr

1665 1670 1675 1680

Asn Ser Asp Pro Thr Asp Glu Phe Phe Leu Arg Asp Phe Ser Thr Lys

1685 1690 1695

Arg Gln Ile Ile Asp Ala Ile Asn Lys Val Ile Tyr Lys Gly Gly Arg

1700 1705 1710

His Ala Asn Thr Arg Val Gly Ile Glu His Leu Leu Lys Asn His Phe

1715 1720 1725

Val Ser Glu Ala Gly Ser Arg Leu Asp Glu Arg Val Pro Gln Ile Ala

1730 1735 1740

Phe Val Ile Thr Gly Gly Lys Ser Val Glu Asp Ala Gln Asp Val Ser

1745 1750 1755 1760

Leu Ala Leu Thr Gln Lys Gly Val Lys Val Phe Ala Val Gly Val Arg

1765 1770 1775

Asn Ile Asp Ser Glu Glu Val Gly Lys Ile Ala Ser Asn Ser Ala Thr

1780 1785 1790

Ala Phe Arg Val Gly Ser Val Gln Glu Leu Ser Glu Leu Ser Glu Thr

1795 1800 1805

Val Leu Glu Thr Leu His Asp Ala Met His Glu Thr Leu Cys Pro Gly

1810 1815 1820

Val Thr Asp Val Ser Lys Ala Cys Asn Leu Glu Val Ile Leu Gly Phe

1825 1830 1835 1840

Asp Gly Ser Arg Asp Gln Asn Val Phe Val Ser Gln Lys Gly Leu Glu

1845 1850 1855

Ser Lys Val Asp Thr Ile Leu Asn Arg Ile Ser Gln Ile Gln Arg Ile

1860 1865 1870

Ser Cys Ser Ser Asn Gln Leu Pro Thr Val Arg Val Ser Val Val Ala

1875 1880 1885

Asn Thr Pro Ser Gly Pro Val Glu Ala Phe Asp Phe Ala Glu Tyr Gln

1890 1895 1900

Pro Asp Leu Phe Glu Lys Phe Arg Thr Met Arg Ser Gln His Pro Tyr

1905 1910 1915 1920

Val Leu Thr Ala Asp Thr Leu Lys Leu Tyr Gln Asn Lys Phe Arg Gln

1925 1930 1935

Ser Ser Pro Asp Thr Val Lys Val Val Ile His Phe Thr Asp Gly Ala

1940 1945 1950

Asp Gly Asp Met Ala Asp Leu Tyr Arg Ala Ser Glu Glu Leu Arg Gln

1955 1960 1965

Ala Gly Val Gln Ala Leu Ile Leu Val Gly Leu Glu Arg Val Ala Asn

1970 1975 1980

Leu Glu Arg Leu Met Gln Val Glu Phe Gly Arg Gly Phe Met Tyr Asp

1985 1990 1995 2000

Arg Pro Leu Arg Leu Asn Leu Leu Asp Leu Asp Tyr Glu Leu Ala Glu

2005 2010 2015

Gln Leu Asp Asn Ile Ala Glu Lys Ala Cys Cys Gly Val Pro Cys Lys

2020 2025 2030

Cys Ser Gly Glu Arg Gly Asp Arg Gly Pro Ile Gly Ser Ile Gly Pro

2035 2040 2045

Lys Gly Ile Ser Gly Glu Asp Gly Tyr Arg Gly Tyr Pro Gly Asp Glu

2050 2055 2060

Gly Gly Pro Gly Glu Arg Gly Pro Pro Gly Val Asn Gly Thr Gln Gly

2065 2070 2075 2080

Phe Gln Gly Cys Pro Gly Gln Arg Gly Val Lys Gly Ser Arg Gly Phe

2085 2090 2095

Pro Gly Glu Lys Gly Glu Leu Gly Glu Ile Gly Leu Asp Gly Leu Asp

2100 2105 2110

Gly Glu Glu Gly Asp Lys Gly Leu Pro Gly Ser Ser Gly Glu Lys Gly

2115 2120 2125

Ser Pro Gly Arg Arg Gly Asp Lys Gly Pro Lys Gly Asp Lys Gly Glu

2130 2135 2140

Arg Gly Asp Val Gly Ile Arg Gly Asp Pro Gly Asp Ser Gly Arg Asp

2145 2150 2155 2160

Ser Gln Gln Arg Gly Pro Lys Gly Glu Thr Gly Asp Ile Gly Pro Met

2165 2170 2175

Gly Leu Pro Gly Arg Asp Gly Ile Pro Gly Ser Pro Gly Asp Pro Gly

2180 2185 2190

Lys Asp Gly Gly Phe Gly Arg Arg Gly Pro Ala Gly Ala Lys Gly Asn

2195 2200 2205

Arg Gly Gly Pro Gly Gln Pro Gly Phe Glu Gly Glu Gln Gly Thr Arg

2210 2215 2220

Gly Ser Gln Gly Pro Pro Gly Pro Ile Gly Pro Pro Gly Leu Ile Gly

2225 2230 2235 2240

Glu Gln Gly Ile Pro Gly Pro Arg Gly Gly Gly Gly Thr Ala Gly Ala

2245 2250 2255

Pro Gly Glu Arg Gly Arg Thr Gly Pro Leu Gly Arg Lys Gly Glu Pro

2260 2265 2270

Gly Glu Pro Gly Pro Lys Gly Gly Thr Gly Asn Arg Gly Pro Arg Gly

2275 2280 2285

Glu Thr Gly Asp Asp Gly Arg Asp Gly Val Gly Ser Glu Gly Arg Arg

2290 2295 2300

Gly Lys Lys Gly Glu Arg Gly Phe Pro Gly Tyr Pro Gly Pro Lys Gly

2305 2310 2315 2320

Thr Pro Gly Glu Pro Gly Ala Asp Gly Pro Pro Gly Pro Lys Gly Ile

2325 2330 2335

Arg Gly Arg Arg Gly Asn Ser Gly Pro Pro Gly Val Val Gly Gln Lys

2340 2345 2350

Gly Asp Pro Gly Tyr Pro Gly Pro Ser Gly His Arg Gly Asn Arg Gly

2355 2360 2365

Asp Ser Val Asp Gln Cys Ala Leu Ile Gln Ser Ile Arg Asp Lys Cys

2370 2375 2380

Pro Cys Cys Tyr Gly Pro Leu Glu Cys Pro Val Phe Pro Thr Glu Leu

2385 2390 2395 2400

Ala Phe Ala Leu Asp Thr Ser Glu Gly Val Thr Gln Asp Thr Phe Ser

2405 2410 2415

Arg Met Arg Glu Val Leu Leu Ser Ile Val Gly Asp Leu Thr Ile Ala

2420 2425 2430

Glu Ser Asn Cys Pro Arg Gly Ala Arg Val Ala Val Val Thr Tyr Asn

2435 2440 2445

Asn Glu Val Thr Thr Glu Ile Arg Phe Ala Asp Ser Lys Lys Lys Ser

2450 2455 2460

Ala Leu Leu Asp Ser Ile Gln Asn Leu Gln Val Ala Leu Thr Ser Lys

2465 2470 2475 2480

Gln Pro Ser Leu Glu Thr Ala Met Ser Phe Val Ala Arg Asn Thr Phe

2485 2490 2495

Lys Arg Val Arg Asn Gly Phe Leu Met Arg Lys Val Ala Ile Phe Phe

2500 2505 2510

Ser Asn Gln Pro Thr Lys Pro Ser Leu Gln Leu Arg Glu Ala Val Leu

2515 2520 2525

Lys Leu Ser Asp Ala Gly Ile Thr Pro Leu Phe Leu Thr Ser Gln Glu

2530 2535 2540

Asp Arg Glu Leu Ile Asn Ala Leu Gln Ile Asn Asn Thr Ala Val Gly

2545 2550 2555 2560

His Ala Leu Val Leu Pro Ala Arg Arg Asp Leu Arg Asp Phe Leu Lys

2565 2570 2575

Asn Val Leu Thr Cys His Val Cys Leu Asp Ile Cys Asn Ile Asp Pro

2580 2585 2590

Ser Cys Gly Phe Gly Asn Trp Arg Pro Ser Phe Arg Asp Arg Arg Ala

2595 2600 2605

Ala Gly Ser Asp Val Asp Ile Asp Leu Ala Phe Ile Leu Asp Ser Ser

2610 2615 2620

Glu Ala Thr Thr Leu Phe Gln Phe Asn Glu Met Lys Lys Tyr Ile Ser

2625 2630 2635 2640

Tyr Met Val Arg Gln Leu Asp Leu Ser Pro Asp Pro Lys Ala Ser Gln

2645 2650 2655

His Phe Ala Arg Val Ala Val Val Gln Gln Ala Thr Tyr Glu Ser Val

2660 2665 2670

Asp Asn Thr Ser Val Pro Pro Val Lys Val Glu Phe Ser Leu Thr Asp

2675 2680 2685

Tyr Gly Ala Lys Glu Lys Leu Leu Asp Phe Leu Ser Arg Arg Met Thr

2690 2695 2700

Gln Leu Gln Gly Thr Met Asp Leu Gly Asn Ala Ile Glu Tyr Thr Ile

2705 2710 2715 2720

Glu Asn Ile Phe Glu Ser Ala Pro Asn Pro Arg Asp Leu Lys Ile Val

2725 2730 2735

Val Leu Met Leu Thr Gly Glu Ile Pro Arg Glu Gln Leu Glu Glu Ala

2740 2745 2750

Gln Arg Ala Ile Leu Gln Ala Lys Cys Lys Gly Tyr Phe Phe Val Val

2755 2760 2765

Leu Gly Ile Gly Arg Lys Val Asn Val Lys Glu Val Tyr Ser Phe Ala

2770 2775 2780

Ser Glu Pro Asn Asp Val Phe Phe Lys Phe Met Asp Lys Ser Thr Glu

2785 2790 2795 2800

Leu Asn Glu Glu Pro Leu Met Arg Phe Gly Arg Leu Leu Pro Ser Phe

2805 2810 2815

Val Gly Ser Gly Asn Ala Phe Tyr Leu Pro Pro Asp Leu Arg Lys Gln

2820 2825 2830

Cys Asp Trp Phe Gln Gly Asp Gln Pro Val Lys Asn Gly Val Lys Phe

2835 2840 2845

Gly His Arg Gln Ile Leu Thr Ser Lys Val Val Thr Thr Met Lys Pro

2850 2855 2860

Val Thr Thr Thr Lys Pro Thr Ser Ile Val Asn Leu Pro Pro Ala Lys

2865 2870 2875 2880

Pro Ala Pro Val Arg Pro Ala Pro Ala Gln Pro Val Leu Ala Lys Pro

2885 2890 2895

Asp Pro Ala Lys Pro Val Ser Ala Lys Ser Val Pro Pro Gln Pro Val

2900 2905 2910

His Ala Gln Pro Asp Pro Ala Gln Pro Val His Val Gln Ser Ala Ser

2915 2920 2925

Ala Gln Thr Ala Ser Ala Lys Pro Val Pro Ala Lys Pro Ala Pro Pro

2930 2935 2940

Gln Thr Ala Ala Ala Lys Pro Val Pro Val Lys Pro Ala Val Pro Ala

2945 2950 2955 2960

Gln Pro Ala Pro Ala Gln Pro Val His Ala Gln Pro Ala Pro Ala Gln

2965 2970 2975

Pro Val Leu Thr Lys Pro Ala Ala Met Lys Pro Ala Ser Ala Asn Lys

2980 2985 2990

Pro Val Ala Ala Lys Pro Val Ala Thr Asn Thr Ala Thr Val Arg Pro

2995 3000 3005

Ala Ser Ala Val Lys Pro Ala Ala Ala Ser Lys Pro Ala Ala Thr Arg

3010 3015 3020

Pro Leu Pro Ala Ala Val Arg Pro Val Ala Thr Lys Pro Glu Ala Pro

3025 3030 3035 3040

Arg Pro Gln Ala Lys Pro Ala Ala Thr Lys Pro Ala Thr Thr Lys Pro

3045 3050 3055

Met Ala Arg Val Ser Arg Glu Val Gln Val Ser Glu Val Thr Glu Asn

3060 3065 3070

Ser Ala Arg Leu His Trp Glu Arg Pro Glu Pro Ser Ser Ser Tyr Phe

3075 3080 3085

Tyr Asp Leu Thr Val Thr Ser Ala His Asp Gln Ser Leu Val Leu Arg

3090 3095 3100

Gln Asn Leu Thr Val Thr Asp Arg Val Ile Gly Gly Leu Leu Ala Gly

3105 3110 3115 3120

Gln Leu Tyr His Val Val Val Val Ser Tyr Leu Gln Ser Gln Val Arg

3125 3130 3135

Ala Ile Tyr Gln Gly Ser Phe Asn Thr Lys Lys Thr Gln Pro Pro Val

3140 3145 3150

Leu Gln Ala Ala His Arg Ala Ser Ser Ser Thr Ile Asn Leu Met Val

3155 3160 3165

Asn Thr Glu Pro Leu Phe Leu Thr Lys Thr Asp Ile Cys Lys Leu Pro

