CN101918846A - 用于进行cvd风险评估的生物化学标志物 - Google Patents
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Abstract
用于对包含新表位的肽片段进行定量的生物测定方法，所述新表位通过以蛋白酶切割动脉粥样硬化斑块的蛋白质例如光亮蛋白聚糖、多功能蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖、双糖链蛋白聚糖、III型胶原蛋白、CRP、ApoE或弹性蛋白而形成，所述方法包括将样品例如尿或血清与对所述新表位具有反应性的抗体相接触，以及测定所述免疫结合配偶体与所述样品中肽片段的结合水平。所述测定可预测心血管疾病事件的风险。
Description
本发明涉及检测对心血管疾病诊断目的和疾病发展预后有价值的生物化学标志物的测定，其包括指示由发生动脉粥样硬化和斑块不稳定性所导致的心血管事件风险的生物化学标志物。
心血管疾病(cardiovascular disease，CVD)是世界范围内致病及死亡的首要原因。目前，尚没有允许诊断并将患者归类为不同风险组以及允许诊断低风险患者的有效且非介入性的诊断方法。诊断和预后工具主要由简单标志物的多变量分析构成，例如年龄、吸烟情况和多种脂质和脂蛋白的浓度。
CVD涵盖数种临床综合征，主要有心绞痛、心肌梗死(冠状动脉栓塞)和中风。所有这些综合征通常都是复杂动脉粥样硬化的后遗症。
动脉粥样硬化开始于童年阶段的内膜增厚，并发展成为动脉内膜中的脂肪条纹，这些病变分别表征为I型和II型。脂肪条纹是动脉粥样硬化发展过程中最早的宏观可见病变，其在所有种族和社会的几乎所有人类中发生。在非致病状态下，内皮细胞(endothelial cell，EC)对白细胞的粘附性相互作用有抗性。但是，动脉粥样化形成过程中动脉壁中促炎症细胞因子以及积累的氧化脂蛋白的作用引发粘附分子的表达，例如主动脉EC表面上的细胞间粘附分子(intercellular adhesion molecule，ICAM)-1和血管细胞粘附分子(vascular cell adhesion molecule，VCAM)-1。这使得白细胞能被内皮表面捕获并移行进血管壁的内膜部分。斑块的发生包括发生移位和凋亡的平滑肌细胞(smooth muscle cell，SMC)个数的增加，其导致基质周转(turnover)增加。受损的胶原蛋白合成可导致纤维帽削弱并产生更易于破裂的动脉粥样硬化斑块；但是，大多数研究者认为，蛋白水解酶例如基质金属蛋白酶(matrix metallo-protease，MMP)及其它蛋白酶的作用对斑块破裂的风险有重要的贡献(Clarkson和Kaplan 509-28)。
斑块可分为两种不同类型：“脆弱的”和“稳定的”斑块。但是，对于详细的组织学分析和对分子的认识，经常使用更详细的分类。斑块的发生有三个主要阶段：起始、脂肪条纹和复杂/晚期斑块(Stary H.C.)。
动脉粥样硬化斑块在动脉内膜内发生，并可根据其组成和结构进行分类。这种分类将病变分为8个类型(Stary H.C.)：
I.内膜中载有脂滴并被其增大的巨噬细胞(巨噬细胞源性泡沫细胞)增多。
II.巨噬细胞源性泡沫细胞与内膜SMC内的脂滴一起在蛋白聚糖层深部积累。泡沫细胞层以脂肪条纹的形式可见。在II型病变中，单核细胞通过单核细胞趋化蛋白(主要是MCP-1)穿透内皮细胞层，所述趋化蛋白在人粥样斑中过表达。早期病变类型(I型和II型)可以在婴儿期开始，但不一定导致斑块破裂。此外，动脉粥样硬化的发展可以在形成III型病变之后结束，斑块的形成是无法预测的(Stary H.C.)。
III.III型病变确定为处于脂肪条纹(II型)和粥样斑(IV型)之间的中间病变。这些病变还含有胞外脂质的混合物，由此使得内膜深部肌肉弹性层中通常紧密相邻的SMC之间的间距扩大。物质混合物可取代通常位于这里的蛋白聚糖和胶原纤维，但是这在动脉粥样化形成的这一阶段造成的影响很小。
IV.粥样斑是动脉粥样硬化的第一个临床体征。细胞外脂质混合物的积累所导致的动脉内膜中SMC的移位以及内膜结构的破坏是IV型病变的标志。脂质核心的形成是这种SMC移位的最终结果。脂质核心的形成导致壁增厚加剧。脂质核心是内膜深处大且界限明确的区域，在此处动脉壁这一部分的正常结构成分已经被致密堆积的泡沫细胞残留物、游离脂滴、胆固醇晶体和钙颗粒所取代。在动脉粥样硬化发展的这一阶段，在正常情况下位于该区域中的SMC减少或者完全失去。任何残留的SMC开始广泛分散，产生长形细胞体，并且常常具有异常厚的基底膜。在此阶段，开始形成覆盖在脂质核心上的层。该层由富含胶原蛋白和蛋白聚糖的细胞间基质、含和不含脂滴的SMC、巨噬细胞和泡沫细胞组成。
V.对IV型病变的应答是形成修复性纤维组织基质，形成纤维“帽”。通常，这些病变会由彼此不规则堆叠的脂质核心和修复性组织的层组成。另外，诸如血肿和血栓形成等事件可额外并发这些病变类型。如果不致命，则这些病变并发症整合到病变中，其上长出修复性基质组织的薄层，其由胶原蛋白和蛋白聚糖组成。在形成所述帽的过程中，动脉粥样硬化斑块中细胞外基质蛋白胶原和蛋白聚糖的含量增加。
VI.内皮的缺损例如裂隙、磨蚀、溃疡、血肿、血栓、出血在并发情况下可导致更复杂的病变类型，称为VI型病变。
VII.该病变经常称为钙化病变，其中病变中超过50％由矿物质组成。除了钙化之外，这些病变还含有丰富的修复性纤维结缔组织。当滞留于此的SMC发生凋亡和崩解时，它们的矿化细胞器变成钙化的一部分。
VIII.钙化病变之后是纤维化病变。纤维化病变可完全由胶原蛋白组成，不含脂质。(Stary H.C.)
心血管事件经常是斑块破裂的结果，其中炎症与蛋白酶的释放减弱了纤维帽的肩部区域，使得斑块中的脂肪物质与血液相接触，沉淀形成附壁血栓(Clarkson和Kaplan)。蛋白酶活性增加连同基质产生的减少导致纤维帽变薄，这被认为是斑块不稳定的标志，其增加了破裂的风险。斑块的脆弱性及其破裂的风险是临床上关注的领域。脆弱斑块(vulnerableplaque，VP)的没有标准定义，但是一般认可与稳定斑块相比存在三种组织学标志：
1)更大的脂质核心(＞全部病变的40％)。
2)更薄的纤维帽(65-150微米)。
3)大量急性炎性细胞。
定义VP的主要标准包括：活跃的炎症(存在单核细胞、巨噬细胞和T细胞)、具有大脂质核心的薄帽、伴随表面血小板凝集的内皮剥蚀、有裂隙的斑块以及＞90％的动脉狭窄。其它次要标准包括：表面钙化结节、斑块内出血、内皮功能障碍以及向外的重塑(Shin，Edelberg和Hong)。
斑块复杂性、不稳定性和破裂可以通过医学治疗和/或生活方式的改变来抑制。但是，在一些情况下，可能需要更为介入性的方法，即血管成形术或旁路手术。
目前，诊断工具是基于仍处于开发之中的静态图象分析，或者基于低技术的方法例如与CVD风险相关的心脏收缩压和舒张压水平。该领域一直致力于开发可更好地鉴别高风险患者的多变量分析。一个这样的模型是SCORE模型(系统性冠状动脉风险评价(Systematic Coronary RiskEvaluation)模型)。1994年，欧洲动脉粥样硬化学会、欧洲心脏病学学会和欧洲高血压学会发表了有关预防冠状动脉心脏疾病的一组建议，并于2003年进行了修订。此指南是基于几种评价技术，其已开发用于评估无症状对象中的CVD风险，即鉴定无症状的高风险患者。SCORE模型整合了性别、年龄、吸烟情况、收缩压和总胆固醇或胆固醇/HDL比值作为风险因素(Graham等)。
为了作出更详细的诊断，SCORE模型是不够的，因此使用了成像技术。因此，主要对高风险组中的患者或者在研究期间使用成像方法。
成像技术
冠状动脉血管造影术(Coronary angiography，CAG)是目前用于确定狭窄程度的金标准成像技术。CAG在两个维度上对血管腔成像，但是其仅限于腔，而非管壁，因此CAG不能区分有稳定斑块的动脉和有脆弱斑块的动脉。CAG常用于确定患者是否需要手术、血管成形术或旁路手术。为了确定腔狭窄位点是否是晚期斑块，需要其它技术，即血管内冠状动脉超声(intravascular coronary ultrasound，IVUS)或血管镜。
IVUS提供了斑块和血管壁的二维截面图，被认为是适合表征血管壁以及钙化的形态和程度的方法，但是不适于评估病变中的脂质。但是，IVUS是介入性的，需要专业技术和一定的费用，因此其使用并不广泛。血管镜检是另一种了解和鉴定动脉粥样硬化的有用方法。血管镜直接观察斑块表面，并且能够检测斑块颜色和血栓形成。但是，血管镜检是介入性的并且在技术上十分困难，目前为止尚不能检测斑块延伸的程度。目前受到许多关注的另一种成像技术是磁共振成象(MRI)。MRI是非介入性的，并且能够鉴定具有高中风风险的颈动脉斑块。另一方面，由于斑块尺寸小和冠状动脉的位置，MRI不是用于对冠状动脉成像的最佳技术。其它成像技术正在开发之中，即弹性成像术(elastography)、热成像术(thermography)和光学相干断层成像术(Schaar等)。
所提到的成像技术都处于开发之中，并且均无法单独地鉴定脆弱斑块，但是它们可用于了解破裂之前的分子事件和斑块周转。目前，在早期阶段诊断CVD的唯一机会是利用目的患者以及患者近亲中产生冠心病、外周动脉疾病和脑血管动脉粥样硬化疾病的一组风险因素。
现有生物化学标志物
目前，已知有几种生物化学标志物是动脉粥样硬化的风险因素。最近，人们致力于测量血清中的生物化学标志物浓度；脂质例如总胆固醇、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)和炎性标志物例如C反应蛋白(C-reactive protein，CRP)、白细胞介素-6(IL-6)、白细胞介素-18(IL-18)、肿瘤坏死因子-α(TNFα)、CD40、CD40配体(CD40L)等。
在脂蛋白标志物中，有至少两个重要的进展。LDL颗粒的大小似乎预示了动脉粥样硬化发展的程度。相比于大颗粒浓度的增加，小LDL颗粒浓度的增加与CVD风险更加相关(Gardner，Fortmann，and Krauss)。
HDL-C水平与甘油三酯强相关，高甘油三酯水平与CHD高风险相关。Jeppesen等的群体研究(2003)发现高TG/低HDL-C是IHD(ischemicheart disease，缺血性心脏病)最强的风险因素(Jeppesen等)。
脂质谱对于风险因素的评价来说非常重要，但是无法了解和测量与斑块周转相关的分子事件。已经有建议将许多生物化学标志物作为CVD的风险因素，尽管这不是该疾病的特异性产物。它们包括CRP和骨钠尿肽(Bone natriuretic peptide，BNP)(参见表1)。表1总结了一些已知的CVD标志物。
| 标志物 | 类型 | 说明 |
| C反应蛋白(CRP) | 炎性 | 在肝中产生，在炎性状态中增加。 |
| 妊娠相关血浆蛋白(PAPP-A) | 炎性 | 锌结合蛋白，其作为酶，特别是金属肽酶。 |
| 白细胞介素-6(IL-6) | 炎性细胞因子 | 在心力衰竭和心肌梗死中水平升高。 |
| 白细胞介素-8(IL-8) | 炎性细胞因子 | 在心肌梗死中水平升高。 |
| 白细胞介素-18 | 炎性细胞因子 | 在心肌梗死中水平升高。 |
| TNF-α(肿瘤坏死因子) | 细胞因子 | 在心力衰竭的情况下浓度升高。 |
| MCP-1 | 趋化因子 | 从血中募集单核细胞进入早期动脉粥样硬化病变中。 |
| 细胞间粘附分子-1(ICAM-1) | 粘附分子 | 在心肌梗死和中风中水平升高。 |
| 血管细胞粘附分子-1(VCAM-1) | 粘附分子 | 在心肌梗死和中风中水平升高。 |
| 脑钠尿肽(Brainnatriuretic peptide，BNP) | 神经激素活性 | 在正常健康心脏的心房和心室中产生 |
| 脂蛋白相关性磷脂酶A2(Lp-PLA2) | 磷脂酶 | LDLx相关性Lp-PLA2具有促动脉硬化作用。 |
| 肌酐磷酸激酶(CK-MB) | 酶 | 可用作心肌梗死的早期检测。 |
| 髓过氧化物酶(MPO) | 血红素酶 | 活化金属蛋白酶并促进斑块失稳。 |
| 肌球蛋白 | 血红素蛋白 | 在组织坏死时释放。 |
| CD40L | 蛋白质 | 在动脉粥样化的早期阶段通过斑块破裂而被释放。在中风中升高。 |
| 肌钙蛋白T(TnT) | 蛋白质 | 风险分级的工具 |
| 心脏型脂肪酸结合蛋白(H-FABP) | 蛋白质 | H-FABP在梗死后立刻从心脏释放 |
| 微白蛋白尿 | 蛋白质 | 血管内皮功能障碍的标志物 |
| 低密度脂蛋白胆固醇(LDL-C) | 脂蛋白 | 在血液中运输胆固醇 |
| 高密度脂蛋白胆固醇(HDL-C) | 脂蛋白 | 具有抗氧化剂和抗炎特性 |
| 甘油三酯 | 脂质 | |
| PIIINP | 前胶原 | III型胶原蛋白周转的标志物 |
表1：目前CVD中生物化学标志物的选择
因此，已经提出将一组不同生物化学标志物作为心血管事件的标志物。Wang等(2006)测定了参与Framingham研究的3200位患者的10种不同生物化学标志物，其记载于表1。结论是，对10种生物化学标志物的测量仅对高于标准风险因素的诊断有一定贡献。在10种生物化学标志物中，B型钠尿肽水平、C反应蛋白水平和尿白蛋白/肌酐比值显示出标志物与死亡/心血管事件之间的最高相关性(Wang等)。
C反应蛋白
C反应蛋白(CRP)是肝脏应答于不同临床状况例如炎症、感染或外伤而产生的急性期血清蛋白(Gabay&Kushner 1999)。CRP的产生是由受损或病变组织释放的细胞因子例如IL-6诱导的。CRP的生理作用仍然未知，对其促炎症或抗炎症作用的讨论一直在进行。
有越来越多的证据证明，CRP是人类CVD的风险因素。在Ridker等(2002)的研究中，在由28000位健康妇女组成的大群体中对急性心肌梗死、中风、冠状动脉血运重建或者CVD所致死亡的发生进行了八年随访，显示CRP是比LDL胆固醇更好的未来心血管事件的预测物。许多其它研究也报道，基线CRP水平构成了心血管事件的独立风险因素(Thompson等1995，Mendall等1996，Kuller等1996，Ridker等1997，Tracy等1997，Ridker等2000)。
已有推测认为，循环CRP仅反映动脉粥样硬化过程中发生的一般性炎症，而不是疾病发病的活性组分。但是，也有一些证据支持这种观点，即CRP在动脉粥样化形成中有作用。首先，产生CRP的慢性感染也与CVD风险增加相关(Leinonen&Saikku 2002)。其次，我们和其他人在不同程度的动脉粥样硬化病变中鉴定到CRP(Reynolds&Vance 1987，Hatanaka等1995)。最后，CRP已显示出在体外具有促动脉粥样化特性：CRP可活化内皮细胞产生粘附分子(Pasceri等2000)。其还可降低内皮细胞中eNOS的产生(Venugopal等2002)并增加巨噬细胞对LDL的摄取(Zwaka等2001)。
脑钠尿肽
脑(B型)钠尿肽(BNP)是由心室应答于心室中心肌细胞过度拉伸而分泌的肽类激素。在切割proBNP后，T-proBNP(无活性的N端片段)与活性激素(BNP)一起被释放到血流中。BNP和NT-proBNP都已被建议用作潜在的心血管事件生物化学标志物(Wang等)。
趋化因子
趋化因子也是潜在的CVD标志物；趋化因子是在炎症中产生的低分子量细胞因子。与CVD相关的一种主要趋化因子是单核细胞趋化蛋白1(MCP-1)。MCP-1似乎在将单核细胞募集到动脉粥样硬化病变中起到早期且重要的作用。在使用猴动脉粥样硬化模型的研究中，MCP-1的血浆浓度与斑块大小和斑块并发症高度相关(Register等)。
包括胆固醇的脂质
最近，许多人着眼于测定血清中的胆固醇浓度；总胆固醇以及低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)的浓度。在脂蛋白标志物中，至少有两个重要的进展。首先，LDL颗粒的大小似乎预测了动脉粥样硬化发展的程度。相比于大颗粒浓度的增加，小LDL颗粒浓度的增加与CVD风险更加相关(Gardner等)。其次，LDL颗粒的胆固醇油酸酯含量可能是CVD风险特别重要的标志物。在猴中，含有胆固醇油酸酯的脂蛋白颗粒核心的富集与更严重的冠状动脉动脉粥样硬化强烈正相关(Rudel等)，并且对LDL和HDL胆固醇浓度的贡献有加合性。另外，这些实验动物中的发现也得到了更早的人类研究(Lawrie等)的支持了，其显示与正常对照相比，具有低比例胆固醇亚油酸酯的血浆脂蛋白(相反，具有高比例的胆固醇油酸酯)常见于具有CHD(coronary heart disease，冠心病)并发症的患者。
HDL-C水平与甘油三酯强相关，高甘油三酯水平与更高的CHD风险相关。Jeppesen等的群体研究发现高TG/低HDL-C是IHD(缺血性心脏病)最强的风险因素。
这些脂质谱对于风险因素的评价来说非常重要，但是不能了解和测量与斑块周转相关的分子事件。已经提出将许多生物化学标志物作为CVD的风险因素，尽管不是该疾病的特异性产物。它们包括CRP和ApoE。
脂蛋白
最常用于预测CVD的生物标志物是胆固醇浓度(总胆固醇和胆固醇/HDL比值)。它们与其它风险因素(例如血压和LDL水平)一起使用。在之前提到的SCORE模型中同时使用了这两种因素。LDL水平是重要的，因为LDL在血液中运输胆固醇，氧化LDL的积累可促进动脉粥样硬化(Graham等)。另外，发现CHD与甘油三酯(TG)水平显著相关，其中CHD风险的提高与TG水平提高相关，而不论LDL-C和HDL-C水平如何，但胆固醇水平仍被视为CVD主要风险因素之一(Jeppeson等)。
APO-E
载脂蛋白E可见于乳糜微粒、VLDL和HDL中。其主要在肝脏中合成，但也在许多其它器官例如脑、脾、肾中合成(Siest等1995)。ApoE在脂蛋白代谢中起关键作用，这通过作为两种受体(LDL受体和ApoE特异性乳糜微粒残余物受体)的配体来实现。ApoE与这些受体之间的相互作用为胆固醇的代谢调节提供了基础。apoE基因座的多态性导致在大多数人群中存在三个等位基因：ε2、ε3和ε4，其决定了六种apoE表型。同工型之间的差异是112位和158位的一个氨基酸。ApoE2在两个残基处均为半胱氨酸，E4在两个位置均为精氨酸。ApoE3在112位是半胱氨酸，在158位是精氨酸。等位基因的频率在不同的人群中是不同的。一些研究评估了apoE多态性与动脉粥样硬化之间可能的关系。14项观察研究的综合分析证明，在男性和女性中ε4等位基因都与冠心病相关联(Wilson等1996)。此外，ε4等位基因已经与颈动脉动脉粥样硬化相关联(Terry等1996，Cattin等1997，Haraki等2002)。
ApoE为299个氨基酸长，其将脂蛋白、脂溶性维生素和胆固醇运送进入淋巴系统，并进一步运送进入血液循环。ApoE主要在肝脏中合成。目前，ApoE有七种哺乳动物受体，其属于保守的低密度脂蛋白受体基因家族。
其他生物化学标志物
微白蛋白尿(白蛋白/肌酐的水平)也是潜在的独立标志物。尿白蛋白排泄率是肾脏变化的标志物，与少量肌酐升高进行比较后，其可指示动脉粥样硬化(Wang等)。
在前胶原蛋白标志物中，已研究将III型胶原蛋白周转率(PIIINP)的标志物作为高血压的预后标志物，并已将其与心肌梗死相关联。Satta等研究了腹主动脉瘤(abdominal aortic aneurysm，AAA)与血液中前胶原(PIIINP)浓度的相关性。他们显示，在患有AAA的患者中III型胶原蛋白的周转增加，这可能是由于合成增强、降解增强或其两者的组合。在同一实验中，测定I型前胶原蛋白(PICP)的羧基端前肽，在动脉瘤囊中I型胶原蛋白没有加速合成。
斑块的蛋白质谱
人动脉可以分为大动脉或弹性动脉、中动脉或肌肉动脉以及小动脉。动脉壁由内膜、中膜和外膜构成，其由内弹性层和外弹性层隔开。内膜由结缔组织、平滑肌细胞和少量分离的巨噬细胞组成。内膜的边界可以定义为内皮的腔表面与内弹性层之间的层。
动脉内膜可进一步分为两层。内层称为蛋白聚糖层，由丰富的蛋白聚糖、平滑肌细胞和巨噬细胞构成。下层(肌弹性组织层)由丰富的平滑肌细胞和弹性纤维构成。在正常情况下，内膜的这两层在光学显微镜下几乎不可见，但是在发生内膜增厚时明显且显著。中膜是动脉壁的肌肉部分，其由平滑肌细胞、弹性蛋白、胶原纤维构成。
外膜(外层)是高度微血管化的，其含有胶原蛋白、弹性纤维、平滑肌细胞和淋巴通道。
人动脉粥样硬化斑块的特征是纤维帽覆盖的富脂质核心，所述纤维帽由纤维状胶原蛋白、弹性蛋白、蛋白聚糖和SMC构成。透明质多糖(hyaluronan)这种蛋白聚糖是细胞外基质主要的非纤维成分，其具有通过调节诸如脂质积累、血栓形成和细胞增殖及迁移的事件以及通过影响组织的材料特性来影响病变发生的潜力(Wight 1995)。也存在浸润的ApoE和CRP，我们已经证明这两者在动脉粥样硬化疾病的不同阶段均位于冠状动脉粥样硬化斑块中。
ApoE和CRP在人中的分布
下表2显示人体中ApoE和CRP的分布。
表2：
| 蛋白质 | 表达部位 |
| APOE | 血、血清、血浆、肝、唾液、单核细胞、小脑、脑脊液、额叶皮层、海马、颞皮层 |
| CRP | 血、肾、肝、腹水、血浆、血清 |
下表3举例说明在体内和/或体外证明的ApoE和CRP与蛋白质的已知相互作用。
表3
| 蛋白质 | 与蛋白质的相互作用 |
| ApoE | 白蛋白、淀粉样βA4蛋白、巨球蛋白、微管相关蛋白τ、LDL受体、组织蛋白酶B、神经丝3、磷脂转移蛋白、朊蛋白、VLDL受体、B类清道夫受体、 |
| CRP | 血清淀粉样蛋白P、补体因子H、纤连蛋白1、组蛋白1、FCγRI、FCγRIIb、CD32、血小板糖蛋白VI、瘦素。非蛋白的相互作用：钙、胆固醇 |
胶原蛋白在人类中的分布
胶原蛋白在人体中分布很广，即胶原蛋白构成了人体中约30％的蛋白量。在表4中，列出了主要的胶原蛋白类型及其主要组织分布。
I型胶原蛋白是最丰富的胶原蛋白，可见于多数结缔组织中。其对于骨和皮肤的结构至关重要。人体中胶原蛋白的主要含量分布在皮肤和骨骼中，其中主要的胶原蛋白组分是I型和III型胶原蛋白。III型胶原蛋白是大动脉的主要成分，还发现在富含I型胶原蛋白的组织中有较少量存在。另外，IV型胶原蛋白可见于基底膜中以及血管和神经周围。V型胶原蛋白最常见的定位是在特征性胶原纤维中，与I型和HI型胶原蛋白相关联(Garrone等)。
一些胶原蛋白具有有限的组织分布：例如II型，其仅发现于软骨中(Mayne R.)。
胶原纤维常由超过一种胶原类型组成。例如，I型胶原纤维经常含有少量的III型、V型和XII型胶原蛋白，而软骨的II型胶原纤维还含有IX和XI型胶原蛋白。
动脉中的胶原蛋白
在动脉中，发现了六种类型的胶原蛋白(I、III、IV、V、VI和VIII型)，其中I型和III型最为丰富，占胶原含量的80-90％。I型和III型在血管壁中也是占优势的。它们似乎以不同的量共分布于动脉壁的全部三层中，I型和III型胶原的合成倾向于位于内膜中(Mayne R)。
斑块中的胶原和其它结构蛋白——周转
在动脉粥样硬化斑块发展过程中，胶原蛋白在纤维帽中积累(StaryH.C.)。在Katsuda等(1992)的研究中，在人主动脉组织的所有病变阶段的增厚内膜中发现了I、III和IV型胶原。VI型胶原蛋白分布在内膜细胞区域以及晚期病变的基底膜中，也在伸长的SMC周围检测到。对I型和III型的早期研究提供了动脉粥样硬化壁中相同分布的证据(Shekhonin等)。根据McCullagh等(1980)，III型是正常人主动脉中膜中的主要胶原(可提取胶原的约70％)。Eriksen等(2006)最近的研究发现，人主动脉瓣中总胶原蛋白含量根据狭窄程度而降低。认为狭窄的分子机制与动脉粥样硬化相似。在健康主动脉瓣中，胶原组成主要是I型和III型。在狭窄过程中，胶原蛋白总含量降低，推测其是由于I型胶原蛋白周转的增加。I型胶原蛋白占总胶原蛋白的约60-70％；而III型胶原蛋白的比例在健康瓣膜和钙化瓣膜中都是30-40％。
V型胶原蛋白也在晚期动脉粥样硬化病变中增加，其分布在主动脉中膜和斑块内皮下区域的整个细胞外基质中(McCullagh等)。
似乎一致的是，在动脉粥样硬化斑块中发现的主要胶原蛋白类型是I型和III型，它们在健康的和动脉粥样硬化的血管中是否有相同的分布有待进一步研究。
在Katsuda等(1992)的研究中，在更晚期病变的粥样斑中心未检测到胶原蛋白。
弹性蛋白
弹性蛋白是体内最稳定的蛋白质之一，其发现于大多数由其弹性和回弹力所致的结缔组织中。弹性蛋白在动脉壁的蛋白质含量中占优势，其中它是主要的细胞外基质蛋白。
弹性蛋白是弹性纤维的主要成分，并且与钙化相关。血管钙化在血管壁内两个不同的部位发生：内膜和中膜。内膜钙化涉及动脉粥样硬化，主要是在坏死的核心内。钙化的弹性纤维构成了斑块的肩区，在此处斑块最易于破裂；表明弹性纤维的钙化可影响斑块的稳定性(Bobryshev V.V.)。在动脉粥样硬化中，弹性纤维的含量随着脂质的沉积而降低，这使得对弹性蛋白降解酶的敏感性提高。因此，与胶原蛋白相反，弹性蛋白含量随着病变的发展而降低。
弹性蛋白在人中的分布
表5显示了人体中弹性蛋白的分布。
表5：
| 蛋白质 | 表达部位 |
| 弹性蛋白 | 主动脉及其它血管、肺、皮肤成纤维细胞 |
表6显示了体内和/或体外证明的弹性蛋白与蛋白质的已知相互作用。
表6：
| 蛋白质 | 与蛋白质的相互作用 |
| 弹性蛋白 | 核心蛋白聚糖、弹性酶、原纤蛋白、纤原白(Fibulin)、溶菌酶、赖氨酰氧化酶、半乳凝素、双糖链蛋白聚糖、巢蛋白、Ficolin、蛋白酶3。 |
作为基质成分的蛋白聚糖
蛋白聚糖(PG)是主要定位于血管壁细胞间基质中的多糖-蛋白质大分子(Salisbury和Wagner 1981)。PG是具有以下特征的大分子：存在一个或多个称为GAG的长的无支链高度多阴离子糖侧链，其通过连接区与核心蛋白质共价连接。GAG的重复单元由氨基糖(N-乙酰基葡萄糖胺(GlcNAc)或者N-乙酰基半乳糖胺(GalNAc))和己糖醛酸(葡萄糖醛酸(GlcA)或艾杜糖醛酸(IdoA))组成。所述重复单元中的一个或两个糖含有一个或多个硫酸基团(Rodriguez-Lee 2007)。除了GAG链之外，大多数核心蛋白质还带有N-和/或O-连接的寡糖。
PG的分类和命名
PG是一组高度异质的大分子。一种类型的核心蛋白质在连接的GAG链的数目和类型上可有所不同。链的长度和硫酸化残基沿链的排列也可不同。
根据重复二糖单元的结构分为四个主要的GAG类别：硫酸软骨素(CS)和硫酸皮肤素(DS)；硫酸肝素(HS)和肝素；透明质多糖；以及硫酸角蛋白(KS)。
透明质多糖是最简单的GAG。与所有其它的相反，它不含有任何硫酸化糖。其所有二糖单元都是相同的，其链长非常长，不连接任何核心蛋白质。
KS是硫酸化多聚半乳糖胺链。KS-I最先描述于角膜中，其与核心蛋白质中的天冬酰胺残基N-连接，而KS-II或软骨KS与丝氨酸或苏氨酸残基O-连接(Funderburgh 2000)。
可根据几个参数对PG进行分类：
-所连接的GAG链(含有CS/DS或HS的PG)
-相对于细胞的拓扑分布(细胞外和基底膜PG，细胞相关PG或细胞内PG)
-核心蛋白质同源性(透明凝集聚糖(hyalectan)，小的富亮氨酸PG(small leucine-rich PG，SLRP)
硫酸软骨素/皮肤素PG(多功能蛋白聚糖(versican)、聚集蛋白聚糖(aggrecan)、神经蛋白聚糖(neurocan)和短蛋白聚糖(brevican))属于透明质多糖结合蛋白聚糖家族。此基因家族总称为透明凝集聚糖。每个家族成员具有特征性分布，聚集蛋白聚糖在软骨中占优势，神经蛋白聚糖和短蛋白聚糖在中枢神经系统中占优势，多功能蛋白聚糖在多种软组织包括动脉壁中存在。多功能蛋白聚糖的基因和蛋白结构符合结构域模板。氨基端球形末端(G1)结合GAG透明质多糖，羧基端球形结构域(G3)类似于选择素蛋白家族，由与两个表皮生长因子(EGF)结构域和补体调节区域相邻的C型凝集素组成。多功能蛋白聚糖核心蛋白质的中间区域由两个大外显子编码，其确定了多功能蛋白聚糖的CS附着区域。外显子7编码的区域称为αGAG，而外显子8编码的区域称为βGAG。四种mRNA转录本来自于多功能蛋白聚糖的选择性剪接，得到V0、V1、V2和V3，其核心蛋白质的长度以及所连接GAG数目不同(Dours-Zimmermann和Zimmermann)。人多功能蛋白聚糖中潜在GAG连接位点的数目为：V0为17-23个，V1为12-15个，V2为5-8个，V3没有(Wight 617-23)。
核心蛋白聚糖和双糖链蛋白聚糖是SLRP家族的成员，所述家族包含至少9个成员，其分为三类(I、II和III)以及不同的亚家族。它们全都具有下述特征：存在含有富亮氨酸重复的中央结构域，以实现强蛋白质-蛋白质相互作用。核心蛋白聚糖和双糖链蛋白聚糖是I类的成员，显示最高的家族氨基酸同源性(约57％)，是仅有的具有前肽的SLRP。所述前肽在物种间高度保守，可作为木糖基转移酶的识别序列，该酶是参与GAG链合成的第一种酶。
多功能蛋白聚糖、核心蛋白聚糖和双糖链蛋白聚糖是哺乳动物动脉壁基质中主要的CS/DS PG(Wight等1986)。多功能蛋白聚糖V0核心蛋白质的大小是370kDa，约为核心蛋白聚糖36kDa和双糖链蛋白聚糖38kDa的十倍大。侧链显示宽尺寸范围，但是通常平均为每个约40-90kDa。
硫酸肝素蛋白聚糖(HSPG)分为五个不同的细胞结合和细胞外周PG类别，它们占哺乳动物细胞表面、基底膜和ECM中HS的至少95％。细胞结合HSPG包括整合的膜多配体蛋白聚糖(syndecan)和锚定的磷脂酰肌醇蛋白聚糖(glypican)。细胞外周HSPG主要包括基底膜蛋白聚糖(perlecan)、agrin。这些PG称为细胞外周的，是因为它们通过整合素与质膜紧密关联(Whitelock和Iozzo)。
基底膜蛋白聚糖是模块化HSPG，其在几乎所有基底膜和间充质器官及结缔组织中表达，是脊椎动物和无脊椎动物中所发现的最大的单链多肽之一。基底膜蛋白聚糖的五个模块及其HS侧链参与许多分子间相互作用，例如与成纤维细胞生长因子-2、血管内皮生长因子(VEGF)、血小板衍生生长因子(PDGF)以及其它基质蛋白质相互作用。人基底膜蛋白聚糖的核心蛋白质约为470kDa，加上许多O-连接寡糖和4个HS侧链，可达到超过800kDa的分子量(Knox和Whitelock)。
蛋白聚糖分布
蛋白聚糖(PG)是在人体中几乎到处都有分布的大分子。PG的结构和大小差别非常大。所有PG的基本结构包括核心蛋白质和至少一个(但经常是很多)糖链——糖胺多糖(GAG)。PG可见于细胞内、细胞表面和细胞外基质中。PG的结构多样性提示了多种生物学功能，参见表7。
表7
表7给出了PG分布和功能的概况。
动脉中的蛋白聚糖
至少五种PG类型存在于动脉壁的细胞外基质中；多功能蛋白聚糖，其与透明质多糖相互作用形成大的聚集体；小富亮氨酸核心蛋白聚糖和双糖链蛋白聚糖，其与纤维状基质组分如胶原和弹性蛋白相互作用；硫酸肝素-基底膜蛋白聚糖，其是基底膜的组分，以及硫酸角蛋白-光亮蛋白聚糖(Talusan等)。
多功能蛋白聚糖是在动脉粥样硬化病变中积累的数种ECM分子之一。尽管许多研究显示多功能蛋白聚糖明显能够结合LDL，但是在坏死核心的富脂质中心中一般检测不到多功能蛋白聚糖。
光亮蛋白聚糖已显示直接结合巨噬细胞，并增强巨噬细胞的迁移。因此，光亮蛋白聚糖可直接影响血管内膜中巨噬细胞的行为，以及刺激坏死核心的形成，其为晚期动脉粥样硬化病变的特征(Funderburgh等1997)。
双糖链蛋白聚糖可见于纤维帽中。多功能蛋白聚糖和双糖链蛋白聚糖具有LDL亲和力，并形成加速LDL氧化的不溶复合物。双糖链蛋白聚糖可通过将脂蛋白截留在动脉壁中而促进动脉粥样硬化的发病。动脉内膜中蛋白聚糖代谢的变化构成了动脉粥样硬化的初期病变，蛋白聚糖的积累在动脉粥样硬化的发展中具有重要的作用(Kunz J.)。
有报道称，通过基于质谱的分析和免疫组织化学发现基底膜蛋白聚糖在人内膜增生中是内膜细胞外基质的中心组分之一。
表8显示了一些PG在正常动脉和动脉粥样硬化动脉的PG免疫组织化学染色中的分布(Evanko等)。
表8
参与基质重塑的蛋白聚糖
对非人灵长类中动脉粥样硬化发展的研究证明，特定PG的积累随着病变严重程度而变化，并随细胞和生长因子的分布而变化，表明不同的PG在动脉粥样硬化的发展过程中起不同的作用。不同水平的特定PG可通过对改变纤维性基质组分(例如弹性蛋白和胶原)的结构排列的贡献而直接影响组织的材料特性。
多功能蛋白聚糖和透明质多糖显示在基质中相似的定位，表明在动脉粥样化形成中两者之间形成聚集体。多功能蛋白聚糖和透明质多糖在早期病变中的显著增加可提示它们在早期动脉粥样硬化病变中起作用，例如SMC和白细胞的增殖和迁移。此外，多功能蛋白聚糖和透明质多糖是人再狭窄病变的主要基质组分，已在体外显示出对血管病变后的新生内膜增厚有贡献。由于脂蛋白结合多功能蛋白聚糖的硫酸软骨素链，动脉粥样化形成中早期富含多功能蛋白聚糖还可使得细胞外基质更易于增加脂质截留。这一想法得到了移植性动脉病中多功能蛋白聚糖与脱辅基蛋白(a)和载脂蛋白E共定位的支持(Evanko等)。斑块中多功能蛋白聚糖的丧失可导致基质不稳定。
这也被血管病变后观察到的多功能蛋白聚糖基因上调所证明。在动脉粥样化形成的所有阶段也鉴定到多功能蛋白聚糖；在早期发生斑块的内膜中，还遍及晚期病变中以及在充满脂质的坏死核心的边界上和斑块血栓界面上(Wight和Merrilees 2005)。这些观察结果将多功能蛋白聚糖与脂质积累、炎症和血栓形成关联起来。此外，多功能蛋白聚糖在ECM的组装以及弹性纤维原纤维形成的控制中起重要作用，这对于血管病期间ECM的重塑非常重要(Wight和Merrilees 2005)。
双糖链蛋白聚糖在动脉细胞生物学中的作用尚不清楚。一些免疫组织化学研究显示，双糖链蛋白聚糖与人再狭窄病变中的I型和III型胶原蛋白的染色相关(Evanko等)。
还通过产生双糖链蛋白聚糖基因无效突变的纯合BALB/cA小鼠进一步显示了双糖链蛋白聚糖作为基质蛋白质的重要性，其中50％的双糖链蛋白聚糖缺陷型雄性小鼠在生命的前3个月内由于主动脉破裂而突然死亡。此观察结果表明双糖链蛋白聚糖对于主动脉壁结构和功能的完整性来说是必需的，还表明了双糖链蛋白聚糖基因缺陷在人主动脉剥离和破裂的发病中可能的作用。(Heegaard等2007)
其它研究显示，双糖链蛋白聚糖在灵长类动脉中是与弹性蛋白相关联的主要PG；这些观察结果与人冠状动脉病中观察到的结果相似(Evanko等)。
核心蛋白聚糖已显示出与胶原蛋白结合并调节胶原纤维的形成(Brown和Vogel)(Danielson等)。
蛋白酶谱
蛋白酶水解肽键，并且导致粥样斑中的细胞外基质蛋白质例如胶原、蛋白聚糖和弹性蛋白发生降解，参见表9。在动脉粥样硬化斑块中，发现了三种主要类型：金属蛋白酶类(即MMP)、丝氨酸蛋白酶类和半胱氨酸蛋白酶类(即组织蛋白酶)。组织蛋白酶类和MMP导致所有细胞外基质蛋白质降解。因为基质对于斑块稳定性来说是至关重要的，所以蛋白酶将其从纤维帽除去可引起斑块的破裂(Stary H.C.)。
在表9中列出了在动脉粥样硬化斑块中发现的多种蛋白酶。
表9
| 蛋白酶 | 降解底物 |
| 组织蛋白酶K | 蛋白聚糖、弹性蛋白、胶原蛋白 |
| 组织蛋白酶S | 蛋白聚糖、弹性蛋白、胶原蛋白 |
| 组织蛋白酶L | 蛋白聚糖、I型胶原蛋白 |
| 组织蛋白酶B | 蛋白聚糖 |
| MMP-1 | I、II和III型胶原蛋白 |
| MMP-2 | 蛋白聚糖、弹性蛋白 |
| MMP-3 | 蛋白聚糖、III型胶原并、弹性蛋白 |
| MMP-8 | 蛋白聚糖、I、II和III型胶原蛋白 |
| MMP-9 | 弹性蛋白、I和III型胶原蛋白 |
| MMP-13 | 蛋白聚糖、I、II和III型胶原蛋白 |
| MMP-18 | I型胶原蛋白 |
表9在动脉粥样硬化斑块中检测到的蛋白酶
怀疑斑块中MMP表达的主要来源与巨噬细胞和SMC活性有关。斑块中的巨噬细胞含有丰富的MMP-1、-8、-9和-13，其与胶原和蛋白聚糖原位降解的位点共定位(Kunz J.)。此外，我们的数据表明MMP-8和组织蛋白酶K定位于动脉粥样硬化斑块中。
基质金属蛋白酶(MMP)
MMP是一大组内肽酶，其能够降解ECM的多数组分。目前，已鉴定到超过25种MMP。金属蛋白酶类的特征在于含有金属原子(通常为锌)的活性位点，并以酶原的形式分泌。特异性组织抑制剂TIMP调控MMP的活性。动脉粥样硬化斑块中发现有很多种MMP。它们最常位于作为纤维帽边界的巨噬细胞中、SMC和巨噬细胞中的斑块肩部内，但很少在纤维帽内部鉴定到(Kunz J.)。
MMP根据其底物特异性分为不同的组：降解纤丝胶原(如I、II、III和V型胶原以及蛋白聚糖)的胶原酶；降解蛋白聚糖、IV、V、VII型胶原和弹性蛋白的明胶酶；对蛋白聚糖和弹性蛋白有活性的基质降解酶(Rouis M)。这三个亚类在动脉粥样硬化斑块的基质重塑方面特别重要。
明胶酶
不溶性弹性蛋白被MMP-2和-9消化，这两者都属于MMP的明胶酶家族。MMP-9在影响动脉粥样硬化斑块的大小和组成上起到重要的作用。在不稳定的人动脉粥样硬化斑块中以及斑块的脆弱区域中，已观察到MMP-9较高的表达和浓度。此外，与具有稳定心绞痛的患者相比，在具有不稳定心绞痛的患者中更经常在冠状动脉斑块的细胞内发现MMP-9(表示活跃合成)。血液MMP-9水平与冠状动脉粥样硬化相关地升高，预测不良的心血管事件(Sundstrom和Vasan)。Kuzuya等(2006)最近的研究显示MMP-2负责纤维帽中SMC的积累，由此诱导斑块的不稳定。
基质降解酶
MMP-3属于基质降解酶，其能够降解弹性蛋白和蛋白聚糖。Yamada等(2002)的研究显示，MMP-3被证实可以是预测女性心肌梗死遗传风险的可靠手段。
胶原酶
MMP-1、-8和-13均已在动脉粥样硬化斑块中鉴定到，它们在这里降解蛋白聚糖以及I型和III型胶原。
MMP-1、-8和-13是胶原酶，其将胶原切割成两个片段，其进一步被MMP-2、-3或-9降解。
MMP-8由中性粒细胞表达，不常见于人粥样斑中，但是已在动脉粥样硬化斑块中鉴定到。MMP-8可能部分地负责纤维帽的降解，因为MMP-8具有I型胶原蛋白的偏好性(Herman等)，其降解I型胶原的活性是MMP-1和13的三倍。这得到了Turu等(2006)的支持，在该研究中，具有脆弱斑块的患者血浆中MMP-8的含量显著高于具有稳定斑块的患者。
已有报道MMP-13切割SLRPS，对双糖链蛋白聚糖具有高特异性。MMP-13在特异性切割位点(...G177/V178)降解双糖链蛋白聚糖，这之前已由Monfort等(2005)证实，并且提出其在骨关节炎中软骨退化的早期检测中起重要作用。
组织蛋白酶
人半胱氨酸组织蛋白酶由11个成员组成，包括组织蛋白酶B、K、L和S，其主要在细胞的内体/溶酶体区室内表达。组织蛋白酶能够催化蛋白聚糖、胶原蛋白和弹性蛋白的水解性降解。
相比于正常主动脉，在腹主动脉瘤(AAA)中发现了高水平的组织蛋白酶S、K和L。正常人血管SMC含有的组织蛋白酶K无法通过免疫染色检出，但是动脉粥样硬化斑块内的细胞明显是阳性的。组织蛋白酶K定位于易于破裂的区域，例如纤维帽、斑块肩部以及斑块破裂的实际部位(Chapman等)。发现在动脉粥样硬化斑块中组织蛋白酶S与弹性蛋白降解增加的区域共定位，在组织蛋白酶S和K缺陷型小鼠中观察到动脉粥样硬化减少(Liu等)。
组织蛋白酶L和K都降解数种蛋白聚糖以及I型和II型胶原蛋白，组织蛋白酶K在共价交联的三螺旋内降解，而组织蛋白酶L仅在非螺旋端肽区域进行切割。组织蛋白酶K定位于纤维帽和斑块肩部。正常动脉中组织蛋白酶K的表达极低。人早期动脉粥样硬化病变中显示在内膜和中间的SMC中表达组织蛋白酶K。在晚期动脉粥样硬化斑块中，组织蛋白酶K主要定位于纤维帽的巨噬细胞和SMC中(Lutgens等)。与正常动脉相比，动脉粥样硬化病变中组织蛋白酶K蛋白水平提高，而组织蛋白酶K的mRNA水平在动脉粥样硬化动脉和正常动脉中相似。此外，已显示与早期动脉粥样硬化病变和包含血栓的病变相比，蛋白酶K mRNA和蛋白水平在晚期但稳定的人动脉粥样硬化斑块中组织是最高的(Chapman等)。
在早期人动脉粥样硬化病变和脂肪条纹的内膜和中间SMC中，组织蛋白酶S仅稀少地表达。在晚期动脉粥样硬化斑块中，组织蛋白酶S定位于纤维帽的巨噬细胞和SMC中。沿血管本身以及斑块微血管的腔排列的EC也表达组织蛋白酶S。此外，与正常动脉相比，人粥样斑中组织蛋白酶S mRNA和蛋白水平升高(Lutgens等)。组织蛋白酶S可降解蛋白聚糖、弹性蛋白和胶原蛋白(Liu等)。
目前，CVD风险的确定是在动脉粥样硬化发展的晚期阶段进行的；此时具有显著的纤维斑块破裂的风险。需要一种在较早阶段和晚期阶段都提供动脉粥样硬化或CVD风险之相关信息的诊断或预后测定。Katsuda等(1992)的发现表明，存在将胶原蛋白从晚期病变中除去的酶促机制，实际上提示了新表位在动脉硬化中的重要作用。
本发明提供了一种对包含新表位的肽片段进行定量的生物测定法，所述新表位是由蛋白酶切割动脉粥样硬化斑块的蛋白质而形成的，所述方法包括使包含所述肽片段的样品与对所述新表位具有特异性结合亲和力的免疫结合配偶体相接触，以及测定所述样品中所述免疫结合配偶体与肽片段结合的水平。
所述测定的结果可产生指示特定患者中动脉粥样硬化斑块破裂风险程度或者患者动脉粥样硬化斑块脆弱状态的指标。
可建议所述指标的值高于阈值水平的患者通过斑块成像方法(包括上文所述的那些)进行进一步研究，或者建议其服用治疗动脉粥样硬化的药物或者进行动脉粥样硬化的手术治疗，这些后续研究或治疗可构成本发明方法的一部分。
动脉粥样硬化斑块的蛋白质包括光亮蛋白聚糖、多功能蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖、双糖链蛋白聚糖、III型胶原、CRP、ApoE和弹性蛋白。不认为I型胶原是动脉粥样硬化斑块的蛋白质。动脉粥样硬化斑块中存在的以比体内其它地方更高的水平暴露于蛋白酶的蛋白质是特别有意义的。
所述免疫学结合配偶体可对包含C端新表位或N端新表位的肽片段具有特异性结合亲和力。
蛋白聚糖测定
所述肽片段可以是蛋白聚糖多功能蛋白聚糖(SEQ ID NO：1)、光亮蛋白聚糖(SEQ ID NO：2)、基底膜蛋白聚糖(SEQ ID NO：3)、双糖链蛋白聚糖(SEQ ID NO：4)和核心蛋白聚糖(SEQ ID NO：5)的片段，其全部都在正常和动脉粥样硬化的动脉中鉴定到。蛋白聚糖与弹性蛋白和胶原蛋白是构成动脉粥样硬化斑块和斑块帽的主要蛋白质中的一部分。蛋白聚糖含量在动脉粥样硬化发展过程中发生变化，使得蛋白聚糖的新表位有可能成为疾病分期和疾病发展的良好标志物。尤其是因为多功能蛋白聚糖和光亮蛋白聚糖在许多其它器官中并不丰富，这使得它们成为更具特异性的生物化学标志物的候选。
一些候选蛋白酶可能负责消化斑块中的蛋白聚糖，因为文献中报道了动脉粥样硬化斑块中的许多不同的蛋白酶。最可能的是，这是最终导致斑块破裂的一系列复杂过程的结果。但是，在我们的评估中，早期阶段可以由一组MMP组成，而晚期阶段可更多地依赖于组织蛋白酶对基质的降解，根据疾病阶段而产生不同的新表位谱。我们确定了表4中所列酶产生光亮蛋白聚糖、多功能蛋白聚糖、双糖链蛋白聚糖、基底膜蛋白聚糖和核心蛋白聚糖，得到至少下列切割产物：
| 蛋白酶 | 双糖链蛋白聚糖 | SEQ ID NO |
| MMP-3 | K＊SVPKEISPDTTLLDLQNNDISE＊L | 6 |
| MMP-3 | L＊KSVPKEISPDTTLLDLQNNDISE＊L | 7 |
| MMP-9 | E＊NSGFEPGAFDGLKLNYLRISEAK＊L | 8 |
| MMP-9 | G＊LKSVPKEISPDTTLLDLQNNDISE＊L | 9 |
| MMP-12 | Y＊LRISEAKLTGIPKDLPET＊L | 10 |
| MMP-13 | G＊LKSVPKEISPDTTLLDLQNNDISE＊L | 11 |
| MMP-13 | ＊LTGIPKDLPETLNELHLDHNKIQAIE＊ | 12 |