3170 3175 3180

Lys Asp Ala Gly Thr Cys Glu Asp Phe Lys Leu Leu Trp His Tyr Asp

3185 3190 3195 3200

Leu Glu Ser Lys Ser Cys Lys Arg Phe Trp Tyr Gly Gly Cys Gly Gly

3205 3210 3215

Asn Glu Asn Arg Phe His Ser Gln Glu Glu Cys Glu Lys Met Cys Ser

3220 3225 3230

Pro Glu Leu Ser Val

3235

<210> 7

<211> 1025

<212> PRT

<213> Mus musculus

<400> 7

Met Arg Leu Ala His Ala Leu Leu Pro Leu Leu Leu Gln Ala Cys Trp

1 5 10 15

Val Ala Thr Gln Asp Ile Gln Gly Ser Lys Ala Ile Ala Phe Gln Asp

20 25 30

Cys Pro Val Asp Leu Phe Phe Val Leu Asp Thr Ser Glu Ser Val Ala

35 40 45

Leu Arg Leu Lys Pro Tyr Gly Ala Leu Val Asp Lys Val Lys Ser Phe

50 55 60

Thr Lys Arg Phe Ile Asp Asn Leu Arg Asp Arg Tyr Tyr Arg Cys Asp

65 70 75 80

Arg Asn Leu Val Trp Asn Ala Gly Ala Leu His Tyr Ser Asp Glu Val

85 90 95

Glu Ile Ile Arg Gly Leu Thr Arg Met Pro Ser Gly Arg Asp Glu Leu

100 105 110

Lys Ala Ser Val Asp Ala Val Lys Tyr Phe Gly Lys Gly Thr Tyr Thr

115 120 125

Asp Cys Ala Ile Lys Lys Gly Leu Glu Glu Leu Leu Ile Gly Gly Ser

130 135 140

His Leu Lys Glu Asn Lys Tyr Leu Ile Val Val Thr Asp Gly His Pro

145 150 155 160

Leu Glu Gly Tyr Lys Glu Pro Cys Gly Gly Leu Glu Asp Ala Val Asn

165 170 175

Glu Ala Lys His Leu Gly Ile Lys Val Phe Ser Val Ala Ile Thr Pro

180 185 190

Asp His Leu Glu Pro Arg Leu Ser Ile Ile Ala Thr Asp His Thr Tyr

195 200 205

Arg Arg Asn Phe Thr Ala Ala Asp Trp Gly His Ser Arg Asp Ala Glu

210 215 220

Glu Val Ile Ser Gln Thr Ile Asp Thr Ile Val Asp Met Ile Lys Asn

225 230 235 240

Asn Val Glu Gln Val Cys Cys Ser Phe Glu Cys Gln Ala Ala Arg Gly

245 250 255

Pro Pro Gly Pro Arg Gly Asp Pro Gly Tyr Glu Gly Glu Arg Gly Lys

260 265 270

Pro Gly Leu Pro Gly Glu Lys Gly Glu Ala Gly Asp Pro Gly Arg Pro

275 280 285

Gly Asp Leu Gly Pro Val Gly Tyr Gln Gly Met Lys Gly Glu Lys Gly

290 295 300

Ser Arg Gly Glu Lys Gly Ser Arg Gly Pro Lys Gly Tyr Lys Gly Glu

305 310 315 320

Lys Gly Lys Arg Gly Ile Asp Gly Val Asp Gly Met Lys Gly Glu Thr

325 330 335

Gly Tyr Pro Gly Leu Pro Gly Cys Lys Gly Ser Pro Gly Phe Asp Gly

340 345 350

Ile Gln Gly Pro Pro Gly Pro Lys Gly Asp Ala Gly Ala Phe Gly Met

355 360 365

Lys Gly Glu Lys Gly Glu Ala Gly Ala Asp Gly Glu Ala Gly Arg Pro

370 375 380

Gly Asn Ser Gly Ser Pro Gly Asp Glu Gly Asp Pro Gly Glu Pro Gly

385 390 395 400

Pro Pro Gly Glu Lys Gly Glu Ala Gly Asp Glu Gly Asn Ala Gly Pro

405 410 415

Asp Gly Ala Pro Gly Glu Arg Gly Gly Pro Gly Glu Arg Gly Pro Arg

420 425 430

Gly Thr Pro Gly Val Arg Gly Pro Arg Gly Asp Pro Gly Glu Ala Gly

435 440 445

Pro Gln Gly Asp Gln Gly Arg Glu Gly Pro Val Gly Ile Pro Gly Asp

450 455 460

Ser Gly Glu Ala Gly Pro Ile Gly Pro Lys Gly Tyr Arg Gly Asp Glu

465 470 475 480

Gly Pro Pro Gly Pro Glu Gly Leu Arg Gly Ala Pro Gly Pro Val Gly

485 490 495

Pro Pro Gly Asp Pro Gly Leu Met Gly Glu Arg Gly Glu Asp Gly Pro

500 505 510

Pro Gly Asn Gly Thr Glu Gly Phe Pro Gly Phe Pro Gly Tyr Pro Gly

515 520 525

Asn Arg Gly Pro Pro Gly Leu Asn Gly Thr Lys Gly Tyr Pro Gly Leu

530 535 540

Lys Gly Asp Glu Gly Glu Val Gly Asp Pro Gly Glu Asp Asn Asn Asp

545 550 555 560

Ile Ser Pro Arg Gly Val Lys Gly Ala Lys Gly Tyr Arg Gly Pro Glu

565 570 575

Gly Pro Gln Gly Pro Pro Gly His Val Gly Pro Pro Gly Pro Asp Glu

580 585 590

Cys Glu Ile Leu Asp Ile Ile Met Lys Met Cys Ser Cys Cys Glu Cys

595 600 605

Thr Cys Gly Pro Ile Asp Ile Leu Phe Val Leu Asp Ser Ser Glu Ser

610 615 620

Ile Gly Leu Gln Asn Phe Glu Ile Ala Lys Asp Phe Ile Ile Lys Val

625 630 635 640

Ile Asp Arg Leu Ser Lys Asp Glu Leu Val Lys Phe Glu Pro Gly Gln

645 650 655

Ser His Ala Gly Val Val Gln Tyr Ser His Asn Gln Met Gln Glu His

660 665 670

Val Asp Met Arg Ser Pro Asn Val Arg Asn Ala Gln Asp Phe Lys Glu

675 680 685

Ala Val Lys Lys Leu Gln Trp Met Ala Gly Gly Thr Phe Thr Gly Glu

690 695 700

Ala Leu Gln Tyr Thr Arg Asp Arg Leu Leu Pro Pro Thr Gln Asn Asn

705 710 715 720

Arg Ile Ala Leu Val Ile Thr Asp Gly Arg Ser Asp Thr Gln Arg Asp

725 730 735

Thr Thr Pro Leu Ser Val Leu Cys Gly Ala Asp Ile Gln Val Val Ser

740 745 750

Val Gly Ile Lys Asp Val Phe Gly Phe Val Ala Gly Ser Asp Gln Leu

755 760 765

Asn Val Ile Ser Cys Gln Gly Leu Ser Gln Gly Arg Pro Gly Ile Ser

770 775 780

Leu Val Lys Glu Asn Tyr Ala Glu Leu Leu Asp Asp Gly Phe Leu Lys

785 790 795 800

Asn Ile Thr Ala Gln Ile Cys Ile Asp Lys Lys Cys Pro Asp Tyr Thr

805 810 815

Cys Pro Ile Thr Phe Ser Ser Pro Ala Asp Ile Thr Ile Leu Leu Asp

820 825 830

Ser Ser Ala Ser Val Gly Ser His Asn Phe Glu Thr Thr Lys Val Phe

835 840 845

Ala Lys Arg Leu Ala Glu Arg Phe Leu Ser Ala Gly Arg Ala Asp Pro

850 855 860

Ser Gln Asp Val Arg Val Ala Val Val Gln Tyr Ser Gly Gln Gly Gln

865 870 875 880

Gln Gln Pro Gly Arg Ala Ala Leu Gln Phe Leu Gln Asn Tyr Thr Val

885 890 895

Leu Ala Ser Ser Val Asp Ser Met Asp Phe Ile Asn Asp Ala Thr Asp

900 905 910

Val Asn Asp Ala Leu Ser Tyr Val Thr Arg Phe Tyr Arg Glu Ala Ser

915 920 925

Ser Gly Ala Thr Lys Lys Arg Val Leu Leu Phe Ser Asp Gly Asn Ser

930 935 940

Gln Gly Ala Thr Ala Glu Ala Ile Glu Lys Ala Val Gln Glu Ala Gln

945 950 955 960

Arg Ala Gly Ile Glu Ile Phe Val Val Val Val Gly Pro Gln Val Asn

965 970 975

Glu Pro His Ile Arg Val Leu Val Thr Gly Lys Thr Ala Glu Tyr Asp

980 985 990

Val Ala Phe Gly Glu Arg His Leu Phe Arg Val Pro Asn Tyr Gln Ala

995 1000 1005

Leu Leu Arg Gly Val Leu Tyr Gln Thr Val Ser Arg Lys Val Ala Leu

1010 1015 1020

Gly

1025

<210> 8

<211> 1034

<212> PRT

<213> Mus musculus

<400> 8

Met Thr Thr Ile Lys Met Leu Gln Gly Pro Leu Ser Val Leu Leu Ile

1 5 10 15

Gly Gly Leu Leu Gly Val Leu His Ala Gln Gln Gln Glu Ala Ile Ser

20 25 30

Pro Gln Glu Gln Glu Ala Val Ser Pro Asp Ile Ser Thr Thr Glu Arg

35 40 45

Asn Asn Asn Cys Pro Glu Lys Ala Asp Cys Pro Val Asn Val Tyr Phe

50 55 60

Val Leu Asp Thr Ser Glu Ser Val Ala Met Gln Ser Pro Thr Asp Ser

65 70 75 80

Leu Leu Tyr His Met Gln Gln Phe Val Pro Gln Phe Ile Ser Gln Leu

85 90 95

Gln Asn Glu Phe Tyr Leu Asp Gln Val Ala Leu Ser Trp Arg Tyr Gly

100 105 110

Gly Leu His Phe Ser Asp Gln Val Glu Val Phe Ser Pro Pro Gly Ser

115 120 125

Asp Arg Ala Ser Phe Thr Lys Ser Leu Gln Gly Ile Arg Ser Phe Arg

130 135 140

Arg Gly Thr Phe Thr Asp Cys Ala Leu Ala Asn Met Thr Gln Gln Ile

145 150 155 160

Arg Gln His Val Gly Lys Gly Val Val Asn Phe Ala Val Val Ile Thr

165 170 175

Asp Gly His Val Thr Gly Ser Pro Cys Gly Gly Ile Lys Met Gln Ala

180 185 190

Glu Arg Ala Arg Glu Glu Gly Ile Arg Leu Phe Ala Val Ala Pro Asn

195 200 205

Arg Asn Leu Asn Glu Gln Gly Leu Arg Asp Ile Ala Asn Ser Pro His

210 215 220

Glu Leu Tyr Arg Asn Asn Tyr Ala Thr Met Arg Pro Asp Ser Thr Glu

225 230 235 240

Ile Asp Gln Asp Thr Ile Asn Arg Ile Ile Lys Val Met Lys His Glu

245 250 255

Ala Tyr Gly Glu Cys Tyr Lys Val Ser Cys Leu Glu Ile Pro Gly Pro

260 265 270

His Gly Pro Lys Gly Tyr Arg Gly Gln Lys Gly Ala Lys Gly Asn Met

275 280 285

Gly Glu Pro Gly Glu Pro Gly Gln Lys Gly Arg Gln Gly Asp Pro Gly

290 295 300

Ile Glu Gly Pro Ile Gly Phe Pro Gly Pro Lys Gly Val Pro Gly Phe

305 310 315 320

Lys Gly Glu Lys Gly Glu Phe Gly Ser Asp Gly Arg Lys Gly Ala Pro

325 330 335

Gly Leu Ala Gly Lys Asn Gly Thr Asp Gly Gln Lys Gly Lys Leu Gly

340 345 350

Arg Ile Gly Pro Pro Gly Cys Lys Gly Asp Pro Gly Ser Arg Gly Pro

355 360 365

Asp Gly Tyr Pro Gly Glu Ala Gly Ser Pro Gly Glu Arg Gly Asp Gln

370 375 380

Gly Ala Lys Gly Asp Ser Gly Arg Pro Gly Arg Arg Gly Pro Pro Gly

385 390 395 400

Asp Pro Gly Asp Lys Gly Ser Lys Gly Tyr Gln Gly Asn Asn Gly Ala

405 410 415

Pro Gly Ser Pro Gly Val Lys Gly Gly Lys Gly Gly Pro Gly Pro Arg

420 425 430

Gly Pro Lys Gly Glu Pro Gly Arg Arg Gly Asp Pro Gly Thr Lys Gly

435 440 445

Gly Pro Gly Ser Asp Gly Pro Lys Gly Glu Lys Gly Asp Pro Gly Pro

450 455 460

Glu Gly Pro Arg Gly Leu Ala Gly Glu Val Gly Ser Lys Gly Ala Lys

465 470 475 480

Gly Asp Arg Gly Leu Pro Gly Pro Arg Gly Pro Gln Gly Ala Leu Gly

485 490 495

Glu Pro Gly Lys Gln Gly Ser Arg Gly Asp Pro Gly Asp Ala Gly Pro

500 505 510

Arg Gly Asp Ser Gly Gln Pro Gly Pro Lys Gly Asp Pro Gly Arg Pro

515 520 525

Gly Phe Ser Tyr Pro Gly Pro Arg Gly Thr Pro Gly Glu Lys Gly Glu

530 535 540

Pro Gly Pro Pro Gly Pro Glu Gly Gly Arg Gly Asp Phe Gly Leu Lys

545 550 555 560

Gly Thr Pro Gly Arg Lys Gly Asp Lys Gly Glu Pro Ala Asp Pro Gly

565 570 575

Pro Pro Gly Glu Pro Gly Pro Arg Gly Pro Arg Gly Ile Pro Gly Pro

580 585 590

Glu Gly Glu Pro Gly Pro Pro Gly Asp Pro Gly Leu Thr Glu Cys Asp

595 600 605

Val Met Thr Tyr Val Arg Glu Thr Cys Gly Cys Cys Asp Cys Glu Lys

610 615 620

Arg Cys Gly Ala Leu Asp Val Val Phe Val Ile Asp Ser Ser Glu Ser

625 630 635 640

Ile Gly Tyr Thr Asn Phe Thr Leu Glu Lys Asn Phe Val Ile Asn Val

645 650 655

Val Asn Arg Leu Gly Ala Ile Ala Lys Asp Pro Lys Ser Glu Thr Gly

660 665 670

Thr Arg Val Gly Val Val Gln Tyr Ser His Glu Gly Thr Phe Glu Ala

675 680 685

Ile Arg Leu Asp Asp Glu Arg Val Asn Ser Leu Ser Ser Phe Lys Glu

690 695 700

Ala Val Lys Asn Leu Glu Trp Ile Ala Gly Gly Thr Trp Thr Pro Ser

705 710 715 720

Ala Leu Lys Phe Ala Tyr Asn Gln Leu Ile Lys Glu Ser Arg Arg Gln

725 730 735

Lys Thr Arg Val Phe Ala Val Val Ile Thr Asp Gly Arg His Asp Pro

740 745 750

Arg Asp Asp Asp Leu Asn Leu Arg Ala Leu Cys Asp Arg Asp Val Thr

755 760 765

Val Thr Ala Ile Gly Ile Gly Asp Met Phe His Glu Thr His Glu Ser

770 775 780

Glu Asn Leu Tyr Ser Ile Ala Cys Asp Lys Pro Gln Gln Val Arg Asn

785 790 795 800

Met Thr Leu Phe Ser Asp Leu Val Ala Glu Lys Phe Ile Asp Asp Met

805 810 815

Glu Asp Val Leu Cys Pro Asp Pro Gln Ile Val Cys Pro Glu Leu Pro

820 825 830

Cys Gln Thr Glu Leu Tyr Val Ala Gln Cys Thr Gln Arg Pro Val Asp

835 840 845

Ile Val Phe Leu Leu Asp Gly Ser Glu Arg Leu Gly Glu Gln Asn Phe

850 855 860

His Lys Val Arg Arg Phe Val Glu Asp Val Ser Arg Arg Leu Thr Leu

865 870 875 880

Ala Arg Arg Asp Asp Asp Pro Leu Asn Ala Arg Met Ala Leu Leu Gln

885 890 895

Tyr Gly Ser Gln Asn Gln Gln Gln Val Ala Phe Pro Leu Thr Tyr Asn

900 905 910

Val Thr Thr Ile His Glu Ala Leu Glu Arg Ala Thr Tyr Leu Asn Ser

915 920 925

Phe Ser His Val Gly Thr Gly Ile Val His Ala Ile Asn Asn Val Val

930 935 940

Arg Gly Ala Arg Gly Gly Ala Arg Arg His Ala Glu Leu Ser Phe Val

945 950 955 960

Phe Leu Thr Asp Gly Val Thr Gly Asn Asp Ser Leu Glu Glu Ser Val

965 970 975

His Ser Met Arg Lys Gln Asn Val Val Pro Thr Val Val Ala Val Gly

980 985 990

Gly Asp Val Asp Met Asp Val Leu Thr Lys Ile Ser Leu Gly Asp Arg

995 1000 1005

Ala Ala Ile Phe Arg Glu Lys Asp Phe Asp Ser Leu Ala Gln Pro Ser

1010 1015 1020

Phe Phe Asp Arg Phe Ile Arg Trp Ile Cys

1025 1030

<210> 9

<211> 3284

<212> PRT

<213> Mus musculus

<400> 9

Met Arg Lys His Arg His Leu Pro Leu Val Ala Val Phe Ser Leu Leu

1 5 10 15

Leu Ser Gly Ile Ala Thr Thr His Ala Gln Gln His Gly Asp Val Lys

20 25 30

Asn Gly Ala Ala Ala Asp Ile Val Phe Leu Val Asp Ser Ser Trp Ser

35 40 45

Ala Gly Lys Asp Arg Phe Leu Leu Val Gln Glu Phe Leu Ser Asp Val

50 55 60

Val Glu Ser Leu Ala Val Gly Asp Asn Asp Phe His Phe Ala Leu Val

65 70 75 80

Arg Leu Asn Gly Asn Pro His Thr Glu Phe Leu Leu Asn Thr Tyr His

85 90 95

Ser Lys Gln Glu Val Leu Ser His Ile Val Asn Met Ser Tyr Ile Gly

100 105 110

Gly Ser Asn Gln Thr Gly Lys Gly Leu Glu Tyr Val Ile His Ser His

115 120 125

Leu Thr Glu Ala Ser Gly Ser Arg Ala Ala Asp Gly Val Pro Gln Val

130 135 140

Ile Ile Val Leu Thr Asp Gly Gln Ser Glu Asp Gly Phe Ala Leu Pro

145 150 155 160

Ser Ala Glu Leu Lys Ser Ala Asp Val Asn Val Phe Ala Val Gly Val

165 170 175

Glu Gly Ala Asp Glu Arg Ala Leu Gly Glu Val Ala Ser Glu Pro Leu

180 185 190

Ser Met His Val Phe Asn Leu Glu Asn Val Thr Ser Leu His Gly Leu

195 200 205

Val Gly Asn Leu Val Ser Cys Ile His Ser Ser Val Asn Pro Glu Arg

210 215 220

Ala Gly Asp Lys Glu Ser Leu Lys Asp Ile Thr Ala Gln Asp Ser Ala

225 230 235 240

Asp Ile Ile Phe Leu Ile Asp Gly Ser Gln Asn Thr Gly Asn Ala Asn

245 250 255

Phe Asp Val Ile Arg Asp Phe Leu Val Asn Val Leu Glu Arg Leu Ser

260 265 270

Val Gly Asn Gln Gln Val Gln Val Gly Val Val Gln Tyr Ser Glu Glu

275 280 285

Pro Ile Thr Met Phe Ser Leu Asn Ser Tyr Pro Ser Lys Ala Ala Val

290 295 300

Leu Asp Ala Val Lys Gly Leu Ser Leu Val Gly Gly Glu Ser Ala Asn

305 310 315 320

Ile Gly Gln Ala Leu Asp Phe Val Val Glu Asn His Phe Thr Arg Ala

325 330 335

Gly Gly Ser Arg Val Glu Glu Gly Val Pro Gln Val Leu Val Leu Ile

340 345 350

Ser Ala Gly Pro Ser Ser Asp Glu Ile Arg Asp Ser Val Val Ala Leu

355 360 365

Lys Gln Ala Ser Val Phe Ser Phe Gly Leu Gly Ala Gln Ala Ala Ser

370 375 380

Arg Ala Glu Leu Gln His Ile Ala Thr Asp Asp Ser Leu Val Phe Thr

385 390 395 400

Val Pro Glu Phe Arg Ser Phe Gly Asp Leu Gln Glu Gln Ile Leu Pro

405 410 415

Tyr Leu Val Gly Val Ala Gln Arg His Ile Val Leu Gln Pro Pro Ala

420 425 430

Ile Val Thr Gln Val Met Glu Val Asn Lys Arg Asp Ile Val Phe Leu

435 440 445

Val Asp Gly Ser Ser Ser Leu Gly Pro Ser Asn Phe Asn Ala Ile Arg

450 455 460

Asp Phe Val Thr Arg Val Ile Gln Arg Leu Glu Ile Gly Gln Asp Leu

465 470 475 480

Val Gln Val Ser Val Ala Gln Tyr Ala Asp Thr Val Lys Pro Glu Phe

485 490 495

Tyr Leu Asn Ser Tyr Thr Asn Lys Arg Asp Ala Ile Thr Ala Val Arg

500 505 510

Lys Met Arg Ala Leu Asn Gly Ser Ala Leu Tyr Thr Gly Ser Ser Leu

515 520 525

Asp Phe Val Arg Asn Asn Leu Phe Thr Ser Ser Ala Gly His Arg Ala

530 535 540

Ala Glu Gly Val Pro Lys Leu Leu Val Leu Ile Thr Gly Gly Lys Ser

545 550 555 560

Leu Asp Glu Val Ser Gln Pro Ala Gln Glu Leu Lys Arg Gly Ser Ile

565 570 575

Met Ala Leu Ala Val Gly Ser Lys Ala Ala Asp Glu Asp Glu Leu Lys

580 585 590

Glu Ile Ala Phe Asp Ser Ser Leu Val Phe Ile Pro Ala Glu Phe Arg

595 600 605

Pro Ala Pro Leu Gln Asn Met Leu Pro Ser Leu Met Ala Pro Leu Arg

610 615 620

Thr Leu Thr Gly Thr Thr Glu Val His Val Asn Lys Arg Asp Ile Ile

625 630 635 640

Phe Leu Leu Asp Gly Ser Asp Asn Val Gly Lys Asn Asn Phe Pro Tyr

645 650 655

Val Arg Asp Phe Val Thr Asn Leu Val Asn Ser Leu Asp Val Gly Ser

660 665 670

Asp Asn Ile Arg Val Gly Leu Val Gln Phe Ser Asp Thr Pro Val Thr

675 680 685

Glu Phe Ser Leu Asp Thr Tyr Gln Thr Lys Ser Glu Leu Leu Ala His

690 695 700

Leu Arg Arg Leu Gln Leu Lys Gly Gly Ser Gly Leu Asn Ala Gly Ser

705 710 715 720

Ala Leu Ser Tyr Ile His Ala Asn His Phe Thr Glu Ala Gly Gly Ser

725 730 735

Arg Thr Arg Glu His Val Pro Gln Leu Leu Leu Leu Leu Met Ala Gly

740 745 750

Pro Ser Glu Asp Ala Tyr Leu Gln Ala Ala Asn Ala Leu Val Arg Ser

755 760 765

Gly Val Leu Thr Phe Cys Val Gly Thr Asn Arg Ala Asp Lys Ala Glu

770 775 780

Leu Glu His Ile Ala Phe Asn Pro Ser Leu Val Tyr Leu Met Asp Asp

785 790 795 800

Phe Arg Ser Leu Pro Ser Leu Pro Gln Gln Leu Ile Gln Pro Leu Thr

805 810 815

Thr Tyr Val Ser Gly Gly Val Gln Glu Val Pro Leu Ser Gln Pro Glu

820 825 830

Ser Lys Arg Asp Ile Leu Phe Leu Phe Asp Gly Ser Val Asn Val Leu

835 840 845

Gly Gln Phe Pro Ala Val Arg Asp Phe Leu Tyr Arg Ile Ile Glu Glu

850 855 860

Leu Asp Val Lys Pro Asp Gly Thr Arg Val Ala Ile Ala Gln Phe Ser

865 870 875 880

Asp Asp Val Arg Leu Glu Ser Arg Phe Ser Glu His Gln Thr Lys Ala

885 890 895

Glu Ile Leu Asn Leu Val Lys Lys Met Lys Leu Lys Thr Gly Lys Ala

900 905 910

Leu Asn Leu Gly Tyr Ala Leu Asp Tyr Ala Leu Arg Asn Ile Phe Val

915 920 925

Arg Ser Ala Gly Ser Arg Ile Glu Asp Asn Val Gln Gln Phe Leu Val

930 935 940

Leu Leu Val Ala Gly Arg Ser Ser Asp Ala Val Ala Gly Pro Ala Ser

945 950 955 960

Ser Leu Lys Gln Arg Gly Val Val Pro Phe Ile Phe Gln Ala Lys Asn

965 970 975