| ADAMTS4 | K＊RISEAKLTGIPKDLPETLNE＊L | 13 |
| ADAMTS4 | Q＊AIELEDLLRYSK＊L | 14 |
| ADAMTS4 | Q＊AIELEDLLRY＊S | 15 |
| ADAMTS4 | S＊EAKLTGIPKDLPETLNE＊L | 16 |
| ADAMTS4 | -＊LKAVPKEISPDTTLLDLQNNDISE＊L | 17 |
| MMP-8 | T＊LLDLQNNDISELRKDD＊F | 18 |
| MMP-8 | A＊IELEDLLRYS＊K | 19 |
| 组织蛋白酶S | E＊NSGFEPGAFDGLK＊L | 20 |
| 蛋白酶 | 核心蛋白聚糖 | |
| MMP-12 | M＊IVIELGTNPLK＊S | 21 |
| MMP-3 | E＊DEASGIGPEVPDDR＊D | 22 |
| MMP-3 | E＊LHLDGNKISRVDAAS＊L | 23 |
| MMP-3 | L＊VNNKISKVSPGAFTPL＊V | 24 |
| MMP-3 | A＊LILVNNKISKVSPGAFTPLVKLER＊L | 25 |
| MMP-9 | F＊SNPVQYWEIQPSTFR＊C | 26 |
| 组织蛋白酶K | K＊SSGIENGAFQGMK＊K | 27 |
| 组织蛋白酶K | K＊SSGIENGAFQGMKKLS＊Y | 28 |
| ADAMTS1 | N＊KITEIKDGDFK＊N | 29 |
| ADAMTS1 | Q＊GLPPSLTELHLDGNK＊I | 30 |
| 多功能蛋白聚糖 | ||
| 未知 | K＊LLASDAGLYR＊C | 31 |
| 未知 | ＊LATVGELQAAWR＊N | 32 |
| 未知 | K＊ETTVLVAQNGNIK＊I | 33 |
| 光亮蛋白聚糖 | ||
| 未知 | -＊SLEDLQLTHNK＊I | 34 |
| 未知 | R＊LKEDAVSAAFK＊G | 35 |
| 基底膜蛋白聚糖 | ||
| 未知 | R＊SIEYSPQLEDAGSR＊E | 36 |
| 未知 | R＊LEGDTLIIPR＊V | 37 |
| ADAMTS4 | E＊VSEAVVEKLEPEYR＊- | 38 |
| ADAMTS4 | R＊EVSEAVVEKLEPEYR＊- | 39 |
| ADAMTS4 | R＊SIEYSPQLED＊A | 40 |
表4、蛋白酶产生的肽——蛋白聚糖的切割产物。＊代表切割位点
因此，在本发明的方法中，所述肽片段优选包含蛋白酶在其上述任一部分序列中＊号标明的位点切割多功能蛋白聚糖、光亮蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖或双糖链蛋白聚糖而形成的新表位。
另外，在本发明的方法中，所述肽片段优选包含通过一种(或多种)蛋白酶在下列任一多功能蛋白聚糖、光亮蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖和双糖链蛋白聚糖部分序列中的位点切割下列蛋白聚糖而形成的新表位：多功能蛋白聚糖、光亮蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖和双糖链蛋白聚糖；或者所述免疫结合配偶体可与下列序列之一特异性反应：
| 序列 | SEQ ID NO |
| SVPKEISPDTTLLDLQNNDISE | 41 |
| KSVPKEISPDTTLLDLQNNDISE | 42 |
| NSGFEPGAFDGLKLNYLRISEAK | 43 |
| LKSVPKEISPDTTLLDLQNNDISE | 44 |
| LRISEAKLTGIPKDLPET | 45 |
| LKSVPKEISPDTTLLDLQNNDISE | 46 |
| LTGIPKDLPETLNELHLDHNKIQAIE | 47 |
| IVIELGTNPLK | 48 |
| LLASDAGLYR | 49 |
| LATVGELQAAWR | 50 |
| ETTVLVAQNGNIK | 51 |
| SLEDLQLTHNK | 52 |
| LKEDAVSAAFK | 53 |
| SIEYSPQLEDAGSR | 54 |
| LEGDTLIIPR | 55 |
| RISEAKLTGIPKDLPETLNE | 56 |
| AIELEDLLRYSK | 57 |
| AIELEDLLRY | 58 |
| EAKLTGIPKDLPETLNE | 59 |
| LKAVPKEISPDTTLLDLQNNDISE | 60 |
| LLDLQNNDISELRKDD | 61 |
| IELEDLLRYS | 62 |
| NSGFEPGAFDGLK | 63 |
| DEASGIGPEVPDDR | 64 |
| LHLDGNKISRVDAAS | 65 |
| VNNKISKVSPGAFTPL | 66 |
| LILVNNKISKVSPGAFTPLVKLER | 67 |
| SNPVQYWEIQPSTFR | 68 |
| SSGIENGAFQGMK | 69 |
| SSGIENGAFQGMKKLS | 70 |
| KITEIKDGDFK | 71 |
| GLPPSLTELHLDGNK | 72 |
| VSEAVVEKLEPEYR | 73 |
| EVSEAVVEKLEPEYR | 74 |
| SIEYSPQLEDASAKEFR | 75 |
表10、蛋白聚糖切割的肽片段。
优选地，所述免疫结合配偶体不与完整的多功能蛋白聚糖、光亮蛋白聚糖、核心蛋白聚糖、基底膜蛋白聚糖和双糖链蛋白聚糖反应。优选地，如果延长经过所产生片段的相应C端和N端，则所述免疫结合配偶体不与上文所列的序列反应。
免疫结合配偶体可与切割多功能蛋白聚糖、光亮蛋白聚糖、核心蛋白聚糖、基底膜蛋白聚糖和双糖链蛋白聚糖类型而形成的C端或N端新表位特异性反应。
因此，合适的免疫结合配偶体可与肽N端的表11中下列任一序列特异性反应：
| SEQ ID NO | ||
| 双糖链蛋白聚糖 | SVPKEI | 76 |
| NSGFEP | 77 | |
| LKSVPK | 78 | |
| LRISEA | 79 | |
| GLKLNY | 80 | |
| LKSVPK | 81 | |
| QCSDLG | 82 | |
| LTGIPK | 83 | |
| RISEAK | 84 | |
| AIELED | 85 | |
| EAKLTG | 86 | |
| LKAVPK | 87 | |
| LLDLQN | 88 | |
| IELEDL | 89 | |
| NSGFEP | 90 | |
| 核心蛋白聚糖 | IVIELG | 91 |
| NGLNQM | 92 | |
| DEASGI | 93 |
| LHLDGN | 94 | |
| VNNKIS | 95 | |
| LILVNN | 96 | |
| SNPVQY | 97 | |
| SSGIEN | 98 | |
| KITEIK | 99 | |
| GLPPSL | 100 | |
| 多功能蛋白聚糖 | LLASDA | 101 |
| LATVGE | 102 | |
| ETTVLV | 103 | |
| SLTVVK | 104 | |
| ENQDAR | 105 | |
| NGFDQC | 106 | |
| 光亮蛋白聚糖 | SLEDLQ | 107 |
| LKEDAV | 108 | |
| HLQHNR | 109 | |
| LQHNRL | 110 | |
| 基底膜蛋白聚糖 | SIEYSP | 111 |
| LVNFTR | 112 | |
| VSEAVV | 113 | |
| EVSEAV | 114 | |
| SIEYSP | 115 |
表11、蛋白酶产生的蛋白聚糖肽片段的N端序列
或者与肽C端的表12中下列任一序列反应：
| SEQ ID NO | ||
| 双糖链蛋白聚糖 | NNDISE | 116 |
| RISEAK | 117 | |
| LRKDDF | 118 | |
| KDLPET | 119 | |
| LNELHL | 120 | |
| YWEVQP | 121 | |
| KIQAIE | 122 | |
| PETLNE | 123 | |
| LLRYSK | 124 | |
| EDLLRY | 125 | |
| NNDISE | 126 | |
| ELRKDD | 127 | |
| DLLRYS | 128 | |
| AFDGLK | 129 | |
| 核心蛋白聚糖 | GTNPLK | 130 |
| SSGIEN | 131 | |
| EVPDDR | 132 | |
| RVDAAS | 133 | |
| GAFTPL | 134 | |
| LVKLER | 135 |
| QPSTFR | 136 | |
| AFQGMK | 137 | |
| GMKKLS | 138 | |
| KDGDFK | 139 | |
| HLDGNK | 140 | |
| 多功能蛋白聚糖 | CDVMYG | 141 |
| NGFDQC | 142 | |
| QNGNIK | 143 | |
| IGQDYK | 144 | |
| 光亮蛋白聚糖 | QLTHNK | 145 |
| VSAAFK | 146 | |
| GLKSLE | 147 | |
| 基底膜蛋白聚糖 | EDAGSR | 148 |
| EFREVS | 149 | |
| VAQQDS | 150 | |
| LEPEYR | 151 | |
| SAKEFR | 152 |
表12、蛋白酶产生的蛋白聚糖肽片段的C端序列
通过将蛋白聚糖或其它动脉粥样硬化斑块蛋白质暴露于本文所述的任何酶以及分离并测序由此产生的肽，可以鉴定出限定能以类似方式测定的新表位的其它切割位点。
胶原蛋白测定
所述肽片段可以是III型胶原蛋白的片段(SEQ ID NO：153)，优选成熟III型胶原蛋白，即非III型胶原蛋白前肽。动脉粥样硬化斑块中主要的蛋白质是I型和III型胶原蛋白以及弹性蛋白，而蛋白聚糖仅仅对斑块的基质有次要的贡献。在动脉粥样硬化斑块中发现的三种主要蛋白质中，I型和III型胶原蛋白占优势地位，而弹性蛋白在动脉的蛋白质谱中占有优势，但不是斑块的主要蛋白质成分。I型胶原蛋白在体内各处都很丰富，而III型具有更有限的组织定位，由此(按照我们的观点)是更特异性的生物化学标志物候选。
一些候选蛋白酶可能负责消化斑块中的胶原，因为文献中报道了动脉粥样硬化斑块中的许多不同的蛋白酶。最可能的是，这是最终导致斑块破裂的一系列复杂过程的结果。但是，在我们的评估中，早期阶段可以由一组MMP组成，而晚期水平可更多地依赖于组织蛋白酶K对基质的降解，导致根据疾病水平产生不同的新表位谱。我们确定了下表中所列的酶在至少下列切割位点(记为＊)切割III型胶原蛋白：
| 蛋白酶 | 新表位 | SEQ ID NO |
| MMP-1 | A＊GIPGAPGLMGARGPPGPA＊G | 154 |
| MMP-1 | K＊GDPGPPGIPGRNGDPGI＊P | 155 |
| MMP-1 | G＊LAGPPGMPGPRGSPGPQG＊V | 156 |
| MMP-1 | G＊ERGLPGPPGIKGPAGIPGF＊P | 157 |
| MMP-1 | G＊IAGITGARGLAGPPGMPGPR＊G | 158 |
| MMP-1 | G＊IKGHRGFPGNPGAPGSPGPAG＊Q | 159 |
| MMP-1 | A＊RGLAGPPGMPGPRGSPGPQGV＊K | 160 |
| MMP-1 | I＊TGARGLAGPPGMPGPRGSPGPQG＊V | 161 |
| MMP-1 | I＊TGARGLAGPPGMPGPRGSPGPQGV＊K | 162 |
| MMP-1 | G＊ITGARGLAGPPGMPGPRGSPGPQG＊V | 163 |
| MMP-1 | G＊VKGESGKPGANGLSGERGPPGPQG＊L | 164 |
| MMP-1 | G＊SRGAPGPQGPRGDKGETGERGAAG＊I | 165 |
| MMP-1 | P＊KGDAGQPGEKGSPGAQGPPGAPGPLG＊I | 166 |
| MMP-1 | G＊ITGARGLAGPPGMPGPRGSPGPQGV＊K | 167 |
| MMP-1 | G＊LRGGAGPPGPEGGKGAAGPPGPPGAAGTPG＊L | 168 |
| MMP-1 | G＊HAGAQGPPGPPGINGSPGGKGEMGPAGIPGAPG＊L | 169 |
| MMP-1 | A＊GKSGDRGESGPAGPAGAPGPAGSRGAPGPQGPRGDKGETGERGAAG＊I | 170 |
| MMP-1 | G＊LQGLPGTGGPPGENGKPGEPGPKGDAGAPGAPGGKGDAGAPGERGPPG＊L | 171 |
| MMP-3 | G＊ERGLPGPPGIKGPAGIPGF＊P | 172 |
| MMP-3 | A＊VGGLAGYPGPAGPPGPPGPPGT＊S | 173 |
| MMP-3 | K＊DGTSGHPGPIGPPGPRGNRGER＊G | 174 |
| MMP-3 | A＊VGGLAGYPGPAGPPGPPGPPGTSGHPG＊S | 175 |
| MMP-3 | G＊IAGITGARGLAGPPGMPGPRGSPGPQG＊V | 176 |
| MMP-3 | A＊PGAPGGKGDAGAPGERGPPGLAGAPGLRG＊G | 177 |
| MMP-3 | A＊VGGLAGYPGPAGPPGPPGPPGTSGHPGSPG＊S | 178 |
| MMP-2 | A＊IGSPGPAGPRGPVGPSGPPG＊K | 179 |
| MMP-3和-8 | G＊AIGSPGPAGPRGPVGPSGPPG＊K | 180 |
| MMP-8 | P＊AGQQGAIGSPGPA＊G | 181 |
| MMP-8 | G＊GPPGVAGPPGGSGPAGPP＊G | 182 |
| MMP-8 | L＊AGPPGMPGPRGSPGPQG＊V | 183 |
| MMP-8 | G＊LSGERGPPGPQGLPGLA＊G | 184 |
| MMP-8 | R＊GLAGPPGMPGPRGSPGPQG＊V | 185 |
| MMP-8 | G＊LAGPPGMPGPRGSPGPQGV＊K | 186 |
| MMP-8 | R＊GLAGPPGMPGPRGSPGPQGV＊K | 187 |
| MMP-8 | G＊PQGPPGKNGETGPQGPPGP＊T | 188 |
| MMP-8 | G＊VKGERGSPGGPGAAGFPGAR＊G | 189 |
| MMP-8 | A＊RGLAGPPGMPGPRGSPGPQG＊V | 190 |
| MMP-8 | N＊GLSGERGPPGPQGLPGLAGTA＊G | 191 |
| MMP-8 | A＊VGGLAGYPGPAGPPGPPGPPGT＊S | 192 |
| MMP-8 | G＊SPGGKGEMGPAGIPGAPGLMGA＊R | 193 |
| MMP-8 | T＊GARGLAGPPGMPGPRGSPGPQG＊V | 194 |
| MMP-8 | V＊KGESGKPGANGLSGERGPPGPQG＊L | 195 |
| MMP-8 | G＊VKGERGSPGGPGAAGFPGARGLPGPPGSNGNPGPPGPSGSPGKDGPPGPAG＊N | 196 |
| MMP-8 | G＊SPGAQGPPGAPGPLGIAGITGARGLAGPPG＊M | 197 |
| MMP-8 | R＊GAPGEKGEGGPPGVAGPPGGSGPAGPPGPQ＊G | 198 |
| MMP-8 | R＊GAPGEKGEGGPPGVAGPPGGSGPAGPPGPQ＊G | 199 |
| MMP-8 | G＊IAGITGARGLAGPPGMPGPRGSPGPQG＊V | 200 |
| MMP-9 | G＊IKGPAGIPGFPG＊M | 201 |
| MMP-9 | G＊QPGVMGFPGPKG＊N | 202 |
| MMP-9 | G＊IKGPAGIPGFPGMK＊G | 203 |
| MMP-9 | G＊IKGPAGIPGFPGMKG＊H | 204 |
| MMP-9 | I＊PGAPGLMGARGPPGPAG＊A | 205 |
| MMP-9 | G＊ERGLPGPPGIKGPAGIP＊G | 206 |
| MMP-9 | G＊IPGAPGLMGARGPPGPAG＊A | 207 |
| MMP-9 | G＊FRGPAGPNGIPGEKGPAG＊E | 208 |
| MMP-9 | P＊GIPGQPGSPGSPGPPGIC＊E | 209 |
| MMP-9 | G＊ERGLPGPPGIKGPAGIPGF＊P | 210 |
| MMP-9 | A＊VGGLAGYPGPAGPPGPPGPPG＊T | 211 |
| MMP-9 | G＊VKGERGSPGGPGAAGFPGARG＊L | 212 |
| MMP-9 | G＊DAGAPGAPGGKGDAGAPGERGPPG＊L | 213 |
| MMP-9 | Q＊GPPGPTGPGGDKGDTGPPGPQGL＊Q | 214 |
| MMP-9 | G＊INGSPGGKGEMGPAGIPGAPGLM＊G | 215 |
| MMP-9 | Q＊GPPGEPGQAGPSGPPGPPGAIGPS＊G | 216 |
| MMP-9 | P＊GPPGINGSPGGKGEMGPAGIPGAP＊G | 217 |
| MMP-9 | R＊GLPGPPGSNGNPGPPGPSGSPGKDGPPGPAG＊N | 218 |
| MMP-9 | G＊KNGETGPQGPPGPTGPGGDKGDTGPPGPQG＊L | 219 |
| MMP-9 | G＊LPGIAGPRGSPGERGETGPPGPAGFPGAPG＊Q | 220 |
| MMP-9 | G＊INGSPGGKGEMGPAGIPGAPGLMGARGPPGPAG＊A | 221 |
| MMP-9 | P＊GINGSPGGKGEMGPAGIPGAPGLMGARGPPGPAG＊A | 222 |
| MMP-9 | P＊PGENGKPGEPGPKGDAGAPGAPGGKGDAGAPGERGPPG＊L | 223 |
| MMP-9 | G＊LKGENGLPGENGAPGPMGPRGAPGERGRPGLPGAAG＊A | 224 |
| MMP-9 | G＊NTGAPGSPGVSGPKGDAGQPGEKGSPGAQGPPGAPGPLG＊I | 225 |
| MMP-9 | G＊LMGARGPPGPAGANGAPGLRGGAGEPGKNGAKGEPGPRG＊E | 226 |
| MMP-9 | G＊LRGGAGPPGPEGGKGAAGPPGPPGAAGTPGLQGMPGERGGLGSPGPKG＊D | 227 |
| MMP-8和-9 | G＊QQGAIGSPGPAGPRGPVGPSGPPG＊K | 228 |
| MMP-9 | K＊GDPGPPGIPGRNGDPGIPGQPG＊S | 229 |
| MMP-9 | G＊LRGGAGPPGPEGGKGAAGPPGPPG＊A | 230 |
| MMP-9 | G＊KNGETGPQGPPGPTGPGGDKGDTGPPGPQG＊L | 231 |
| MMP-9 | G＊YQGPPGEPGQAGPSGPPGPPG＊A | 232 |
| MMP-9 | G＊VAGPPGGSGPAGPPGPQG＊V | 233 |
| MMP-8，-9和-13 | G＊DKGEPGGPGADGVPGKDGPRGPTGPIGPPGPAG＊Q | 234 |
| ADAMTS-5 | Q＊GHAGAQGPPGPPGIN＊G | 235 |
| 组织蛋白酶K | A＊GERGAPGPA＊G | 236 |
| 组织蛋白酶K | A＊GIPGFPGMK＊G | 237 |
| 组织蛋白酶K | F＊PGMKGHRGFD＊G | 238 |
| 组织蛋白酶K | G＊FPGARGLPGPPG＊S | 239 |
| 组织蛋白酶K | A＊GFPGARGLPGPPG＊S | 240 |
| 组织蛋白酶K | P＊PGPPGPPGTSGHP＊G | 241 |
| 组织蛋白酶K | G＊FPGMKGHRGFD＊G | 242 |
| 组织蛋白酶K | Q＊PGDKGEGGAPGLPGI＊A | 243 |
| 组织蛋白酶K | R＊GDKGETGERGAAGIK＊G | 244 |
| 组织蛋白酶K | D＊GRNGEKGETGAPGLK＊G | 245 |
| 组织蛋白酶K | A＊GQPGDKGEGGAPGLPGIA＊G | 246 |
| 组织蛋白酶K | G＊GPPGENGKPGEPGPKGD＊A | 247 |
| 组织蛋白酶K | A＊GIPGFPGMKGHRGFD＊G | 248 |
| 组织蛋白酶K | R＊GGAGEPGKNGAKGEPGPR＊G | 249 |
| 组织蛋白酶K | K＊GERGSPGGPGAAGFPGARGLPGPP＊G | 250 |
| 组织蛋白酶K | I＊PGVPGAKGEDGKDGSPGEPGANGLP＊G | 251 |
| 组织蛋白酶K | G＊AAGFPGARGLPGPPGSNGNPGPPGPS＊G | 252 |
| 组织蛋白酶K | R＊PGPPGPSGPRGQPGVMGFPGPKGN＊D | 253 |
| 组织蛋白酶K | Q＊GPPGPPGINGSPGGKGEMGPAGIPGAP＊G | 254 |
| 组织蛋白酶K | A＊GKDGESGRPGRPGERGLPGPPGIK＊G | 255 |
| 组织蛋白酶K | A＊GARGNDGARGSDGQPGPPGPPGTAGFPG＊S | 256 |
| 组织蛋白酶K | S＊PGVSGPKGDAGQPGEKGSPGAQGPPGAPG＊P | 257 |
| 组织蛋白酶K | R＊GSDGQPGPPGPPGTAGFPGSPGAKGEVGPA＊G | 258 |
| 组织蛋白酶K | Q＊GPPGPPGINGSPGGKGEMGPAGIPGAPGLM＊G | 259 |
| 组织蛋白酶K | A＊GPPGPPGPPGTSGHPGSPGSPGYQGPPGEPG＊Q | 260 |
| 组织蛋白酶K | F＊PGAPGQNGEPGGKGERGAPGEKGEGGPPGVA＊G | 261 |
| 组织蛋白酶K | A＊GFPGAPGQNGEPGGKGERGAPGEKGEGGPPG＊V | 262 |
| 组织蛋白酶K | A＊GARGNDGARGSDGQPGPPGPPGTAGFPGSPGAKGEVGPA＊G | 263 |
| 组织蛋白酶K | R＊GAAGEPGRDGVPGGPGMRGMPGSPGGPGSDGKPGPPGSQGESGRPGPPGPS＊G | 264 |
| 组织蛋白酶S | G＊IAGITGARGL＊A | 265 |
| 组织蛋白酶S | AGPPGPPGAAGTPGLQGM | 266 |
| 组织蛋白酶S | N＊GLSGERGPPGPQGLPG＊L | 267 |
| 组织蛋白酶S | M＊GARGPPGPAGANGAPGLR＊G | 268 |
| 组织蛋白醇S | N＊GLSGERGPPGPQGLPGLA＊G | 269 |
| 组织蛋白酶S | G＊IAGITGARGLAGPPGMPGPRG＊S | 270 |
| 组织蛋白酶S | G＊IAGITGARGLAGPPGMPGPRGSPGPQG＊V | 271 |
| 组织蛋白酶S | R＊GGAGPPGPEGGKGAAGPPGPPGAAGTPGLQ＊G | 272 |
| 组织蛋白醇S | S＊GPKGDAGQPGEKGSPGAQGPPGAPGPLG＊I | 273 |
| 组织蛋白酶S | G＊IAGITGARGLAGPPGMPGPRGSPGPQGVK＊G | 274 |
| 组织蛋白酶S | A＊VGGLAGYPGPAGPPGPPGPPGTSGHPGSPGSPGYQ＊G | 275 |
| 组织蛋白酶S | E＊PGPQGHAGAQGPPGPPGINGSPGGKGEMGPAGIPGAPG＊L | 276 |
| ADAMTS1 | I＊PGFPGMKGHR＊G | 277 |
| ADAMTS1 | R＊GSPGGPGAAGFPGAR＊G | 278 |
| ADAMTS1 | K＊GPAGIPGFPGMKGHR＊G | 279 |
| ADAMTS1 | R＊GLAGPPGMPGPRGSPGPQ＊G | 280 |
| ADAMTS1 | A＊GITGARGLAGPPGMPGPR＊G | 281 |
| ADAMTS1 | L＊GIAGITGARGLAGPPGMPGPR＊G | 282 |
| ADAMTS1 | T＊GARGLAGPPGMPGPRGSPGPQ＊G | 283 |
| ADAMTS1 | Q＊GPPGPPGINGSPGGKGEMGPAG＊I | 284 |
| ADAMTS1 | L＊PGPPGIKGPAGIPGFPGMKGHR＊G | 285 |
| ADAMTS1 | A＊GITGARGLAGPPGMPGPRGSPGPQ＊G | 286 |
| ADAMTS1 | T＊GARGLAGPPGMPGPRGSPGPQGVK＊G | 287 |
| ADAMTS1 | R＊GLPGPPGIKGPAGIPGFPGMKGHR＊G | 288 |
| ADAMTS1 | G＊RPGLPGAAGARGNDGARGSDGQPGPPG＊P | 289 |
| ADAMTS1 | N＊GAPGPMGPRGAPGERGRPGLPGAAGAR＊G | 290 |
| ADAMTS1 | A＊GSRGAPGPQGPRGDKGETGERGAAGIK＊G | 291 |
| ADAMTS1 | R＊GLAGPPGMPGPRGSPGPQGVKGESGKPGAN＊G | 292 |
| ADAMTS1 | R＊GLAGPPGMPGPRGSPGPQGVKGESGKPGANGL＊S | 293 |
| ADAMTS1 | P＊GPPGSNGNPGPPGPSGSPGKDGPPGPAGNTGAPGS＊P | 294 |
| ADAMTS1 | T＊GARGLAGPPGMPGPRGSPGPQGVKGESGKPGAN＊G | 295 |
| ADAMTS1 | R＊GAPGEKGEGGPPGVAGPPGGSGPAGPPGPQGVKGER＊G | 296 |
| ADAMTS1 | G＊GPPGVAGPPGGSGPAGPPGPQGVKGERGSPGGPGAAGF＊P | 297 |
| ADAMTS1 | K＊SGDRGESGPAGPAGAPGPAGSRGAPGPQGPRGDKGETGERGAAGIK＊G | 298 |
| ADAMTS4 | I＊PGFPGMKGHR＊G | 299 |
| ADAMTS4 | R＊GLAGPPGMPGPR＊G | 300 |
| ADAMTS4 | G＊PQGLQGLPGTGGPP＊G | 301 |
| ADAMTS4 | K＊GPAGIPGFPGMKGHR＊G | 302 |
| ADAMTS4 | R＊GLAGPPGMPGPRGSPGPQG＊V | 303 |
| ADAMTS4 | G＊GPPGENGKPGEPGPKGDAGAP＊G | 304 |
| ADAMTS4 | A＊PGFRGPAGPNGIPGEKGPAGER＊G | 305 |
| ADAMTS4 | E＊KGSPGAQGPPGAPGPLGIAGITGAR＊G | 306 |
| ADAMTS4 | L＊PGPPGIKGPAGIPGFPGMKGHR＊G | 307 |
| ADAMTS4 | R＊GAPGFRGPAGPNGIPGEKGPAGER＊G | 308 |
| ADAMTS4 | R＊GLPGPPGIKGPAGIPGFPGMKGHR＊G | 309 |
| ADAMTS4 | R＊GPVGPSGPPGKDGTSGHPGPIGPPGPR＊G | 310 |
| ADAMTS4 | A＊PGPQGPRGDKGETGERGAAGIKGHR＊G | 311 |
| ADAMTS4 | R＊GAPGPQGPRGDKGETGERGAAGIKGHR＊G | 312 |
| ADAMTS4 | R＊GFPGNPGAPGSPGPAGQQGAIGSPGPAGPR＊G | 313 |
| ADAMTS4 | L＊PGPPGIKGPAGIPGFPGMKGHRGFDGR＊N | 314 |
| ADAMTS4 | D＊AGQPGEKGSPGAQGPPGAPGPLGIAGITGAR＊G | 315 |
| ADAMTS4 | R＊GPTGPIGPPGPAGQPGDKGEGGAPGLPGIAGPR＊G | 316 |
| ADAMTS4 | K＊GDAGQPGEKGSPGAQGPPGAPGPLGIAGITGAR＊G | 317 |
| ADAMTS4 | R＊NGEKGETGAPGLKGENGLPGENGAPGPMGPR＊G | 318 |
| ADAMTS4 | A＊PGFRGPAGPNGIPGEKGPAGERGAPGPAGPRGA＊A | 319 |
| ADAMTS4 | R＊GAPGFRGPAGPNGIPGEKGPAGERGAPGPAGPR＊G | 320 |
| ADAMTS4 | R＊GSPGERGETGPPGPAGFPGAPGQNGEPGGKGER＊G | 321 |
| ADAMTS4 | G＊HAGAQGPPGPPGINGSPGGKGEMGPAGIPGAPGLMG＊A | 322 |
| ADAMTS4 | R＊GLAGPPGMPGPRGSPGPQGVKGESGKPGANGLSGER＊G | 323 |
| ADAMTS8 | L＊GIAGITGARGL＊A | 324 |
| ADAMTS8 | I＊PGFPGMKGHR＊G | 325 |
| ADAMTS8 | R＊GLAGPPGMPGPR＊G | 326 |
| ADAMTS8 | Q＊GPPGAPGPLGIAGITGAR＊G | 327 |
| ADAMTS8 | A＊GITGARGLAGPPGMPGPR＊G | 328 |
| ADAMTS8 | A＊GIPGAPGLMGARGPPGPAGAN＊G | 329 |
| ADAMTS8 | R＊GLAGPPGMPGPRGSPGPQGVKG＊E | 330 |
| ADAMTS8 | K＊GSPGAQGPPGAPGPLGIAGITGAR＊G | 331 |
| ADAMTS8 | L＊PGPPGIKGPAGIPGFPGMKGHR＊G | 332 |
| ADAMTS8 | K＊DGTSGHPGPIGPPGPRGNRGER＊G | 333 |
| ADAMTS8 | A＊GITGARGLAGPPGMPGPRGSPGPQ＊G | 334 |
| ADAMTS8 | R＊GLAGPPGMPGPRGSPGPQGVKGESG＊K | 335 |
| ADAMTS8 | R＊GLAGPPGMPGPRGSPGPQGVKGESGKPGAN＊G | 336 |
| ADAMTS8 | R＊GLAGPPGMPGPRGSPGPQGVKGESGKPGANGL＊S | 337 |
| ADAMTS8 | P＊GPPGSNGNPGPPGPSGSPGKDGPPGPAGNTGAPGS＊P | 338 |
| ADAMTS8 | R＊GAPGEKGEGGPPGVAGPPGGSGPAGPPGPQGVKGER＊G | 339 |
| ADAMTS8 | K＊SGDRGESGPAGPAGAPGPAGSRGAPGPQGPRGDKGETGERGA＊A | 340 |
| ADAMTS8 | R＊GAPGEKGEGGPPGVAGPPGGSGPAGPPGPQGVKGERGSPGGPGAAGFPGAR＊G | 341 |
| MMP9 | _＊AIGPSG______＊_ | 342 |
| 未知 | -AGGFAP＊ | 781 |
因此，在本发明的方法中，所述肽片段优选包含由蛋白酶在上述任一III型胶原蛋白部分序列中＊号标明的位点切割III型胶原蛋白而形成的新表位。
另外，在本发明的方法中，所述肽片段优选包含由一种(或多种)蛋白酶在上述任一III型胶原蛋白的部分序列中的位点切割III型胶原蛋白而形成的新表位，或者所述免疫结合配偶体与上表中任一项中＊号之间的序列特异性反应。
优选地，所述免疫结合配偶体不与完整的III型胶原蛋白反应。优选地，如果延长经过相应的切割位点，则所述免疫结合配偶体不与上文所列的序列反应。
所述免疫结合配偶体可以与切割III型胶原蛋白而形成的C端或N端新表位特异性反应。
因此，合适的免疫结合配偶体可以与肽N端的下列任一序列具有特异性反应性：(每个序列后为序列编号)
| GIPGAP 343 | GDPGPP 408 | LAGPPG 470 | ERGLPG 534 | IAGITG 598 |
| IKGHRG 344 | RGLAGP 409 | TGARGL 471 | ITGARG 599 | |
| VKGESG 345 | SRGAPG 410 | KGDAGQ 472 | ITGARG 535 | LRGGAG 600 |
| HAGAQG 346 | GKSGDR 411 | LQGLPG 473 | ERGLPG 536 | KDGTSG 763 |
| DGTSGH 347 | VGGLAG 412 | IAGITG 474 | PGAPGG 537 | VGGLAG 601 |
| IGSPGP 348 | AIGSPG 413 | AGQQGA 475 | GPPGVA 538 | AGPPGM 602 |
| LSGERG 349 | GLAGPP 414 | LAGPPG 476 | GLAGPP 539 | PQGPPG 603 |
| VKGERG 350 | RGLAGP 415 | GLSGER 477 | VGGLAG 540 | SPGGKG 604 |
| GARGLA 351 | KGESGK 416 | VKGERG 478 | SPGAQG 541 | GAPGEK 605 |
| GAPGEK 352 | IAGITG 417 | IKGPAG 479 | QPGVMG 542 | IKGPAG 606 |
| IKGPAG 353 | PGAPGL 418 | ERGLPG 480 | IPGAPG 543 | FRGPAG 607 |
| GIPGQP 354 | ERGLPG 419 | VGGLAG 481 | VKGERG 544 | DAGAPG 608 |
| GPPGPT 355 | INGSPG 420 | GPPGEP 482 | GPPGIN 545 | GLPGPP 609 |
| KNGETG 356 | LPGIAG 421 | INGSPG 483 | GINGSP 546 | PGENGK 610 |
| LKGENG 357 | NTGAPG 422 | LMGARG 484 | LRGGAG 547 | QQGAIG 611 |
| GDPGPP 358 | LRGGAG 423 | KNGETG 485 | YQGPPG 548 | VAGPPG 612 |
| DKGEPG 359 | GHAGAQ 424 | GERGAP 486 | GIPGFP 549 | PGMKGH 613 |
| FPGARG 360 | GFPGAR 425 | PGPPGP 487 | FPGMKG 550 | PGDKGE 614 |
| GDKGET 361 | GRNGEK 426 | GQPGDK 488 | GPPGEN 551 | |
| GGAGEP 362 | GERGSP 427 | PGVPGA 489 | AAGFPG 552 | |
| GPPGPP 363 | GKDGES 428 | GARGND 490 | PGVSGP 553 | GSDGQP 615 |
| PGAPGQ 491 | GFPGAP 554 | GARGND 616 | ||
| GAAGEP 365 | IAGITG 429 | GPPGPP 492 | GLSGER 555 | GARGPP 617 |
| GLSGER 366 | IAGITG 493 | GGAGPP 556 | GPKGDA 618 | |
| IAGITG 367 | GPKGDA 430 | VGGLAG 557 | PGPQGH 619 | |
| PGFPGM 368 | GSPGGP 431 | GPAGIP 494 | GLAGPP 558 | |
| GIAGIT 369 | GPPGPP 495 | PGPPGI 559 | GITGAR 620 | |
| GARGLA 370 | GLPGPP 432 | RPGLPG 496 | GAPGPM 560 | GSRGAP 621 |
| GLAGPP 371 | GPPGSN 497 | GARGLA 561 | GAPGEK 622 | |
| GPPGVA 372 | SGDRGE 433 | PGFPGM 498 | GLAGPP 562 | PQGLQG 623 |
| GPAGIP 373 | GLAGPP 434 | GPPGEN 499 | PGFRGP 563 | KGSPGA 624 |
| PGPPGI 374 | GAPGFR 435 | GLPGPP 500 | GPVGPS 564 | PGPQGP 625 |
| GAPGPQ 375 | GFPGNP 436 | PGPPGI 501 | AGQPGE 565 | GPTGPI 626 |
| GDAGQP 376 | NGEKGE 437 | PGFRGP 502 | GAPGFR 566 | GSPGER 627 |
| HAGAQG 377 | GLAGPP 438 | GIAGIT 503 | PGFPGM 567 | |
| GPPGAP 378 | GITGAR 439 | GIPGAP 504 | GLAGPP 568 | GSPGAQ 628 |
| DGTSGH 440 | GITGAR 505 | GLAGPP 629 | ||
| GLAGPP 379 | GPPGSN 441 | GAPGEK 506 | SGDRGE 569 | GAPGEK 630 |
| AIGPSG 380 |
或者与肽C端的下列任一序列具有特异性反应性：
| GPPGPA 381 | NGDPGI 442 | SPGPQG 507 | AGIPGF 570 | GMPGPR 631 |
| SPGPAG 382 | PGPQGV 443 | PPGPQG 508 | ERGAAG 571 | PGPLGI 632 |
| AAGTPG 383 | IPGAPG 444 | ERGPPG 509 | PGPPGT 572 | GNRGER 633 |
| TSGHPG 384 | SPGPQG 445 | APGLRG 510 | HPGSPG 573 | PSGPPG 634 |
| PSGPPG 385 | GSPGPA 446 | GPAGPP 511 | SPGPQG 574 | GLPGLA 635 |
| QGPPGP 447 | SPGPQG 512 | GLAGTA 575 | PGPPGT 636 | |
| PGLMGA 386 | LAGPPG 513 | GPPGPQ 576 | GPPGPQ 637 | |
| SPGPQG 387 | IPGFPG 448 | FPGPKG 514 | GFPGMK 577 | FPGMKG 638 |
| GPAGIP 449 | PPGPAG 515 | EKGPAG 578 | GPPGIC 640 | |
| PPGPPG 388 | FPGARG 450 | PGPQGL 579 | GAPGLM 641 | |
| GAIGPS 389 | GIPGAP 451 | FPGAPG 580 | ||
| PPGPAG 390 | ERGPPG 452 | LPGAAG 516 | APGPLG 581 | EPGPRG 642 |
| SPGPKG 391 | PSGPPG 453 | IPGQPG 517 | ||
| PPGPAG 392 | GPPGIN 454 | GAPGPA 518 | GFPGMK 582 | GHRGFD 643 |
| LPGPPG 393 | GTSGHP 455 | GHRGFD 519 | PGLPGI 583 | GAAGIK 644 |
| GAPGLK 394 | GLPGIA 456 | PGPKGD 520 | GHRGFD 584 | GEPGPR 645 |
| GLPGPP 395 | GANGLP 457 | GPPGPS 521 | PGPKGN 585 | GIPGAP 646 |
| GPPGIK 396 | TAGFPG 458 | PPGAPG 522 | GEVGPA 586 | GAPGLM 647 |
| GPPGVA 397 | EGGPPG 459 | GEVGPA 523 | GPPGPS 587 | TGARGL 648 |
| TPGLQG 398 | PQGLPG 460 | GAPGLR 524 | GLPGLA 588 | MPGPRG 649 |
| GTPGLQ 399 | APGPLG 461 | GPQGVK 525 | GSPGYQ 589 | GMKGHR 650 |
| GFPGAR 400 | GSPGPQ 462 | GMPGPR 526 | EMGPAG 590 | GPQGVK 651 |
| QPGPPG 401 | GAAGAR 463 | GAAGIK 527 | GKPGAN 591 | PGANGL 652 |
| TGAPGS 402 | GVKGER 464 | PGAAGF 528 | GMPGPR 592 | GTGGPP 653 |
| SPGPQG 403 | GDAGAP 465 | GPAGER 529 | GITGAR S93 | GPPGPR 654 |
| GPAGPR 404 | RGFDGR 466 | GIAGPR 530 | AGPRGA 594 | GGKGER 655 |
| APGLMG 405 | GLSGER 467 | TGARGL 531 | GPAGAN 595 | PQGVKG 656 |
| GNRGER 406 | GSPGPQ 468 | VKGESG 532 | GKPGAN 596 | PGANGL 657 |
| TGAPGS 407 | GVKGER 469 | TGERGA 533 | GFPGAR 597 |
通过将III型胶原蛋白或另一种动脉粥样硬化斑块蛋白质暴露于本文所述的任何酶以及分离并测序由此产生的肽，可以鉴定出限定能以类似方式测定的新表位的其它切割位点。
CRP和ApoE测定
所述肽片段可以是CRP(SEQ ID NO：658)或ApoE(SEQ ID NO：659)的片段。对于ApoE，优选所选片段在所鉴定的全部ApoE同种型ε2、ε3和ε4中都存在。
尽管CRP和ApoE在人体各处都很丰富，但它们在动脉粥样硬化组织中的定位使其暴露于局部蛋白酶的作用。因此，这些分子是作为生物化学标志物的良好且特异的候选。
一些候选蛋白酶可能负责消化斑块中的CRP和ApoE，因为文献中报道了动脉粥样硬化斑块中的许多不同的蛋白酶。最可能的是，这是最终导致斑块破裂的一系列复杂过程的结果。但是，在我们的评估中，早期阶段可以由一组MMP组成，而晚期水平可更多地依赖于组织蛋白酶K对基质的降解，导致根据疾病水平产生不同的新表位谱。通过大量纯化天然蛋白质的体外切割，我们确定了下表中所列的酶在至少下列切割位点(记为＊)切割CRP和ApoE：