Ala Asn Pro Ser Glu Leu Glu Gln Ile Val Leu Ser Pro Ala Phe Ile

980 985 990

Leu Ala Ala Glu Ser Leu Pro Lys Ile Gly Asp Leu Gln Ser Gln Ile

995 1000 1005

Val Ser Leu Leu Lys Ala Glu Gln Gly Ser Gly Pro Val Ser Gly Glu

1010 1015 1020

Lys Asp Val Val Phe Leu Ile Asp Gly Ser Glu Gly Val Arg Ser Gly

1025 1030 1035 1040

Phe Pro Leu Leu Lys Asp Phe Val Gln Arg Val Val Glu Ser Leu Asp

1045 1050 1055

Val Gly Pro Asp Arg Val Arg Val Ala Leu Val Gln Tyr Ser Asp Arg

1060 1065 1070

Thr Arg Pro Glu Phe Tyr Leu Asn Ser His Met Asp Gln Gln Gly Val

1075 1080 1085

Ile Ser Ala Ile Arg Arg Leu Thr Leu Leu Gly Gly Pro Thr Pro Asn

1090 1095 1100

Thr Gly Ala Ala Leu Glu Phe Val Leu Arg Asn Ile Leu Thr Ser Ser

1105 1110 1115 1120

Thr Gly Ser Arg Ile Ala Glu Gly Val Pro Gln Leu Leu Ile Val Leu

1125 1130 1135

Thr Ala Glu Pro Ser Gly Asp Asp Val Arg Gly Pro Ser Val Val Leu

1140 1145 1150

Lys Gln Gly Gly Ala Val Pro Ile Gly Ile Gly Ile Gly Asn Ala Asp

1155 1160 1165

Ile Ser Glu Met Gln Thr Ile Ser Phe Ile Pro Asp Phe Ala Val Ala

1170 1175 1180

Ile Pro Thr Phe Arg Glu Leu Gly Thr Ile Gln Gln Val Ile Ser Glu

1185 1190 1195 1200

Arg Val Ile Gln Leu Asn Arg Glu Glu Leu Ser Ser Leu Lys Pro Ile

1205 1210 1215

Leu Thr Pro Ser Thr Gly Ala Gly Val Gly Ser Lys Lys Asp Val Val

1220 1225 1230

Phe Leu Ile Asp Gly Ser Arg Asn Ala Gly Pro Glu Phe Gln Tyr Ile

1235 1240 1245

Arg Thr Leu Ile Glu Arg Ile Val Glu Tyr Leu Asp Ile Gly Phe Asp

1250 1255 1260

Thr Thr Arg Val Ala Val Ile Gln Phe Ser Glu Asp Ser Lys Met Glu

1265 1270 1275 1280

Phe Pro Leu Asn Ala His Phe Ser Lys Asp Glu Val Gln Asn Ala Val

1285 1290 1295

Arg Arg Leu Arg Pro Lys Gly Gly Ser Gln Val Tyr Ile Gly Asn Ala

1300 1305 1310

Leu Glu Tyr Val Leu Lys Asn Ile Phe Gln Arg Pro Leu Gly Ser Arg

1315 1320 1325

Ile Glu Glu Gly Val Pro Gln Phe Leu Val Leu Ile Ser Ser Gly Lys

1330 1335 1340

Ser Asp Asp Glu Val Asp Asp Ser Ala Val Glu Leu Lys Gln Phe Gly

1345 1350 1355 1360

Val Ala Pro Leu Thr Ile Ala Arg His Thr Asp Gln Glu Glu Leu Val

1365 1370 1375

Lys Ile Ser Leu Ser Pro Glu Tyr Val Tyr Ser Val Ser Thr Phe Arg

1380 1385 1390

Glu Leu Pro Arg Leu Glu Gln Lys Leu Leu Thr Pro Ile Thr Thr Leu

1395 1400 1405

Thr Ser Gln Gln Ile His Gln Ile Leu Ala Ser Thr Arg Tyr Pro Pro

1410 1415 1420

Ser Val Val Glu Ser Asp Ala Ala Asp Ile Val Phe Leu Ile Asp Ser

1425 1430 1435 1440

Ser Asp Ala Val Lys Pro Asp Gly Ile Ala His Ile Arg Asp Phe Val

1445 1450 1455

Ser Arg Ile Val Arg Arg Leu Asn Ile Gly Pro Ser Lys Val Arg Ile

1460 1465 1470

Gly Val Val Gln Phe Ser Asn Asp Val Phe Pro Glu Phe Tyr Leu Lys

1475 1480 1485

Thr His Lys Ser Gln Ser Ser Val Leu Glu Ala Ile Arg Arg Leu Arg

1490 1495 1500

Phe Lys Gly Gly Ser Pro Leu Asn Thr Gly Arg Ala Leu Glu Phe Val

1505 1510 1515 1520

Ala Arg Asn Leu Phe Val Lys Ser Ala Gly Ser Arg Ile Glu Asp Gly

1525 1530 1535

Val Pro Gln His Leu Val Leu Phe Leu Gly Gly Lys Ser Gln Asp Asp

1540 1545 1550

Val Ala Arg His Ala Gln Val Ile Ser Ser Ser Gly Ile Val Ser Leu

1555 1560 1565

Gly Ile Gly Asp Arg Asn Ile Asp Arg Thr Asp Leu Gln Thr Ile Thr

1570 1575 1580

Asn Asp Pro Arg Leu Val Phe Thr Val Arg Glu Phe Arg Glu Leu Pro

1585 1590 1595 1600

Asn Ile Glu Glu Arg Val Met Leu Ser Phe Gly Pro Ser Gly Ala Thr

1605 1610 1615

Pro Gln Pro Pro Gly Val Asp Leu Pro Ser Pro Ser Arg Pro Glu Lys

1620 1625 1630

Lys Lys Ala Asp Ile Val Phe Leu Leu Asp Gly Ser Ile Asn Phe Arg

1635 1640 1645

Arg Asp Ser Phe Gln Glu Val Leu Arg Phe Ala Ser Glu Ile Val Asp

1650 1655 1660

Thr Val Tyr Glu Asp Gly Asp Ser Ile Arg Val Gly Leu Val Gln Tyr

1665 1670 1675 1680

Asn Ser Asp Pro Thr Asp Glu Phe Phe Leu Arg Asp Phe Ser Thr Lys

1685 1690 1695

Arg Gln Ile Ile Asp Ala Ile Asn Lys Val Val Tyr Lys Gly Gly Arg

1700 1705 1710

His Ala Asn Thr Arg Val Gly Ile Glu His Leu Leu Arg Asn His Phe

1715 1720 1725

Val Pro Glu Ala Gly Ser Arg Leu Asp Glu Arg Val Pro Gln Ile Ala

1730 1735 1740

Phe Val Ile Thr Gly Gly Lys Ser Val Glu Asp Ala Gln Asp Val Ser

1745 1750 1755 1760

Leu Ala Leu Thr Gln Lys Gly Val Lys Val Phe Ala Val Gly Val Arg

1765 1770 1775

Asn Ile Asp Ser Glu Glu Val Gly Lys Ile Ala Ser Asn Ser Ala Thr

1780 1785 1790

Ala Phe Arg Val Gly Ser Val Gln Glu Leu Ser Glu Leu Ser Glu Thr

1795 1800 1805

Val Leu Glu Thr Leu His Asp Ala Met His Glu Thr Leu Cys Pro Gly

1810 1815 1820

Val Thr Asp Val Ser Lys Ala Cys Asn Leu Glu Val Ile Leu Gly Phe

1825 1830 1835 1840

Asp Gly Ser Arg Asp Gln Asn Val Phe Val Ser Gln Lys Gly Leu Glu

1845 1850 1855

Ser Lys Val Asp Ile Ile Leu Asn Arg Ile Ser Gln Ile Gln Arg Ile

1860 1865 1870

Ser Cys Ser Gly Asn Gln Leu Pro Thr Val Arg Val Ser Val Met Ala

1875 1880 1885

Asn Thr Pro Ser Gly Pro Val Glu Ala Phe Asp Phe Ala Glu Tyr Gln

1890 1895 1900

Pro Glu Leu Phe Glu Lys Phe Arg Asn Met Arg Ser Gln Arg Pro Tyr

1905 1910 1915 1920

Val Leu Thr Ala Asp Thr Leu Lys Leu Tyr Gln Asn Lys Phe Arg Gln

1925 1930 1935

Ser Ser Pro Asp Thr Val Lys Val Val Ile His Phe Thr Asp Gly Ala

1940 1945 1950

Asp Gly Asp Met Ala Asp Leu Tyr Arg Ala Ser Glu Glu Leu Arg Gln

1955 1960 1965

Ala Gly Ala Gln Ala Leu Ile Leu Val Gly Leu Glu Arg Val Ala Asn

1970 1975 1980

Leu Glu Arg Leu Met His Leu Glu Phe Gly Arg Gly Phe Met Tyr Asp

1985 1990 1995 2000

Arg Pro Leu Arg Leu Asn Leu Leu Asp Leu Asp Tyr Glu Leu Ala Glu

2005 2010 2015

Gln Leu Asp Asn Ile Ala Glu Lys Ala Cys Cys Gly Val Pro Cys Lys

2020 2025 2030

Cys Ser Gly Glu Arg Gly Asp Arg Gly Pro Ile Gly Ser Ile Gly Pro

2035 2040 2045

Lys Gly Ile Ser Gly Glu Asp Gly Tyr Arg Gly Tyr Pro Gly Asp Glu

2050 2055 2060

Gly Gly Pro Gly Glu Arg Gly Pro Pro Gly Val Asn Gly Thr Gln Gly

2065 2070 2075 2080

Phe Gln Gly Cys Pro Gly Gln Arg Gly Val Lys Gly Ser Arg Gly Phe

2085 2090 2095

Pro Gly Glu Lys Gly Glu Leu Gly Glu Ile Gly Leu Asp Gly Leu Asp

2100 2105 2110

Gly Glu Glu Gly Asp Lys Gly Leu Pro Gly Ser Ser Gly Glu Lys Gly

2115 2120 2125

Ser Pro Gly Arg Arg Gly Asp Lys Gly Pro Lys Gly Asp Lys Gly Glu

2130 2135 2140

Arg Gly Asp Val Gly Ile Arg Gly Asp Pro Gly Asp Ser Gly Arg Asp

2145 2150 2155 2160

Ser Gln Gln Arg Gly Pro Lys Gly Glu Thr Gly Asp Ile Gly Pro Met

2165 2170 2175

Gly Leu Pro Gly Arg Asp Gly Ile Pro Gly Ser Pro Gly Asp Pro Gly

2180 2185 2190

Lys Asp Gly Gly Ser Gly Arg Arg Gly Pro Ala Gly Ala Lys Gly Asn

2195 2200 2205

Arg Gly Gly Pro Gly Gln Pro Gly Phe Glu Gly Glu Gln Gly Thr Arg

2210 2215 2220

Gly Ser Gln Gly Pro Pro Gly Pro Ile Gly Pro Pro Gly Leu Ile Gly

2225 2230 2235 2240

Glu Gln Gly Ile Pro Gly Pro Arg Gly Gly Gly Gly Thr Ala Gly Ala

2245 2250 2255

Pro Gly Glu Arg Gly Arg Thr Gly Pro Leu Gly Arg Lys Gly Glu Pro

2260 2265 2270

Gly Glu Pro Gly Pro Lys Gly Ser Ile Gly Asn Arg Gly Pro Arg Gly

2275 2280 2285

Glu Thr Gly Asp Asp Gly Arg Asp Gly Val Gly Ser Glu Gly Arg Arg

2290 2295 2300

Gly Lys Lys Gly Glu Arg Gly Phe Pro Gly Tyr Pro Gly Pro Lys Gly

2305 2310 2315 2320

Thr Pro Gly Glu Pro Gly Ala Asp Gly Pro Pro Gly Pro Lys Gly Ile

2325 2330 2335

Arg Gly Arg Arg Gly Asn Ser Gly Pro Pro Gly Ala Thr Gly Gln Lys

2340 2345 2350

Gly Asp Pro Gly Tyr Pro Gly Pro Ser Gly His Lys Gly Asn Arg Gly

2355 2360 2365

Asp Ser Val Asp Gln Cys Ala Leu Ile Gln Ser Ile Arg Asp Lys Cys

2370 2375 2380

Pro Cys Cys Tyr Gly Pro Leu Glu Cys Pro Val Phe Pro Thr Glu Leu

2385 2390 2395 2400

Ala Phe Ala Leu Asp Thr Ser Glu Gly Val Thr Gln Asp Thr Phe Ser

2405 2410 2415

Arg Met Arg Glu Val Leu Leu Gly Ile Val Gly Asp Leu Thr Ile Ala

2420 2425 2430

Glu Ser Asn Cys Pro Arg Gly Ala Arg Val Ala Val Val Thr Tyr Asn

2435 2440 2445

Asn Glu Val Thr Thr Glu Ile Arg Phe Ala Asp Ser Lys Lys Lys Ser

2450 2455 2460

Ala Leu Leu Asp Ser Ile Gln Asn Leu Gln Val Ala Leu Thr Ser Lys

2465 2470 2475 2480