表13、特异性蛋白酶产生的CRP和ApoE片段。
| 蛋白酶/蛋白 | 新表位 | SEQ ID NO |
| APOE+MMP3 | A＊KVEQAVETEPEPELR＊Q | 660 |
| APOE+MMP9 | A＊KVEQAVETEPEPELR＊Q | 661 |
| APOE+MMP1 | V＊AEVRAKLEEQAQQI＊R | 662 |
| APOE+MMP3 | A＊KVEQAVETEPEPELR＊Q | 663 |
| APOE+MMP3 | A＊MLGQSTEELRV＊R(M-氧化) | 664 |
| APOE+ADAMTS1 | E＊QAVETEPEPELR＊Q | 665 |
| APOE+ADAMTS1 | R＊QQTEWQSGQRWE＊L | 666 |
| APOE+ADAMTS1 | L＊AVYQAGAREGAERGLS＊A | 667 |
| APOE+ADAMTS1 | R＊AKLEEQAQQIR＊L | 668 |
| APOE+ADAMTS1 | A＊KLEEQAQQIRLQ＊A | 669 |
| APOE+组织蛋白酶K | A＊KVEQAVETEPEPELR＊Q | 670 |
| APOE+组织蛋白酶K | K＊VEQAVETEPEPELR＊Q | 671 |
| APOE+组织蛋白酶K | E＊QAVETEPEPELR＊Q | 672 |
| APOE+组织蛋白酶K | D＊EVKEQVAEVRAKLE＊E | 673 |
| 蛋白酶/蛋白 | 新表位 | |
| CRP+CatK | K＊ESDTSYVSLKAPLT＊K | 674 |
| CRP+CatK | G＊GNFEGSQSLVGDIG＊N | 675 |
| CRP+MMP9 | A＊LKYEVQGEVFTKPQ＊L | 676 |
| CRP+MMP9 | G＊IVEFWVDGKPRV＊R | 677 |
| CRP+MMP1/MMP3 | R＊KAFVFPKE＊S | 678 |
| CRP+MMP3 | K＊YEVQGEVFTKPQLWP＊- | 679 |
| CRP+MMP3 | D＊SFGGNFEGSQS＊L | 680 |
| CRP+MMP3 | D＊FVLSPDEINT＊I | 681 |
| CRP+MMP3 | S＊LKKGYTVGAEA＊S | 682 |
| CRP+MMP3 | A＊FGQTDMSRKA＊F | 683 |
| CRP+MMP3 | S＊LKKGYTVGAEAS＊I | 684 |
| CRP+MMP3 | G＊EVFTKPQLWP＊- | 685 |
| CRP+MMP3 | S＊IILGQEQDSFGGN＊F | 686 |
| CRP+MMP3 | K＊YEVQGEVFTKPQ＊L | 687 |
因此，在本发明的方法中，所述肽片段优选包含由蛋白酶在下列任一CRP和ApoE部分序列中以＊标记的位点切割CRP和ApoE而形成的新表位，或者所述免疫结合配偶体与下述序列之一的＊号之间定义的序列特异性反应。
表14、CRP和ApoE的切割片段。
| ApoE片段 |
| A＊KVEQAVETEPEPELR＊Q |
| A＊KVEQAVETEPEPELR＊Q |
| V＊AEVRAKLEEQAQQI＊R |
| A＊KVEQAVETEPEPELR＊Q |
| A＊MLGQSTEELRV＊R(M-氧化) |
| E＊QAVETEPEPELR＊Q |
| R＊QQTEWQSGQRWE＊L |
| L＊AVYQAGAREGAERGLS＊A |
| R＊AKLEEQAQQIR＊L |
| A＊KLEEQAQQIRLQ＊A |
| A＊KVEQAVETEPEPELR＊Q |
| K＊VEQAVETEPEPELR＊Q |
| E＊QAVETEPEPELR＊Q |
| D＊EVKEQVAEVRAKLE＊E |
| CRP片段 |
| K＊ESDTSYVSLKAPLT＊K |
| G＊GNFEGSQSLVGDIG＊N |
| A＊LKYEVQGEVFTKPQ＊L |
| G＊IVE FWVDGKPRV＊R |
| R＊KAFVFPKE＊S |
| K＊YEVQGEVFTKPQLWP＊- |
| D＊SFGGNFEGSQS＊L |
| D＊FVLSPDEINT＊I |
| S＊LKKGYTVGAEA＊S |
| A＊FGQTDMSRKA＊F |
| S＊LKKGYTVGAEAS＊I |
| G＊EVFTKPQLWP＊- |
| S＊IILGQEQDSFGGN＊F |
| K＊YEVQGEVFTKPQ＊L |
因此，合适的免疫结合配偶体可以对肽N端的下列任一序列具有特异性反应性：
| APOE | SEQ ID NO | CRP | SEQ ID NO |
| KVEQAV | 688 | AFVFPK | 699 |
| AEVRAK | 689 | YEVQGE | 700 |
| MLGQST | 690 | KAFVFP | 701 |
| QAVETE | 691 | SFGGNF | 702 |
| QQTEWQ | 692 | FVLSPD | 703 |
| AVYQAG | 693 | LKKGYT | 704 |
| AKLEEQ | 694 | FGQTDM | 705 |
| KLEEQA | 695 | LKKGYT | 706 |
| VEQAVE | 696 | IILGQE | 707 |
| QAVETE | 697 | YEVQGE | 708 |
| EVKEQV | 698 | LKYEVQ | 709 |
| IVEFWV | 710 | ||
| ESDTSY | 711 | ||
| GNFEGS | 712 |
或者对肽C端与下列任一序列具有特异性反应性：
通过将CRP和ApoE或另一种动脉粥样硬化斑块蛋白质暴露于本文所述的任何酶以及分离并测序由此产生的肽，可鉴定出限定可以类似方式测定之新表位的其它切割位点。
弹性蛋白测定
所述肽片段可以是弹性蛋白(SEQ ID NO：735)的片段。尽管弹性蛋白在人体各处都很丰富，但它们在动脉粥样硬化组织中的定位使其暴露于局部蛋白酶的作用，因此这些分子是作为动脉粥样硬化斑块周转的生物化学标志物的良好且特异的候选。
一些候选蛋白酶可能负责消化斑块中的弹性蛋白，因为文献中报道了动脉粥样硬化斑块中的许多不同的蛋白酶。最可能的是，这是最终导致斑块破裂的一系列复杂过程的结果。但是，在我们的评估中，早期阶段可以由一组MMP组成，而晚期阶段可更多地依赖于组织蛋白酶K对基质的降解，根据疾病水平而产生不同的新表位谱。通过大量纯化天然蛋白质的体外切割，我们确定了下表中所列的酶在至少下列切割位点(记为＊)切割弹性蛋白：
表15、特异性蛋白酶产生的弹性蛋白片段
| 蛋白酶/蛋白 | 新表位 | SEQ ID NO |
| ADAMTS4 | A＊RPGVGVGGIPTYGVGAGG＊F | 736 |
| 组织蛋白酶K | G＊LPYTTGKLPYGYGPG＊G | 737 |
| 组织蛋白酶S | G＊VAPGVGVAPGVGVAPGIGPGGVA＊A | 738 |
| 组织蛋白酶S | G＊GAGVPGVPGAIPGIGGIAGVG＊T | 739 |
| ADAMTS4 | G＊GAGVPGVPGAIPGIGGIAGVG＊T | 740 |
| 组织蛋白酶K | G＊VGISPEAQAAAAAK＊A | 741 |
| ADAMTS1 | G＊VGISPEAQAAAAAK＊A | 742 |
因此，在本发明的方法中，所述肽片段优选包含由蛋白酶在下列任一弹性蛋白部分序列中以＊号标记的位点切割弹性蛋白而形成的新表位，或者所述免疫结合配偶体对下述序列之一中＊号之间所定义序列具有特异性反应性。
表16、弹性蛋白的切割片段。
| 弹性蛋白片段 |
| A＊RPGVGVGGIPTYGVGAGG＊F |
| G＊LPYTTGKLPYGYGPG＊G |
| G＊VAPGVGVAPGVGVAPGIGPGGVA＊A |
| G＊GAGVPGVPGAIPGIGGIAGVG＊T |
| G＊GAGVPGVPGAIPGIGGIAGVG＊T |
| G＊VGISPEAQAAAAAK＊A |
| G＊VGISPEAQAAAAAK＊A |
| A＊RPGVGVGGIPTYGVGAGG＊F |
| G＊LPYTTGKLPYGYGPG＊G |
因此，合适的免疫结合配偶体可以与肽N端的下列任一序列具有特异性反应性：
| 弹性蛋白 | SEQ ID NO |
| RPGVGV | 743 |
| LPYTTG | 744 |
| VAPGVG | 745 |
| GAGVPG | 746 |
| VGISPE | 747 |
| RPGVGV | 748 |
| LPYTTG | 749 |
或者与肽C端的以下任一序列具有特异性反应性：
| 弹性蛋白 | SEQ ID NO |
| GVGAGG | 750 |
| YGYGPG | 751 |
| GPGGVA | 752 |
| GIAGVG | 753 |
通过将弹性蛋白或另一种动脉粥样硬化斑块蛋白质暴露于本文所述的任何酶以及分离并测序由此产生的肽，可鉴定出限定可以类似方式测定之新表位的其它切割位点。
可分别对多于一种上述肽进行测定，并将其结果相结合，或者可同时测定多于一种上述的肽。
本发明测定的结果可以与一种或多种其它测定的生物标志物相结合，形成诊断或预后值的复合指标。
本文使用的术语“免疫结合配偶体”包括多克隆抗体和单克隆抗体，以及抗体的特异性结合片段例如Fab或F(ab′)2。因此，所述免疫结合配偶体可以是单克隆抗体或者具有特异性结合亲和力的单克隆抗体片段。
本文使用的术语“蛋白质”包括脂蛋白和蛋白聚糖及其他蛋白质(非蛋白质)天然缀合物。
一般地，所有先前已知的免疫测定形式都可用于本发明，包括异质和均质的形式，夹心法测定、竞争测定、酶联测定、放射性免疫测定等等。因此，任选地，所述方法以竞争性免疫测定的形式进行，其中将所述免疫结合配偶体和竞争剂在所述样品存在下一起孵育，所述竞争剂与样品中的肽片段竞争结合该免疫结合配偶体。
所述竞争剂可以是合成肽，或是通过切割新表位所属蛋白以暴露新表位而形成的纯化天然肽。因此，所述肽可来源于多功能蛋白聚糖、光亮蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖、双糖链蛋白聚糖、III型胶原蛋白、ApoE、CRP或弹性蛋白中的任一种。
一种合适的方法可以是使用单克隆抗体或抗体结合片段进行的竞争免疫测定，所述单克隆抗体或抗体结合片段与任一这些蛋白质片段中的新表位或者来自动脉粥样硬化斑块的其他肽片段上的新表位结合。包被于微滴定板固体表面上的适当选择的合成肽可与样品竞争结合所述单克隆抗体或结合片段。或者，带有单克隆抗体或结合片段所识别新表位的一种或多种蛋白质的纯化天然片段可用于固体表面上。另一种替代方案是将单克隆抗体或结合片段固定于固体表面，然后将样品与适当连接信号分子(例如辣根过氧化物酶或生物素)的合成肽共孵育。所述样品可以是尿、血清、血、血浆或其它样品，例如动脉粥样硬化斑块活组织检查。
在某些优选方法中，所述样品是来自患者的样品，所述方法还包括将测得的所述肽片段结合水平与下列特征值进行比较：(a)相当的健康个体和/或(b)病理动脉粥样硬化状况，以及任选地将所测定较高的肽水平(通常由较高水平的结合来表示)与更严重的所述状况程度相关联。
本发明的一个方面涉及开发识别上述新表位的单克隆抗体。这可通过下述方案来实现，用合成肽免疫小鼠，所述合成肽来自于目的蛋白质分子的氨基酸序列(包括上文所列序列或者在其中终止的序列)；将来自所选小鼠的脾细胞与骨髓瘤细胞融合；以及测定单克隆抗体与相关合成肽上新表位的结合。可通过要求与合成肽具有反应性但与C延长形式的免疫肽(对于C端新表位)或者N端延长形式的免疫肽(对于N端新表位)无反应性，来确保新表位的特异性。也可对针对新表位的抗体进行评估，以确定不能与天然蛋白质结合。或者，可通过要求抗体反应性负依赖于与末端氨基酸之一共价连接的生物素或其他官能团的存在，来确保对新表位的特异性。
本发明包括对新表位具有特异性免疫反应性的免疫结合配偶体，所述新表位是通过蛋白酶在任一上述部分序列的末端位点切割所述蛋白质而形成的，所述免疫结合配偶体可以是例如单克隆抗体或其结合片段。
本发明包括产生针对C端或N端新表位的单克隆抗体的细胞系，所述新表位是通过在任一上述部分序列的序列末端位点切割动脉粥样硬化斑块蛋白质而形成的。
本发明还提供包含C端或N端新表位的肽，所述新表位是通过在任一上述蛋白质部分序列中切割所述蛋白质而形成的。这样的肽可以作为半抗原与载体缀合，用以产生对所述肽的免疫应答，或者固定到固体表面或与可检测标记缀合用于免疫测定。
本发明还包括编码包含C端或N端新表位的肽的分离核酸分子，所述新表位是通过在任一上述部分序列中切割所述蛋白质而形成的。
本发明还包括包含核酸序列的载体，所述核酸序列包含表达信号以及编码表达包含C端或N端新表位的肽的编码序列，所述新表位是通过在任一上述部分序列中切割所述蛋白质而形成的，本发明还包括用此载体转化并表达所述肽的宿主细胞。
本发明的另一个方面涉及试剂盒，其可方便地用于实施上述方法。此试剂盒可包含(1)用合成肽包被的微滴定板；(2)对所述合成肽具有反应性的本发明单克隆抗体或抗体结合片段；和(3)带标记的抗小鼠IgG免疫球蛋白。或者，此试剂盒可包含(1)用纯化的天然蛋白质片段包被的微滴定板；(2)识别任一所述蛋白质片段上新表位并对所述纯化片段具有反应性的单克隆抗体；和(3)带标记的抗小鼠IgG免疫球蛋白。或者，此试剂盒可包含(1)用链霉亲和素包被的微滴定板；(2)与生物素相连的合成肽；(3)识别所述蛋白质片段上新表位并对所述合成肽具有反应性的单克隆抗体；和(4)带标记的抗小鼠IgG免疫球蛋白。另一种替代方案可以是包含以下的试剂盒：(1)用链霉亲和素包被的微滴定板；(2)与生物素相连的合成肽；(3)识别所述蛋白质片段上新表位(并对所述合成肽具有反应性)并且与辣根过氧化物酶缀合的单克隆抗体。
因此，本发明包括免疫测定试剂盒，其包含如本文所述的免疫结合配偶体以及与所述免疫结合配偶体结合的竞争剂，并任选地包含以下一种或多种：洗涤试剂、缓冲剂、终止试剂、酶标记、酶标记底物、校准标准品、抗小鼠抗体和进行所述免疫测定的说明。
本文所述测定可用于诊断患者的动脉粥样硬化疾病。另外，所述测定可用于评估疾病进展并监测对治疗的反应。本发明的免疫结合配偶体还可用于免疫染色，以显示本文所述任一动脉粥样硬化斑块蛋白质切割产物的存在情况或位置。
下面参考附图进一步解释和说明本发明，其中：
图1显示使用单克隆小鼠抗体对具有III型病变的主动脉样品进行双糖链蛋白聚糖染色(分别为2、4、4和10倍放大)。
图2显示使用单克隆小鼠抗体对具有III型病变的主动脉样品进行组织蛋白酶K染色(分别为2、4、10和10倍放大)。
图3显示使用单克隆小鼠抗体对具有V型病变的主动脉样品进行双糖链蛋白聚糖染色(分别为2、4、10和10倍放大)。
图4显示使用单克隆小鼠抗体对包含V型病变的主动脉样品进行组织蛋白酶K染色(分别为2、4、10和10x倍放大)。
图5显示通过以下蛋白酶产生的双糖链蛋白聚糖切割产物：MMP2、MMP3、MMP8、组织蛋白酶K、组织蛋白酶S、组织蛋白酶B和组织蛋白酶L。M＝Rainbow标记物，-enz＝未进行酶消化，利用实施例2的凝胶进行。
图6至8显示实施例4所得的竞争研究结果。
图9显示实施例6所得的竞争研究结果。
图10和11显示实施例7所得的竞争研究结果。
实施例1
为了分析蛋白聚糖和蛋白酶的定位，我们对来自于冠状动脉左前降支(left coronary descending arteries，LAD)的人动脉样品进行了免疫组织化学染色。下文中，证明了组织蛋白酶K蛋白酶与双糖链蛋白聚糖共定位。
如图1和2中所示的免疫组织化学染色显示了双糖链蛋白聚糖与组织蛋白酶K的共定位。这可表明双糖链蛋白聚糖是组织蛋白酶K的优选底物。对主动脉样品进行了相同的免疫组织化学染色，其中形成了动脉粥样硬化斑块，并因此导致巨噬细胞性泡沫细胞浸润物和钙化替代了正常主动脉结构。这些免疫染色的结果汇总在图3和4中。
双糖链蛋白聚糖和组织蛋白酶K的免疫组织化学染色显示在发展的动脉粥样硬化病变中共定位。综合这些结果产生了下列假说：双糖链蛋白聚糖中组织蛋白酶K的特异性切割位点导致动脉粥样硬化病变中的新表位产生增加。为了检验这一假说，我们使用不同的蛋白酶切割双糖链蛋白聚糖。
实施例2
用于评估降解片段的双糖链蛋白聚糖降解。通过下列蛋白酶切割来自牛关节软骨的双糖链蛋白聚糖(B8041-Sigma-Aldrich)：MMP2、MMP3、MMP8、组织蛋白酶K、组织蛋白酶S、组织蛋白酶B和组织蛋白酶L。将由上述蛋白酶的酶促切割产生的蛋白聚糖片段在10％Bis-Tris凝胶上分离，然后通过“Silver Express”银染试剂盒(Invitrogen目录号LC6100，批号341099)进行银染。蛋白水解产生的双糖链蛋白聚糖的分离以及银染的结果在图5中显示。
实施例3
用与卵白蛋白缀合的来自III型胶原的肽免疫小鼠。对血清筛选与缀合生物素的所筛选肽序列的反应性。产生分泌单克隆抗体的克隆，并使用筛选序列进行筛选。检查克隆的以下方面：缺少与延长形式靶标肽的反应性以及缺少与无义肽的反应性，所述延长形式靶标肽延续了III型胶原中的临近序列(反选肽)。所有靶序列阳性克隆均不与延长或无义序列反应。
所述靶序列、免疫原、筛选序列和反选序列如下：
| No： | 靶序列 | 免疫原 | 筛选序列 | 反选序列 | 小鼠编号 |
| NB51 | KNGETG 356 | KNGETGPQGPGGC-OVA | KNGETGPQGP-PG-K-生物素 | KDGETGAAGPPGK-生物素KDGEAGAQGPPGK-生物素PGKNGETPGPQ-GP-K-生物素 | 278；279；289；345；346；347 |
| NB26 | IAGITG 429 | IAGITGARGLGGC-KLH | IAGITGARGL-AG-K-生物素IAGLTGARGL-AG-K-生物素 | LGIAGITGARGL-AG-K-生物素 | 146；147；148；149；156；157； |
| NB52 | IAGITG | IAGITGARGLGGC-OVA | IAGITGARGL-AG-K-生物素IAGLTGARGL-AG-K-生物素 | LGIAGITGARGL-AG-K-生物素 | 348；349；357；358；359； |
| NB27 | KDGTSG763 | KDGTSGHPGPGGC-OVA | KDGTSGHPGP-IG-K-生物素KDGSSGHPGP-IG-K-生物素 | PGKDGTSGHP-GP-K-生物素 | 158；159；167；168；169；178； |
| NB67 | APGPLG581 | OVA-CGG-GPPGAPGPLG | 生物素-AQ-GPPGAPGPLG生物素-AQ-GPPGSPGPLG | 生物素-DD-GPSGAEGPPG生物素-GP-PGAPGPLGIA | 167；168；169；178；179；189； |
| NB68 | NTGAPG422 | NTGAPGSPGV-CGG-OVA | NTGAPGSPGVSG-K-生物素NSGSPGNPGVAG-K-生物素 | AGNTGAPGSP-GV-生物素 | 234；235；236；237；238；239； |
| NB69 | AIGPSG380 | AIGPSGPAGK-GGC-OVA(808680) | AIGPSGPAGKDG-K-生物素AIGPAGPAGKDG-K-生物素 | PGAIGPSGPAG-KD-生物素 | 245；246；247；248；249；256； |
| NB57 | AGGFAP781 | KLH-CGG-EKAGGFAP | 生物素-CG-EKAGGFAP生物素-CG-EKSGGFSP | 生物素-GG-EKAGGFAPYY | 1；2；3；4；5；6； |
实施例4
III型胶原蛋白新表位单克隆抗体与人尿的反应性
在使用免疫肽作为竞争剂的竞争测定形式中确定来自实施例3的所选单克隆抗体克隆与人尿的反应性。在典型方案中，在20℃下用PBS-BTE中10ng/ml生物素-肽对以链霉亲和素包被的96孔板摇动包被30分钟，在洗涤缓冲液中洗涤5遍。加入20μl稀释的样品(尿或肽溶液)。添加如下文所述稀释的100μl未纯化抗体溶液(来自细胞培养物的上清液)。将平板在20℃下以300rpm摇动孵育1小时，然后在洗涤缓冲液中洗涤5遍。添加100μl二抗(POD，1∶5000)，在20℃下以300rpm摇动孵育1小时，然后在洗涤缓冲液中洗涤5遍。添加100μl TMB，避光以300rpm摇动孵育15分钟，然后添加100μl终止液。在ELISA读取仪上以450nm读取平板，以650nm作为参照。这样，平板上的肽与溶液中的肽发生对抗体的竞争，通过过氧化物酶显色反应确定与平板结合的抗体量。
四个不同克隆的结果显示于图6。可以看出，每种所述抗体都检测出尿中的相关序列。
对一个选定的克隆进行另外的竞争研究，以测试免疫肽与被MMP9体外切割的天然III型胶原蛋白之间对抗体结合的竞争。被切割的胶原、KNGETG肽和该序列延长形式的结果显示于图7。可以看出，所述抗体结合免疫肽序列和被酶切割的胶原蛋白，但是不结合延长的序列。
对同一克隆进行的其它竞争研究见于图8，其中竞争剂分别是KNGETG肽、人血清、大鼠血清、FCS(胎牛血清)和动脉粥样硬化斑块提取物。可以看出，所述抗体与所述肽、所述斑块提取物以及人血清反应，但是不与大鼠血清或FCS反应。
实施例5
产生针对核心蛋白聚糖、双糖链蛋白聚糖和多功能蛋白聚糖序列的抗血清
如实施例3中所述，产生抗血清并获得单克隆抗体，不同在于使用下列免疫原、筛选序列和反选序列。
| No： | 表位 | 靶序列 | 免疫原 | 筛选序列 | 反选序列 | 小鼠编号 |
| NB62 | 核心蛋白聚糖-176N | IVIELG91 | IVIELGTNPL-GGC-KLH | IVIELGTNPL-KS-K-生物素LVIELGGNPL-KN-K-生物素IVVELGGNPL-TN-K-生物素 | QMIVIELGTNPLK-K-生物素NVLVIELGGNPL-K-生物素 | 7；8；9；10；12；13 |
| NB63 | 双糖链蛋白聚糖-108C | NNDISE116 | OVA-CGG-LDLQNNDISE | 生物素-TL-LDLQNNDISE | 生物素-LDLQNNDISELR | 14；15；16；17；18；19 |
| NB64 | 多功能蛋白聚糖-87N | QNGNIK143 | QNGNIKIGQD-GGC-KLH | QNGNIKIGQD-YK-生物素QDGNIKIGQD-YK-生物素 | VAQNGNIKIGQD-K-生物素VAQDGNIKIGQD-K-生物素 | 23；2425；26；27；28； |
实施例6
核心蛋白聚糖新表位单克隆抗体与人尿的反应性
基本如实施例5所述使用一种抗核心蛋白聚糖未纯化单克隆抗体(NB62)进行竞争性ELISA。
结果显示于图9。可观察到针对产生和选择该抗体的肽序列以及针对尿的反应性，但针对无关肽序列NB18则不然。
实施例7
多功能蛋白聚糖新表位单克隆抗体与人尿的反应性
基本如实施例5使用针对序列(NB64)产生的两种抗多功能蛋白聚糖未纯化单克隆抗体克隆进行竞争性ELISA。
各个克隆的结果显示于图10和11。在每种情况下，可观察到针对产生和选择该抗体的肽序列以及针对尿的反应性，但是针对无关肽序列NB18则不然。
在本说明书中，除非另外指明，否则词语“或”以下述运算符含义使用：当满足所述情况之一或同时满足时返回真值，相反，运算符“异或”要求仅满足条件之一。词语“包含”以“包括”的含义使用，而不表示“由......组成”。上文给出的在先教导通过引用并入本文。
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序列表
<110>Nordic Bioscience A/s
<120>用于CVD风险评估的生物化学标志物
<130>P15861WO
<150>GB 0721713.6
<151>2007-11-05
<150>GB 0722748.1
<151>2007-11-20
<150>GB 0802814.4
<151>2008-02-15
<160>800
<170>PatentIn version 3.5
<210>1
<211>3396
<212>PRT
<213>人
<400>1
Met Phe Ile Asn Ile Lys Ser Ile Leu Trp Met Cys Ser Thr Leu Ile
1 5 10 15
Val Thr His Ala Leu His Lys Val Lys Val Gly Lys Ser Pro Pro Val
20 25 30
Arg Gly Ser Leu Ser Gly Lys Val Ser Leu Pro Cys His Phe Ser Thr
35 40 45
Met Pro Thr Leu Pro Pro Ser Tyr Asn Thr Ser Glu Phe Leu Arg Ile
50 55 60
Lys Trp Ser Lys Ile Glu Val Asp Lys Asn Gly Lys Asp Leu Lys Glu
65 70 75 80
Thr Thr Val Leu Val Ala Gln Asn Gly Asn Ile Lys Ile Gly Gln Asp
85 90 95
Tyr Lys Gly Arg Val Ser Val Pro Thr His Pro Glu Ala Val Gly Asp
100 105 110
Ala Ser Leu Thr Val Val Lys Leu Leu Ala Ser Asp Ala Gly Leu Tyr
115 120 125
Arg Cys Asp Val Met Tyr Gly Ile Glu Asp Thr Gln Asp Thr Val Ser
130 135 140
Leu Thr Val Asp Gly Val Val Phe His Tyr Arg Ala Ala Thr Ser Arg
145 150 155 160
Tyr Thr Leu Asn Phe Glu Ala Ala Gln Lys Ala Cys Leu Asp Val Gly
165 170 175
Ala Val Ile Ala Thr Pro Glu Gln Leu Phe Ala Ala Tyr Glu Asp Gly
180 185 190
Phe Glu Gln Cys Asp Ala Gly Trp Leu Ala Asp Gln Thr Val Arg Tyr
195 200 205
Pro Ile Arg Ala Pro Arg Val Gly Cys Tyr Gly Asp Lys Met Gly Lys
210 215 220
Ala Gly Val Arg Thr Tyr Gly Phe Arg Ser Pro Gln Glu Thr Tyr Asp
225 230 235 240
Val Tyr Cys Tyr Val Asp His Leu Asp Gly Asp Val Phe His Leu Thr
245 250 255
Val Pro Ser Lys Phe Thr Phe Glu Glu Ala Ala Lys Glu Cys Glu Asn
260 265 270
Gln Asp Ala Arg Leu Ala Thr Val Gly Glu Leu Gln Ala Ala Trp Arg
275 280 285
Asn Gly Phe Asp Gln Cys Asp Tyr Gly Trp Leu Ser Asp Ala Ser Val
290 295 300
Arg His Pro Val Thr Val Ala Arg Ala Gln Cys Gly Gly Gly Leu Leu
305 310 315 320
Gly Val Arg Thr Leu Tyr Arg Phe Glu Asn Gln Thr Gly Phe Pro Pro
325 330 335
Pro Asp Ser Arg Phe Asp Ala Tyr Cys Phe Lys Pro Lys Glu Ala Thr
340 345 350
Thr Ile Asp Leu Ser Ile Leu Ala Glu Thr Ala Ser Pro Ser Leu Ser
355 360 365
Lys Glu Pro Gln Met Val Ser Asp Arg Thr Thr Pro Ile Ile Pro Leu
370 375 380
Val Asp Glu Leu Pro Val Ile Pro Thr Glu Phe Pro Pro Val Gly Asn
385 390 395 400
Ile Val Ser Phe Glu Gln Lys Ala Thr Val Gln Pro Gln Ala Ile Thr
405 410 415
Asp Ser Leu Ala Thr Lys Leu Pro Thr Pro Thr Gly Ser Thr Lys Lys
420 425 430
Pro Trp Asp Met Asp Asp Tyr Ser Pro Ser Ala Ser Gly Pro Leu Gly
435 440 445
Lys Leu Asp Ile Ser Glu Ile Lys Glu Glu Val Leu Gln Ser Thr Thr
450 455 460
Gly Val Ser His Tyr Ala Thr Asp Ser Trp Asp Gly Val Val Glu Asp
465 470 475 480
Lys Gln Thr Gln Glu Ser Val Thr Gln Ile Glu Gln Ile Glu Val Gly
485 490 495
Pro Leu Val Thr Ser Met Glu Ile Leu Lys His Ile Pro Ser Lys Glu
500 505 510
Phe Pro Val Thr Glu Thr Pro Leu Val Thr Ala Arg Met Ile Leu Glu
515 520 525
Ser Lys Thr Glu Lys Lys Met Val Ser Thr Val Ser Glu Leu Val Thr
530 535 540
Thr Gly His Tyr Gly Phe Thr Leu Gly Glu Glu Asp Asp Glu Asp Arg
545 550 555 560
Thr Leu Thr Val Gly Ser Asp Glu Ser Thr Leu Ile Phe Asp Gln Ile
565 570 575
Pro Glu Val Ile Thr Val Ser Lys Thr Ser Glu Asp Thr Ile His Thr
580 585 590
His Leu Glu Asp Leu Glu Ser Val Ser Ala Ser Thr Thr Val Ser Pro
595 600 605
Leu Ile Met Pro Asp Asn Asn Gly Ser Ser Met Asp Asp Trp Glu Glu
610 615 620
Arg Gln Thr Ser Gly Arg Ile Thr Glu Glu Phe Leu Gly Lys Tyr Leu
625 630 635 640
Ser Thr Thr Pro Phe Pro Ser Gln His Arg Thr Glu Ile Glu Leu Phe
645 650 655
Pro Tyr Ser Gly Asp Lys Ile Leu Val Glu Gly Ile Ser Thr Val Ile
660 665 670
Tyr Pro Ser Leu Gln Thr Glu Met Thr His Arg Arg Glu Arg Thr Glu
675 680 685
Thr Leu Ile Pro Glu Met Arg Thr Asp Thr Tyr Thr Asp Glu Ile Gln
690 695 700
Glu Glu Ile Thr Lys Ser Pro Phe Met Gly Lys Thr Glu Glu Glu Val
705 710 715 720
Phe Ser Gly Met Lys Leu Ser Thr Ser Leu Ser Glu Pro Ile His Val
725 730 735
Thr Glu Ser Ser Val Glu Met Thr Lys Ser Phe Asp Phe Pro Thr Leu
740 745 750
Ile Thr Lys Leu Ser Ala Glu Pro Thr Glu Val Arg Asp Met Glu Glu
755 760 765
Asp Phe Thr Ala Thr Pro Gly Thr Thr Lys Tyr Asp Glu Asn Ile Thr
770 775 780
Thr Val Leu Leu Ala His Gly Thr Leu Ser Val Glu Ala Ala Thr Val
785 790 795 800
Ser Lys Trp Ser Trp Asp Glu Asp Asn Thr Thr Ser Lys Pro Leu Glu
805 810 815
Ser Thr Glu Pro Ser Ala Ser Ser Lys Leu Pro Pro Ala Leu Leu Thr
820 825 830
Thr Val Gly Met Asn Gly Lys Asp Lys Asp Ile Pro Ser Phe Thr Glu
835 840 845
Asp Gly Ala Asp Glu Phe Thr Leu Ile Pro Asp Ser Thr Gln Lys Gln
850 855 860
Leu Glu Glu Val Thr Asp Glu Asp Ile Ala Ala His Gly Lys Phe Thr
865 870 875 880
Ile Arg Phe Gln Pro Thr Thr Ser Thr Gly Ile Ala Glu Lys Ser Thr
885 890 895
Leu Arg Asp Ser Thr Thr Glu Glu Lys Val Pro Pro Ile Thr Ser Thr
900 905 910
Glu Gly Gln Val Tyr Ala Thr Met Glu Gly Ser Ala Leu Gly Glu Val
915 920 925
Glu Asp Val Asp Leu Ser Lys Pro Val Ser Thr Val Pro Gln Phe Ala
930 935 940
His Thr Ser Glu Val Glu Gly Leu Ala Phe Val Ser Tyr Ser Ser Thr
945 950 955 960
Gln Glu Pro Thr Thr Tyr Val Asp Ser Ser His Thr Ile Pro Leu Ser
965 970 975
Val Ile Pro Lys Thr Asp Trp Gly Val Leu Val Pro Ser Val Pro Ser
980 985 990
Glu Asp Glu Val Leu Gly Glu Pro Ser Gln Asp Ile Leu Val Ile Asp
995 1000 1005
Gln Thr Arg Leu Glu Ala Thr Ile Ser Pro Glu Thr Met Arg Thr
1010 1015 1020
Thr Lys Ile Thr Glu Gly Thr Thr Gln Glu Glu Phe Pro Trp Lys
1025 1030 1035
Glu Gln Thr Ala Glu Lys Pro Val Pro Ala Leu Ser Ser Thr Ala
1040 1045 1050
Trp Thr Pro Lys Glu Ala Val Thr Pro Leu Asp Glu Gln Glu Gly
1055 1060 1065
Asp Gly Ser Ala Tyr Thr Val Ser Glu Asp Glu Leu Leu Thr Gly
1070 1075 1080
Ser Glu Arg Val Pro Val Leu Glu Thr Thr Pro Val Gly Lys Ile
1085 1090 1095
Asp His Ser Val Ser Tyr Pro Pro Gly Ala Val Thr Glu His Lys
1100 1105 1110
Val Lys Thr Asp Glu Val Val Thr Leu Thr Pro Arg Ile Gly Pro
1115 1120 1125
Lys Val Ser Leu Ser Pro Gly Pro Glu Gln Lys Tyr Glu Thr Glu
1130 1135 1140
Gly Ser Ser Thr Thr Gly Phe Thr Ser Ser Leu Ser Pro Phe Ser
1145 1150 1155
Thr His Ile Thr Gln Leu Met Glu Glu Thr Thr Thr Glu Lys Thr
1160 1165 1170
Ser Leu Glu Asp Ile Asp Leu Gly Ser Gly Leu Phe Glu Lys Pro
1175 1180 1185
Lys Ala Thr Glu Leu Ile Glu Phe Ser Thr Ile Lys Val Thr Val
1190 1195 1200
Pro Ser Asp Ile Thr Thr Ala Phe Ser Ser Val Asp Arg Leu His
1205 1210 1215
Thr Thr Ser Ala Phe Lys Pro Ser Ser Ala Ile Thr Lys Lys Pro
1220 1225 1230
Pro Leu Ile Asp Arg Glu Pro Gly Glu Glu Thr Thr Ser Asp Met
1235 1240 1245
Val Ile Ile Gly Glu Ser Thr Ser His Val Pro Pro Thr Thr Lau
1250 1255 1260
Glu Asp Ile Val Ala Lys Glu Thr Glu Thr Asp Ile Asp Arg Glu
1265 1270 1275
Tyr Phe Thr Thr Ser Ser Pro Pro Ala Thr Gln Pro Thr Arg Pro
1280 1285 1290
Pro Thr Val Glu Asp Lys Glu Ala Phe Gly Pro Gln Ala Leu Ser
1295 1300 1305
Thr Pro Gln Pro Pro Ala Ser Thr Lys Phe His Pro Asp Ile Asn
1310 1315 1320
Val Tyr Ile Ile Glu Val Arg Glu Asn Lys Thr Gly Arg Met Ser
1325 1330 1335
Asp Leu Ser Val Ile Gly His Pro Ile Asp Ser Glu Ser Lys Glu
1340 1345 1350
Asp Glu Pro Cys Ser Glu Glu Thr Asp Pro Val His Asp Leu Met
1355 1360 1365
Ala Glu Ile Leu Pro Glu Phe Pro Asp Ile Ile Glu Ile Asp Leu
1370 1375 1380
Tyr His Ser Glu Glu Asn Glu Glu Glu Glu Glu Glu Cys Ala Asn
1385 1390 1395
Ala Thr Asp Val Thr Thr Thr Pro Ser Val Gln Tyr Ile Asn Gly
1400 1405 1410
Lys His Leu Val Thr Thr Val Pro Lys Asp Pro Glu Ala Ala Glu
1415 1420 1425
Ala Arg Arg Gly Gln Phe Glu Ser Val Ala Pro Ser Gln Asn Phe
1430 1435 1440
Ser Asp Ser Ser Glu Ser Asp Thr His Pro Phe Val Ile Ala Lys
1445 1450 1455
Thr Glu Leu Ser Thr Ala Val Gln Pro Asn Glu Ser Thr Glu Thr
1460 1465 1470
Thr Glu Ser Leu Glu Val Thr Trp Lys Pro Glu Thr Tyr Pro Glu
1475 1480 1485
Thr Ser Glu His Phe Ser Gly Gly Glu Pro Asp Val Phe Pro Thr
1490 1495 1500
Val Pro Phe His Glu Glu Phe Glu Ser Gly Thr Ala Lys Lys Gly
1505 1510 1515
Ala Glu Ser Val Thr Glu Arg Asp Thr Glu Val Gly His Gln Ala
1520 1525 1530
His Glu His Thr Glu Pro Val Ser Leu Phe Pro Glu Glu Ser Ser
1535 1540 1545
Gly Glu Ile Ala Ile Asp Gln Glu Ser Gln Lys Ile Ala Phe Ala
1550 1555 1560
Arg Ala Thr Glu Val Thr Phe Gly Glu Glu Val Glu Lys Ser Thr
1565 1570 1575
Ser Val Thr Tyr Thr Pro Thr Ile Val Pro Ser Ser Ala Ser Ala
1580 1585 1590
Tyr Val Ser Glu Glu Glu Ala Val Thr Leu Ile Gly Asn Pro Trp
1595 1600 1605
Pro Asp Asp Leu Leu Ser Thr Lys Glu Ser Trp Val Glu Ala Thr
1610 1615 1620
Pro Arg Gln Val Val Glu Leu Ser Gly Ser Ser Ser Ile Pro Ile
1625 1630 1635
Thr Glu Gly Ser Gly Glu Ala Glu Glu Asp Glu Asp Thr Met Phe
1640 1645 1650
Thr Met Val Thr Asp Leu Ser Gln Arg Asn Thr Thr Asp Thr Leu
1655 1660 1665
Ile Thr Leu Asp Thr Ser Arg Ile Ile Thr Glu Ser Phe Phe Glu
1670 1675 1680
Val Pro Ala Thr Thr Ile Tyr Pro Val Ser Glu Gln Pro Ser Ala
1685 1690 1695
Lys Val Val Pro Thr Lys Phe Val Ser Glu Thr Asp Thr Ser Glu
1700 1705 1710
Trp Ile Ser Ser Thr Thr Val Glu Glu Lys Lys Arg Lys Glu Glu
1715 1720 1725
Glu Gly Thr Thr Gly Thr Ala Ser Thr Phe Glu Val Tyr Ser Ser
1730 1735 1740
Thr Gln Arg Ser Asp Gln Leu Ile Leu Pro Phe Glu Leu Glu Ser
1745 1750 1755
Pro Asn Val Ala Thr Ser Ser Asp Ser Gly Thr Arg Lys Ser Phe
1760 1765 1770
Met Ser Leu Thr Thr Pro Thr Gln Ser Glu Arg Glu Met Thr Asp
1775 1780 1785
Ser Thr Pro Val Phe Thr Glu Thr Asn Thr Leu Glu Asn Leu Gly
1790 1795 1800
Ala Gln Thr Thr Glu His Ser Ser Ile His Gln Pro Gly Val Gln
1805 1810 1815
Glu Gly Leu Thr Thr Leu Pro Arg Ser Pro Ala Ser Val Phe Met
1820 1825 1830
Glu Gln Gly Ser Gly Glu Ala Ala Ala Asp Pro Glu Thr Thr Thr
1835 1840 1845
Val Ser Ser Phe Ser Leu Asn Val Glu Tyr Ala Ile Gln Ala Glu
1850 1855 1860
Lys Glu Val Ala Gly Thr Leu Ser Pro His Val Glu Thr Thr Phe
1865 1870 1875
Ser Thr Glu Pro Thr Gly Leu Val Leu Ser Thr Val Met Asp Arg
1880 1885 1890
Val Val Ala Glu Asn Ile Thr Gln Thr Ser Arg Glu Ile Val Ile
1895 1900 1905
Ser Glu Arg Leu Gly Glu Pro Asn Tyr Gly Ala Glu Ile Arg Gly
1910 1915 1920
Phe Ser Thr Gly Phe Pro Leu Glu Glu Asp Phe Ser Gly Asp Phe
1925 1930 1935
Arg Glu Tyr Ser Thr Val Ser His Pro Ile Ala Lys Glu Glu Thr
1940 1945 1950
Val Met Met Glu Gly Ser Gly Asp Ala Ala Phe Arg Asp Thr Gln
1955 1960 1965
Thr Ser Pro Ser Thr Val Pro Thr Ser Val His Ile Ser His Ile
1970 1975 1980
Ser Asp Ser Glu Gly Pro Ser Ser Thr Met Val Ser Thr Ser Ala
1985 1990 1995
Phe Pro Trp Glu Glu Phe Thr Ser Ser Ala Glu Gly Ser Gly Glu
2000 2005 2010
Gln Leu Val Thr Val Ser Ser Ser Val Val Pro Val Leu Pro Ser
2015 2020 2025
Ala Val Gln Lys Phe Ser Gly Thr Ala Ser Ser Ile Ile Asp Glu
2030 2035 2040
Gly Leu Gly Glu Val Gly Thr Val Asn Glu Ile Asp Arg Arg Ser
2045 2050 2055
Thr Ile Leu Pro Thr Ala Glu Val Glu Gly Thr Lys Ala Pro Val
2060 2065 2070
Glu Lys Glu Glu Val Lys Val Ser Gly Thr Val Ser Thr Asn Phe
2075 2080 2085
Pro Gln Thr Ile Glu Pro Ala Lys Leu Trp Ser Arg Gln Glu Val
2090 2095 2100
Asn Pro Val Arg Gln Glu Ile Glu Ser Glu Thr Thr Ser Glu Glu
2105 2110 2115
Gln Ile Gln Glu Glu Lys Ser Phe Glu Ser Pro Gln Asn Ser Pro
2120 2125 2130
Ala Thr Glu Gln Thr Ile Phe Asp Ser Gln Thr Phe Thr Glu Thr
2135 2140 2145
Glu Leu Lys Thr Thr Asp Tyr Ser Val Leu Thr Thr Lys Lys Thr
2150 2155 2160
Tyr Ser Asp Asp Lys Glu Met Lys Glu Glu Asp Thr Ser Leu Val
2165 2170 2175
Asn Met Ser Thr Pro Asp Pro Asp Ala Asn Gly Leu Glu Ser Tyr
2180 2185 2190
Thr Thr Leu Pro Glu Ala Thr Glu Lys Ser His Phe Phe Leu Ala
2195 2200 2205
Thr Ala Leu Val Thr Glu Ser Ile Pro Ala Glu His Val Val Thr
2210 2215 2220
Asp Ser Pro Ile Lys Lys Glu Glu Ser Thr Lys His Phe Pro Lys
2225 2230 2235
Gly Met Arg Pro Thr Ile Gln Glu Ser Asp Thr Glu Leu Leu Phe
2240 2245 2250
Ser Gly Leu Gly Ser Gly Glu Glu Val Leu Pro Thr Leu Pro Thr
2255 2260 2265
Glu Ser Val Asn Phe Thr Glu Val Glu Gln Ile Asn Asn Thr Leu
2270 2275 2280
Tyr Pro His Thr Ser Gln Val Glu Ser Thr Ser Ser Asp Lys Ile
2285 2290 2295
Glu Asp Phe Asn Arg Met Glu Asn Val Ala Lys Glu Val Gly Pro
2300 2305 2310
Leu Val Ser Gln Thr Asp Ile Phe Glu Gly Ser Gly Ser Val Thr
2315 2320 2325
Ser Thr Thr Leu Ile Glu Ile Leu Ser Asp Thr Gly Ala Glu Gly
2330 2335 2340
Pro Thr Val Ala Pro Leu Pro Phe Ser Thr Asp Ile Gly His Pro
2345 2350 2355
Gln Asn Gln Thr Val Arg Trp Ala Glu Glu Ile Gln Thr Ser Arg
2360 2365 2370
Pro Gln Thr Ile Thr Glu Gln Asp Ser Asn Lys Asn Ser Ser Thr
2375 2380 2385
Ala Glu Ile Asn Glu Thr Thr Thr Ser Ser Thr Asp Phe Leu Ala
2390 2395 2400
Arg Ala Tyr Gly Phe Glu Met Ala Lys Glu Phe Val Thr Ser Ala
2405 2410 2415
Pro Lys Pro Ser Asp Leu Tyr Tyr Glu Pro Ser Gly Glu Gly Ser
2420 2425 2430
Gly Glu Val Asp Ile Val Asp Ser Phe His Thr Ser Ala Thr Thr
2435 2440 2445
Gln Ala Thr Arg Gln Glu Ser Ser Thr Thr Phe Val Ser Asp Gly
2450 2455 2460
Ser Leu Glu Lys His Pro Glu Val Pro Ser Ala Lys Ala Val Thr
2465 2470 2475
Ala Asp Gly Phe Pro Thr Val Ser Val Met Leu Pro Leu His Ser
2480 2485 2490
Glu Gln Asn Lys Ser Ser Pro Asp Pro Thr Ser Thr Leu Ser Asn
2495 2500 2505
Thr Val Ser Tyr Glu Arg Ser Thr Asp Gly Ser Phe Gln Asp Arg
2510 2515 2520
Phe Arg Glu Phe Glu Asp Ser Thr Leu Lys Pro Asn Arg Lys Lys
2525 2530 2535
Pro Thr Glu Asn Ile Ile Ile Asp Leu Asp Lys Glu Asp Lys Asp
2540 2545 2550
Leu Ile Leu Thr Ile Thr Glu Ser Thr Ile Leu Glu Ile Leu Pro
2555 2560 2565
Glu Leu Thr Ser Asp Lys Asn Thr Ile Ile Asp Ile Asp His Thr
2570 2575 2580
Lys Pro Val Tyr Glu Asp Ile Leu Gly Met Gln Thr Asp Ile Asp
2585 2590 2595
Thr Glu Val Pro Ser Glu Pro His Asp Ser Asn Asp Glu Ser Asn
2600 2605 2610
Asp Asp Ser Thr Gln Val Gln Glu Ile Tyr Glu Ala Ala Val Asn
2615 2620 2625
Leu Ser Leu Thr Glu Glu Thr Phe Glu Gly Ser Ala Asp Val Leu
2630 2635 2640
Ala Ser Tyr Thr Gln Ala Thr His Asp Glu Ser Met Thr Tyr Glu
2645 2650 2655
Asp Arg Ser Gln Leu Asp His Met Gly Phe His Phe Thr Thr Gly
2660 2665 2670
Ile Pro Ala Pro Ser Thr Glu Thr Glu Leu Asp Val Leu Leu Pro
2675 2680 2685
Thr Ala Thr Ser Leu Pro Ile Pro Arg Lys Ser Ala Thr Val Ile
2690 2695 2700
Pro Glu Ile Glu Gly Ile Lys Ala Glu Ala Lys Ala Leu Asp Asp
2705 2710 2715
Met Phe Glu Ser Ser Thr Leu Ser Asp Gly Gln Ala Ile Ala Asp
2720 2725 2730
Gln Ser Glu Ile Ile Pro Thr Leu Gly Gln Phe Glu Arg Thr Gln
2735 2740 2745
Glu Glu Tyr Glu Asp Lys Lys His Ala Gly Pro Ser Phe Gln Pro
2750 2755 2760
Glu Phe Ser Ser Gly Ala Glu Glu Ala Leu Val Asp His Thr Pro
2765 2770 2775
Tyr Leu Ser Ile Ala Thr Thr His Leu Met Asp Gln Ser Val Thr
2780 2785 2790
Glu Val Pro Asp Val Met Glu Gly Ser Asn Pro Pro Tyr Tyr Thr
2795 2800 2805
Asp Thr Thr Leu Ala Val Ser Thr Phe Ala Lys Leu Ser Ser Gln
2810 2815 2820
Thr Pro Ser Ser Pro Leu Thr Ile Tyr Ser Gly Ser Glu Ala Ser
2825 2830 2835
Gly His Thr Glu Ile Pro Gln Pro Ser Ala Leu Pro Gly Ile Asp
2840 2845 2850
Val Gly Ser Ser Val Met Ser Pro Gln Asp Ser Phe Lys Glu Ile
2855 2860 2865
His Val Asn Ile Glu Ala Thr Phe Lys Pro Ser Ser Glu Glu Tyr
2870 2875 2880
Leu His Ile Thr Glu Pro Pro Ser Leu Ser Pro Asp Thr Lys Leu
2885 2890 2895
Glu Pro Ser Glu Asp Asp Gly Lys Pro Glu Leu Leu Glu Glu Met
2900 2905 2910
Glu Ala Ser Pro Thr Glu Leu Ile Ala Val Glu Gly Thr Glu Ile
2915 2920 2925
Leu Gln Asp Phe Gln Asn Lys Thr Asp Gly Gln Val Ser Gly Glu
2930 2935 2940
Ala Ile Lys Met Phe Pro Thr Ile Lys Thr Pro Glu Ala Gly Thr
2945 2950 2955
Val Ile Thr Thr Ala Asp Glu Ile Glu Leu Glu Gly Ala Thr Gln
2960 2965 2970
Trp Pro His Ser Thr Ser Ala Ser Ala Thr Tyr Gly Val Glu Ala
2975 2980 2985
Gly Val Val Pro Trp Leu Ser Pro Gln Thr Ser Glu Arg Pro Thr
2990 2995 3000
Leu Ser Ser Ser Pro Glu Ile Asn Pro Glu Thr Gln Ala Ala Leu
3005 3010 3015
Ile Arg Gly Gln Asp Ser Thr Ile Ala Ala Ser Glu Gln Gln Val
3020 3025 3030
Ala Ala Arg Ile Leu Asp Ser Asn Asp Gln Ala Thr Val Asn Pro
3035 3040 3045
Val Glu Phe Asn Thr Glu Val Ala Thr Pro Pro Phe Ser Leu Leu
3050 3055 3060
Glu Thr Ser Asn Glu Thr Asp Phe Leu Ile Gly Ile Asn Glu Glu
3065 3070 3075
Ser Val Glu Gly Thr Ala Ile Tyr Leu Pro Gly Pro Asp Arg Cys
3080 3085 3090
Lys Met Asn Pro Cys Leu Asn Gly Gly Thr Cys Tyr Pro Thr Glu
3095 3100 3105
Thr Ser Tyr Val Cys Thr Cys Val Pro Gly Tyr Ser Gly Asp Gln
3110 3115 3120
Cys Glu Leu Asp Phe Asp Glu Cys His Ser Asn Pro Cys Arg Asn
3125 3130 3135
Gly Ala Thr Cys Val Asp Gly Phe Asn Thr Phe Arg Cys Leu Cys
3140 3145 3150
Leu Pro Ser Tyr Val Gly Ala Leu Cys Glu Gln Asp Thr Glu Thr
3155 3160 3165
Cys Asp Tyr Gly Trp His Lys Phe Gln Gly Gln Cys Tyr Lys Tyr
3170 3175 3180
Phe Ala His Arg Arg Thr Trp Asp Ala Ala Glu Arg Glu Cys Arg
3185 3190 3195
Leu Gln Gly Ala His Leu Thr Ser Ile Leu Ser His Glu Glu Gln
3200 3205 3210
Met Phe Val Asn Arg Val Gly His Asp Tyr Gln Trp Ile Gly Leu
3215 3220 3225
Asn Asp Lys Met Phe Glu His Asp Phe Arg Trp Thr Asp Gly Ser
3230 3235 3240
Thr Leu Gln Tyr Glu Asn Trp Arg Pro Asn Gln Pro Asp Ser Phe
3245 3250 3255
Phe Ser Ala Gly Glu Asp Cys Val Val Ile Ile Trp His Glu Asn
3260 3265 3270
Gly Gln Trp Asn Asp Val Pro Cys Asn Tyr His Leu Thr Tyr Thr
3275 3280 3285
Cys Lys Lys Gly Thr Val Ala Cys Gly Gln Pro Pro Val Val Glu
3290 3295 3300
Asn Ala Lys Thr Phe Gly Lys Met Lys Pro Arg Tyr Glu Ile Asn
3305 3310 3315
Ser Leu Ile Arg Tyr His Cys Lys Asp Gly Phe Ile Gln Arg His
3320 3325 3330
Leu Pro Thr Ile Arg Cys Leu Gly Asn Gly Arg Trp Ala Ile Pro
3335 3340 3345
Lys Ile Thr Cys Met Asn Pro Ser Ala Tyr Gln Arg Thr Tyr Ser
3350 3355 3360
Met Lys Tyr Phe Lys Asn Ser Ser Ser Ala Lys Asp Asn Ser Ile
3365 3370 3375
Asn Thr Ser Lys His Asp His Arg Trp Ser Arg Arg Trp Gln Glu
3380 3385 3390
Ser Arg Arg
3395
<210>2
<211>338
<212>PRT
<213>人
<400>2
Met Ser Leu Ser Ala Phe Thr Leu Phe Leu Ala Leu Ile Gly Gly Thr
1 5 10 15
Ser Gly Gln Tyr Tyr Asp Tyr Asp Phe Pro Leu Ser Ile Tyr Gly Gln
20 25 30
Ser Ser Pro Asn Cys Ala Pro Glu Cys Asn Cys Pro Glu Ser Tyr Pro
35 40 45
Ser Ala Met Tyr Cys Asp Glu Leu Lys Leu Lys Ser Val Pro Met Val
50 55 60
Pro Pro Gly Ile Lys Tyr Leu Tyr Leu Arg Asn Asn Gln Ile Asp His
65 70 75 80
Ile Asp Glu Lys Ala Phe Glu Asn Val Thr Asp Leu Gln Trp Leu Ile
85 90 95
Leu Asp His Asn Leu Leu Glu Asn Ser Lys Ile Lys Gly Arg Val Phe
100 105 110
Ser Lys Leu Lys Gln Leu Lys Lys Leu His Ile Asn His Asn Asn Leu
115 120 125
Thr Glu Ser Val Gly Pro Leu Pro Lys Ser Leu Glu Asp Leu Gln Leu
130 135 140
Thr His Asn Lys Ile Thr Lys Leu Gly Ser Phe Glu Gly Leu Val Asn
145 150 155 160
Leu Thr Phe Ile His Leu Gln His Asn Arg Leu Lys Glu Asp Ala Val
165 170 175
Ser Ala Ala Phe Lys Gly Leu Lys Ser Leu Glu Tyr Leu Asp Leu Ser
180 185 190
Phe Asn Gln Ile Ala Arg Leu Pro Ser Gly Leu Pro Val Ser Leu Leu
195 200 205
Thr Leu Tyr Leu Asp Asn Asn Lys Ile Ser Asn Ile Pro Asp Glu Tyr
210 215 220
Phe Lys Arg Phe Asn Ala Leu Gln Tyr Leu Arg Leu Ser His Asn Glu
225 230 235 240
Leu Ala Asp Ser Gly Ile Pro Gly Asn Ser Phe Asn Val Ser Ser Leu
245 250 255
Val Glu Leu Asp Leu Ser Tyr Asn Lys Leu Lys Asn Ile Pro Thr Val
260 265 270
Asn Glu Asn Leu Glu Asn Tyr Tyr Leu Glu Val Asn Gln Leu Glu Lys
275 280 285
Phe Asp Ile Lys Ser Phe Cys Lys Ile Leu Gly Pro Leu Ser Tyr Ser
290 295 300
Lys Ile Lys His Leu Arg Leu Asp Gly Asn Arg Ile Ser Glu Thr Ser
305 310 315 320
Leu Pro Pro Asp Met Tyr Glu Cys Leu Arg Val Ala Asn Glu Val Thr
325 330 335
Leu Asn
<210>3
<211>4391
<212>PRT
<213>人
<400>3
Met Gly Trp Arg Ala Pro Gly Ala Leu Leu Leu Ala Leu Leu Leu His
1 5 10 15
Gly Arg Leu Leu Ala Val Thr His Gly Leu Arg Ala Tyr Asp Gly Leu
20 25 30
Ser Leu Pro Glu Asp Ile Glu Thr Val Thr Ala Ser Gln Met Arg Trp
35 40 45
Thr His Ser Tyr Leu Ser Asp Asp Glu Asp Met Leu Ala Asp Ser Ile
50 55 60
Ser Gly Asp Asp Leu Gly Ser Gly Asp Leu Gly Ser Gly Asp Phe Gln
65 70 75 80
Met Val Tyr Phe Arg Ala Leu Val Asn Phe Thr Arg Ser Ile Glu Tyr
85 90 95
Ser Pro Gln Leu Glu Asp Ala Gly Ser Arg Glu Phe Arg Glu Val Ser
100 105 110
Glu Ala Val Val Asp Thr Leu Glu Ser Glu Tyr Leu Lys Ile Pro Gly
115 120 125
Asp Gln Val Val Ser Val Val Phe Ile Lys Glu Leu Asp Gly Trp Val
130 135 140
Phe Val Glu Leu Asp Val Gly Ser Glu Gly Asn Ala Asp Gly Ala Gln
145 150 155 160
Ile Gln Glu Met Leu Leu Arg Val Ile Ser Ser Gly Ser Val Ala Ser
165 170 175
Tyr Val Thr Ser Pro Gln Gly Phe Gln Phe Arg Arg Leu Gly Thr Val
180 185 190
Pro Gln Phe Pro Arg Ala Cys Thr Glu Ala Glu Phe Ala Cys His Ser
195 200 205
Tyr Asn Glu Cys Val Ala Leu Glu Tyr Arg Cys Asp Arg Arg Pro Asp
210 215 220
Cys Arg Asp Met Ser Asp Glu Leu Asn Cys Glu Glu Pro Val Leu Gly
225 230 235 240
Ile Ser Pro Thr Phe Ser Leu Leu Val Glu Thr Thr Ser Leu Pro Pro
245 250 255
Arg Pro Glu Thr Thr Ile Met Arg Gln Pro Pro Val Thr His Ala Pro
260 265 270
Gln Pro Leu Leu Pro Gly Ser Val Arg Pro Leu Pro Cys Gly Pro Gln
275 280 285
Glu Ala Ala Cys Arg Asn Gly His Cys Ile Pro Arg Asp Tyr Leu Cys
290 295 300
Asp Gly Gln Glu Asp Cys Glu Asp Gly Ser Asp Glu Leu Asp Cys Gly
305 310 315 320
Pro Pro Pro Pro Cys Glu Pro Asn Glu Phe Pro Cys Gly Asn Gly His
325 330 335
Cys Ala Leu Lys Leu Trp Arg Cys Asp Gly Asp Phe Asp Cys Glu Asp
340 345 350
Arg Thr Asp Glu Ala Asn Cys Pro Thr Lys Arg Pro Glu Glu Val Cys
355 360 365
Gly Pro Thr Gln Phe Arg Cys Val Ser Thr Asn Met Cys Ile Pro Ala
370 375 380
Ser Phe His Cys Asp Glu Glu Ser Asp Cys Pro Asp Arg Ser Asp Glu
385 390 395 400
Phe Gly Cys Met Pro Pro Gln Val Val Thr Pro Pro Arg Glu Ser Ile
405 410 415
Gln Ala Ser Arg Gly Gln Thr Val Thr Phe Thr Cys Val Ala Ile Gly
420 425 430
Val Pro Thr Pro Ile Ile Asn Trp Arg Leu Asn Trp Gly His Ile Pro
435 440 445
Ser His Pro Arg Val Thr Val Thr Ser Glu Gly Gly Arg Gly Thr Leu
450 455 460
Ile Ile Arg Asp Val Lys Glu Ser Asp Gln Gly Ala Tyr Thr Cys Glu
465 470 475 480
Ala Met Asn Ala Arg Gly Met Val Phe Gly Ile Pro Asp Gly Val Leu
485 490 495
Glu Leu Val Pro Gln Arg Gly Pro Cys Pro Asp Gly His Phe Tyr Leu
500 505 510
Glu His Ser Ala Ala Cys Leu Pro Cys Phe Cys Phe Gly Ile Thr Ser
515 520 525
Val Cys Gln Ser Thr Arg Arg Phe Arg Asp Gln Ile Arg Leu Arg Phe
530 535 540
Asp Gln Pro Asp Asp Phe Lys Gly Val Asn Val Thr Met Pro Ala Gln
545 550 555 560
Pro Gly Thr Pro Pro Leu Ser Ser Thr Gln Leu Gln Ile Asp Pro Ser
565 570 575
Leu His Glu Phe Gln Leu Val Asp Leu Ser Arg Arg Phe Leu Val His
580 585 590
Asp Ser Phe Trp Ala Leu Pro Glu Gln Phe Leu Gly Asn Lys Val Asp
595 600 605
Ser Tyr Gly Gly Ser Leu Arg Tyr Asn Val Arg Tyr Glu Leu Ala Arg
610 615 620
Gly Met Leu Glu Pro Val Gln Arg Pro Asp Val Val Leu Val Gly Ala
625 630 635 640
Gly Tyr Arg Leu Leu Ser Arg Gly His Thr Pro Thr Gln Pro Gly Ala
645 650 655
Leu Asn Gln Arg Gln Val Gln Phe Ser Glu Glu His Trp Val His Glu
660 665 670
Ser Gly Arg Pro Val Gln Arg Ala Glu Leu Leu Gln Val Leu Gln Ser
675 680 685
Leu Glu Ala Val Leu Ile Gln Thr Val Tyr Asn Thr Lys Met Ala Ser
690 695 700
Val Gly Leu Ser Asp Ile Ala Met Asp Thr Thr Val Thr His Ala Thr
705 710 715 720
Ser His Gly Arg Ala His Ser Val Glu Glu Cys Arg Cys Pro Ile Gly
725 730 735
Tyr Ser Gly Leu Ser Cys Glu Ser Cys Asp Ala His Phe Thr Arg Val
740 745 750
Pro Gly Gly Pro Tyr Leu Gly Thr Cys Ser Gly Cys Ser Cys Asn Gly
755 760 765
His Ala Ser Ser Cys Asp Pro Val Tyr Gly His Cys Leu Asn Cys Gln
770 775 780
His Asn Thr Glu Gly Pro Gln Cys Asn Lys Cys Lys Ala Gly Phe Phe
785 790 795 800
Gly Asp Ala Met Lys Ala Thr Ala Thr Ser Cys Arg Pro Cys Pro Cys
805 810 815
Pro Tyr Ile Asp Ala Ser Arg Arg Phe Ser Asp Thr Cys Phe Leu Asp
820 825 830
Thr Asp Gly Gln Ala Thr Cys Asp Ala Cys Ala Pro Gly Tyr Thr Gly
835 840 845
Arg Arg Cys Glu Ser Cys Ala Pro Gly Tyr Glu Gly Asn Pro Ile Gln
850 855 860
Pro Gly Gly Lys Cys Arg Pro Val Asn Gln Glu Ile Val Arg Cys Asp
865 870 875 880
Glu Arg Gly Ser Met Gly Thr Ser Gly Glu Ala Cys Arg Cys Lys Asn
885 890 895
Asn Val Val Gly Arg Leu Cys Asn Glu Cys Ala Asp Gly Ser Phe His
900 905 910
Leu Ser Thr Arg Asn Pro Asp Gly Cys Leu Lys Cys Phe Cys Met Gly
915 920 925
Val Ser Arg His Cys Thr Ser Ser Ser Trp Ser Arg Ala Gln Leu His
930 935 940
Gly Ala Ser Glu Glu Pro Gly His Phe Ser Leu Thr Asn Ala Ala Ser
945 950 955 960
Thr His Thr Thr Asn Glu Gly Ile Phe Ser Pro Thr Pro Gly Glu Leu
965 970 975
Gly Phe Ser Ser Phe His Arg Leu Leu Ser Gly Pro Tyr Phe Trp Ser
980 985 990
Leu Pro Ser Arg Phe Leu Gly Asp Lys Val Thr Ser Tyr Gly Gly Glu
995 1000 1005
Leu Arg Phe Thr Val Thr Gln Arg Ser Gln Pro Gly Ser Thr Pro
1010 1015 1020
Leu His Gly Gln Pro Leu Val Val Leu Gln Gly Asn Asn Ile Ile
1025 1030 1035
Leu Glu His His Val Ala Gln Glu Pro Ser Pro Gly Gln Pro Ser
1040 1045 1050
Thr Phe Ile Val Pro Phe Arg Glu Gln Ala Trp Gln Arg Pro Asp
1055 1060 1065
Gly Gln Pro Ala Thr Arg Glu His Leu Leu Met Ala Leu Ala Gly
1070 1075 1080
Ile Asp Thr Leu Leu Ile Arg Ala Ser Tyr Ala Gln Gln Pro Ala
1085 1090 1095
Glu Ser Arg Val Ser Gly Ile Ser Met Asp Val Ala Val Pro Glu
1100 1105 1110
Glu Thr Gly Gln Asp Pro Ala Leu Glu Val Glu Gln Cys Ser Cys
1115 1120 1125
Pro Pro Gly Tyr Arg Gly Pro Ser Cys Gln Asp Cys Asp Thr Gly
1130 1135 1140
Tyr Thr Arg Thr Pro Ser Gly Leu Tyr Leu Gly Thr Cys Glu Arg
1145 1150 1155
Cys Ser Cys His Gly His Ser Glu Ala Cys Glu Pro Glu Thr Gly
1160 1165 1170
Ala Cys Gln Gly Cys Gln His His Thr Glu Gly Pro Arg Cys Glu
1175 1180 1185
Gln Cys Gln Pro Gly Tyr Tyr Gly Asp Ala Gln Arg Gly Thr Pro
1190 1195 1200
Gln Asp Cys Gln Leu Cys Pro Cys Tyr Gly Asp Pro Ala Ala Gly
1205 1210 1215
Gln Ala Ala His Thr Cys Phe Leu Asp Thr Asp Gly His Pro Thr
1220 1225 1230
Cys Asp Ala Cys Ser Pro Gly His Ser Gly Arg His Cys Glu Arg
1235 1240 1245
Cys Ala Pro Gly Tyr Tyr Gly Asn Pro Ser Gln Gly Gln Pro Cys
1250 1255 1260
Gln Arg Asp Ser Gln Val Pro Gly Pro Ile Gly Cys Asn Cys Asp
1265 1270 1275
Pro Gln Gly Ser Val Ser Ser Gln Cys Asp Ala Ala Gly Gln Cys
1280 1285 1290
Gln Cys Lys Ala Gln Val Glu Gly Leu Thr Cys Ser His Cys Arg
1295 1300 1305
Pro His His Phe His Leu Ser Ala Ser Asn Pro Asp Gly Cys Leu
1310 1315 1320
Pro Cys Phe Cys Met Gly Ile Thr Gln Gln Cys Ala Ser Ser Ala
1325 1330 1335
Tyr Thr Arg His Leu Ile Ser Thr His Phe Ala Pro Gly Asp Phe
1340 1345 1350
Gln Gly Phe Ala Leu Val Asn Pro Gln Arg Asn Ser Arg Leu Thr
1355 1360 1365
Gly Glu Phe Thr Val Glu Pro Val Pro Glu Gly Ala Gln Leu Ser
1370 1375 1380
Phe Gly Asn Phe Ala Gln Leu Gly His Glu Ser Phe Tyr Trp Gln
1385 1390 1395
Leu Pro Glu Thr Tyr Gln Gly Asp Lys Val Ala Ala Tyr Gly Gly
1400 1405 1410
Lys Leu Arg Tyr Thr Leu Ser Tyr Thr Ala Gly Pro Gln Gly Ser
1415 1420 1425
Pro Leu Ser Asp Pro Asp Val Gln Ile Thr Gly Asn Asn Ile Met
1430 1435 1440
Leu Val Ala Ser Gln Pro Ala Leu Gln Gly Pro Glu Arg Arg Ser
1445 1450 1455
Tyr Glu Ile Met Phe Arg Glu Glu Phe Trp Arg Arg Pro Asp Gly
1460 1465 1470
Gln Pro Ala Thr Arg Glu His Leu Leu Met Ala Leu Ala Asp Leu
1475 1480 1485
Asp Glu Leu Leu Ile Arg Ala Thr Phe Ser Ser Val Pro Leu Val
1490 1495 1500
Ala Ser Ile Ser Ala Val Ser Leu Glu Val Ala Gln Pro Gly Pro
1505 1510 1515
Ser Asn Arg Pro Arg Ala Leu Glu Val Glu Glu Cys Arg Cys Pro
1520 1525 1530
Pro Gly Tyr Ile Gly Leu Ser Cys Gln Asp Cys Ala Pro Gly Tyr
1535 1540 1545
Thr Arg Thr Gly Ser Gly Leu Tyr Leu Gly His Cys Glu Leu Cys
1550 1555 1560
Glu Cys Asn Gly His Ser Asp Leu Cys His Pro Glu Thr Gly Ala
1565 1570 1575
Cys Ser Gln Cys Gln His Asn Ala Ala Gly Glu Phe Cys Glu Leu
1580 1585 1590
Cys Ala Pro Gly Tyr Tyr Gly Asp Ala Thr Ala Gly Thr Pro Glu
1595 1600 1605
Asp Cys Gln Pro Cys Ala Cys Pro Leu Thr Asn Pro Glu Asn Met
1610 1615 1620
Phe Ser Arg Thr Cys Glu Ser Leu Gly Ala Gly Gly Tyr Arg Cys
1625 1630 1635
Thr Ala Cys Glu Pro Gly Tyr Thr Gly Gln Tyr Cys Glu Gln Cys
1640 1645 1650
Gly Pro Gly Tyr Val Gly Asn Pro Ser Val Gln Gly Gly Gln Cys
1655 1660 1665
Leu Pro Glu Thr Asn Gln Ala Pro Leu Val Val Glu Val His Pro
1670 1675 1680
Ala Arg Ser Ile Val Pro Gln Gly Gly Ser His Ser Leu Arg Cys
1685 1690 1695
Gln Val Ser Gly Ser Pro Pro His Tyr Phe Tyr Trp Ser Arg Glu
1700 1705 1710
Asp Gly Arg Pro Val Pro Ser Gly Thr Gln Gln Arg His Gln Gly
1715 1720 1725
Ser Glu Leu His Phe Pro Ser Val Gln Pro Ser Asp Ala Gly Val
1730 1735 1740
Tyr Ile Cys Thr Cys Arg Asn Leu His Gln Ser Asn Thr Ser Arg
1745 1750 1755
Ala Glu Leu Leu Val Thr Glu Ala Pro Ser Lys Pro Ile Thr Val
1760 1765 1770
Thr Val Glu Glu Gln Arg Ser Gln Ser Val Arg Pro Gly Ala Asp
1775 1780 1785