Gln Gln Ser Leu Glu Thr Ala Met Ser Phe Val Ala Arg Asn Thr Phe

2485 2490 2495

Lys Arg Val Arg Ser Gly Phe Leu Met Arg Lys Val Ala Val Phe Phe

2500 2505 2510

Ser Asn Lys Pro Thr Arg Ala Ser Pro Gln Leu Arg Glu Ala Val Leu

2515 2520 2525

Lys Leu Ser Asp Ala Gly Ile Thr Pro Leu Phe Leu Thr Ser Gln Glu

2530 2535 2540

Asp Arg Gln Leu Ile Asn Ala Leu Gln Ile Asn Asn Thr Ala Val Gly

2545 2550 2555 2560

His Ala Leu Val Leu Pro Ala Arg Arg Asp Leu Thr Asp Phe Leu Lys

2565 2570 2575

Asn Val Leu Thr Cys His Val Cys Leu Asp Ile Cys Asn Ile Asp Pro

2580 2585 2590

Ser Cys Gly Phe Gly Ser Trp Arg Pro Ser Phe Arg Asp Arg Arg Ala

2595 2600 2605

Ala Gly Ser Asp Val Asp Ile Asp Leu Ala Phe Ile Leu Asp Ser Ser

2610 2615 2620

Glu Ala Thr Thr Leu Phe Gln Phe Asn Glu Met Lys Lys Tyr Ile Gly

2625 2630 2635 2640

Tyr Val Ile Arg Gln Leu Asp Leu Ser Pro Asp Pro Lys Ala Ser Gln

2645 2650 2655

His Phe Ala Arg Val Ala Val Val Gln Gln Ser Thr Tyr Glu Ser Val

2660 2665 2670

Asp Asn Ala Ser Val Pro Pro Val Lys Val Glu Phe Ser Leu Thr Asp

2675 2680 2685

Tyr Gly Ala Lys Glu Lys Leu Leu Asp Phe Leu Ser Arg Arg Met Thr

2690 2695 2700

Gln Leu Gln Gly Thr Met Gly Leu Gly Asn Ala Ile Glu Tyr Thr Ile

2705 2710 2715 2720

Glu Asn Ile Phe Glu Ser Ala Pro Asn Pro Arg Asp Leu Lys Ile Met

2725 2730 2735

Val Leu Met Leu Thr Gly Asp Met Gln Arg Gln Gln Leu Glu Glu Ala

2740 2745 2750

Gln Arg Ala Ile Leu Gln Ala Lys Cys Lys Gly Tyr Phe Phe Val Val

2755 2760 2765

Leu Gly Ile Gly Arg Lys Val Asn Ile Lys Glu Val Tyr Ser Phe Ala

2770 2775 2780

Ser Glu Pro Asn Asp Val Phe Phe Lys Phe Val Asp Lys Ser Thr Glu

2785 2790 2795 2800

Leu Asn Glu Glu Pro Leu Met Arg Phe Gly Arg Leu Leu Pro Ser Phe

2805 2810 2815

Val Ser Ser Glu Asn Ala Phe Tyr Leu Pro Pro Asp Leu Arg Lys Gln

2820 2825 2830

Cys Asp Trp Phe Gln Gly Asp Gln Pro Val Lys Asn Gly Val Lys Phe

2835 2840 2845

Gly His Lys Gln Ile Asn Pro Pro His Thr Ala Asn Ser Ser Leu Thr

2850 2855 2860

Ser Lys Val Val Thr Thr Met Lys Pro Val Thr Thr Thr Lys Pro Thr

2865 2870 2875 2880

Ala Ile Val Asn Leu Pro Pro Ala Lys Pro Ala Pro Ala Arg Pro Ala

2885 2890 2895

Pro Ala Gln Pro Val Leu Ala Lys Pro Asp Pro Ala Lys Pro Ala Gln

2900 2905 2910

Ala Arg Pro Ala Pro Ala Lys Pro Ala Ser Ala Lys Leu Val Pro Pro

2915 2920 2925

Gln Pro Val His Val Gln Pro Ala Pro Ala Gln Thr Ala Ser Val Arg

2930 2935 2940

Pro Ala Pro Ala Lys Pro Ala Pro Pro Gln Pro Ala Ala Ala Lys Pro

2945 2950 2955 2960

Val Pro Ala Lys Pro Ala Val Pro Ala Gln Pro Ala Pro Pro Gln Pro

2965 2970 2975

Ala Ala Ala Lys Pro Val Pro Ala Lys Pro Ala Val Pro Ala Gln Pro

2980 2985 2990

Ala Pro Pro Gln Pro Ala Ala Ala Lys Pro Val Pro Ala Lys Pro Ala

2995 3000 3005

Val Pro Ala Gln Pro Ala Ala Ala Gln Pro Met Pro Ala Gln Pro Val

3010 3015 3020

Leu Thr Lys Ser Ala Ala Val Lys Pro Ala Ser Ala Asn Lys Pro Val

3025 3030 3035 3040

Ala Ala Lys Pro Val Ala Thr Asn Thr Ala Thr Ala Thr Ala Arg Pro

3045 3050 3055

Ala Leu Ala Ala Lys Pro Ala Ala Ala Lys Pro Ala Ala Thr Arg Pro

3060 3065 3070

Leu Ala Ala Ala Ile Arg Pro Val Ala Thr Lys Pro Glu Ala Pro Arg

3075 3080 3085

Gln Gln Ala Lys Pro Ala Ala Thr Lys Pro Ala Thr Thr Lys Pro Leu

3090 3095 3100

Ala Arg Val Ser Arg Glu Val Gln Val Ser Glu Val Thr Glu Asn Ser

3105 3110 3115 3120

Ala Arg Leu His Trp Glu Arg Pro Glu Pro Ser Ser Ser Phe Phe Tyr

3125 3130 3135

Asp Leu Thr Val Thr Ser Ala His Asp Gln Ser Leu Val Leu Arg Gln

3140 3145 3150

Asn Leu Thr Val Thr Asp Arg Val Ile Gly Gly Leu Leu Ala Gly Gln

3155 3160 3165

Leu Tyr His Val Val Val Val Ser Tyr Leu Gln Ser Gln Val Arg Ala

3170 3175 3180

Ile Tyr Gln Gly Ser Phe Asn Thr Lys Lys Thr Gln Pro Pro Pro Leu

3185 3190 3195 3200

Gln Ala Ala His Arg Ala Ser Ser Ser Thr Ile Asn Leu Met Val Asn

3205 3210 3215

Thr Glu Pro Leu Phe Leu Thr Lys Thr Asp Ile Cys Lys Leu Ser Arg

3220 3225 3230

Asp Ala Gly Thr Cys Val Asp Phe Lys Leu Leu Trp His Tyr Asp Leu

3235 3240 3245

Glu Ser Lys Ser Cys Lys Arg Phe Trp Tyr Gly Gly Cys Gly Gly Asn

3250 3255 3260

Glu Asn Arg Phe His Ser Gln Glu Glu Cys Glu Lys Met Cys Ser Pro

3265 3270 3275 3280

Asp Leu Leu Val

<210> 10

<211> 1027

<212> PRT

<213> Bos taurus

<400> 10

Met Arg Leu Pro Arg Ala Leu Leu Pro Leu Leu Leu Gln Ala Cys Trp

1 5 10 15

Ala Ser Ala Gln Asp Asp Pro Val Ala Ser Arg Ala Ile Ala Phe Gln

20 25 30

Asp Cys Pro Val Asp Leu Phe Phe Val Leu Asp Thr Ser Glu Ser Val

35 40 45

Ala Leu Arg Leu Lys Pro Tyr Gly Ala Leu Val Asp Lys Val Lys Ser

50 55 60

Phe Thr Lys Arg Phe Ile Asp Asn Leu Asn Asp Arg Tyr Tyr Arg Cys

65 70 75 80

Asp Arg Asn Leu Val Trp Asn Ala Gly Ala Leu His Tyr Ser Asp Glu

85 90 95

Val Glu Ile Ile Arg Gly Leu Thr Arg Met Pro Ser Gly Arg Asp Glu

100 105 110

Leu Lys Ser Ser Val Asp Ala Val Lys Tyr Phe Gly Lys Gly Thr Tyr

115 120 125

Thr Asp Cys Ala Ile Lys Lys Gly Leu Glu Glu Leu Leu Val Gly Gly

130 135 140

Ser His Leu Lys Glu Asn Lys Tyr Leu Val Val Val Thr Asp Gly His

145 150 155 160

Pro Leu Glu Gly Tyr Lys Glu Pro Cys Gly Gly Leu Glu Asp Ala Val

165 170 175

Asn Glu Ala Lys His Leu Gly Ile Lys Val Phe Ser Val Ala Ile Thr

180 185 190

Pro Asp His Leu Glu Pro Arg Leu Ser Ile Ile Ala Thr Asp His Thr

195 200 205

Tyr Arg Arg Asn Phe Thr Ala Ala Asp Trp Gly Gln Ser Arg Asp Ala

210 215 220

Glu Glu Val Ile Ser Gln Thr Ile Asp Thr Ile Thr Asp Met Ile Lys

225 230 235 240

Asn Asn Val Glu Gln Val Cys Cys Ser Phe Glu Cys Gln Pro Ala Arg

245 250 255

Gly Pro Pro Gly Pro Arg Gly Asp Pro Gly Tyr Glu Gly Glu Arg Gly

260 265 270

Lys Pro Gly Leu Pro Gly Glu Lys Gly Glu Ala Gly Asp Pro Gly Arg

275 280 285

Pro Gly Asp Leu Gly Pro Val Gly Tyr Gln Gly Met Lys Gly Glu Lys

290 295 300

Gly Ser Arg Gly Glu Lys Gly Ser Arg Gly Pro Lys Gly Tyr Lys Gly

305 310 315 320

Glu Lys Gly Lys Arg Gly Met Asp Gly Val Asp Gly Met Lys Gly Glu

325 330 335

Thr Gly Phe Pro Gly Leu Pro Gly Cys Lys Gly Ser Pro Gly Phe Asp

340 345 350

Gly Ile Gln Gly Pro Pro Gly Pro Lys Gly Asp Pro Gly Ala Phe Gly

355 360 365

Leu Lys Gly Gln Lys Gly Glu Pro Gly Ala Asp Gly Glu Pro Gly Arg

370 375 380

Pro Gly Ser Thr Gly Pro Pro Gly Asp Glu Gly Glu Pro Gly Glu Pro

385 390 395 400

Gly Pro Pro Gly Glu Lys Gly Glu Ala Gly Asp Glu Gly Asn Ala Gly

405 410 415

Pro Asp Gly Ala Pro Gly Glu Arg Gly Gly Pro Gly Glu Arg Gly Pro

420 425 430

Arg Gly Thr Pro Gly Ala Arg Gly Pro Arg Gly Asp Pro Gly Glu Ala

435 440 445

Gly Pro Gln Gly Asp Gln Gly Arg Glu Gly Pro Val Gly Val Pro Gly

450 455 460

Asp Pro Gly Glu Ala Gly Pro Ile Gly Pro Lys Gly Tyr Arg Gly Asp

465 470 475 480

Glu Gly Pro Pro Gly Thr Glu Gly Pro Lys Gly Ala Pro Gly Pro Ala

485 490 495

Gly Pro Pro Gly Asp Pro Gly Leu Met Gly Glu Arg Gly Glu Asp Gly

500 505 510

Pro Pro Gly Asn Gly Thr Glu Gly Phe Pro Gly Phe Pro Gly Tyr Pro

515 520 525

Gly Ser Arg Gly Pro Pro Gly Ile Asn Gly Thr Lys Gly Tyr Pro Gly

530 535 540

Leu Lys Gly Asp Glu Gly Glu Ala Gly Asp Pro Gly Glu Asp Asn Asn

545 550 555 560

Asp Ile Ala Ala Arg Gly Ala Lys Gly Ala Lys Gly Tyr Arg Gly Pro

565 570 575

Glu Gly Pro Gln Gly Pro Pro Gly His Val Gly Pro Pro Gly Pro Asp

580 585 590

Glu Cys Glu Ile Leu Asp Ile Ile Met Lys Met Cys Ser Cys Cys Glu

595 600 605

Cys Lys Cys Gly Pro Ile Asp Ile Leu Phe Val Leu Asp Ser Ser Glu

610 615 620

Ser Ile Gly Leu Gln Asn Phe Glu Ile Ala Lys Asp Phe Ile Val Lys

625 630 635 640

Val Ile Asp Arg Leu Ser Lys Asp Glu Leu Val Lys Phe Glu Pro Gly

645 650 655

Gln Ser His Ala Gly Val Val Gln Tyr Ser His Asn Gln Met Gln Glu

660 665 670

His Val Asp Leu Arg Asp Pro Asn Ile Arg Asn Ala Gln Asp Leu Lys

675 680 685

Glu Ala Ile Lys Lys Leu Gln Trp Met Gly Gly Gly Thr Phe Thr Gly

690 695 700

Glu Ala Leu Gln Tyr Thr Arg Ser Arg Leu Leu Pro Pro Thr Pro Asn

705 710 715 720