Val Thr Phe Ile Cys Thr Ala Lys Ser Lys Ser Pro Ala Tyr Thr
1790 1795 1800
Leu Val Trp Thr Arg Leu His Asn Gly Lys Leu Pro Thr Arg Ala
1805 1810 1815
Met Asp Phe Asn Gly Ile Leu Thr Ile Arg Asn Val Gln Leu Ser
1820 1825 1830
Asp Ala Gly Thr Tyr Val Cys Thr Gly Ser Asn Met Phe Ala Met
1835 1840 1845
Asp Gln Gly Thr Ala Thr Leu His Val Gln Ala Ser Gly Thr Leu
1850 1855 1860
Ser Ala Pro Val Val Ser Ile His Pro Pro Gln Leu Thr Val Gln
1865 1870 1875
Pro Gly Gln Leu Ala Glu Phe Arg Cys Ser Ala Thr Gly Ser Pro
1880 1885 1890
Thr Pro Thr Leu Glu Trp Thr Gly Gly Pro Gly Gly Gln Leu Pro
1895 1900 1905
Ala Lys Ala Gln Ile His Gly Gly Ile Leu Arg Leu Pro Ala Val
1910 1915 1920
Glu Pro Thr Asp Gln Ala Gln Tyr Leu Cys Arg Ala His Ser Ser
1925 1930 1935
Ala Gly Gln Gln Val Ala Arg Ala Val Leu His Val His Gly Gly
1940 1945 1950
Gly Gly Pro Arg Val Gln Val Ser Pro Glu Arg Thr Gln Val His
1955 1960 1965
Ala Gly Arg Thr Val Arg Leu Tyr Cys Arg Ala Ala Gly Val Pro
1970 1975 1980
Ser Ala Thr Ile Thr Trp Arg Lys Glu Gly Gly Ser Leu Pro Pro
1985 1990 1995
Gln Ala Arg Ser Glu Arg Thr Asp Ile Ala Thr Leu Leu Ile Pro
2000 2005 2010
Ala Ile Thr Thr Ala Asp Ala Gly Phe Tyr Leu Cys Val Ala Thr
2015 2020 2025
Ser Pro Ala Gly Thr Ala Gln Ala Arg Ile Gln Val Val Val Leu
2030 2035 2040
Ser Ala Ser Asp Ala Ser Pro Pro Pro Val Lys Ile Glu Ser Ser
2045 2050 2055
Ser Pro Ser Val Thr Glu Gly Gln Thr Leu Asp Leu Asn Cys Val
2060 2065 2070
Val Ala Gly Ser Ala His Ala Gln Val Thr Trp Tyr Arg Arg Gly
2075 2080 2085
Gly Ser Leu Pro Pro His Thr Gln Val His Gly Ser Arg Leu Arg
2090 2095 2100
Leu Pro Gln Val Ser Pro Ala Asp Ser Gly Glu Tyr Val Cys Arg
2105 2110 2115
Val Glu Asn Gly Ser Gly Pro Lys Glu Ala Ser Ile Thr Val Ser
2120 2125 2130
Val Leu His Gly Thr His Ser Gly Pro Ser Tyr Thr Pro Val Pro
2135 2140 2145
Gly Ser Thr Arg Pro Ile Arg Ile Glu Pro Ser Ser Ser His Val
2150 2155 2160
Ala Glu Gly Gln Thr Leu Asp Leu Asn Cys Val Val Pro Gly Gln
2165 2170 2175
Ala HiS Ala Gln Val Thr Trp His Lys Arg Gly Gly Ser Leu Pro
2180 2185 2190
Ala Arg His Gln Thr His Gly Ser Leu Leu Arg Leu His Gln Val
2195 2200 2205
Thr Pro Ala Asp Ser Gly Glu Tyr Val Cys His Val Val Gly Thr
2210 2215 2220
Ser Gly Pro Leu Glu Ala Ser Val Leu Val Thr Ile Glu Ala Ser
2225 2230 2235
Val Ile Pro Gly Pro Ile Pro Pro Val Arg Ile Glu Ser Ser Ser
2240 2245 2250
Ser Thr Val Ala Glu Gly Gln Thr Leu Asp Leu Ser Cys Val Val
2255 2260 2265
Ala Gly Gln Ala His Ala Gln Val Thr Trp Tyr Lys Arg Gly Gly
2270 2275 2280
Ser Leu Pro Ala Arg His Gln Val Arg Gly Ser Arg Leu Tyr Ile
2285 2290 2295
Phe Gln Ala Ser Pro Ala Asp Ala Gly Gln Tyr Val Cys Arg Ala
2300 2305 2310
Ser Asn Gly Met Glu Ala Ser Ile Thr Val Thr Val Thr Gly Thr
2315 2320 2325
Gln Gly Ala Asn Leu Ala Tyr Pro Ala Gly Ser Thr Gln Pro Ile
2330 2335 2340
Arg Ile Glu Pro Ser Ser Ser Gln Val Ala Glu Gly Gln Thr Leu
2345 2350 2355
Asp Leu Asn Cys Val Val Pro Gly Gln Ser His Ala Gln Val Thr
2360 2365 2370
Trp His Lys Arg Gly Gly Ser Leu Pro Val Arg His Gln Thr His
2375 2380 2385
Gly Ser Leu Leu Arg Leu Tyr Gln Ala Ser Pro Ala Asp Ser Gly
2390 2395 2400
Glu Tyr Val Cys Arg Val Leu Gly Ser Ser Val Pro Leu Glu Ala
2405 2410 2415
Ser Val Leu Val Thr Ile Glu Pro Ala Gly Ser Val Pro Ala Leu
2420 2425 2430
Gly Val Thr Pro Thr Val Arg Ile Glu Ser Ser Ser Ser Gln Val
2435 2440 2445
Ala Glu Gly Gln Thr Leu Asp Leu Asn Cys Leu Val Ala Gly Gln
2450 2455 2460
Ala His Ala Gln Val Thr Trp His Lys Arg Gly Gly Ser Leu Pro
2465 2470 2475
Ala Arg His Gln Val His Gly Ser Arg Leu Arg Leu Leu Gln Val
2480 2485 2490
Thr Pro Ala Asp Ser Gly Glu Tyr Val Cys Arg Val Val Gly Ser
2495 2500 2505
Ser Gly Thr Gln Glu Ala Ser Val Leu Val Thr Ile Gln Gln Arg
2510 2515 2520
Leu Ser Gly Ser His Ser Gln Gly Val Ala Tyr Pro Val Arg Ile
2525 2530 2535
Glu Ser Ser Ser Ala Ser Leu Ala Asn Gly His Thr Leu Asp Leu
2540 2545 2550
Asn Cys Leu Val Ala Ser Gln Ala Pro His Thr Ile Thr Trp Tyr
2555 2560 2565
Lys Arg Gly Gly Ser Leu Pro Ser Arg His Gln Ile Val Gly Ser
2570 2575 2580
Arg Leu Arg Ile Pro Gln Val Thr Pro Ala Asp Ser Gly Glu Tyr
2585 2590 2595
Val Cys His Val Ser Asn Gly Ala Gly Ser Arg Glu Thr Ser Leu
2600 2605 2610
Ile Val Thr Ile Gln Gly Ser Gly Ser Ser His Val Pro Ser Val
2615 2620 2625
Ser Pro Pro Ile Arg Ile Glu Ser Ser Ser Pro Thr Val Val Glu
2630 2635 2640
Gly Gln Thr Leu Asp Leu Asn Cys Val Val Ala Arg Gln Pro Gln
2645 2650 2655
Ala Ile Ile Thr Trp Tyr Lys Arg Gly Gly Ser Leu Pro Ser Arg
2660 2665 2670
His Gln Thr His Gly Ser His Leu Arg Leu His Gln Met Ser Val
2675 2680 2685
Ala Asp Ser Gly Glu Tyr Val Cys Arg Ala Asn Asn Asn Ile Asp
2690 2695 2700
Ala Leu Glu Ala Ser Ile Val Ile Ser Val Ser Pro Ser Ala Gly
2705 2710 2715
Ser Pro Ser Ala Pro Gly Ser Ser Met Pro Ile Arg Ile Glu Ser
2720 2725 2730
Ser Ser Ser His Val Ala Glu Gly Glu Thr Leu Asp Leu Asn Cys
2735 2740 2745
Val Val Pro Gly Gln Ala His Ala Gln Val Thr Trp His Lys Arg
2750 2755 2760
Gly Gly Ser Leu Pro Ser His His Gln Thr Arg Gly Ser Arg Leu
2765 2770 2775
Arg Leu His His Val Ser Pro Ala Asp Ser Gly Glu Tyr Val Cys
2780 2785 2790
Arg Val Met Gly Ser Ser Gly Pro Leu Glu Ala Ser Val Leu Val
2795 2800 2805
Thr Ile Glu Ala Ser Gly Ser Ser Ala Val His Val Pro Ala Pro
2810 2815 2820
Gly Gly Ala Pro Pro Ile Arg Ile Glu Pro Ser Ser Ser Arg Val
2825 2830 2835
Ala Glu Gly Gln Thr Leu Asp Leu Lys Cys Val Val Pro Gly Gln
2840 2845 2850
Ala His Ala Gln Val Thr Trp His Lys Arg Gly Gly Asn Leu Pro
2855 2860 2865
Ala Arg His Gln Val His Gly Pro Leu Leu Arg Leu Asn Gln Val
2870 2875 2880
Ser Pro Ala Asp Ser Gly Glu Tyr Ser Cys Gln Val Thr Gly Ser
2885 2890 2895
Ser Gly Thr Leu Glu Ala Ser Val Leu Val Thr Ile Glu Pro Ser
2900 2905 2910
Ser Pro Gly Pro Ile Pro Ala Pro Gly Leu Ala Gln Pro Ile Tyr
2915 2920 2925
Ile Glu Ala Ser Ser Ser His Val Thr Glu Gly Gln Thr Leu Asp
2930 2935 2940
Leu Asn Cys Val Val Pro Gly Gln Ala His Ala Gln Val Thr Trp
2945 2950 2955
Tyr Lys Arg Gly Gly Ser Leu Pro Ala Arg His Gln Thr His Gly
2960 2965 2970
Ser Gln Leu Arg Leu His Leu Val Ser Pro Ala Asp Ser Gly Glu
2975 2980 2985
Tyr Val Cys Arg Ala Ala Ser Gly Pro Gly Pro Glu Gln Glu Ala
2990 2995 3000
Ser Phe Thr Val Thr Val Pro Pro Ser Glu Gly Ser Ser Tyr Arg
3005 3010 3015
Leu Arg Ser Pro Val Ile Ser Ile Asp Pro Pro Ser Ser Thr Val
3020 3025 3030
Gln Gln Gly Gln Asp Ala Ser Phe Lys Cys Leu Ile His Asp Gly
3035 3040 3045
Ala Ala Pro Ile Ser Leu Glu Trp Lys Thr Arg Asn Gln Glu Leu
3050 3055 3060
Glu Asp Asn Val His Ile Ser Pro Asn Gly Ser Ile Ile Thr Ile
3065 3070 3075
Val Gly Thr Arg Pro Ser Asn His Gly Thr Tyr Arg Cys Val Ala
3080 3085 3090
Ser Asn Ala Tyr Gly Val Ala Gln Ser Val Val Asn Leu Ser Val
3095 3100 3105
His Gly Pro Pro Thr Val Ser Val Leu Pro Glu Gly Pro Val Trp
3110 3115 3120
Val Lys Val Gly Lys Ala Val Thr Leu Glu Cys Val Ser Ala Gly
3125 3130 3135
Glu Pro Arg Ser Ser Ala Arg Trp Thr Arg Ile Ser Ser Thr Pro
3140 3145 3150
Ala Lys Leu Glu Gln Arg Thr Tyr Gly Leu Met Asp Ser His Ala
3155 3160 3165
Val Leu Gln Ile Ser Ser Ala Lys Pro Ser Asp Ala Gly Thr Tyr
3170 3175 3180
Val Cys Leu Ala Gln Asn Ala Leu Gly Thr Ala Gln Lys Gln Val
3185 3190 3195
Glu Val Ile Val Asp Thr Gly Ala Met Ala Pro Gly Ala Pro Gln
3200 3205 3210
Val Gln Ala Glu Glu Ala Glu Leu Thr Val Glu Ala Gly His Thr
3215 3220 3225
Ala Thr Leu Arg Cys Ser Ala Thr Gly Ser Pro Ala Pro Thr Ile
3230 3235 3240
His Trp Ser Lys Leu Arg Ser Pro Leu Pro Trp Gln His Arg Leu
3245 3250 3255
Glu Gly Asp Thr Leu Ile Ile Pro Arg Val Ala Gln Gln Asp Ser
3260 3265 3270
Gly Gln Tyr Ile Cys Asn Ala Thr Ser Pro Ala Gly His Ala Glu
3275 3280 3285
Ala Thr Ile Ile Leu His Val Glu Ser Pro Pro Tyr Ala Thr Thr
3290 3295 3300
Val Pro Glu His Ala Ser Val Gln Ala GlV Glu Thr Val Gln Leu
3305 3310 3315
Gln Cys Leu Ala His Gly Thr Pro Pro Leu Thr Phe Gln Trp Ser
3320 3325 3330
Arg Val Gly Ser Ser Leu Pro Gly Arg Ala Thr Ala Arg Asn Glu
3335 3340 3345
Leu Leu His Phe Glu Arg Ala Ala Pro Glu Asp Ser Gly Arg Tyr
3350 3355 3360
Arg Cys Arg Val Thr Asn Lys Val Gly Ser Ala Glu Ala Phe Ala
3365 3370 3375
Gln Leu Leu Val Gln Gly Pro Pro Gly Ser Leu Pro Ala Thr Ser
3380 3385 3390
Ile Pro Ala Gly Ser Thr Pro Thr Val Gln Val Thr Pro Gln Leu
3395 3400 3405
Glu Thr Lys Ser Ile Gly Ala Ser Val Glu Phe His Cys Ala Val
3410 3415 3420
Pro Ser Asp Arg Gly Thr Gln Leu Arg Trp Phe Lys Glu Gly Gly
3425 3430 3435
Gln Leu Pro Pro Gly His Ser Val Gln Asp Gly Val Leu Arg Ile
3440 3445 3450
Gln Asn Leu Asp Gln Ser Cys Gln Gly Thr Tyr Ile Cys Gln Ala
3455 3460 3465
His Gly Pro Trp Gly Lys Ala Gln Ala Ser Ala Gln Leu Val Ile
3470 3475 3480
Gln Ala Leu Pro Ser Val Leu Ile Asn Ile Arg Thr Ser Val Gln
3485 3490 3495
Thr Val Val Val Gly His Ala Val Glu Phe Glu Cys Leu Ala Leu
3500 3505 3510
Gly Asp Pro Lys Pro Gln Val Thr Trp Ser Lys Val Gly Gly His
3515 3520 3525
Leu Arg Pro Gly Ile Val Gln Ser Gly Gly Val Val Arg Ile Ala
3530 3535 3540
His Val Glu Leu Ala Asp Ala Gly Gln Tyr Arg Cys Thr Ala Thr
3545 3550 3555
Asn Ala Ala Gly Thr Thr Gln Ser His Val Leu Leu Leu Val Gln
3560 3565 3570
Ala Leu Pro Gln Ile Ser Met Pro Gln Glu Val Arg Val Pro Ala
3575 3580 3585
Gly Ser Ala Ala Val Phe Pro Cys Ile Ala Ser Gly Tyr Pro Thr
3590 3595 3600
Pro Asp Ile Ser Trp Ser Lys Leu Asp Gly Ser Leu Pro Pro Asp
3605 3610 3615
Ser Arg Leu Glu Asn Asn Met Leu Met Leu Pro Ser Val Arg Pro
3620 3625 3630
Gln Asp Ala Gly Thr Tyr Val Cys Thr Ala Thr Asn Arg Gln Gly
3635 3640 3645
Lys Val Lys Ala Phe Ala His Leu Gln Val Pro Glu Arg Val Val
3650 3655 3660
Pro Tyr Phe Thr Gln Thr Pro Tyr Ser Phe Leu Pro Leu Pro Thr
3665 3670 3675
Ile Lys Asp Ala Tyr Arg Lys Phe Glu Ile Lys Ile Thr Phe Arg
3680 3685 3690
Pro Asp Ser Ala Asp Gly Met Leu Leu Tyr Asn Gly Gln Lys Arg
3695 3700 3705
Val Pro Gly Ser Pro Thr Asn Leu Ala Asn Arg Gln Pro Asp Phe
3710 3715 3720
Ile Ser Phe Gly Leu Val Gly Gly Arg Pro Glu Phe Arg Phe Asp
3725 3730 3735
Ala Gly Ser Gly Met Ala Thr Ile Arg His Pro Thr Pro Leu Ala
3740 3745 3750
Leu Gly His Phe His Thr Val Thr Leu Leu Arg Ser Leu Thr Gln
3755 3760 3765
Gly Ser Leu Ile Val Gly Asp Leu Ala Pro Val Asn Gly Thr Ser
3770 3775 3780
Gln Gly Lys Phe Gln Gly Leu Asp Leu Asn Glu Glu Leu Tyr Leu
3785 3790 3795
Gly Gly Tyr Pro Asp Tyr Gly Ala Ile Pro Lys Ala Gly Leu Ser
3800 3805 3810
Ser Gly Phe Ile Gly Cys Val Arg Glu Leu Arg Ile Gln Gly Glu
3815 3820 3825
Glu Ile Val Phe His Asp Leu Asn Leu Thr Ala His Gly Ile Ser
3830 3835 3840
His Cys Pro Thr Cys Arg Asp Arg Pro Cys Gln Asn Gly Gly Gln
3845 3850 3855
Cys His Asp Ser Glu Ser Ser Ser Tyr Val Cys Val Cys Pro Ala
3860 3865 3870
Gly Phe Thr Gly Ser Arg Cys Glu His Ser Gln Ala Leu His Cys
3875 3880 3885
His Pro Glu Ala Cys Gly Pro Asp Ala Thr Cys Val Asn Arg Pro
3890 3895 3900
Asp Gly Arg Gly Tyr Thr Cys Arg Cys His Leu Gly Arg Ser Gly
3905 3910 3915
Leu Arg Cys Glu Glu Gly Val Thr Val Thr Thr Pro Ser Leu Ser
3920 3925 3930
Gly Ala Gly Ser Tyr Leu Ala Leu Pro Ala Leu Thr Asn Thr His
3935 3940 3945
His Glu Leu Arg Leu Asp Val Glu Phe Lys Pro Leu Ala Pro Asp
3950 3955 3960
Gly Val Leu Leu Phe Ser Gly Gly Lys Ser Gly Pro Val Glu Asp
3965 3970 3975
Phe Val Ser Leu Ala Met Val Gly Gly His Leu Glu Phe Arg Tyr
3980 3985 3990
Glu Leu Gly Ser Gly Leu Ala Val Leu Arg Ser Ala Glu Pro Leu
3995 4000 4005
Ala Leu Gly Arg Trp His Arg Val Ser Ala Glu Arg Leu Asn Lys
4010 4015 4020
Asp Gly Ser Leu Arg Val Asn Gly Gly Arg Pro Val Leu Arg Ser
4025 4030 4035
Ser Pro Gly Lys Ser Gln Gly Leu Asn Leu His Thr Leu Leu Tyr
4040 4045 4050
Leu Gly Gly Val Glu Pro Ser Val Pro Leu Ser Pro Ala Thr Asn
4055 4060 4065
Met Ser Ala His Phe Arg Gly Cys Val Gly Glu Val Ser Val Asn
4070 4075 4080
Gly Lys Arg Leu Asp Leu Thr Tyr Ser Phe Leu Gly Ser Gln Gly
4085 4090 4095
Ile Gly Gln Cys Tyr Asp Ser Ser Pro Cys Glu Arg Gln Pro Cys
4100 4105 4110
Gln His Gly Ala Thr Cys Met Pro Ala Gly Glu Tyr Glu Phe Gln
4115 4120 4125
Cys Leu Cys Arg Asp Gly Phe Lys Gly Asp Leu Cys Glu His Glu
4130 4135 4140
Glu Asn Pro Cys Gln Leu Arg Glu Pro Cys Leu His Gly Gly Thr
4145 4150 4155
Cys Gln Gly Thr Arg Cys Leu Cys Leu Pro Gly Phe Ser Gly Pro
4160 4165 4170
Arg Cys Gln Gln Gly Ser Gly His Gly Ile Ala Glu Ser Asp Trp
4175 4180 4185
His Leu Glu Gly Ser Gly Gly Asn Asp Ala Pro Gly Gln Tyr Gly
4190 4195 4200
Ala Tyr Phe His Asp Asp Gly Phe Leu Ala Phe Pro Gly His Val
4205 4210 4215
Phe Ser Arg Ser Leu Pro Glu Val Pro Glu Thr Ile Glu Leu Glu
4220 4225 4230
Val Arg Thr Ser Thr Ala Ser Gly Leu Leu Leu Trp Gln Gly Val
4235 4240 4245
Glu Val Gly Glu Ala Gly Gln Gly Lys Asp Phe Ile Ser Leu Gly
4250 4255 4260
Leu Gln Asp Gly His Leu Val Phe Arg Tyr Gln Leu Gly Ser Gly
4265 4270 4275
Glu Ala Arg Leu Val Ser Glu Asp Pro Ile Asn Asp Gly Glu Trp
4280 4285 4290
His Arg Val Thr Ala Leu Arg Glu Gly Arg Arg Gly Ser Ile Gln
4295 4300 4305
Val Asp Gly Glu Glu Leu Val Ser Gly Arg Ser Pro Gly Pro Asn
4310 4315 4320
Val Ala Val Asn Ala Lys Gly Ser Val Tyr Ile Gly Gly Ala Pro
4325 4330 4335
Asp Val Ala Thr Leu Thr Gly Gly Arg Phe Ser Ser Gly Ile Thr
4340 4345 4350
Gly Cys Val Lys Asn Leu Val Leu His Ser Ala Arg Pro Gly Ala
4355 4360 4365
Pro Pro Pro Gln Pro Leu Asp Leu Gln His Arg Ala Gln Ala Gly
4370 4375 4380
Ala Asn Thr Arg Pro Cys Pro Ser
4385 4390
<210>4
<211>368
<212>PRT
<213>人
<400>4
Met Trp Pro Leu Trp Arg Leu Val Ser Leu Leu Ala Leu Ser Gln Ala
1 5 10 15
Leu Pro Phe Glu Gln Arg Gly Phe Trp Asp Phe Thr Leu Asp Asp Gly
20 25 30
Pro Phe Met Met Asn Asp Glu Glu Ala Ser Gly Ala Asp Thr Ser Gly
35 40 45
Val Leu Asp Pro Asp Ser Val Thr Pro Thr Tyr Ser Ala Met Cys Pro
50 55 60
Phe Gly Cys His Cys His Leu Arg Val Val Gln Cys Ser Asp Leu Gly
65 70 75 80
Leu Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp
85 90 95
Leu Gln Asn Asn Asp Ile Ser Glu Leu Arg Lys Asp Asp Phe Lys Gly
100 105 110
Leu Gln His Leu Tyr Ala Leu Val Leu Val Asn Asn Lys Ile Ser Lys
115 120 125
Ile His Glu Lys Ala Phe Ser Pro Leu Arg Lys Leu Gln Lys Leu Tyr
130 135 140
Ile Ser Lys Asn His Leu Val Glu Ile Pro Pro Asn Leu Pro Ser Ser
145 150 155 160
Leu Val Glu Leu Arg Ile His Asp Asn Arg Ile Arg Lys Val Pro Lys
165 170 175
Gly Val Phe Ser Gly Leu Arg Asn Met Asn Cys Ile Glu Met Gly Gly
180 185 190
Asn Pro Leu Glu Asn Ser Gly Phe Glu Pro Gly Ala Phe Asp Gly Leu
195 200 205
Lys Leu Asn Tyr Leu Arg Ile Ser Glu Ala Lys Leu Thr Gly Ile Pro
210 215 220
Lys Asp Leu Pro Glu Thr Leu Asn Glu Leu His Leu Asp His Asn Lys
225 230 235 240
Ile Gln Ala Ile Glu Leu Glu Asp Leu Leu Arg Tyr Ser Lys Leu Tyr
245 250 255
Arg Leu Gly Leu Gly His Asn Gln Ile Arg Met Ile Glu Asn Gly Ser
260 265 270
Leu Ser Phe Leu Pro Thr Leu Arg Glu Leu His Leu Asp Asn Asn Lys
275 280 285
Leu Ala Arg Val Pro Ser Gly Leu Pro Asp Leu Lys Leu Leu Gln Val
290 295 300
Val Tyr Leu His Ser Asn Asn Ile Thr Lys Val Gly Val Asn Asp Phe
305 310 315 320
Cys Pro Met Gly Phe Gly Val Lys Arg Ala Tyr Tyr Asn Gly Ile Ser
325 330 335
Leu Phe Asn Asn Pro Val Pro Tyr Trp Glu Val Gln Pro Ala Thr Phe
340 345 350
Arg Cys Val Thr Asp Arg Leu Ala Ile Gln Phe Gly Asn Tyr Lys Lys
355 360 365
<210>5
<211>359
<212>PRT
<213>人
<400>5
Met Lys Ala Thr Ile Ile Leu Leu Leu Leu Ala Gln Val Ser Trp Ala
1 5 10 15
Gly Pro Phe Gln Gln Arg Gly Leu Phe Asp Phe Met Leu Glu Asp Glu
20 25 30
Ala Ser Gly Ile Gly Pro Glu Val Pro Asp Asp Arg Asp Phe Glu Pro
35 40 45
Ser Leu Gly Pro Val Cys Pro Phe Arg Cys Gln Cys His Leu Arg Val
50 55 60
Val Gln Cys Ser Asp Leu Gly Leu Asp Lys Val Pro Lys Asp Leu Pro
65 70 75 80
Pro Asp Thr Thr Leu Leu Asp Leu Gln Asn Asn Lys Ile Thr Glu Ile
85 90 95
Lys Asp Gly Asp Phe Lys Asn Leu Lys Asn Leu His Ala Leu Ile Leu
100 105 110
Val Asn Asn Lys Ile Ser Lys Val Ser Pro Gly Ala Phe Thr Pro Leu
115 120 125
Val Lys Leu Glu Arg Leu Tyr Leu Ser Lys Asn Gln Leu Lys Glu Leu
130 135 140
Pro Glu Lys Met Pro Lys Thr Leu Gln Glu Leu Arg Ala His Glu Asn
145 150 155 160
Glu Ile Thr Lys Val Arg Lys Val Thr Phe Asn Gly Leu Asn Gln Met
165 170 175
Ile Val Ile Glu Leu Gly Thr Asn Pro Leu Lys Ser Ser Gly Ile Glu
180 185 190
Asn Gly Ala Phe Gln Gly Met Lys Lys Leu Ser Tyr Ile Arg Ile Ala
195 200 205
Asp Thr Asn Ile Thr Ser Ile Pro Gln Gly Leu Pro Pro Ser Leu Thr
210 215 220
Glu Leu His Lsu Asp Gly Asn Lys Ile Ser Arg Val Asp Ala Ala Ser
225 230 235 240
Leu Lys Gly Leu Asn Asn Leu Ala Lys Leu Gly Leu Ser Phe Asn Ser
245 250 255
Ile Ser Ala Val Asp Asn Gly Ser Leu Ala Asn Thr Pro His Leu Arg
260 265 270
Glu Leu His Leu Asp Asn Asn Lys Leu Thr Arg Val Pro Gly Gly Leu
275 280 285
Ala Glu His Lys Tyr Ile Gln Val Val Tyr Leu His Asn Asn Asn Ile
290 295 300
Ser Val Val Gly Ser Ser Asp Phe Cys Pro Pro Gly His Asn Thr Lys
305 310 315 320
Lys Ala Ser Tyr Ser Gly Val Ser Leu Phe Ser Asn Pro Val Gln Tyr
325 330 335
Trp Glu Ile Gln Pro Ser Thr Phe Arg Cys Val Tyr Val Arg Ser Ala
340 345 350
Ile Gln Leu Gly Asn Tyr Lys
355
<210>6
<211>24
<212>PRT
<213>人
<400>6
Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp Leu
1 5 10 15
Gln Asn Asn Asp Ile Ser Glu Leu
20
<210>7
<211>25
<212>PRT
<213>人
<400>7
Leu Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp
1 5 10 15
Leu Gln Asn Asn Asp Ile Ser Glu Leu
20 25
<210>8
<211>25
<212>PRT
<213>人
<400>8
Glu Asn Ser Gly Phe Glu Pro Gly Ala Phe Asp Gly Leu Lys Leu Asn
1 5 10 15
Tyr Leu Arg Ile Ser Glu Ala Lys Leu
20 25
<210>9
<211>26
<212>PRT
<213>人
<400>9
Gly Leu Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu
1 5 10 15
Asp Leu Gln Asn Asn Asp Ile Ser Glu Leu
20 25
<210>10
<211>20
<212>PRT
<213>人
<400>10
Tyr Leu Arg Ile Ser Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu
1 5 10 15
Pro Glu Thr Leu
20
<210>11
<211>26
<212>PRT
<213>人
<400>11
Gly Leu Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu
1 5 10 15
Asp Leu Gln Asn Asn Asp Ile Ser Glu Leu
20 25
<210>12
<211>26
<212>PRT
<213>人
<400>12
Leu Thr Gly Ile Pro Lys Asp Leu Pro Glu Thr Leu Asn Glu Leu His
1 5 10 15
Leu Asp His Asn Lys Ile Gln Ala Ile Glu
20 25
<210>13
<211>22
<212>PRT
<213>人
<400>13
Lys Arg Ile Ser Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu Pro
1 5 10 15
Glu Thr Leu Asn Glu Leu
20
<210>14
<211>14
<212>PRT
<213>人
<400>14
Gln Ala Ile Glu Leu Glu Asp Leu Leu Arg Tyr Ser Lys Leu
1 5 10
<210>15
<211>12
<212>PRT
<213>人
<400>15
Gln Ala Ile Glu Leu Glu Asp Leu Leu Arg Tyr Ser
1 5 10
<210>16
<211>19
<212>PRT
<213>人
<400>16
Ser Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu Pro Glu Thr Leu
1 5 10 15
Asn Glu Leu
<210>17
<211>25
<212>PRT
<213>人
<400>17
Leu Lys Ala Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp
1 5 10 15
Leu Gln Asn Asn Asp Ile Ser Glu Leu
20 25
<210>18
<211>18
<212>PRT
<213>人
<400>18
Thr Leu Leu Asp Leu Gln Asn Asn Asp Ile Ser Glu Leu Arg Lys Asp
1 5 10 15
Asp Phe
<210>19
<211>12
<212>PRT
<213>人
<400>19
Ala Ile Glu Leu Glu Asp Leu Leu Arg Tyr Ser Lys
1 5 10
<210>20
<211>15
<212>PRT
<213>人
<400>20
Glu Asn Ser Gly Phe Glu Pro Gly Ala Phe Asp Gly Leu Lys Leu
1 5 10 15
<210>21
<211>13
<212>PRT
<213>人
<400>21
Met Ile Val Ile Glu Leu Gly Thr Asn Pro Leu Lys Ser
1 5 10
<210>22
<211>13
<212>PRT
<213>人
<400>22
Met Ile Val Ile Glu Leu Gly Thr Asn Pro Leu Lys Ser
1 5 10
<210>23
<211>17
<212>PRT
<213>人
<400>23
Glu Leu His Leu Asp Gly Asn Lys Ile Ser Arg Val Asp Ala Ala Ser
1 5 10 15
Leu
<210>24
<211>18
<212>PRT
<213>人
<400>24
Leu Val Asn Asn Lys Ile Ser Lys Val Ser Pro Gly Ala Phe Thr Pro
1 5 10 15
Leu Val
<210>25
<211>26
<212>PRT
<213>人
<400>25
Ala Leu Ile Leu Val Asn Asn Lys Ile Ser Lys Val Ser Pro Gly Ala
1 5 10 15
Phe Thr Pro Leu Val Lys Leu Glu Arg Leu
20 25
<210>26
<211>17
<212>PRT
<213>人
<400>26
Phe Ser Asn Pro Val Gln Tyr Trp Glu Ile Gln Pro Ser Thr Phe Arg
1 5 10 15
Cys
<210>27
<211>15
<212>PRT
<213>人
<400>27
Lys Ser Ser Gly Ile Glu Asn Gly Ala Phe Gln Gly Met Lys Lys
1 5 10 15
<210>28
<211>18
<212>PRT
<213>人
<400>28
Lys Ser Ser Gly Ile Glu Asn Gly Ala Phe Gln Gly Met Lys Lys Leu
1 5 10 15
Ser Tyr
<210>29
<211>13
<212>PRT
<213>人
<400>29
Asn Lys Ile Thr Glu Ile Lys Asp Gly Asp Phe Lys Asn
1 5 10
<210>30
<211>17
<212>PRT
<213>人
<400>30
Gln Gly Leu Pro Pro Ser Leu Thr Glu Leu His Leu Asp Gly Asn Lys
1 5 10 15
Ile
<210>31
<211>12
<212>PRT
<213>人
<400>31
Lys Leu Leu Ala Ser Asp Ala Gly Leu Tyr Arg Cys
1 5 10
<210>32
<211>13
<212>PRT
<213>人
<400>32
Leu Ala Thr Val Gly Glu Leu Gln Ala Ala Trp Arg Asn
1 5 10
<210>33
<211>15
<212>PRT
<213>人
<400>33
Lys Glu Thr Thr Val Leu Val Ala Gln Asn Gly Asn Ile Lys Ile
1 5 10 15
<210>34
<211>12
<212>PRT
<213>人
<400>34
Ser Leu Glu Asp Leu Gln Leu Thr His Asn Lys Ile
1 5 10
<210>35
<211>13
<212>PRT
<213>人
<400>35
Arg Leu Lys Glu Asp Ala Val Ser Ala Ala Phe Lys Gly
1 5 10
<210>36
<211>16
<212>PRT
<213>人
<400>36
Arg Ser Ile Glu Tyr Ser Pro Gln Leu Glu Asp Ala Gly Ser Arg Glu
1 5 10 15
<210>37
<211>12
<212>PRT
<213>人
<400>37
Arg Leu Glu Gly Asp Thr Leu Ile Ile Pro Arg Val
1 5 10
<210>38
<211>15
<212>PRT
<213>人
<400>38
Glu Val Ser Glu Ala Val Val Glu Lys Leu Glu Pro Glu Tyr Arg
1 5 10 15
<210>39
<211>16
<212>PRT
<213>人
<400>39
Arg Glu Val Ser Glu Ala Val Val Glu Lys Leu Glu Pro Glu Tyr Arg
1 5 10 15
<210>40
<211>12
<212>PRT
<213>人
<400>40
Arg Ser Ile Glu Tyr Ser Pro Gln Leu Glu Asp Ala
1 5 10
<210>41
<211>22
<212>PRT
<213>人
<400>41
Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp Leu Gln
1 5 10 15
Asn Asn Asp Ile Ser Glu
20
<210>42
<211>23
<212>PRT
<213>人
<400>42
Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp Leu
1 5 10 15
Gln Asn Asn Asp Ile Ser Glu
20
<210>43
<211>23
<212>PRT
<213>人
<400>43
Asn Ser Gly Phe Glu Pro Gly Ala Phe Asp Gly Leu Lys Leu Asn Tyr
1 5 10 15
Leu Arg Ile Ser Glu Ala Lys
20
<210>44
<211>24
<212>PRT
<213>人
<400>44
Leu Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp
1 5 10 15
Leu Gln Asn Asn Asp Ile Ser Glu
20
<210>45
<211>18
<212>PRT
<213>人
<400>45
Leu Arg Ile Ser Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu Pro
1 5 10 15
Glu Thr
<210>46
<211>24
<212>PRT
<213>人
<400>46
Leu Lys Ser Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp
1 5 10 15
Leu Gln Asn Asn Asp Ile Ser Glu
20
<210>47
<211>26
<212>PRT
<213>人
<400>47
Leu Thr Gly Ile Pro Lys Asp Leu Pro Glu Thr Leu Asn Glu Leu His
1 5 10 15
Leu Asp His Asn Lys Ile Gln Ala Ile Glu
20 25
<210>48
<211>11
<212>PRT
<213>人
<400>48
Ile Val Ile Glu Leu Gly Thr Asn Pro Leu Lys
1 5 10
<210>49
<211>10
<212>PRT
<213>人
<400>49
Leu Leu Ala Ser Asp Ala Gly Leu Tyr Arg
1 5 10
<210>50
<211>12
<212>PRT
<213>人
<400>50
Leu Ala Thr Val Gly Glu Leu Gln Ala Ala Trp Arg
1 5 10
<210>51
<211>13
<212>PRT
<213>人
<400>51
Glu Thr Thr Val Leu Val Ala Gln Asn Gly Asn Ile Lys
1 5 10
<210>52
<211>11
<212>PRT
<213>人
<400>52
Ser Leu Glu Asp Leu Gln Leu Thr His Asn Lys
1 5 10
<210>53
<211>11
<212>PRT
<213>人
<400>53
Leu Lys Glu Asp Ala Val Ser Ala Ala Phe Lys
1 5 10
<210>54
<211>14
<212>PRT
<213>人
<400>54
Ser Ile Glu Tyr Ser Pro Gln Leu Glu Asp Ala Gly Ser Arg
1 5 10
<210>55
<211>10
<212>PRT
<213>人
<400>55
Leu Glu Gly Asp Thr Leu Ile Ile Pro Arg
1 5 10
<210>56
<211>20
<212>PRT
<213>人
<400>56
Arg Ile Ser Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu Pro Glu
1 5 10 15
Thr Leu Asn Glu
20
<210>57
<211>12
<212>PRT
<213>人
<400>57
Ala Ile Glu Leu Glu Asp Leu Leu Arg Tyr Ser Lys
1 5 10
<210>58
<211>10
<212>PRT
<213>人
<400>58
Ala Ile Glu Leu Glu Asp Leu Leu Arg Tyr
1 5 10
<210>59
<211>17
<212>PRT
<213>人
<400>59
Glu Ala Lys Leu Thr Gly Ile Pro Lys Asp Leu Pro Glu Thr Leu Asn
1 5 10 15
Glu
<210>60
<211>24
<212>PRT
<213>人
<400>60
Leu Lys Ala Val Pro Lys Glu Ile Ser Pro Asp Thr Thr Leu Leu Asp
1 5 10 15
Leu Gln Asn Asn Asp Ile Ser Glu
20
<210>61
<21l>16
<212>PRT
<213>人
<400>61
Leu Leu Asp Leu Gln Asn Asn Asp Ile Ser Glu Leu Arg Lys Asp Asp
1 5 10 15
<210>62
<211>10
<212>PRT
<213>人
<400>62
Ile Glu Leu Glu Asp Leu Leu Arg Tyr Ser
1 5 10
<210>63
<211>13
<212>PRT
<213>人
<400>63
Asn Ser Gly Phe Glu Pro Gly Ala Phe Asp Gly Leu Lys
1 5 10
<210>64
<211>14
<212>PRT
<213>人
<400>64
Asp Glu Ala Ser Gly Ile Gly Pro Glu Val Pro Asp Asp Arg
1 5 10
<210>65
<211>15
<212>PRT
<213>人
<400>65
Leu His Leu Asp Gly Asn Lys Ile Ser Arg Val Asp Ala Ala Ser
1 5 10 15
<210>66
<211>16
<212>PRT
<213>人
<400>66
Val Asn Asn Lys Ile Ser Lys Val Ser Pro Gly Ala Phe Thr Pro Leu
1 5 10 15
<210>67
<211>24
<212>PRT
<213>人
<400>67
Leu Ile Leu Val Asn Asn Lys Ile Ser Lys Val Ser Pro Gly Ala Phe
1 5 10 15
Thr Pro Leu Val Lys Leu Glu Arg
20
<210>68
<211>15
<212>PRT
<213>人
<400>68
Ser Asn Pro Val Gln Tyr Trp Glu Ile Gln Pro Ser Thr Phe Arg
1 5 10 15
<210>69
<211>13
<212>PRT
<213>人
<400>69
Ser Ser Gly Ile Glu Asn Gly Ala Phe Gln Gly Met Lys
1 5 10
<210>70
<211>16
<212>PRT
<213>人
<400>70
Ser Ser Gly Ile Glu Asn Gly Ala Phe Gln Gly Met Lys Lys Leu Ser
1 5 10 15
<210>71
<211>11
<212>PRT
<213>人
<400>71
Lys Ile Thr Glu Ile Lys Asp Gly Asp Phe Lys
1 5 10
<210>72
<211>15
<212>PRT
<213>人
<400>72
Gly Leu Pro Pro Ser Leu Thr Glu Leu His Leu Asp Gly Asn Lys
1 5 10 15
<210>73
<211>14
<212>PRT
<213>人
<400>73
Val Ser Glu Ala Val Val Glu Lys Leu Glu Pro Glu Tyr Arg
1 5 10
<210>74
<211>15
<212>PRT
<213>人
<400>74
Glu Val Ser Glu Ala Val Val Glu Lys Leu Glu Pro Glu Tyr Arg
1 5 10 15
<210>75
<211>17
<212>PRT
<213>人
<400>75
Ser Ile Glu Tyr Ser Pro Gln Leu Glu Asp Ala Ser Ala Lys Glu Phe
1 5 10 15
Arg
<210>76
<211>6
<212>PRT
<213>人
<400>76
Ser Val Pro Lys Glu Ile
1 5
<210>77
<211>6
<212>PRT
<213>人
<400>77
Asn Ser Gly Phe Glu Pro
1 5
<210>78
<211>6
<212>PRT
<213>人
<400>78
Leu Lys Ser Val Pro Lys
1 5
<210>79
<211>6
<212>PRT
<213>人
<400>79
Leu Arg Ile Ser Glu Ala
1 5
<210>80
<211>6
<212>PRT
<213>人
<400>80
Gly Leu Lys Leu Asn Tyr
1 5
<210>81
<211>6
<212>PRT
<213>人
<400>81
Leu Lys Ser Val Pro Lys
1 5
<210>82
<211>6
<212>PRT
<213>人
<400>82
Gln Cys Ser Asp Leu Gly
1 5
<210>83
<211>6
<212>PRT
<213>人
<400>83
Leu Thr Gly Ile Pro Lys
1 5
<210>84
<211>6
<212>PRT
<213>人
<400>84
Arg Ile Ser Glu Ala Lys
1 5
<210>85
<211>6
<212>PRT
<213>人
<400>85
Ala Ile Glu Leu Glu Asp
1 5
<210>86
<211>6
<212>PRT
<213>人
<400>86
Glu Ala Lys Leu Thr Gly
1 5
<210>87
<211>6
<212>PRT
<213>人
<400>87
Leu Lys Ala Val Pro Lys
1 5
<210>88
<211>6
<212>PRT
<213>人
<400>88
Leu Leu Asp Leu Gln Asn
1 5
<210>89
<211>6
<212>PRT
<213>人
<400>89
Ile Glu Leu Glu Asp Leu
1 5
<210>90
<211>6
<212>PRT
<213>人
<400>90
Asn Ser Gly Phe Glu Pro
1 5
<210>91
<211>6
<212>PRT
<213>人
<400>91
Ile Val Ile Glu Leu Gly
1 5
<210>92
<211>6
<212>PRT
<213>人
<400>92
Asn Gly Leu Asn Gln Met
1 5
<210>93
<211>6
<212>PRT
<213>人
<400>93
Asp Glu Ala Ser Gly Ile
1 5
<210>94
<211>6
<212>PRT
<213>人
<400>94
Leu His Leu Asp Gly Asn
1 5
<210>95
<211>6
<212>PRT
<213>人
<400>95
Val Asn Asn Lys Ile Ser
1 5
<210>96
<211>6
<212>PRT
<213>人
<400>96
Leu Ile Leu Val Asn Asn
1 5
<210>97
<211>6
<212>PRT
<213>人
<400>97
Ser Asn Pro Val Gln Tyr
1 5
<210>98
<211>6
<212>PRT
<213>人
<400>98
Ser Ser Gly Ile Glu Asn
1 5
<210>99
<211>6
<212>PRT
<213>人
<400>99
Lys Ile Thr Glu Ile Lys
1 5
<210>100
<211>6
<212>PRT
<213>人
<400>100
Gly Leu Pro Pro Ser Leu
1 5
<210>101
<211>6
<212>PRT
<213>人
<400>101
Leu Leu Ala Ser Asp Ala
1 5
<210>102
<211>6
<212>PRT
<213>人
<400>102
Leu Ala Thr Val Gly Glu
1 5
<210>103
<211>6
<212>PRT
<213>人
<400>103
Glu Thr Thr Val Leu Val
1 5
<210>104
<211>6
<212>PRT
<213>人
<400>104
Ser Leu Thr Val Val Lys
1 5
<210>105
<211>6
<212>PRT
<213>人
<400>105
Glu Asn Gln Asp Ala Arg
1 5
<210>106
<211>6
<212>PRT
<213>人
<400>106
Asn Gly Phe Asp Gln Cys
1 5
<210>107
<211>6
<212>PRT
<213>人
<400>107
Ser Leu Glu Asp Leu Gln
1 5
<210>108
<211>6
<212>PRT
<213>人
<400>108
Leu Lys Glu Asp Ala Val
1 5
<210>109
<211>6
<212>PRT
<213>人
<400>109
His Leu Gln His Asn Arg
1 5
<210>110
<211>6
<212>PRT
<213>人
<400>110
Leu Gln His Asn Arg Leu
1 5
<210>111
<211>6
<212>PRT
<213>人
<400>111
Ser Ile Glu Tyr Ser Pro
1 5
<210>112
<211>6
<212>PRT
<213>人
<400>112
Leu Val Asn Phe Thr Arg
1 5
<210>113
<211>6
<212>PRT
<213>人
<400>113
Val Ser Glu Ala Val Val
1 5
<210>114
<211>6
<212>PRT
<213>人
<400>114
Glu Val Ser Glu Ala Val
1 5
<210>115
<211>6
<212>PRT
<213>人
<400>115
Ser Ile Glu Tyr Ser Pro
1 5
<210>116
<211>6
<212>PRT
<213>人
<400>116
Asn Asn Asp Ile Ser Glu
1 5
<210>117
<211>6
<212>PRT
<213>人
<400>117
Arg Ile Ser Glu Ala Lys
1 5
<210>118
<211>6
<212>PRT
<213>人
<400>118
Leu Arg Lys Asp Asp Phe
1 5
<210>119
<211>6
<212>PRT
<213>人
<400>119
Lys Asp Leu Pro Glu Thr
1 5
<210>120
<211>6
<212>PRT
<213>人
<400>120
Leu Asn Glu Leu His Leu
1 5
<210>121
<211>6
<212>PRT
<213>人
<400>121
Tyr Trp Glu Val Gln Pro
1 5
<210>122
<211>6
<212>PRT
<213>人
<400>122
Lys Ile Gln Ala Ile Glu
1 5
<210>123
<211>6
<212>PRT
<213>人
<400>123
Pro Glu Thr Leu Asn Glu
1 5
<210>124
<211>6
<212>PRT
<213>人
<400>124
Leu Leu Arg Tyr Ser Lys
1 5
<210>125
<211>6
<212>PRT
<213>人
<400>125
Glu Asp Leu Leu Arg Tyr
1 5
<210>126
<211>6
<212>PRT
<213>人
<400>126
Asn Asn Asp Ile Ser Glu
1 5
<210>127
<211>6
<212>PRT
<213>人
<400>127
Glu Leu Arg Lys Asp Asp
1 5
<210>128
<211>6
<212>PRT
<213>人
<400>128
Asp Leu Leu Arg Tyr Ser
1 5
<210>129
<211>6
<212>PRT
<213>人
<400>129
Ala Phe Asp Gly Leu Lys
1 5
<210>130
<211>6
<212>PRT
<213>人
<400>130
Gly Thr Asn Pro Leu Lys
1 5
<210>131
<211>6
<212>PRT
<213>人
<400>131
Ser Ser Gly Ile Glu Asn
1 5
<210>132
<211>6
<212>PRT
<213>人
<400>132
Glu Val Pro Asp Asp Arg
1 5
<210>133
<211>6
<212>PRT
<213>人
<400>133
Arg Val Asp Ala Ala Ser
1 5
<210>134
<211>6
<212>PRT
<213>人
<400>134
Gly Ala Phe Thr Pro Leu
1 5
<210>135
<211>6
<212>PRT
<213>人
<400>135
Leu Val Lys Leu Glu Arg
1 5
<210>136
<211>6
<212>PRT
<213>人
<400>136
Gln Pro Ser Thr Phe Arg
1 5
<210>137
<211>6
<212>PRT
<213>人
<400>137
Ala Phe Gln Gly Met Lys
1 5
<210>138
<211>6
<212>PRT
<213>人
<400>138
Gly Met Lys Lys Leu Ser
1 5
<210>139
<211>6
<212>PRT
<213>人
<400>139
Lys Asp Gly Asp Phe Lys
1 5
<210>140
<211>6
<212>PRT
<213>人
<400>140
His Leu Asp Gly Asn Lys
1 5
<210>141
<211>6
<212>PRT
<213>人
<400>141
Cys Asp Val Met Tyr Gly
1 5
<210>142
<211>6
<212>PRT
<213>人
<400>142
Asn Gly Phe Asp Gln Cys
1 5
<210>143
<211>6
<212>PRT
<213>人
<400>143
Gln Asn Gly Ile Asn Lys
1 5
<210>144
<211>6
<212>PRT
<213>人
<400>144
Ile Gly Gln Asp Tyr Lys
1 5
<210>145
<211>6
<212>PRT
<213>人
<400>145
Gln Leu Thr His Asn Lys
1 5
<210>146
<211>6
<212>PRT
<213>人
<400>146
Val Ser Ala Ala Phe Lys
1 5
<210>147
<211>6
<212>PRT
<213>人
<400>147
Gly Leu Lys Ser Leu Glu
1 5
<210>148
<211>6
<212>PRT
<213>人
<400>148
Glu Asp Ala Gly Ser Arg
1 5
<210>149
<211>6
<212>PRT
<213>人
<400>149
Glu Phe Arg Glu Val Ser
1 5
<210>150
<211>6
<212>PRT
<213>人
<400>150
Val Ala Gln Gln Asp Ser
1 5
<210>151
<211>6
<212>PRT
<213>人
<400>151
Leu Glu Pro Glu Tyr Arg
1 5
<210>152
<211>6
<212>PRT
<213>人
<400>152
Ser Ala Lys Glu Phe Arg
1 5
<210>153
<211>1466
<212>PRT
<213>人
<400>153
Met Met Ser Phe Val Gln Lys Gly Ser Trp Leu Leu Leu Ala Leu Leu
1 5 10 15
His Pro Thr Ile Ile Leu Ala Gln Gln Glu Ala Val Glu Gly Gly Cys
20 25 30
Ser His Leu Gly Gln Ser Tyr Ala Asp Arg Asp Val Trp Lys Pro Glu
35 40 45
Pro Cys Gln Ile Cys Val Cys Asp Ser Gly Ser Val Leu Cys Asp Asp
50 55 60
Ile Ile Cys Asp Asp Gln Glu Leu Asp Cys Pro Asn Pro Glu Ile Pro
65 70 75 80
Phe Gly Glu Cys Cys Ala Val Cys Pro Gln Pro Pro Thr Ala Pro Thr
85 90 95
Arg Pro Pro Asn Gly Gln Gly Pro Gln Gly Pro Lys Gly Asp Pro Gly
100 105 110
Pro Pro Gly Ile Pro Gly Arg Asn Gly Asp Pro Gly Ile Pro Gly Gln
115 120 125
Pro Gly Ser Pro Gly Ser Pro Gly Pro Pro Gly Ile Cys Glu Ser Cys
130 135 140
Pro Thr Gly Pro Gln Asn Tyr Ser Pro Gln Tyr Asp Ser Tyr Asp Val
145 150 155 160
Lys Ser Gly Val Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala
165 170 175
Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Thr Ser Gly His Pro Gly
180 185 190
Ser Pro Gly Ser Pro Gly Tyr Gln Gly Pro Pro Gly Glu Pro Gly Gln
195 200 205
Ala Gly Pro Ser Gly Pro Pro Gly Pro Pro Gly Ala Ile Gly Pro Ser
210 215 220
Gly Pro Ala Gly Lys Asp Gly Glu Ser Gly Arg Pro Gly Arg Pro Gly
225 230 235 240
Glu Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly Ile
245 250 255
Pro Gly Phe Pro Gly Met Lys Gly His Arg Gly Phe Asp Gly Arg Asn
260 265 270
Gly Glu Lys Gly Glu Thr Gly Ala Pro Gly Leu Lys Gly Glu Asn Gly
275 280 285
Leu Pro Gly Glu Asn Gly Ala Pro Gly Pro Met Gly Pro Arg Gly Ala
290 295 300
Pro Gly Glu Arg Gly Arg Pro Gly Leu Pro Gly Ala Ala Gly Ala Arg
305 310 315 320
Gly Asn Asp Gly Ala Arg Gly Ser Asp Gly Gln Pro Gly Pro Pro Gly
325 330 335
Pro Pro Gly Thr Ala Gly Phe Pro Gly Ser Pro Gly Ala Lys Gly Glu
340 345 350
Val Gly Pro Ala Gly Ser Pro Gly Ser Asn Gly Ala Pro Gly Gln Arg
355 360 365
Gly Glu Pro Gly Pro Gln Gly His Ala Gly Ala Gln Gly Pro Pro Gly
370 375 380
Pro Pro Gly Ile Asn Gly Ser Pro Gly Gly Lys Gly Glu Met Gly Pro
385 390 395 400
Ala Gly Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro
405 410 415
Gly Pro Ala Gly Ala Asn Gly Ala Pro Gly Leu Arg Gly Gly Ala Gly
420 425 430
Glu Pro Gly Lys Asn Gly Ala Lys Gly Glu Pro Gly Pro Arg Gly Glu
435 440 445
Arg Gly Glu Ala Gly Ile Pro Gly Val Pro Gly Ala Lys Gly Glu Asp
450 455 460
Gly Lys Asp Gly Ser Pro Gly Glu Pro Gly Ala Asn Gly Leu Pro Gly
465 470 475 480
Ala Ala Gly Glu Arg Gly Ala Pro Gly Phe Arg Gly Pro Ala Gly Pro
485 490 495
Asn Gly Ile Pro Gly Glu Lys Gly Pro Ala Gly Glu Arg Gly Ala Pro
500 505 510
Gly Pro Ala Gly Pro Arg Gly Ala Ala Gly Glu Pro Gly Arg Asp Gly
515 520 525
Val Pro Gly Gly Pro Gly Met Arg Gly Met Pro Gly Ser Pro Gly Gly
530 535 540
Pro Gly Ser Asp Gly Lys Pro Gly Pro Pro Gly Ser Gln Gly Glu Ser
545 550 555 560
Gly Arg Pro Gly Pro Pro Gly Pro Ser Gly Pro Arg Gly Gln Pro Gly
565 570 575
Val Met Gly Phe Pro Gly Pro Lys Gly Asn Asp Gly Ala Pro Gly Lys
580 585 590
Asn Gly Glu Arg Gly Gly Pro Gly Gly Pro Gly Pro Gln Gly Pro Pro
595 600 605
Gly Lys Asn Gly Glu Thr Gly Pro Gln Gly Pro Pro Gly Pro Thr Gly
610 615 620
Pro Gly Gly Asp Lys Gly Asp Thr Gly Pro Pro Gly Pro Gln Gly Leu
625 630 635 640
Gln Gly Leu Pro Gly Thr Gly Gly Pro Pro Gly Glu Asn Gly Lys Pro
645 650 655
Gly Glu Pro Gly Pro Lys Gly Asp Ala Gly Ala Pro Gly Ala Pro Gly
660 665 670
Gly Lys Gly Asp Ala Gly Ala Pro Gly Glu Arg Gly Pro Pro Gly Leu
675 680 685
Ala Gly Ala Pro Gly Leu Arg Gly Gly Ala Gly Pro Pro Gly Pro Glu
690 695 700
Gly Gly Lys Gly Ala Ala Gly Pro Pro Gly Pro Pro Gly Ala Ala Gly
705 710 715 720
Thr Pro Gly Leu Gln Gly Met Pro Gly Glu Arg Gly Gly Leu Gly Ser
725 730 735
Pro Gly Pro Lys Gly Asp Lys Gly Glu Pro Gly Gly Pro Gly Ala Asp
740 745 750
Gly Val Pro Gly Lys Asp Gly Pro Arg Gly Pro Thr Gly Pro Ile Gly
755 760 765
Pro Pro Gly Pro Ala Gly Gln Pro Gly Asp Lys Gly Glu Gly Gly Ala
770 775 780
Pro Gly Leu Pro Gly Ile Ala Gly Pro Arg Gly Ser Pro Gly Glu Arg
785 790 795 800
Gly Glu Thr Gly Pro Pro Gly Pro Ala Gly Phe Pro Gly Ala Pro Gly
805 810 815
Gln Asn Gly Glu Pro Gly Gly Lys Gly Glu Arg Gly Ala Pro Gly Glu
820 825 830
Lys Gly Glu Gly Gly Pro Pro Gly Val Ala Gly Pro Pro Gly Gly Ser
835 840 845
Gly Pro Ala Gly Pro Pro Gly Pro Gln Gly Val Lys Gly Glu Arg Gly
850 855 860
Ser Pro Gly Gly Pro Gly Ala Ala Gly Phe Pro Gly Ala Arg Gly Leu
865 870 875 880
Pro Gly Pro Pro Gly Ser Asn Gly Asn Pro Gly Pro Pro Gly Pro Ser
885 890 895
Gly Ser Pro Gly Lys Asp Gly Pro Pro Gly Pro Ala Gly Asn Thr Gly
900 905 910
Ala Pro Gly Ser Pro Gly Val Ser Gly Pro Lys Gly Asp Ala Gly Gln
915 920 925
Pro Gly Glu Lys Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro
930 935 940
Gly Pro Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly
945 950 955 960
Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly Val
965 970 975
Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly Leu Ser Gly Glu Arg
980 985 990
Gly Pro Pro Gly Pro Gln Gly Leu Pro Gly Leu Ala Gly Thr Ala Gly
995 1000 1005
Glu Pro Gly Arg Asp Gly Asn Pro Gly Ser Asp Gly Leu Pro Gly
1010 1015 1020
Arg Asp Gly Ser Pro Gly Gly Lys Gly Asp Arg Gly Glu Asn Gly
1025 1030 1035
Ser Pro Gly Ala Pro Gly Ala Pro Gly His Pro Gly Pro Pro Gly
1040 1045 1050
Pro Val Gly Pro Ala Gly Lys Ser Gly Asp Arg Gly Glu Ser Gly
1055 1060 1065
Pro Ala Gly Pro Ala Gly Ala Pro Gly Pro Ala Gly Ser Arg Gly
1070 1075 1080
Ala Pro Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly Glu Thr Gly
1085 1090 1095
Glu Arg Gly Ala Ala Gly Ile Lys Gly His Arg Gly Phe Pro Gly
1100 1105 1110
Asn Pro Gly Ala Pro Gly Ser Pro Gly Pro Ala Gly Gln Gln Gly
1115 1120 1125
Ala Ile Gly Ser Pro Gly Pro Ala Gly Pro Arg Gly Pro Val Gly
1130 1135 1140
Pro Ser Gly Pro Pro Gly Lys Asp Gly Thr Ser Gly His Pro Gly
1145 1150 1155
Pro Ile Gly Pro Pro Gly Pro Arg Gly Asn Arg Gly Glu Arg Gly
1160 1165 1170
Ser Glu Gly Ser Pro Gly His Pro Gly Gln Pro Gly Pro Pro Gly
1175 1180 1185
Pro Pro Gly Ala Pro Gly Pro Cys Cys Gly Gly Val Gly Ala Ala
1190 1195 1200
Ala Ile Ala Gly Ile Gly Gly Glu Lys Ala Gly Gly Phe Ala Pro
1205 1210 1215
Tyr Tyr Gly Asp Glu Pro Met Asp Phe Lys Ile Asn Thr Asp Glu
1220 1225 1230
Ile Met Thr Ser Leu Lys Ser Val Asn Gly Gln Ile Glu Ser Leu
1235 1240 1245
Ile Ser Pro Asp Gly Ser Arg Lys Asn Pro Ala Arg Asn Cys Arg
1250 1255 1260
Asp Leu Lys Phe Cys His Pro Glu Leu Lys Ser Gly Glu Tyr Trp
1265 1270 1275
Val Asp Pro Asn Gln Gly Cys Lys Leu Asp Ala Ile Lys Val Phe
1280 1285 1290
Cys Asn Met Glu Thr Gly Glu Thr Cys Ile Ser Ala Asn Pro Leu
1295 1300 1305
Asn Val Pro Arg Lys His Trp Trp Thr Asp Ser Ser Ala Glu Lys
1310 1315 1320
Lys His Val Trp Phe Gly Glu Ser Met Asp Gly Gly Phe Gln Phe
1325 1330 1335
Ser Tyr Gly Asn Pro Glu Leu Pro Glu Asp Val Leu Asp Val Gln
1340 1345 1350
Leu Ala Phe Leu Arg Leu Leu Ser Ser Arg Ala Ser Gln Asn Ile
1355 1360 1365
Thr Tyr His Cys Lys Asn Ser Ile Ala Tyr Met Asp Gln Ala Ser
1370 1375 1380
Gly Asn Val Lys Lys Ala Leu Lys Leu Met Gly Ser Asn Glu Gly
1385 1390 1395
Glu Phe Lys Ala Glu Gly Asn Ser Lys Phe Thr Tyr Thr Val Leu
1400 1405 1410
Glu Asp Gly Cys Thr Lys His Thr Gly Glu Trp Ser Lys Thr Val
1415 1420 1425
Phe Glu Tyr Arg Thr Arg Lys Ala Val Arg Leu Pro Ile Val Asp
1430 1435 1440
Ile Ala Pro Tyr Asp Ile Gly Gly Pro Asp Gln Glu Phe Gly Val
1445 1450 1455
Asp Val Gly Pro Val Cys Phe Leu
1460 1465
<210>154
<211>20
<212>PRT
<213>人
<400>154
Ala Gly Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro
1 5 10 15
Gly Pro Ala Gly
20
<210>155
<211>19
<212>PRT
<213>人
<400>155
Lys Gly Asp Pro Gly Pro Pro Gly Ile Pro Gly Arg Asn Gly Asp Pro
1 5 10 15
Gly Ile Pro
<210>156
<211>20
<212>PRT
<213>人
<400>156
Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro Gly
1 5 10 15
Pro Gln Gly Val
20
<210>157
<211>21
<212>PRT
<213>人
<400>157
Gly Glu Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly
1 5 10 15
Ile Pro Gly Phe Pro
20
<210>158
<211>22
<212>PRT
<213>人
<400>158