Asn Arg Ile Ala Leu Val Ile Thr Asp Gly Arg Ser Asp Thr Gln Arg

725 730 735

Asp Thr Thr Pro Leu Ser Val Leu Cys Gly Pro Asp Ile Gln Val Val

740 745 750

Ser Val Gly Ile Lys Asp Val Phe Gly Leu Ala Ala Gly Ser Asp Gln

755 760 765

Leu Asn Val Ile Ser Cys Gln Gly Leu Ala Pro Gln Gly Arg Pro Gly

770 775 780

Ile Ser Leu Val Lys Glu Asn Tyr Ala Glu Leu Leu Asp Asp Gly Phe

785 790 795 800

Leu Lys Asn Ile Thr Ala Gln Ile Cys Ile Asp Lys Lys Cys Pro Asp

805 810 815

Tyr Ser Cys Pro Ile Thr Phe Ser Ser Pro Ala Asp Ile Thr Ile Leu

820 825 830

Leu Asp Gly Ser Ala Ser Val Gly Ser His Asn Phe Asp Ile Thr Lys

835 840 845

Arg Phe Ala Lys Arg Leu Ala Glu Arg Phe Leu Thr Ala Ser Arg Thr

850 855 860

Asp Pro Gly Gln Asp Val Arg Val Ala Val Val Gln Tyr Ser Gly Thr

865 870 875 880

Gly Gln Gln Arg Pro Glu Arg Ala Ala Leu Gln Phe Leu Gln Asn Tyr

885 890 895

Thr Val Leu Ala Asn Thr Val Asp Ser Met Asp Phe Phe Asn Asp Ala

900 905 910

Thr Asp Val Met Asp Ala Leu Gly Tyr Val Thr Arg Phe Tyr Arg Glu

915 920 925

Ala Ser Ser Asn Ala Ala Lys Lys Arg Leu Leu Leu Phe Ser Asp Gly

930 935 940

Asn Ser Gln Gly Ala Thr Pro Ala Ala Ile Glu Lys Ala Val Gln Glu

945 950 955 960

Ala Gln Arg Ala Gly Val Glu Ile Phe Ala Val Val Val Gly Arg Gln

965 970 975

Val Asn Glu Pro His Val Arg Val Leu Val Thr Gly Lys Ala Ala Glu

980 985 990

Tyr Asp Val Val Phe Gly Glu Arg His Leu Phe Arg Val Pro Ser Tyr

995 1000 1005

Gln Ala Leu Leu Arg Gly Val Phe Tyr Gln Thr Val Ser Arg Lys Val

1010 1015 1020

Ala Leu Asp

1025

<210> 11

<211> 979

<212> PRT

<213> Bos taurus

<400> 11

Met Leu Arg Arg Lys Gly Ala Ala Lys Met Leu Arg Ser Pro Cys Ser

1 5 10 15

Ala Leu Leu Leu Trp Gly Leu Leu Gly Ala Val His Ala Gln Gln Gln

20 25 30

Glu Val Ile Ser Pro Gly Pro Ser Asp Arg Asn Ser Cys Pro Glu Lys

35 40 45

Ala Asp Cys Pro Val His Val Tyr Phe Val Leu Asp Thr Ser Glu Ser

50 55 60

Ile Thr Met Gln Ser Pro Thr Asp Ser Leu Leu Tyr His Met Gln Gln

65 70 75 80

Phe Val Leu Gln Phe Ile Ser Gln Leu Gln Asp Glu Leu Tyr Leu Asp

85 90 95

Gln Val Ala Leu Ser Trp Arg Tyr Gly Gly Leu His Phe Ser Asp Leu

100 105 110

Val Glu Val Phe Ser Pro Pro Gly Ser Asp Arg Ala Ser Phe Thr Lys

115 120 125

Ser Leu Gln Ser Ile Ser Ser Phe Arg Arg Gly Thr Phe Thr Asp Cys

130 135 140

Met Leu Ala Asn Met Thr Gln Glu Val Arg Arg His Val Gly Lys Gly

145 150 155 160

Val Val Asn Phe Ala Val Val Ile Thr Asp Gly His Val Thr Gly Ser

165 170 175

Pro Cys Gly Gly Ile Lys Leu Gln Ala Glu Arg Ala Arg Glu Glu Gly

180 185 190

Ile Arg Leu Phe Ala Val Pro Pro Asn Leu Lys Leu Asn Glu Gln Gly

195 200 205

Leu Arg Asp Ile Ala Asn Thr Pro His Glu Leu Tyr Arg Asn Asn Tyr

210 215 220

Ala Thr Met Arg Pro Asp Ser Thr Glu Ile Asp Gln Asp Thr Ile Asn

225 230 235 240

Arg Ile Ile Lys Val Met Val Ser Gly Arg Ala Gly Cys Tyr Lys Val

245 250 255

Ser Cys Leu Glu Ile Pro Gly Pro Pro Gly Pro Lys Gly Tyr Arg Gly

260 265 270

Gln Lys Gly Ala Lys Gly Asn Met Gly Glu Pro Gly Glu Pro Gly Gln

275 280 285

Lys Gly Arg Gln Gly Asp Pro Gly Ile Glu Gly Pro Ile Gly Phe Pro

290 295 300

Gly Pro Lys Gly Lys Leu Gly Arg Ile Gly Pro Pro Gly Cys Lys Gly

305 310 315 320

Asp Thr Gly Asp Arg Gly Pro Asp Gly Tyr Val Gly Glu Ala Gly Ser

325 330 335

Pro Gly Glu Arg Gly Asp Gln Gly Ser Lys Val Asp Arg Leu Ala Met

340 345 350

Ala Arg Ala Gly Gln Ser Arg Trp Gly His His Pro Ser Arg Ala Phe

355 360 365

Ser Leu Pro Thr Ala Pro Gly Leu Asp Ala Gln Glu Ala Leu Ser Leu

370 375 380

Lys Thr Arg Pro Gly Ala Arg Gly Cys Pro His Met Gly Gly Arg Arg

385 390 395 400

Gly Asp Pro Gly Thr Lys Gly Gly Pro Gly Ser Asp Gly Pro Lys Gly

405 410 415

Glu Lys Gly Asp Pro Gly Pro Glu Gly Pro Arg Gly Leu Ala Gly Glu

420 425 430

Val Gly Asn Lys Gly Ala Lys Gly Asp Arg Gly Leu Pro Gly Pro Arg

435 440 445

Gly Pro Gln Gly Thr Val Gly Glu Pro Gly Lys Gln Gly Ser Arg Gly

450 455 460

Asp Pro Gly Asp Ala Gly Pro Arg Gly Asp Ser Gly Gln Pro Gly Pro

465 470 475 480

Lys Val Cys Pro Leu Pro Thr Leu Gln Asp Gly Ala Gly Arg Cys Pro

485 490 495

Val Ser Gln Gly Gly Arg Gly Asp Phe Gly Ser Lys Gly Glu Pro Gly

500 505 510

Arg Lys Gly Gln Lys Gly Glu Pro Val Ser Thr Ser Met Pro Arg Ala

515 520 525

Glu Val Ser Pro Trp Ala Gly Gly Gln Arg Gly Asp Pro Pro Ala Pro

530 535 540

Arg Ser Pro Gly Ser Ala Leu Leu Pro Gly Ser Ala Asp Pro Thr Thr

545 550 555 560

Leu Pro Ala Pro Ala Asp Cys Glu Lys Arg Cys Gly Ala Leu Asp Val

565 570 575

Val Phe Val Ile Asp Ser Ser Glu Ser Ile Gly Tyr Thr Asn Phe Thr

580 585 590

Leu Glu Lys Asn Phe Val Ile Asn Val Val Asn Arg Leu Gly Ala Ile

595 600 605

Ala Lys Asp Pro Lys Ser Glu Thr Gly Thr Arg Val Gly Val Val Gln

610 615 620

Tyr Ser His Glu Gly Thr Phe Glu Ala Ile Gln Leu Asp Asp Glu Arg

625 630 635 640

Ile Asp Ser Leu Ser Ser Phe Lys Glu Ala Val Lys Asn Leu Glu Trp

645 650 655

Ile Ala Gly Gly Thr Trp Thr Pro Ser Ala Leu Lys Phe Ala Tyr Asn

660 665 670

Lys Leu Ile Lys Glu Ser Arg Arg Gln Lys Thr Arg Val Phe Ala Val

675 680 685

Val Ile Thr Asp Gly Arg His Asp Pro Arg Asp Asp Asp Leu Asn Leu

690 695 700

Arg Ala Leu Cys Asn His Glu Val Thr Val Thr Ala Ile Gly Ile Gly

705 710 715 720

Asp Met Phe His Glu Lys His Glu Ser Glu Asn Leu Tyr Ser Ile Ala

725 730 735

Cys Asp Lys Pro Gln Gln Val Arg Asn Met Thr Leu Phe Ser Asp Leu

740 745 750

Val Ala Glu Lys Phe Ile Asp Asp Met Glu Asp Val Leu Cys Pro Asp

755 760 765

Pro Gln Ile Val Cys Pro Asp Leu Pro Cys Gln Thr Glu Leu Tyr Val

770 775 780

Ala Gln Cys Thr Gln Arg Pro Val Asp Ile Val Phe Leu Leu Asp Gly

785 790 795 800

Ser Glu Arg Leu Gly Glu Gln Asn Phe His Lys Val Arg Arg Phe Val

805 810 815

Glu Glu Val Ser Arg Arg Leu Thr Leu Ala Arg Lys Asp Asp Asp Pro

820 825 830

Leu Asn Ala Arg Val Ala Leu Leu Gln Phe Gly Gly Pro Arg Glu Gln

835 840 845

Gln Val Ala Phe Pro Leu Thr Ser Asn Leu Thr Val Ile Gln Glu Ala

850 855 860

Leu Ala Ser Ala Arg Tyr Leu Asn Ser Phe Ser His Val Gly Thr Gly

865 870 875 880

Ile Val Gln Ala Ile Asn Gln Val Val Gln Gly Ala Arg Ala Gly Ala

885 890 895

Arg Arg His Ala Glu Leu Ser Phe Val Phe Leu Thr Asp Gly Val Thr

900 905 910

Gly Asn Asp Ser Leu Asp Glu Ala Val His Ser Met Arg Lys Gln Asn

915 920 925

Val Val Pro Thr Val Val Ala Val Gly Ser Asp Val Asp Thr Asp Val

930 935 940

Leu Ser Lys Ile Ser Leu Gly Asp Pro Ala Ala Val Phe Arg Glu Lys

945 950 955 960

Asp Tyr Asp Ser Leu Ala Gln Pro Gly Phe Phe Asp Arg Phe Ile Arg

965 970 975

Trp Ile Cys

<210> 12

<211> 3132

<212> PRT

<213> Bos taurus

<400> 12

Met Arg Lys His Arg His Leu Pro Leu Val Ala Ile Leu Cys Leu Phe

1 5 10 15

Phe Ser Gly Phe Ser Phe Thr Arg Gly Gln Gln Gln Pro Asp Val Lys

20 25 30

Asn Gly Ala Ala Ala Asp Ile Ile Phe Leu Val Asp Ser Ser Trp Ser

35 40 45

Ile Gly Lys Glu His Phe Gln Leu Val Arg Glu Phe Leu Tyr Asp Val

50 55 60

Ile Glu Ser Leu Ala Val Gly Asp Asn Asp Phe Arg Phe Ala Leu Val

65 70 75 80

Gln Phe Asn Gly Asn Pro His Thr Glu Phe Leu Phe Asn Thr Tyr Arg

85 90 95

Ser Lys Gln Glu Val Leu Ser His Val Ser Asn Met Ser Tyr Ile Gly

100 105 110

Gly Ser Asn Gln Thr Gly Lys Gly Leu Ala Tyr Val Met Gln Asn His

115 120 125

Leu Thr Glu Ala Ala Gly Ser Arg Ala Ser Asp Gly Val Pro Gln Val

130 135 140

Ile Val Val Leu Thr His Gly His Ser Glu Asp Gly Leu Ala Leu Pro

145 150 155 160

Ser Ala Glu Leu Lys Ser Ala Asp Val Asn Val Phe Ala Ile Gly Val

165 170 175

Glu Asp Ala Asp Glu Ala Ala Leu Lys Glu Ile Ala Ser Glu Pro Leu

180 185 190

Asn Met His Val Phe Asn Leu Glu Asn Tyr Thr Ser Leu His Asp Ile

195 200 205

Val Gly Asn Leu Val Ala Cys Val Arg Ser Ser Met Ala Pro Glu Arg

210 215 220

Ala Gly Gly Thr Glu Ile Pro Lys Asp Ile Thr Ala Gln Asp Ser Ala

225 230 235 240

Asp Ile Ile Phe Leu Ile Asp Gly Ser Asn Asn Thr Gly Ser Val Asn

245 250 255

Phe Ala Val Ile Leu Asp Phe Leu Val Asn Leu Leu Glu Arg Leu Ser