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly
1 5 10 15
Met Pro Gly Pro Arg Gly
20
<210>159
<211>23
<212>PRT
<213>人
<400>159
Gly Ile Lys Gly His Arg Gly Phe Pro Gly Asn Pro Gly Ala Pro Gly
1 5 10 15
Ser Pro Gly Pro Ala Gly Gln
20
<210>160
<211>23
<212>PRT
<213>人
<400>160
Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser
1 5 10 15
Pro Gly Pro Gln Gly Val Lys
20
<210>161
<211>25
<212>PRT
<213>人
<400>161
Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro
1 5 10 15
Arg Gly Ser Pro Gly Pro Gln Gly Val
20 25
<210>162
<211>26
<212>PRT
<213>人
<400>162
Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro
1 5 10 15
Arg Gly Ser Pro Gly Pro Gln Gly Val Lys
20 25
<210>163
<211>26
<212>PRT
<213>人
<400>163
Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly
1 5 10 15
Pro Arg Gly Ser Pro Gly Pro Gln Gly Val
20 25
<210>164
<211>26
<212>PRT
<213>人
<400>164
Gly Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly Leu Ser Gly
1 5 10 15
Glu Arg Gly Pro Pro Gly Pro Gln Gly Leu
20 25
<210>165
<211>26
<212>PRT
<213>人
<400>165
Gly Ser Arg Gly Ala Pro Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly
1 5 10 15
Glu Thr Gly Glu Arg Gly Ala Ala Gly Ile
20 25
<210>166
<211>28
<212>PRT
<213>人
<400>166
Pro Lys Gly Asp Ala Gly Gln Pro Gly Glu Lys Gly Ser Pro Gly Ala
1 5 10 15
Gln Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly Ile
20 25
<210>167
<211>27
<212>PRT
<213>人
<400>167
Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly
1 5 10 15
Pro Arg Gly Ser Pro Gly Pro Gln Gly Val Lys
20 25
<210>168
<211>32
<212>PRT
<213>人
<400>168
Gly Leu Arg Gly Gly Ala Gly Pro Pro Gly Pro Glu Gly Gly Lys Gly
1 5 10 15
Ala Ala Gly Pro Pro Gly Pro Pro Gly Ala Ala Gly Thr Pro Gly Leu
20 25 30
<210>169
<211>35
<212>PRT
<213>人
<400>169
Gly His Ala Gly Ala Gln Gly Pro Pro Gly Pro Pro Gly Ile Asn Gly
1 5 10 15
Ser Pro Gly Gly Lys Gly Glu Met Gly Pro Ala Gly Ile Pro Gly Ala
20 25 30
Pro Gly Leu
35
<210>170
<211>48
<212>PRT
<213>人
<400>170
Ala Gly Lys Ser Gly Asp Arg Gly Glu Ser Gly Pro Ala Gly Pro Ala
1 5 10 15
Gly Ala Pro Gly Pro Ala Gly Ser Arg Gly Ala Pro Gly Pro Gln Gly
20 25 30
Pro Arg Gly Asp Lys Gly Glu Thr Gly Glu Arg Gly Ala Ala Gly Ile
35 40 45
<210>171
<211>50
<212>PRT
<213>人
<400>171
Gly Leu Gln Gly Leu Pro Gly Thr Gly Gly Pro Pro Gly Glu Asn Gly
1 5 10 15
Lys Pro Gly Glu Pro Gly Pro Lys Gly Asp Ala Gly Ala Pro Gly Ala
20 25 30
Pro Gly Gly Lys Gly Asp Ala Gly Ala Pro Gly Glu Arg Gly Pro Pro
35 40 45
Gly Leu
50
<210>172
<211>21
<212>PRT
<213>人
<400>172
Gly Glu Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly
1 5 10 15
Ile Pro Gly Phe Pro
20
<210>173
<211>24
<212>PRT
<213>人
<400>173
Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala Gly Pro Pro Gly
1 5 10 15
Pro Pro Gly Pro Pro Gly Thr Ser
20
<210>174
<211>24
<212>PRT
<213>人
<400>174
Lys Asp Gly Thr Ser Gly His Pro Gly Pro Ile Gly Pro Pro Gly Pro
1 5 10 15
Arg Gly Asn Arg Gly Glu Arg Gly
20
<210>175
<211>29
<212>PRT
<213>人
<400>175
Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala Gly Pro Pro Gly
1 5 10 15
Pro Pro Gly Pro Pro Gly Thr Ser Gly His Pro Gly Ser
20 25
<210>176
<211>29
<212>PRT
<213>人
<400>176
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly
1 5 10 15
Met Pro Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly Val
20 25
<210>177
<211>31
<212>PRT
<213>人
<400>177
Ala Pro Gly Ala Pro Gly Gly Lys Gly Asp Ala Gly Ala Pro Gly Glu
1 5 10 15
Arg Gly Pro Pro Gly Leu Ala Gly Ala Pro Gly Leu Arg Gly Gly
20 25 30
<210>178
<211>32
<212>PRT
<213>人
<400>178
Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala Gly Pro Pro Gly
1 5 10 15
Pro Pro Gly Pro Pro Gly Thr Ser Gly His Pro Gly Ser Pro Gly Ser
20 25 30
<210>179
<211>22
<212>PRT
<213>人
<400>179
Ala Ile Gly Ser Pro Gly Pro Ala Gly Pro Arg Gly Pro Val Gly Pro
1 5 10 15
Ser Gly Pro Pro Gly Lys
20
<210>180
<211>23
<212>PRT
<213>人
<400>180
Gly Ala Ile Gly Ser Pro Gly Pro Ala Gly Pro Arg Gly Pro Val Gly
1 5 10 15
Pro Ser Gly Pro Pro Gly Lys
20
<210>181
<211>15
<212>PRT
<213>人
<400>181
Pro Ala Gly Gln Gln Gly Ala Ile Gly Ser Pro Gly Pro Ala Gly
1 5 10 15
<210>182
<211>20
<212>PRT
<213>人
<400>182
Gly Gly Pro Pro Gly Val Ala Gly Pro Pro Gly Gly Ser Gly Pro Ala
1 5 10 15
Gly Pro Pro Gly
20
<210>183
<211>19
<212>PRT
<213>人
<400>183
Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro Gly Pro
1 5 10 15
Gln Gly Val
<210>184
<211>19
<212>PRT
<213>人
<400>184
Gly Leu Ser Gly Glu Arg Gly Pro Pro Gly Pro Gln Gly Leu Pro Gly
1 5 10 15
Leu Ala Gly
<210>185
<211>21
<212>PRT
<213>人
<400>185
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val
20
<210>186
<211>21
<212>PRT
<213>人
<400>186
Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro Gly
1 5 10 15
Pro Gln Gly Val Lys
20
<210>187
<211>22
<212>PRT
<213>人
<400>187
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys
20
<210>188
<211>21
<212>PRT
<213>人
<400>188
Gly Pro Gln Gly Pro Pro Gly Lys Asn Gly Glu Thr Gly Pro Gln Gly
1 5 10 15
Pro Pro Gly Pro Thr
20
<210>189
<211>22
<212>PRT
<213>人
<400>189
Gly Val Lys Gly Glu Arg Gly Ser Pro Gly Gly Pro Gly Ala Ala Gly
1 5 10 15
Phe Pro Gly Ala Arg Gly
20
<210>190
<211>22
<212>PRT
<213>人
<400>190
Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser
1 5 10 15
Pro Gly Pro Gln Gly Val
20
<210>191
<211>23
<212>PRT
<213>人
<400>191
Asn Gly Leu Ser Gly Glu Arg Gly Pro Pro Gly Pro Gln Gly Leu Pro
1 5 10 15
Gly Leu Ala Gly Thr Ala Gly
20
<210>192
<211>24
<212>PRT
<213>人
<400>192
Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala Gly Pro Pro Gly
1 5 10 15
Pro Pro Gly Pro Pro Gly Thr Ser
20
<210>193
<211>24
<212>PRT
<213>人
<400>193
Gly Ser Pro Gly Gly Lys Gly Glu Met Gly Pro Ala Gly Ile Pro Gly
1 5 10 15
Ala Pro Gly Leu Met Gly Ala Arg
20
<210>194
<211>24
<212>PRT
<213>人
<400>194
Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg
1 5 10 15
Gly Ser Pro Gly Pro Gln Gly Val
20
<210>195
<211>25
<212>PRT
<213>人
<400>195
Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly Leu Ser Gly Glu
1 5 10 15
Arg Gly Pro Pro Gly Pro Gln Gly Leu
20 25
<210>196
<211>53
<212>PRT
<213>人
<400>196
Gly Val Lys Gly Glu Arg Gly Ser Pro Gly Gly Pro Gly Ala Ala Gly
1 5 10 15
Phe Pro Gly Ala Arg Gly Leu Pro Gly Pro Pro Gly Ser Asn Gly Asn
20 25 30
Pro Gly Pro Pro Gly Pro Ser Gly Ser Pro Gly Lys Asp Gly Pro Pro
35 40 45
Gly Pro Ala Gly Asn
50
<210>197
<211>32
<212>PRT
<213>人
<400>197
Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly
1 5 10 15
Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met
20 25 30
<210>198
<211>32
<212>PRT
<213>人
<400>198
Arg Gly Ala Pro Gly Glu Lys Gly Glu Gly Gly Pro Pro Gly Val Ala
1 5 10 15
Gly Pro Pro Gly Gly Ser Gly Pro Ala Gly Pro Pro Gly Pro Gln Gly
20 25 30
<210>199
<211>32
<212>PRT
<213>人
<400>199
Arg Gly Ala Pro Gly Glu Lys Gly Glu Gly Gly Pro Pro Gly Val Ala
1 5 10 15
Gly Pro Pro Gly Gly Ser Gly Pro Ala Gly Pro Pro Gly Pro Gln Gly
20 25 30
<210>200
<211>29
<212>PRT
<213>人
<400>200
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly
1 5 10 15
Met Pro Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly Val
20 25
<210>201
<211>14
<212>PRT
<213>人
<400>201
Gly Ile Lys Gly Pro Ala Gly Ile Pro Gly Phe Pro Gly Met
1 5 10
<210>202
<211>14
<212>PRT
<213>人
<400>202
Gly Gln Pro Gly Val Met Gly Phe Pro Gly Pro Lys Gly Asn
1 5 10
<210>203
<211>16
<212>PRT
<213>人
<400>203
Gly Ile Lys Gly Pro Ala Gly Ile Pro Gly Phe Pro Gly Met Lys Gly
1 5 10 15
<210>204
<211>17
<212>PRT
<213>人
<400>204
Gly Ile Lys Gly Pro Ala Gly Ile Pro Gly Phe Pro Gly Met Lys Gly
1 5 10 15
His
<210>205
<211>19
<212>PRT
<213>人
<400>205
Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro Gly Pro
1 5 10 15
Ala Gly Ala
<210>206
<211>19
<212>PRT
<213>人
<400>206
Gly Glu Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly
1 5 10 15
Ile Pro Gly
<210>207
<211>20
<212>PRT
<213>人
<400>207
Gly Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro Gly
1 5 10 15
Pro Ala Gly Ala
20
<210>208
<211>20
<212>PRT
<213>人
<400>208
Gly Phe Arg Gly Pro Ala Gly Pro Asn Gly Ile Pro Gly Glu Lys Gly
1 5 10 15
Pro Ala Gly Glu
20
<210>209
<211>20
<212>PRT
<213>人
<400>209
Pro Gly Ile Pro Gly Gln Pro Gly Ser Pro Gly Ser Pro Gly Pro Pro
1 5 10 15
Gly Ile Cys Glu
20
<210>210
<211>21
<212>PRT
<213>人
<400>210
Gly Glu Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly
1 5 10 15
Ile Pro Gly Phe Pro
20
<210>211
<211>23
<212>PRT
<213>人
<400>211
Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala Gly Pro Pro Gly
1 5 10 15
Pro Pro Gly Pro Pro Gly Thr
20
<210>212
<211>23
<212>PRT
<213>人
<400>212
Gly Val Lys Gly Glu Arg Gly Ser Pro Gly Gly Pro Gly Ala Ala Gly
1 5 10 15
Phe Pro Gly Ala Arg Gly Leu
20
<210>213
<211>26
<212>PRT
<213>人
<400>213
Gly Asp Ala Gly Ala Pro Gly Ala Pro Gly Gly Lys Gly Asp Ala Gly
1 5 10 15
Ala Pro Gly Glu Arg Gly Pro Pro Gly Leu
20 25
<210>214
<211>25
<212>PRT
<213>人
<400>214
Gln Gly Pro Pro Gly Pro Thr Gly Pro Gly Gly Asp Lys Gly Asp Thr
1 5 10 15
Gly Pro Pro Gly Pro Gln Gly Leu Gln
20 25
<210>215
<211>25
<212>PRT
<213>人
<400>215
Gly Ile Asn Gly Ser Pro Gly Gly Lys Gly Glu Met Gly Pro Ala Gly
1 5 10 15
Ile Pro Gly Ala Pro Gly Leu Met Gly
20 25
<210>216
<211>26
<212>PRT
<213>人
<400>216
Gln Gly Pro Pro Gly Glu Pro Gly Gln Ala Gly Pro Ser Gly Pro Pro
1 5 10 15
Gly Pro Pro Gly Ala Ile Gly Pro Ser Gly
20 25
<210>217
<211>26
<212>PRT
<213>人
<400>217
Pro Gly Pro Pro Gly Ile Asn Gly Ser Pro Gly Gly Lys Gly Glu Met
1 5 10 15
Gly Pro Ala Gly Ile Pro Gly Ala Pro Gly
20 25
<210>218
<211>33
<212>PRT
<213>人
<400>218
Arg Gly Leu Pro Gly Pro Pro Gly Ser Asn Gly Asn Pro Gly Pro Pro
1 5 10 15
Gly Pro Ser Gly Ser Pro Gly Lys Asp Gly Pro Pro Gly Pro Ala Gly
20 25 30
Asn
<210>219
<211>32
<212>PRT
<213>人
<400>219
Gly Lys Asn Gly Glu Thr Gly Pro Gln Gly Pro Pro Gly Pro Thr Gly
1 5 10 15
Pro Gly Gly Asp Lys Gly Asp Thr Gly Pro Pro Gly Pro Gln Gly Leu
20 25 30
<210>220
<211>32
<212>PRT
<213>人
<400>220
Gly Leu Pro Gly Ile Ala Gly Pro Arg Gly Ser Pro Gly Glu Arg Gly
1 5 10 15
Glu Thr Gly Pro Pro Gly Pro Ala Gly Phe Pro Gly Ala Pro Gly Gln
20 25 30
<210>221
<211>35
<212>PRT
<213>人
<400>221
Gly Ile Asn Gly Ser Pro Gly Gly Lys Gly Glu Met Gly Pro Ala Gly
1 5 10 15
Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro Gly Pro
20 25 30
Ala Gly Ala
35
<210>222
<211>36
<212>PRT
<213>人
<400>222
Pro Gly Ile Asn Gly Ser Pro Gly Gly Lys Gly Glu Met Gly Pro Ala
1 5 10 15
Gly Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro Gly
20 25 30
Pro Ala Gly Ala
35
<210>223
<211>40
<212>PRT
<213>人
<400>223
Pro Pro Gly Glu Asn Gly Lys Pro Gly Glu Pro Gly Pro Lys Gly Asp
1 5 10 15
Ala Gly Ala Pro Gly Ala Pro Gly Gly Lys Gly Asp Ala Gly Ala Pro
20 25 30
Gly Glu Arg Gly Pro Pro Gly Leu
35 40
<210>224
<211>38
<212>PRT
<213>人
<400>224
Gly Leu Lys Gly Glu Asn Gly Leu Pro Gly Glu Asn Gly Ala Pro Gly
1 5 10 15
Pro Met Gly Pro Arg Gly Ala Pro Gly Glu Arg Gly Arg Pro Gly Leu
20 25 30
Pro Gly Ala Ala Gly Ala
35
<210>225
<211>41
<212>PRT
<213>人
<400>225
Gly Asn Thr Gly Ala Pro Gly Ser Pro Gly Val Ser Gly Pro Lys Gly
1 5 10 15
Asp Ala Gly Gln Pro Gly Glu Lys Gly Ser Pro Gly Ala Gln Gly Pro
20 25 30
Pro Gly Ala Pro Gly Pro Leu Gly Ile
35 40
<210>226
<211>41
<212>PRT
<213>人
<400>226
Gly Leu Met Gly Ala Arg Gly Pro Pro Gly Pro Ala Gly Ala Asn Gly
1 5 10 15
Ala Pro Gly Leu Arg Gly Gly Ala Gly Glu Pro Gly Lys Asn Gly Ala
20 25 30
Lys Gly Glu Pro Gly Pro Arg Gly Glu
35 40
<210>227
<211>50
<212>PRT
<213>人
<400>227
Gly Leu Arg Gly Gly Ala Gly Pro Pro Gly Pro Glu Gly Gly Lys Gly
1 5 10 15
Ala Ala Gly Pro Pro Gly Pro Pro Gly Ala Ala Gly Thr Pro Gly Leu
20 25 30
Gln Gly Met Pro Gly Glu Arg Gly Gly Leu Gly Ser Pro Gly Pro Lys
35 40 45
Gly Asp
50
<210>228
<211>26
<212>PRT
<213>人
<400>228
Gly Gln Gln Gly Ala Ile Gly Ser Pro Gly Pro Ala Gly Pro Arg Gly
1 5 10 15
Pro Val Gly Pro Ser Gly Pro Pro Gly Lys
20 25
<210>229
<211>24
<212>PRT
<213>人
<400>229
Lys Gly Asp Pro Gly Pro Pro Gly Ile Pro Gly Arg Asn Gly Asp Pro
1 5 10 15
Gly Ile Pro Gly Gln Pro Gly Ser
20
<210>230
<211>26
<212>PRT
<213>人
<400>230
Gly Leu Arg Gly Gly Ala Gly Pro Pro Gly Pro Glu Gly Gly Lys Gly
1 5 10 15
Ala Ala Gly Pro Pro Gly Pro Pro Gly Ala
20 25
<210>231
<211>32
<212>PRT
<213>人
<400>231
Gly Lys Asn Gly Glu Thr Gly Pro Gln Gly Pro Pro Gly Pro Thr Gly
1 5 10 15
Pro Gly Gly Asp Lys Gly Asp Thr Gly Pro Pro Gly Pro Gln Gly Leu
20 25 30
<210>232
<211>23
<212>PRT
<213>人
<400>232
Gly Tyr Gln Gly Pro Pro Gly Glu Pro Gly Gln Ala Gly Pro Ser Gly
1 5 10 15
Pro Pro Gly Pro Pro Gly Ala
20
<210>233
<211>20
<212>PRT
<213>人
<400>233
Gly Val Ala Gly Pro Pro Gly Gly Ser Gly Pro Ala Gly Pro Pro Gly
1 5 10 15
Pro Gln Gly Val
20
<210>234
<211>35
<212>PRT
<213>人
<400>234
Gly Asp Lys Gly Glu Pro Gly Gly Pro Gly Ala Asp Gly Val Pro Gly
1 5 10 15
Lys Asp Gly Pro Arg Gly Pro Thr Gly Pro Ile Gly Pro Pro Gly Pro
20 25 30
Ala Gly Gln
35
<210>235
<211>17
<212>PRT
<213>人
<400>235
Gln Gly His Ala Gly Ala Gln Gly Pro Pro Gly Pro Pro Gly Ile Asn
1 5 10 15
Gly
<210>236
<211>11
<212>PRT
<213>人
<400>236
Ala Gly Glu Arg Gly Ala Pro Gly Pro Ala Gly
1 5 10
<210>237
<211>11
<212>PRT
<213>人
<400>237
Ala Gly Ile Pro Gly Phe Pro Gly Met Lys Gly
1 5 10
<210>238
<211>12
<212>PRT
<213>人
<400>238
Phe Pro Gly Met Lys Gly His Arg Gly Phe Asp Gly
1 5 10
<210>239
<211>14
<212>PRT
<213>人
<400>239
Gly Phe Pro Gly Ala Arg Gly Leu Pro Gly Pro Pro Gly Ser
1 5 10
<210>240
<211>15
<212>PRT
<213>人
<400>240
Ala Gly Phe Pro Gly Ala Arg Gly Leu Pro Gly Pro Pro Gly Ser
1 5 10 15
<210>241
<211>15
<212>PRT
<213>人
<400>241
Pro Pro Gly Pro Pro Gly Pro Pro Gly Thr Ser Gly His Pro Gly
1 5 10 15
<210>242
<211>13
<212>PRT
<213>人
<400>242
Gly Phe Pro Gly Met Lys Gly His Arg Gly Phe Asp Gly
1 5 10
<210>243
<211>17
<212>PRT
<213>人
<400>243
Gln Pro Gly Asp Lys Gly Glu Gly Gly Ala Pro Gly Leu Pro Gly Ile
1 5 10 15
Ala
<210>244
<211>17
<212>PRT
<213>人
<400>244
Arg Gly Asp Lys Gly Glu Thr Gly Glu Arg Gly Ala Ala Gly Ile Lys
1 5 10 15
Gly
<210>245
<211>17
<212>PRT
<213>人
<400>245
Asp Gly Arg Asn Gly Glu Lys Gly Glu Thr Gly Ala Pro Gly Leu Lys
1 5 10 15
Gly
<210>246
<211>20
<212>PRT
<213>人
<400>246
Ala Gly Gln Pro Gly Asp Lys Gly Glu Gly Gly Ala Pro Gly Leu Pro
1 5 10 15
Gly Ile Ala Gly
20
<210>247
<211>19
<212>PRT
<213>人
<400>247
Gly Gly Pro Pro Gly Glu Asn Gly Lys Pro Gly Glu Pro Gly Pro Lys
1 5 10 15
Gly Asp Ala
<210>248
<211>17
<212>PRT
<213>人
<400>248
Ala Gly Ile Pro Gly Phe Pro Gly Met Lys Gly His Arg Gly Phe Asp
1 5 10 15
Gly
<210>249
<211>20
<212>PRT
<213>人
<400>249
Arg Gly Gly Ala Gly Glu Pro Gly Lys Asn Gly Ala Lys Gly Glu Pro
1 5 10 15
Gly Pro Arg Gly
20
<210>250
<211>26
<212>PRT
<213>人
<400>250
Lys Gly Glu Arg Gly Ser Pro Gly Gly Pro Gly Ala Ala Gly Phe Pro
1 5 10 15
Gly Ala Arg Gly Leu Pro Gly Pro Pro Gly
20 25
<210>251
<211>27
<212>PRT
<213>人
<400>251
Ile Pro Gly Val Pro Gly Ala Lys Gly Glu Asp Gly Lys Asp Gly Ser
1 5 10 15
Pro Gly Glu Pro Gly Ala Asn Gly Leu Pro Gly
20 25
<210>252
<211>28
<212>PRT
<213>人
<400>252
Gly Ala Ala Gly Phe Pro Gly Ala Arg Gly Leu Pro Gly Pro Pro Gly
1 5 10 15
Ser Asn Gly Asn Pro Gly Pro Pro Gly Pro Ser Gly
20 25
<210>253
<211>26
<212>PRT
<213>人
<400>253
Arg Pro Gly Pro Pro Gly Pro Ser Gly Pro Arg Gly Gln Pro Gly Val
1 5 10 15
Met Gly Phe Pro Gly Pro Lys Gly Asn Asp
20 25
<210>254
<211>29
<212>PRT
<213>人
<400>254
Gln Gly Pro Pro Gly Pro Pro Gly Ile Asn Gly Ser Pro Gly Gly Lys
1 5 10 15
Gly Glu Met Gly Pro Ala Gly Ile Pro Gly Ala Pro Gly
20 25
<210>255
<211>26
<212>PRT
<213>人
<400>255
Ala Gly Lys Asp Gly Glu Ser Gly Arg Pro Gly Arg Pro Gly Glu Arg
1 5 10 15
Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly
20 25
<210>256
<211>30
<212>PRT
<213>人
<400>256
Ala Gly Ala Arg Gly Asn Asp Gly Ala Arg Gly Ser Asp Gly Gln Pro
1 5 10 15
Gly Pro Pro Gly Pro Pro Gly Thr Ala Gly Phe Pro Gly Ser
20 25 30
<210>257
<211>31
<212>PRT
<213>人
<400>257
Ser Pro Gly Val Ser Gly Pro Lys Gly Asp Ala Gly Gln Pro Gly Glu
1 5 10 15
Lys Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro
20 25 30
<210>258
<211>32
<212>PRT
<213>人
<400>258
Arg Gly Ser Asp Gly Gln Pro Gly Pro Pro Gly Pro Pro Gly Thr Ala
1 5 10 15
Gly Phe Pro Gly Ser Pro Gly Ala Lys Gly Glu Val Gly Pro Ala Gly
20 25 30
<210>259
<211>32
<212>PRT
<213>人
<400>259
Gln Gly Pro Pro Gly Pro Pro Gly Ile Asn Gly Ser Pro Gly Gly Lys
1 5 10 15
Gly Glu Met Gly Pro Ala Gly Ile Pro Gly Ala Pro Gly Leu Met Gly
20 25 30
<210>260
<211>33
<212>PRT
<213>人
<400>260
Ala Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Thr Ser Gly His Pro
1 5 10 15
Gly Ser Pro Gly Ser Pro Gly Tyr Gln Gly Pro Pro Gly Glu Pro Gly
20 25 30
Gln
<210>261
<211>33
<212>PRT
<213>人
<400>261
Phe Pro Gly Ala Pro Gly Gln Asn Gly Glu Pro Gly Gly Lys Gly Glu
1 5 10 15
Arg Gly Ala Pro Gly Glu Lys Gly Glu Gly Gly Pro Pro Gly Val Ala
20 25 30
Gly
<210>262
<211>33
<212>PRT
<213>人
<400>262
Ala Gly Phe Pro Gly Ala Pro Gly Gln Asn Gly Glu Pro Gly Gly Lys
1 5 10 15
Gly Glu Arg Gly Ala Pro Gly Glu Lys Gly Glu Gly Gly Pro Pro Gly
20 25 30
Val
<210>263
<211>41
<212>PRT
<213>人
<400>263
Ala Gly Ala Arg Gly Asn Asp Gly Ala Arg Gly Ser Asp Gly Gln Pro
1 5 10 15
Gly Pro Pro Gly Pro Pro Gly Thr Ala Gly Phe Pro Gly Ser Pro Gly
20 25 30
Ala Lys Gly Glu Val Gly Pro Ala Gly
35 40
<210>264
<211>53
<212>PRT
<213>人
<400>264
Arg Gly Ala Ala Gly Glu Pro Gly Arg Asp Gly Val Pro Gly Gly Pro
1 5 10 15
Gly Met Arg Gly Met Pro Gly Ser Pro Gly Gly Pro Gly Ser Asp Gly
20 25 30
Lys Pro Gly Pro Pro Gly Ser Gln Gly Glu Ser Gly Arg Pro Gly Pro
35 40 45
Pro Gly Pro Ser Gly
50
<210>265
<211>12
<212>PRT
<213>人
<400>265
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala
1 5 10
<210>266
<211>18
<212>PRT
<213>人
<400>266
Ala Gly Pro Pro Gly Pro Pro Gly Ala Ala Gly Thr Pro Gly Leu Gln
1 5 10 15
Gly Met
<210>267
<211>18
<212>PRT
<213>人
<400>267
Asn Gly Leu Ser Gly Glu Arg Gly Pro Pro Gly Pro Gln Gly Leu Pro
1 5 10 15
Gly Leu
<210>268
<211>20
<212>PRT
<213>人
<400>268
Met Gly Ala Arg Gly Pro Pro Gly Pro Ala Gly Ala Asn Gly Ala Pro
1 5 10 15
Gly Leu Arg Gly
20
<210>269
<211>20
<212>PRT
<213>人
<400>269
Asn Gly Leu Ser Gly Glu Arg Gly Pro Pro Gly Pro Gln Gly Leu Pro
1 5 10 15
Gly Leu Ala Gly
20
<210>270
<211>23
<212>PRT
<213>人
<400>270
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly
1 5 10 15
Met Pro Gly Pro Arg Gly Ser
20
<210>271
<211>29
<212>PRT
<213>人
<400>271
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly
1 5 10 15
Met Pro Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly Val
20 25
<210>272
<211>32
<212>PRT
<213>人
<400>272
Arg Gly Gly Ala Gly Pro Pro Gly Pro Glu Gly Gly Lys Gly Ala Ala
1 5 10 15
Gly Pro Pro Gly Pro Pro Gly Ala Ala Gly Thr Pro Gly Leu Gln Gly
20 25 30
<210>273
<211>30
<212>PRT
<213>人
<400>273
Ser Gly Pro Lys Gly Asp Ala Gly Gln Pro Gly Glu Lys Gly Ser Pro
1 5 10 15
Gly Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly Ile
20 25 30
<210>274
<211>31
<212>PRT
<213>人
<400>274
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly
1 5 10 15
Met Pro Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly Val Lys Gly
20 25 30
<210>275
<211>37
<212>PRT
<213>人
<400>275
Ala Val Gly Gly Leu Ala Gly Tyr Pro Gly Pro Ala Gly Pro Pro Gly
1 5 10 15
Pro Pro Gly Pro Pro Gly Thr Ser Gly His Pro Gly Ser Pro Gly Ser