260 265 270

Ile Gly Thr Gln Gln Ile Arg Val Gly Val Val Gln Tyr Ser Asp Glu

275 280 285

Pro Arg Thr Met Phe Ser Leu Asn Ser Tyr Ser Thr Lys Ala Gln Val

290 295 300

Leu Asp Ala Val Lys Ala Leu Gly Phe Ile Gly Gly Glu Leu Ala Asn

305 310 315 320

Val Gly Leu Ala Leu Asp Phe Val Val Glu Asn His Phe Thr Arg Ala

325 330 335

Gly Gly Ser Arg Ala Glu Glu Gly Val Pro Gln Val Leu Val Leu Ile

340 345 350

Ser Ala Gly Pro Ser Ser Asp Glu Ile Arg Asp Gly Val Val Ala Leu

355 360 365

Lys Gln Ala Ser Val Phe Ser Phe Gly Leu Gly Ala Gln Ala Ala Ser

370 375 380

Lys Ala Glu Leu Gln His Ile Ala Thr Asn Asp Asn Leu Val Phe Thr

385 390 395 400

Val Pro Glu Phe Arg Ser Leu Gly Asp Val Gln Glu Gln Leu Leu Pro

405 410 415

Tyr Ile Val Gly Val Ala Gln Arg His Ile Val Leu Gln Pro Pro Thr

420 425 430

Ile Val Thr Gln Val Ile Glu Val Asn Lys Arg Asp Ile Val Phe Leu

435 440 445

Val Asp Gly Ser Ser Lys Leu Gly Leu Thr Asn Phe Asn Ala Ile Arg

450 455 460

Asp Phe Ile Ala Lys Val Ile Gln Arg Leu Glu Ile Arg Gln Asp Leu

465 470 475 480

Ile Gln Val Ala Val Ala Gln Tyr Ala Asp Thr Val Arg Pro Glu Phe

485 490 495

Tyr Phe Asn Thr Tyr Pro Ser Lys Arg Glu Val Ile Asn Ala Val Arg

500 505 510

Lys Met Lys Ala Leu Asp Gly Ser Ala Leu Tyr Thr Gly Ser Ala Leu

515 520 525

Asp Phe Val Arg Asn Asn Leu Phe Thr Glu Ala Ala Gly Tyr Arg Ala

530 535 540

Ala Glu Gly Val Pro Lys Leu Leu Val Leu Val Thr Gly Gly Lys Ser

545 550 555 560

Leu Asp Ala Val Ser Gln Pro Ala Gln Glu Leu Lys Arg Ser Gly Ile

565 570 575

Leu Ala Phe Ala Val Gly Asn Lys Val Ala Asp Gln Ala Glu Leu Glu

580 585 590

Glu Ile Ala Phe Asp Ser Ser Leu Val Phe Thr Ala Thr Glu Phe Arg

595 600 605

Pro Ala Pro Leu Gln Gly Val Leu Pro Gly Leu Leu Gly Pro Leu Arg

610 615 620

Thr Leu Thr Gly Thr Thr Glu Val Arg Val Asn Lys Arg Asp Ile Ile

625 630 635 640

Phe Leu Leu Asp Gly Ser Ser Asn Val Gly Glu Thr Asn Phe Pro Tyr

645 650 655

Val Arg Asp Phe Val Met Asn Leu Val Asn Ser Leu Asp Val Gly Ser

660 665 670

Asp His Ile Arg Val Gly Leu Val Gln Phe Ser Asp Thr Pro Val Thr

675 680 685

Glu Phe Ser Leu Asn Thr Tyr Pro Thr Lys Ser Glu Leu Leu Ala His

690 695 700

Leu Arg Gln Met Gln Leu Gln Gly Gly Ser Val Leu Asn Thr Gly Ala

705 710 715 720

Ala Leu Ser Tyr Val His Ala Asn His Phe Thr Glu Ala Gly Gly Ser

725 730 735

Arg Ile Gln Asp His Val Pro Gln Leu Leu Leu Leu Leu Thr Ala Gly

740 745 750

Gln Ser Glu Asp Ser Tyr Leu Gln Ala Ala Asn Ala Leu Ala Arg Ala

755 760 765

Gly Ile Leu Thr Phe Cys Val Gly Thr Ser Gln Ala Asp Arg Ala Glu

770 775 780

Leu Glu Glu Ile Ala Phe Asn Pro Gly Leu Val Tyr Leu Met Asp Asp

785 790 795 800

Phe Ser Ser Leu Pro Ala Leu Pro Gln Gln Leu Ile Gln Pro Leu Thr

805 810 815

Thr Tyr Val Ser Gly Gly Val Glu Glu Val Pro Leu Ala Gln Pro Glu

820 825 830

Ser Lys Arg Asp Ile Leu Phe Leu Phe Asp Gly Ser Ala Asn Leu Met

835 840 845

Gly Gln Phe Thr Ala Ala Arg Asp Phe Leu Tyr Lys Val Ile Asp Glu

850 855 860

Leu Asp Val Lys Pro Glu Gly Thr Arg Val Ala Val Ala Gln Phe Ser

865 870 875 880

Asp Asp Val Lys Val Glu Ser Arg Phe Asp Gln His Gln Asn Lys Pro

885 890 895

Glu Ile Leu Asn Leu Val Lys Arg Met Lys Leu Lys Thr Gly Lys Ala

900 905 910

Leu Asn Leu Gly Tyr Ala Leu Asp Tyr Ala Gln Arg Tyr Ile Phe Val

915 920 925

Lys Ser Ala Gly Ser Arg Ile Glu Asp Gly Val Leu Gln Phe Leu Val

930 935 940

Leu Leu Val Ala Gly Lys Ser Ser Asp Arg Val Asp Thr Pro Ala Leu

945 950 955 960

Asn Leu Lys Gln Ser Gly Val Val Pro Phe Ile Leu Gln Ala Lys Asn

965 970 975

Ala Asp Pro Ala Glu Leu Glu Leu Ile Val Pro Ser Pro Ala Phe Ile

980 985 990

Leu Val Ala Glu Ser Leu Pro Lys Ile Gly Asp Leu Gln Pro Gln Ile

995 1000 1005

Val Asn Leu Leu Lys Ser Val Gln Asn Gly Ala Pro Ala Pro Val Ser

1010 1015 1020

Val Glu Lys Asp Val Val Phe Leu Ile Asp Gly Ser Glu Gly Val Arg

1025 1030 1035 1040

Ser Gly Phe Pro Leu Leu Lys Glu Phe Val Gln Arg Val Val Glu Ser

1045 1050 1055

Leu Asp Val Gly Pro Asp Arg Val Arg Val Ala Val Val Gln Tyr Ser

1060 1065 1070

Asp Arg Thr Arg Pro Glu Phe Tyr Leu Asn Ser Tyr Met Asp Gln Gln

1075 1080 1085

Ser Val Val Gly Ala Ile Arg Gly Leu Thr Leu Leu Gly Gly Pro Ala

1090 1095 1100

Pro Asn Thr Gly Ala Ala Leu Glu Phe Val Leu Arg Asn Ile Leu Val

1105 1110 1115 1120

Gly Ser Ala Gly Ser Arg Ile Ala Glu Gly Val Pro Gln Leu Leu Ile

1125 1130 1135

Val Leu Thr Ala Asp Arg Ser Gly Asp Asp Val Arg Gly Pro Ser Val

1140 1145 1150

Val Leu Arg Arg Gly Gly Ala Val Pro Ile Gly Ile Gly Ile Gly Asn

1155 1160 1165

Ala Asp Ile Thr Glu Met Gln Thr Leu Ser Phe Val Pro Asp Phe Ala

1170 1175 1180

Val Val Ile Pro Thr Phe Arg Gln Leu Gly Thr Ile Gln Gln Val Ile

1185 1190 1195 1200

Ser Glu Arg Val Thr Gln Leu Ser Arg Glu Glu Leu Ser Arg Leu Gln

1205 1210 1215

Ala Ser Val Thr Pro Leu Thr Thr Pro Val Val Ser Ser Lys Arg Asp

1220 1225 1230

Val Val Phe Leu Ile Asp Gly Ser Gln Ser Ala Gly Pro Glu Phe Gln

1235 1240 1245

Tyr Ile Arg Thr Leu Ile Glu Arg Leu Val Asp Tyr Leu Asp Val Gly

1250 1255 1260

Phe Asp Thr Thr Arg Val Ala Val Ile Gln Phe Ser Asp Asp Pro Arg

1265 1270 1275 1280

Val Glu Phe Leu Leu Asn Val His Ser Ser Lys Asp Glu Val Gln Asn

1285 1290 1295

Ala Val Arg Arg Leu Arg Pro Lys Gly Gly Arg Gln Val Asn Val Gly

1300 1305 1310

Gly Ala Leu Glu Tyr Val Ala Arg Asn Ile Phe Lys Arg Pro Leu Gly

1315 1320 1325

Ser Arg Ile Glu Glu Gly Val Pro Gln Phe Leu Val Leu Ile Ser Ser

1330 1335 1340

Gly Lys Ser Asp Asp Glu Val Glu Asp Ser Ala Ile Glu Leu Lys Gln

1345 1350 1355 1360

Phe Gly Val Ala Pro Leu Thr Ile Ala Arg Asn Val Asp Gln Glu Glu

1365 1370 1375

Leu Val Lys Ile Ser Leu Ser Pro Glu Tyr Val Phe Ser Val Asn Thr

1380 1385 1390

Phe Arg Glu Leu Pro Ser Leu Glu Gln Lys Leu Leu Thr Pro Leu Thr

1395 1400 1405

Thr Leu Thr Ala Gly Gln Ile Gln Gln Leu Leu Ala Ser Thr Arg Tyr

1410 1415 1420

Pro Pro Pro Ala Val Glu Ser Asp Ala Ala Asp Ile Val Phe Leu Ile

1425 1430 1435 1440

Asp Ser Ser Asp Gly Val Lys Pro Asp Gly Ile Ala His Ile Arg Asp

1445 1450 1455

Phe Val Ile Arg Ile Val Arg Arg Leu Asn Val Gly Pro Asn Lys Val

1460 1465 1470

Arg Ile Gly Val Leu Gln Phe Ser Asn Asp Val Phe Pro Glu Phe Gln

1475 1480 1485

Leu Lys Thr Tyr Lys Ser Gln Ala Ser Val Leu Asp Ala Ile Arg Arg

1490 1495 1500

Leu Arg Phe Lys Gly Gly Ser Pro Leu Asn Thr Gly Lys Ala Leu Glu

1505 1510 1515 1520

Phe Val Ala Arg Asn Tyr Phe Val Lys Ser Ala Gly Ser Arg Ile Glu

1525 1530 1535

Asp Gly Val Pro Gln His Leu Val Leu Phe Leu Gly Gly Lys Ser Gln

1540 1545 1550

Asp Asp Ile Ser Arg Tyr Ser Gln Val Ile Lys Ser Ala Gly Ile Ala

1555 1560 1565

Ser Leu Gly Val Gly Asp Arg Asn Ile Asp Arg Thr Glu Leu Gln Thr

1570 1575 1580

Ile Thr Ser Asp Pro Arg Leu Val Phe Thr Val Arg Glu Phe Arg Asp

1585 1590 1595 1600

Leu Pro Ser Ile Glu Glu Arg Met Val Asn Ser Phe Gly Ser Ser Gly

1605 1610 1615

Val Thr Pro Ala Pro Pro Gly Val Asp Thr Pro Ser Pro Ser Arg Pro

1620 1625 1630

Glu Lys Lys Lys Ala Asp Ile Val Phe Leu Leu Asp Gly Ser Ile Asn

1635 1640 1645

Phe Arg Arg Asp Ser Phe Gln Glu Val Leu Arg Phe Val Ser Glu Ile

1650 1655 1660

Val Asp Thr Val Tyr Glu Gly Gly Asp Ser Ile Gln Val Gly Leu Val

1665 1670 1675 1680

Gln Tyr Asn Ser Asp Pro Thr Asp Glu Phe Phe Leu Lys Asp Phe Pro

1685 1690 1695

Thr Lys Gln Gln Ile Ile Asp Ala Ile Asn Lys Val Val Tyr Lys Gly

1700 1705 1710

Gly Arg His Ala Asn Thr Lys Val Gly Leu Glu His Leu Arg Arg Asn

1715 1720 1725

His Phe Val Pro Glu Ala Gly Ser Arg Leu Asp Gln Arg Val Pro Gln

1730 1735 1740

Ile Ala Phe Val Ile Thr Gly Gly Lys Ser Val Glu Asp Ala Gln Glu

1745 1750 1755 1760

Ala Ser Met Ala Leu Thr Gln Arg Gly Val Lys Val Phe Ala Val Gly

1765 1770 1775

Val Arg Asn Ile Asp Ser Glu Glu Val Gly Lys Ile Ala Ser Asn Ser

1780 1785 1790

Ala Thr Ala Phe Arg Val Gly Asn Val Gln Glu Leu Ser Glu Leu Ser

1795 1800 1805

Glu Gln Val Leu Glu Thr Leu His Asp Ala Met His Glu Thr Leu Cys

1810 1815 1820

Pro Gly Val Thr Asp Val Ser Lys Ala Cys Asn Leu Asp Val Ile Leu

1825 1830 1835 1840

Gly Phe Asp Gly Ser Gly Asp Gln Asn Val Phe Val Ala Gln Lys Gly

1845 1850 1855

Leu Glu Pro Lys Val Asp Thr Ile Leu Arg Arg Ile Ser Gln Met Gln

1860 1865 1870

Lys Ile Ser Cys Ser Gly Ser Gln Leu Pro Thr Val Arg Val Ser Val

1875 1880 1885

Val Ala Leu Thr Pro Ser Gly Pro Val Glu Ala Phe Asp Phe Ala Glu

1890 1895 1900

Tyr Gln Pro Glu Leu Phe Glu Lys Phe Gln Asn Met Arg Ala Gln His

1905 1910 1915 1920

Pro Tyr Val Leu Thr Ala Asp Thr Leu Lys Leu Tyr Gln Asn Lys Phe

1925 1930 1935

Arg Gln Ala Ser Met Asp Asn Val Lys Val Val Ile His Phe Thr Asp

1940 1945 1950

Gly Val Asp Gly Asp Leu Ala Asp Leu Gln Arg Ala Ser Glu Glu Leu

1955 1960 1965

Arg Gln Glu Gly Val Arg Ala Leu Ile Leu Val Gly Leu Glu Arg Val

1970 1975 1980

Ala Asn Leu Glu Gln Leu Met Gln Leu Glu Phe Gly Arg Gly Phe Thr

1985 1990 1995 2000

Tyr Asn Arg Pro Leu Arg Leu Asn Leu Leu Asp Leu Asp Tyr Glu Leu

2005 2010 2015

Ala Glu Gln Leu Asp Asn Ile Ala Glu Lys Ala Cys Cys Gly Ile Pro

2020 2025 2030

Cys Lys Cys Ser Gly Gln Arg Gly Asp Arg Gly Pro Ile Gly Ser Ile

2035 2040 2045

Gly Pro Lys Gly Ile Pro Gly Glu Asp Gly Tyr Arg Gly Tyr Pro Gly

2050 2055 2060

Asp Glu Gly Gly Pro Gly Glu Arg Gly Pro Pro Gly Val Asn Gly Thr

2065 2070 2075 2080

Gln Gly Phe Gln Gly Cys Pro Gly Gln Arg Gly Val Lys Gly Ser Arg

2085 2090 2095

Gly Phe Pro Gly Glu Lys Gly Glu Leu Gly Glu Ile Gly Leu Asp Gly

2100 2105 2110

Leu Asp Gly Glu Asp Gly Asp Lys Gly Leu Pro Gly Thr Ser Gly Glu

2115 2120 2125

Lys Gly Ser Pro Gly Arg Arg Gly Asp Lys Gly Pro Lys Gly Asp Lys

2130 2135 2140

Gly Glu Arg Gly Asp Val Gly Ile Arg Gly Asp Pro Gly Asn Ser Gly

2145 2150 2155 2160

Gln Asp Ser Gln Gln Arg Gly Ala Lys Gly Glu Thr Gly Asp Ile Gly

2165 2170 2175

Pro Val Val Gln Cys Ser Pro Phe Leu Pro Val Gln Ser Asn Leu Pro

2180 2185 2190

Leu Cys Gly Ser Cys Gly Gly Arg Gly Gly Ser Pro Pro Arg Ser Thr

2195 2200 2205

Tyr Val Gly Ile Leu Leu Leu Gln Gly Pro Pro Gly Pro Thr Gly Pro

2210 2215 2220

Pro Gly Leu Ile Gly Glu Gln Gly Ile Pro Gly Pro Arg Val Ser Leu

2225 2230 2235 2240

Ala Trp Thr Leu Ser Lys Ser Gly Glu Pro Gly Asp Pro Gly Pro Lys

2245 2250 2255

Gly Ser Ile Gly Asn Arg Gly Pro Arg Gly Glu Thr Gly Asp Asp Gly

2260 2265 2270

Arg Asp Gly Val Gly Ser Glu Gly Arg Ile Gly Lys Lys Val Phe Ile

2275 2280 2285

Cys Arg Gly Gly Asn Pro Gly Glu Pro Gly Thr Asp Gly Pro Pro Gly

2290 2295 2300

Pro Lys Gly Ile Arg Gly Arg Arg Gly Asn Ser Gly Pro Pro Gly Ile

2305 2310 2315 2320

Ala Gly Gln Lys Gly Asp Pro Gly Tyr Pro Gly Pro Ser Gly Tyr Lys

2325 2330 2335

Gly Ser Arg Gly Asp Ser Met Asp Gln Cys Ala Leu Val Gln Ser Ile

2340 2345 2350

Lys Asp Lys Cys Arg Pro Leu Glu Cys Pro Val Phe Pro Thr Glu Leu

2355 2360 2365

Ala Phe Ala Leu Asp Thr Ser Glu Gly Val Thr Gln Asp Arg Phe Ser

2370 2375 2380

Gln Met Arg Glu Val Val Leu Lys Ile Leu Asp Asp Leu Thr Ile Ala

2385 2390 2395 2400

Glu Ser Asn Cys Pro Arg Gly Ala Arg Val Ala Val Val Thr Tyr Asn

2405 2410 2415

Asn Glu Val Thr Thr Glu Ile Arg Phe Ala Asp Ser Lys Lys Lys Ser

2420 2425 2430

Val Leu Leu Asp Lys Ile Lys Asn Leu Gln Val Ser Leu Thr Ser Lys

2435 2440 2445

Gln Gln Ser Leu Glu Thr Ala Met Ser Phe Val Ala Arg Asn Thr Phe

2450 2455 2460

Lys Arg Val Arg Ser Gly Phe Leu Met Arg Lys Val Ala Val Phe Phe

2465 2470 2475 2480

Ser Asn Lys Pro Thr Arg Ala Thr Pro Gln Leu Arg Glu Ala Val Leu

2485 2490 2495

Lys Leu Ser Asp Ala Gly Ile Thr Pro Leu Phe Leu Thr Ser Gln Glu

2500 2505 2510

Asp Arg Gln Leu Ile Asn Ala Leu Gln Ile Asn Asn Thr Ala Val Gly

2515 2520 2525

His Ala Leu Val Leu Pro Ala Gly Gly Asp Leu Thr Asp Phe Leu Lys

2530 2535 2540

Asn Val Leu Thr Cys His Val Cys Leu Asp Ile Cys Asn Ile Asp Pro

2545 2550 2555 2560

Ser Cys Gly Phe Gly Ser Trp Arg Pro Ser Phe Arg Asp Arg Arg Ala

2565 2570 2575

Ala Gly Ser Asp Val Asp Ile Asp Met Ala Phe Ile Leu Asp Ser Ser

2580 2585 2590

Glu Ser Thr Thr Pro Phe Gln Phe Asn Glu Met Arg Lys Tyr Ile Glu

2595 2600 2605

Tyr Leu Val Arg Gln Leu Asp Val Ser Pro Asp Pro Lys Ala Ser Gln

2610 2615 2620

His Phe Ala Arg Val Ala Val Val Gln His Ala Pro Tyr Glu Ala Val

2625 2630 2635 2640

Asp Asn Ala Ser Val Pro Pro Val Lys Val Glu Phe Ser Leu Thr Asp

2645 2650 2655

Tyr Gly Ser Lys Glu Lys Leu Leu Ala Phe Leu Gly Ser Arg Met Thr

2660 2665 2670

Gln Leu Gln Gly Thr Arg Ala Leu Gly Arg Ala Ile Asp Tyr Thr Ile

2675 2680 2685

Glu Asn Ile Phe Glu Ser Ala Pro Asn Pro Arg Asp Leu Lys Ile Val

2690 2695 2700

Val Leu Met Leu Thr Gly Glu Val Gln Lys Gln Gln Leu Glu Glu Ala

2705 2710 2715 2720

Gln Arg Ala Ile Leu Gln Ala Lys Cys Lys Gly Tyr Phe Phe Val Ile

2725 2730 2735

Leu Gly Ile Gly Arg Lys Val Asn Val Lys Glu Leu Tyr Ser Ser Ala

2740 2745 2750

Ser Glu Pro Asn Asp Val Phe Phe Lys Leu Val Asp Lys Ser Thr Glu

2755 2760 2765

Leu Asn Glu Glu Pro Leu Met Arg Phe Gly Arg Leu Leu Pro Ser Phe

2770 2775 2780

Val Ser Ser Lys Asp Ala Phe Tyr Leu Ser Pro Asp Ile Arg Lys Gln

2785 2790 2795 2800

Cys Asp Trp Phe Gln Ala Asp Gln Pro Ala Lys Asn Leu Val Gln Phe

2805 2810 2815

Gly Tyr Lys Gln Ile Asn Val Pro Asn Asn Val Thr Ser Ser Pro Thr

2820 2825 2830

Ser Lys Leu Val Thr Thr Thr Lys Pro Val Ile Thr Thr Thr Lys Pro

2835 2840 2845

Ile Thr Val Val Asn Leu Pro Ala Ser Lys Pro Ala Ala Thr Arg Pro

2850 2855 2860

Val Asp Glu Arg Pro Ala Ala Gly Arg Ser Val Ala Thr Lys Met Asp

2865 2870 2875 2880

Ser Ala Arg Pro Val Ala Thr Lys Thr Glu Ala Thr Lys Pro Ala Glu

2885 2890 2895

Ala Ala Lys Pro Thr Ala Thr Lys Pro Val Ala Ala Arg Pro Pro Thr

2900 2905 2910

Ala Ala Arg Ser Met Ala Thr Arg Ser Glu Ala Pro Arg Pro Gln Ala

2915 2920 2925

Val Lys Leu Ala Ala Ser Arg Pro Gly Ala Ala Lys Pro Val Val Lys

2930 2935 2940

Ala Pro Arg Glu Ile His Val Ser Glu Val Thr Glu Asn Ser Ala Lys

2945 2950 2955 2960

Leu His Trp Glu Arg Pro Glu Pro Pro Ser Pro Tyr Leu Tyr Asn Leu

2965 2970 2975

Thr Val Thr Ser Ala His Asp Gln Ala Val Val Leu Lys Gln Asn Leu

2980 2985 2990

Thr Val Thr Asp Arg Val Ile Gly Gly Leu Leu Pro Gly Gln Thr Tyr

2995 3000 3005

His Val Thr Val Thr Cys Ser Leu Arg Ser Gln Val Arg Ala Ile Tyr

3010 3015 3020

Gln Gly Ser Phe Ser Thr Lys Lys Ile Gln Pro Pro Pro Pro Gln Thr

3025 3030 3035 3040

Glu Arg Ser Ala Ser Ser Ala Thr Ile Asn Leu Val Val Ser Ala Asp

3045 3050 3055

Arg Leu Ala Gly Ser Lys Ala Asp Ile Cys Lys Leu Pro Lys Asp Gly

3060 3065 3070

Gly Thr Cys Arg Glu Phe Val Leu Lys Trp Tyr Tyr Asp Ser Val Thr

3075 3080 3085

Glu Asn Cys Ala Arg Phe Trp Tyr Gly Gly Cys Gly Gly Asn Glu Asn

3090 3095 3100

Arg Phe Asn Ser Gln Asp Glu Cys Glu Lys Val Cys Pro Pro Val Pro

3105 3110 3115 3120

Ile Lys Gln Pro Gly Val Ile Ala Ala Met Gly Thr

3125 3130

Claims

1.六型胶原蛋白在制备能提高再生神经有序性相关药物中的应用。

2.六型胶原蛋白在制备能提高再生神经有序性的神经移植物中的应用。

3.根据权利要求1或2所述的六型胶原蛋白，其特征在于，所述六型胶原蛋白包括人源性六型胶原蛋白或动物源性同源六型胶原蛋白，所述动物源性同源六型胶原蛋白包括大鼠、小鼠或牛六型胶原蛋白。

4.根据权利要求1或2所述的六型胶原蛋白，其特征在于，所述人源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列1所述的COL6A1蛋白单体、如蛋白质序列2所述的COL6A2蛋白单体以及如蛋白质序列3所述的COL6A3蛋白单体。

5.根据权利要求1或2所述的六型胶原蛋白，其特征在于，所述大鼠源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列4所述的COL6A1蛋白单体、如蛋白质序列5所述的COL6A2蛋白单体、如蛋白质序列6所述的COL6A3蛋白单体。

6.根据权利要求1或2所述的六型胶原蛋白，其特征在于，所述小鼠源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列7所述的COL6A1蛋白单体、如蛋白质序列8所述的COL6A2蛋白单体以及如蛋白质序列9所述的COL6A3蛋白单体。

7.根据权利要求1或2所述的六型胶原蛋白，其特征在于，所述牛源性六型胶原蛋白COL6是由三种蛋白亚基组成的蛋白复合体,其蛋白亚基包括如蛋白质序列10所述的COL6A1六型胶原蛋白单体、如蛋白质序列11所述的COL6A2六型胶原蛋白单体或如蛋白质序列12所述的COL6A3六型胶原蛋白单体。

8.根据权利要求1所述能提高再生神经有序性的药物，其特征在于，所述药物为凝胶剂。

9.根据权利要求2所述制备能提高再生神经有序性的移植物，其特征在于，包括用凝胶灌注或溶液浸泡的方式将六型胶原蛋白负载到神经移植物中。