20 25 30
Pro Gly Tyr Gln Gly
35
<210>276
<211>40
<212>PRT
<213>人
<400>276
Glu Pro Gly Pro Gln Gly His Ala Gly Ala Gln Gly Pro Pro Gly Pro
1 5 10 15
Pro Gly Ile Asn Gly Ser Pro Gly Gly Lys Gly Glu Met Gly Pro Ala
20 25 30
Gly Ile Pro Gly Ala Pro Gly Leu
35 40
<210>277
<211>12
<212>PRT
<213>人
<400>277
Ile Pro Gly Phe Pro Gly Met Lys Gly His Arg Gly
1 5 10
<210>278
<211>17
<212>PRT
<213>人
<400>278
Arg Gly Ser Pro Gly Gly Pro Gly Ala Ala Gly Phe Pro Gly Ala Arg
1 5 10 15
Gly
<210>279
<211>17
<212>PRT
<213>人
<400>279
Lys Gly Pro Ala Gly Ile Pro Gly Phe Pro Gly Met Lys Gly His Arg
1 5 10 15
Gly
<210>280
<211>20
<212>PRT
<213>人
<400>280
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly
20
<210>281
<211>20
<212>PRT
<213>人
<400>281
Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro
1 5 10 15
Gly Pro Arg Gly
20
<210>282
<211>23
<212>PRT
<213>人
<400>282
Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro
1 5 10 15
Gly Met Pro Gly Pro Arg Gly
20
<210>283
<211>23
<212>PRT
<213>人
<400>283
Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg
1 5 10 15
Gly Ser Pro Gly Pro Gln Gly
20
<210>284
<211>24
<212>PRT
<213>人
<400>284
Gln Gly Pro Pro Gly Pro Pro GlyIle Asn Gly Ser Pro Gly Gly Lys
1 5 10 15
Gly Glu Met Gly Pro Ala Gly Ile
20
<210>285
<211>24
<212>PRT
<213>人
<400>285
Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly Ile Pro Gly Phe
1 5 10 15
Pro Gly Met Lys Gly His Arg Gly
20
<210>286
<211>26
<212>PRT
<213>人
<400>286
Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro
1 5 10 15
Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly
20 25
<210>287
<211>26
<212>PRT
<213>人
<400>287
Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg
1 5 10 15
Gly Ser Pro Gly Pro Gln Gly Val Lys Gly
20 25
<210>288
<211>26
<212>PRT
<213>人
<400>288
Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly Ile Pro
1 5 10 15
Gly Phe Pro Gly Met Lys Gly His Arg Gly
20 25
<210>289
<211>29
<212>PRT
<213>人
<400>289
Gly Arg Pro Gly Leu Pro Gly Ala Ala Gly Ala Arg Gly Asn Asp Gly
1 5 10 15
Ala Arg Gly Ser Asp Gly Gln Pro Gly Pro Pro Gly Pro
20 25
<210>290
<211>29
<212>PRT
<213>人
<400>290
Asn Gly Ala Pro Gly Pro Met Gly Pro Arg Gly Ala Pro Gly Glu Arg
1 5 10 15
Gly Arg Pro Gly Leu Pro Gly Ala Ala Gly Ala Arg Gly
20 25
<210>291
<211>29
<212>PRT
<213>人
<400>291
Ala Gly Ser Arg Gly Ala Pro Gly Pro Gln Gly Pro Arg Gly Asp Lys
1 5 10 15
Gly Glu Thr Gly Glu Arg Gly Ala Ala Gly Ile Lys Gly
20 25
<210>292
<211>32
<212>PRT
<213>人
<400>292
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly
20 25 30
<210>293
<211>34
<212>PRT
<213>人
<400>293
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly
20 25 30
Leu Ser
<210>294
<211>37
<212>PRT
<213>人
<400>294
Pro Gly Pro Pro Gly Ser Asn Gly Asn Pro Gly Pro Pro Gly Pro Ser
1 5 10 15
Gly Ser Pro Gly Lys Asp Gly Pro Pro Gly Pro Ala Gly Asn Thr Gly
20 25 30
Ala Pro Gly Ser Pro
35
<210>295
<211>35
<212>PRT
<213>人
<400>295
Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg
1 5 10 15
Gly Ser Pro Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys Pro Gly
20 25 30
Ala Asn Gly
35
<210>296
<211>38
<212>PRT
<213>人
<400>296
Arg Gly Ala Pro Gly Glu Lys Gly Glu Gly Gly Pro Pro Gly Val Ala
1 5 10 15
Gly Pro Pro Gly Gly Ser Gly Pro Ala Gly Pro Pro Gly Pro Gln Gly
20 25 30
Val Lys Gly Glu Arg Gly
35
<210>297
<211>40
<212>PRT
<213>人
<400>297
Gly Gly Pro Pro Gly Val Ala Gly Pro Pro Gly Gly Ser Gly Pro Ala
1 5 10 15
Gly Pro Pro Gly Pro Gln Gly Val Lys Gly Glu Arg Gly Ser Pro Gly
20 25 30
Gly Pro Gly Ala Ala Gly Phe Pro
35 40
<210>298
<211>48
<212>PRT
<213>人
<400>298
Lys Ser Gly Asp Arg Gly Glu Ser Gly Pro Ala Gly Pro Ala Gly Ala
1 5 10 15
Pro Gly Pro Ala Gly Ser Arg Gly Ala Pro Gly Pro Gln Gly Pro Arg
20 25 30
Gly Asp Lys Gly Glu Thr Gly Glu Arg Gly Ala Ala Gly Ile Lys Gly
35 40 45
<210>299
<211>12
<212>PRT
<213>人
<400>299
Ile Pro Gly Phe Pro Gly Met Lys Gly His Arg Gly
1 5 10
<210>300
<211>14
<212>PRT
<213>人
<400>300
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly
1 5 10
<210>301
<211>16
<212>PRT
<213>人
<400>301
Gly Pro Gln Gly Leu Gln Gly Leu Pro Gly Thr Gly Gly Pro Pro Gly
1 5 10 15
<210>302
<211>17
<212>PRT
<213>人
<400>302
Lys Gly Pro Ala Gly Ile Pro Gly Phe Pro Gly Met Lys Gly His Arg
1 5 10 15
Gly
<210>303
<211>21
<212>PRT
<213>人
<400>303
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val
20
<210>304
<211>23
<212>PRT
<213>人
<400>304
Gly Gly Pro Pro Gly Glu Asn Gly Lys Pro Gly Glu Pro Gly Pro Lys
1 5 10 15
Gly Asp Ala Gly Ala Pro Gly
20
<210>305
<211>24
<212>PRT
<213>人
<400>305
Ala Pro Gly Phe Arg Gly Pro Ala Gly Pro Asn Gly Ile Pro Gly Glu
1 5 10 15
Lys Gly Pro Ala Gly Glu Arg Gly
20
<210>306
<211>27
<212>PRT
<213>人
<400>306
Glu Lys Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro
1 5 10 15
Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly
20 25
<210>307
<211>27
<212>PRT
<213>人
<400>307
Glu Lys Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro
1 5 10 15
Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly
20 25
<210>308
<211>26
<212>PRT
<213>人
<400>308
Arg Gly Ala Pro Gly Phe Arg Gly Pro Ala Gly Pro Asn Gly Ile Pro
1 5 10 15
Gly Glu Lys Gly Pro Ala Gly Glu Arg Gly
20 25
<210>309
<211>26
<212>PRT
<213>人
<400>309
Arg Gly Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly Ile Pro
1 5 10 15
Gly Phe Pro Gly Met Lys Gly His Arg Gly
20 25
<210>310
<211>29
<212>PRT
<213>人
<400>310
Arg Gly Pro Val Gly Pro Ser Gly Pro Pro Gly Lys Asp Gly Thr Ser
1 5 10 15
Gly His Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly
20 25
<210>311
<211>27
<212>PRT
<213>人
<400>311
Ala Pro Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly Glu Thr Gly Glu
1 5 10 15
Arg Gly Ala Ala Gly Ile Lys Gly His Arg Gly
20 25
<210>312
<211>29
<212>PRT
<213>人
<400>312
Arg Gly Ala Pro Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly Glu Thr
1 5 10 15
Gly Glu Arg Gly Ala Ala Gly Ile Lys Gly His Arg Gly
20 25
<210>313
<211>32
<212>PRT
<213>人
<400>313
Arg Gly Phe Pro Gly Asn Pro Gly Ala Pro Gly Ser Pro Gly Pro Ala
1 5 10 15
Gly Gln Gln Gly Ala Ile Gly Ser Pro Gly Pro Ala Gly Pro Arg Gly
20 25 30
<210>314
<211>29
<212>PRT
<213>人
<400>314
Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly Ile Pro Gly Phe
1 5 10 15
Pro Gly Met Lys Gly His Arg Gly Phe Asp Gly Arg Asn
20 25
<210>315
<211>33
<212>PRT
<213>人
<400>315
Asp Ala Gly Gln Pro Gly Glu Lys Gly Ser Pro Gly Ala Gln Gly Pro
1 5 10 15
Pro Gly Ala Pro Gly Pro Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg
20 25 30
Gly
<210>316
<211>35
<212>PRT
<213>人
<400>316
Arg Gly Pro Thr Gly Pro Ile Gly Pro Pro Gly Pro Ala Gly Gln Pro
1 5 10 15
Gly Asp Lys Gly Glu Gly Gly Ala Pro Gly Leu Pro Gly Ile Ala Gly
20 25 30
Pro Arg Gly
35
<210>317
<211>35
<212>PRT
<213>人
<400>317
Lys Gly Asp Ala Gly Gln Pro Gly Glu Lys Gly Ser Pro Gly Ala Gln
1 5 10 15
Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly Ile Ala Gly Ile Thr Gly
20 25 30
Ala Arg Gly
35
<210>318
<211>33
<212>PRT
<213>人
<400>318
Arg Asn Gly Glu Lys Gly Glu Thr Gly Ala Pro Gly Leu Lys Gly Glu
1 5 10 15
Asn Gly Leu Pro Gly Glu Asn Gly Ala Pro Gly Pro Met Gly Pro Arg
20 25 30
Gly
<210>319
<211>35
<212>PRT
<213>人
<400>319
Ala Pro Gly Phe Arg Gly Pro Ala Gly Pro Asn Gly Ile Pro Gly Glu
1 5 10 15
Lys Gly Pro Ala Gly Glu Arg Gly Ala Pro Gly Pro Ala Gly Pro Arg
20 25 30
Gly Ala Ala
35
<210>320
<211>35
<212>PRT
<213>人
<400>320
Arg Gly Ala Pro Gly Phe Arg Gly Pro Ala Gly Pro Asn Gly Ile Pro
1 5 10 15
Gly Glu Lys Gly Pro Ala Gly Glu Arg Gly Ala Pro Gly Pro Ala Gly
20 25 30
Pro Arg Gly
35
<210>321
<211>35
<212>PRT
<213>人
<400>321
Arg Gly Ser Pro Gly Glu Arg Gly Glu Thr Gly Pro Pro Gly Pro Ala
1 5 10 15
Gly Phe Pro Gly Ala Pro Gly Gln Asn Gly Glu Pro Gly Gly Lys Gly
20 25 30
Glu Arg Gly
35
<210>322
<211>38
<212>PRT
<213>人
<400>322
Gly His Ala Gly Ala Gln Gly Pro Pro Gly Pro Pro Gly Ile Asn Gly
1 5 10 15
Ser Pro Gly Gly Lys Gly Glu Met Gly Pro Ala Gly Ile Pro Gly Ala
20 25 30
Pro Gly Leu Met Gly Ala
35
<210>323
<211>38
<212>PRT
<213>人
<400>323
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly
20 25 30
Leu Ser Gly Glu Arg Gly
35
<210>324
<211>13
<212>PRT
<213>人
<400>324
Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala
1 5 10
<210>325
<211>12
<212>PRT
<213>人
<400>325
Ile Pro Gly Phe Pro Gly Met Lys Gly His Arg Gly
1 5 10
<210>326
<211>14
<212>PRT
<213>人
<400>326
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly
1 5 10
<210>327
<211>20
<212>PRT
<213>人
<400>327
Gln Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly Ile Ala Gly Ile Thr
1 5 10 15
Gly Ala Arg Gly
20
<210>328
<211>20
<212>PRT
<213>人
<400>328
Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro
1 5 10 15
Gly Pro Arg Gly
20
<210>329
<211>23
<212>PRT
<213>人
<400>329
Ala Gly Ile Pro Gly Ala Pro Gly Leu Met Gly Ala Arg Gly Pro Pro
1 5 10 15
Gly Pro Ala Gly Ala Asn Gly
20
<210>330
<211>24
<212>PRT
<213>人
<400>330
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys Gly Glu
20
<210>331
<211>26
<212>PRT
<213>人
<400>331
Lys Gly Ser Pro Gly Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro Leu
1 5 10 15
Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly
20 25
<210>332
<211>24
<212>PRT
<213>人
<400>332
Leu Pro Gly Pro Pro Gly Ile Lys Gly Pro Ala Gly Ile Pro Gly Phe
1 5 10 15
Pro Gly Met Lys Gly His Arg Gly
20
<210>333
<211>24
<212>PRT
<213>人
<400>333
Lys Asp Gly Thr Ser Gly His Pro Gly Pro Ile Gly Pro Pro Gly Pro
1 5 10 15
Arg Gly Asn Arg Gly Glu Arg Gly
20
<210>334
<211>26
<212>PRT
<213>人
<400>334
Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Pro Pro Gly Met Pro
1 5 10 15
Gly Pro Arg Gly Ser Pro Gly Pro Gln Gly
20 25
<210>335
<211>27
<212>PRT
<213>人
<400>335
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys
20 25
<210>336
<211>32
<212>PRT
<213>人
<400>336
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly
20 25 30
<210>337
<211>34
<212>PRT
<213>人
<400>337
Arg Gly Leu Ala Gly Pro Pro Gly Met Pro Gly Pro Arg Gly Ser Pro
1 5 10 15
Gly Pro Gln Gly Val Lys Gly Glu Ser Gly Lys Pro Gly Ala Asn Gly
20 25 30
Leu Ser
<210>338
<211>37
<212>PRT
<213>人
<400>338
Pro Gly Pro Pro Gly Ser Asn Gly Asn Pro Gly Pro Pro Gly Pro Ser
1 5 10 15
Gly Ser Pro Gly Lys Asp Gly Pro Pro Gly Pro Ala Gly Asn Thr Gly
20 25 30
Ala Pro Gly Ser Pro
35
<210>339
<211>38
<212>PRT
<213>人
<400>339
Arg Gly Ala Pro Gly Glu Lys Gly Glu Gly Gly Pro Pro Gly Val Ala
1 5 10 15
Gly Pro Pro Gly Gly Ser Gly Pro Ala Gly Pro Pro Gly Pro Gln Gly
20 25 30
Val Lys Gly Glu Arg Gly
35
<210>340
<211>44
<212>PRT
<213>人
<400>340
Lys Ser Gly Asp Arg Gly Glu Ser Gly Pro Ala Gly Pro Ala Gly Ala
1 5 10 15
Pro Gly Pro Ala Gly Ser Arg Gly Ala Pro Gly Pro Gln Gly Pro Arg
20 25 30
Gly Asp Lys Gly Glu Thr Gly Glu Arg Gly Ala Ala
35 40
<210>341
<211>53
<212>PRT
<213>人
<400>341
Arg Gly Ala Pro Gly Glu Lys Gly Glu Gly Gly Pro Pro Gly Val Ala
1 5 10 15
Gly Pro Pro Gly Gly Ser Gly Pro Ala Gly Pro Pro Gly Pro Gln Gly
20 25 30
Val Lys Gly Glu Arg Gly Ser Pro Gly Gly Pro Gly Ala Ala Gly Phe
35 40 45
Pro Gly Ala Arg Gly
50
<210>342
<211>6
<212>PRT
<213>人
<400>342
Ala Ile Gly Pro Ser Gly
1 5
<210>343
<211>6
<212>PRT
<213>人
<400>343
Gly Ile Pro Gly Ala Pro
1 5
<210>344
<211>6
<212>PRT
<213>人
<400>344
Ile Lys Gly His Arg Gly
1 5
<210>345
<211>6
<212>PRT
<213>人
<400>345
Val Lys Gly Glu Ser Gly
1 5
<210>346
<211>6
<212>PRT
<213>人
<400>346
His Ala Gly Ala Gln Gly
1 5
<210>347
<211>6
<212>PRT
<213>人
<400>347
Asp Gly Thr Ser Gly His
1 5
<210>348
<211>6
<212>PRT
<213>人
<400>348
Ile Gly Ser Pro Gly Pro
1 5
<210>349
<211>6
<212>PRT
<213>人
<400>349
Leu Ser Gly Glu Arg Gly
1 5
<210>350
<211>6
<212>PRT
<213>人
<400>350
Val Lys Gly Glu Arg Gly
1 5
<210>351
<211>6
<212>PRT
<213>人
<400>351
Gly Ala Arg Gly Leu Ala
1 5
<210>352
<211>6
<212>PRT
<213>人
<400>352
Gly Ala Pro Gly Glu Lys
1 5
<210>353
<211>6
<212>PRT
<213>人
<400>353
Ile Lys Gly Pro Ala Gly
1 5
<210>354
<211>6
<212>PRT
<213>人
<400>354
Gly Ile Pro Gly Gln Pro
1 5
<210>355
<211>6
<212>PRT
<213>人
<400>355
Gly Pro Pro Gly Pro Thr
1 5
<210>356
<211>6
<212>PRT
<213>人
<400>356
Lys Asn Gly Glu Thr Gly
1 5
<210>357
<211>6
<212>PRT
<213>人
<400>357
Leu Lys Gly Glu Asn Gly
1 5
<210>358
<211>6
<212>PRT
<213>人
<400>358
Gly Asp Pro Gly Pro Pro
1 5
<210>359
<211>6
<212>PRT
<213>人
<400>359
Gly Asp Pro Gly Pro Pro
1 5
<210>360
<211>6
<212>PRT
<213>人
<400>360
Phe Pro Gly Ala Arg Gly
1 5
<210>361
<211>6
<212>PRT
<213>人
<400>361
Gly Asp Lys Gly Glu Thr
1 5
<210>362
<211>6
<212>PRT
<213>人
<400>362
Gly Gly Ala Gly Glu Pro
1 5
<210>363
<400>363
000
<210>364
<211>6
<212>PRT
<213>人
<400>364
Gly Pro Pro Gly Pro Pro
1 5
<210>365
<211>6
<212>PRT
<213>人
<400>365
Gly Ala Ala Gly Glu Pro
1 5
<210>366
<211>6
<212>PRT
<213>人
<400>366
Gly Leu Ser Gly Glu Arg
1 5
<210>367
<211>6
<212>PRT
<213>人
<400>367
Ile Ala Gly Ile Thr Gly
1 5
<210>368
<211>6
<212>PRT
<213>人
<400>368
Pro Gly Phe Pro Gly Met
1 5
<210>369
<211>6
<212>PRT
<213>人
<400>369
Gly Ile Ala Gly Ile Thr
1 5
<210>370
<211>6
<212>PRT
<213>人
<400>370
Gly Ala Arg Gly Leu Ala
1 5
<210>371
<211>6
<212>PRT
<213>人
<400>371
Gly Leu Ala Gly Pro Pro
1 5
<210>372
<211>6
<212>PRT
<213>人
<400>372
Gly Pro Pro Gly Val Ala
1 5
<210>373
<211>6
<212>PRT
<213>人
<400>373
Gly Pro Ala Gly Ile Pro
1 5
<210>374
<211>6
<212>PRT
<213>人
<400>374
Pro Gly Pro Pro Gly Ile
1 5
<210>375
<211>6
<212>PRT
<213>人
<400>375
Gly Ala Pro Gly Pro Gln
1 5
<210>376
<211>6
<212>PRT
<213>人
<400>376
Gly Asp Ala Gly Gln Pro
1 5
<210>377
<211>6
<212>PRT
<213>人
<400>377
His Ala Gly Ala Gln Gly
1 5
<210>378
<211>6
<212>PRT
<213>人
<400>378
Gly Pro Pro Gly Ala Pro
1 5
<210>379
<211>6
<212>PRT
<213>人
<400>379
Gly Leu Ala Gly Pro Pro
1 5
<210>380
<211>6
<212>PRT
<213>人
<400>380
Ala Ile Gly Pro Ser Gly
1 5
<210>381
<211>6
<212>PRT
<213>人
<400>381
Gly Pro Pro Gly Pro Ala
1 5
<210>382
<211>6
<212>PRT
<213>人
<400>382
Ser Pro Gly Pro Ala Gly
1 5
<210>383
<211>6
<212>PRT
<213>人
<400>383
Ala Ala Gly Thr Pro Gly
1 5
<210>384
<211>6
<212>PRT
<213>人
<400>384
Thr Ser Gly His Pro Gly
1 5
<210>385
<211>6
<212>PRT
<213>人
<400>385
Pro Ser Gly Pro Pro Gly
1 5
<210>386
<211>6
<212>PRT
<213>人
<400>386
Pro Gly Leu Met Gly Ala
1 5
<210>387
<211>6
<212>PRT
<213>人
<400>387
Ser Pro Gly Pro Gln Gly
1 5
<210>388
<211>6
<212>PRT
<213>人
<400>388
Pro Pro Gly Pro Pro Gly
1 5
<210>389
<211>6
<212>PRT
<213>人
<400>389
Gly Ala Ile Gly Pro Ser
1 5
<210>390
<211>6
<212>PRT
<213>人
<400>390
Pro Pro Gly Pro Ala Gly
1 5
<210>391
<211>6
<212>PRT
<213>人
<400>391
Ser Pro Gly Pro Lys Gly
1 5
<210>392
<211>6
<212>PRT
<213>人
<400>392
Pro Pro Gly Pro Ala Gly
1 5
<210>393
<211>6
<212>PRT
<213>人
<400>393
Leu Pro Gly Pro Pro Gly
1 5
<210>394
<211>6
<212>PRT
<213>人
<400>394
Gly Ala Pro Gly Leu Lys
1 5
<210>395
<211>6
<212>PRT
<213>人
<400>395
Gly Leu Pro Gly Pro Pro
1 5
<210>396
<211>6
<212>PRT
<213>人
<400>396
Gly Pro Pro Gly Ile Lys
1 5
<210>397
<211>6
<212>PRT
<213>人
<400>397
Gly Pro Pro Gly Val Ala
1 5
<210>398
<211>6
<212>PRT
<213>人
<400>398
Thr Pro Gly Leu Gln Gly
1 5
<210>399
<211>6
<212>PRT
<213>人
<400>399
Gly Thr Pro Gly Leu Gln
1 5
<210>400
<211>6
<212>PRT
<213>人
<400>400
Gly Phe Pro Gly Ala Arg
1 5
<210>401
<211>6
<212>PRT
<213>人
<400>401
Gln Pro Gly Pro Pro Gly
1 5
<210>402
<211>6
<212>PRT
<213>人
<400>402
Thr Gly Ala Pro Gly Ser
1 5
<210>403
<211>6
<212>PRT
<213>人
<400>403
Ser Pro Gly Pro Gln Gly
1 5
<210>404
<211>6
<212>PRT
<213>人
<400>404
Gly Pro Ala Gly Pro Arg
1 5
<210>405
<211>6
<212>PRT
<213>人
<400>405
Ala Pro Gly Leu Met Gly
1 5
<210>406
<211>6
<212>PRT
<213>人
<400>406
Gly Asn Arg Gly Glu Arg
1 5
<210>407
<211>6
<212>PRT
<213>人
<400>407
Thr Gly Ala Pro Gly Ser
1 5
<210>408
<211>6
<212>PRT
<213>人
<400>408
Gly Asp Pro Gly Pro Pro
1 5
<210>409
<211>6
<212>PRT
<213>人
<400>409
Arg Gly Leu Ala Gly Pro
1 5
<210>410
<211>6
<212>PRT
<213>人
<400>410
Ser Arg Gly Ala Pro Gly
1 5
<210>411
<211>6
<212>PRT
<213>人
<400>411
Gly Lys Ser Gly Asp Arg
1 5
<210>412
<211>6
<212>PRT
<213>人
<400>412
Val Gly Gly Leu Ala Gly
1 5
<210>413
<211>6
<212>PRT
<213>人
<400>413
Ala Ile Gly Ser Pro Gly
1 5
<210>414
<211>6
<212>PRT
<213>人
<400>414
Gly Leu Ala Gly Pro Pro
1 5
<210>415
<211>6
<212>PRT
<213>人
<400>415
Arg Gly Leu Ala Gly Pro
1 5
<210>416
<211>6
<212>PRT
<213>人
<400>416
Lys Gly Glu Ser Gly Lys
1 5
<210>417
<211>6
<212>PRT
<213>人
<400>417
Ile Ala Gly Ile Thr Gly
1 5
<210>418
<211>6
<212>PRT
<213>人
<400>418
Pro Gly Ala Pro Gly Leu
1 5
<210>419
<211>6
<212>PRT
<213>人
<400>419
Glu Arg Gly Leu Pro Gly
1 5
<210>420
<211>6
<212>PRT
<213>人
<400>420
Ile Asn Gly Ser Pro Gly
1 5
<210>421
<211>6
<212>PRT
<213>人
<400>421
Leu Pro Gly Ile Ala Gly
1 5
<210>422
<211>6
<212>PRT
<213>人
<400>422
Asn Thr Gly Ala Pro Gly
1 5
<210>423
<211>6
<212>PRT
<213>人
<400>423
Leu Arg Gly Gly Ala Gly
1 5
<210>424
<211>6
<212>PRT
<213>人
<400>424
Gly His Ala Gly Ala Gln
1 5
<210>425
<211>6
<212>PRT
<213>人
<400>425
Gly Phe Pro Gly Ala Arg
1 5
<210>426
<211>6
<212>PRT
<213>人
<400>426
Gly Arg Asn Gly Glu Lys
1 5
<210>427
<211>6
<212>PRT
<213>人
<400>427
Gly Glu Arg Gly Ser Pro
1 5
<210>428
<211>6
<212>PRT
<213>人
<400>428
Gly Lys Asp Gly Glu Ser
1 5
<210>429
<211>6
<212>PRT
<213>人
<400>429
Ile Ala Gly Ile Thr Gly
1 5
<210>430
<211>6
<212>PRT
<213>人
<400>430
Gly Pro Lys Gly Asp Ala
1 5
<210>431
<211>6
<212>PRT
<213>人
<400>431
Gly Ser Pro Gly Gly Pro
1 5
<210>432
<211>6
<212>PRT
<213>人
<400>432
Gly Leu Pro Gly Pro Pro
1 5
<210>433
<211>6
<212>PRT
<213>人
<400>433
Ser Gly Asp Arg Gly Glu
1 5
<210>434
<211>6
<212>PRT
<213>人
<400>434
Gly Leu Ala Gly Pro Pro
1 5
<210>435
<211>6
<212>PRT
<213>人
<400>435
Gly Ala Pro Gly Phe Arg
1 5
<210>436
<211>6
<212>PRT
<213>人
<400>436
Gly Phe Pro Gly Asn Pro
1 5
<210>437
<211>6
<212>PRT
<213>人
<400>437
Asn Gly Glu Lys Gly Glu
1 5
<210>438
<211>6
<212>PRT
<213>人
<400>438
Gly Leu Ala Gly Pro Pro
1 5
<210>439
<211>6
<212>PRT
<213>人
<400>439
Gly Ile Thr Gly Ala Arg
1 5
<210>440
<211>6
<212>PRT
<213>人
<400>440
Asp Gly Thr Ser Gly His
1 5
<210>441
<211>6
<212>PRT
<213>人
<400>441
Gly Pro Pro Gly Ser Asn
1 5
<210>442
<211>6
<212>PRT
<213>人
<400>442
Asn Gly Asp Pro Gly Ile
1 5
<210>443
<211>6
<212>PRT
<213>人
<400>443
Pro Gly Pro Gln Gly Val
1 5
<210>444
<211>6
<212>PRT
<213>人
<400>444
Ile Pro Gly Ala Pro Gly
1 5
<210>445
<21l>6
<212>PRT
<213>人
<400>445
Ser Pro Gly Pro Gln Gly
1 5
<210>446
<211>6
<212>PRT
<213>人
<400>446
Gly Ser Pro Gly Pro Ala
1 5
<210>447
<211>6
<212>PRT
<213>人
<400>447
Gln Gly Pro Pro Gly Pro
1 5
<210>448
<211>6
<212>PRT
<213>人
<400>448
Ile Pro Gly Phe Pro Gly
1 5
<210>449
<211>6
<212>PRT
<213>人
<400>449
Gly Pro Ala Gly Ile Pro
1 5
<210>450
<211>6
<212>PRT
<213>人
<400>450
Phe Pro Gly Ala Arg Gly
1 5
<210>451
<211>6
<212>PRT
<213>人
<400>451
Gly Ile Pro Gly Ala Pro
1 5
<210>452
<211>6
<212>PRT
<213>人
<400>452
Glu Arg Gly Pro Pro Gly
1 5
<210>453
<211>6
<212>PRT
<213>人
<400>453
Pro Ser Gly Pro Pro Gly
1 5
<210>454
<211>6
<212>PRT
<213>人
<400>454
Gly Pro Pro Gly Ile Asn
1 5
<210>455
<211>6
<212>PRT
<213>人
<400>455
Gly Thr Ser Gly His Pro
1 5
<210>456
<211>6
<212>PRT
<213>人
<400>456
Gly Leu Pro Gly Ile Ala
1 5
<210>457
<211>6
<212>PRT
<213>人
<400>457
Gly Ala Asn Gly Leu Pro
1 5
<210>458
<211>6
<212>PRT
<213>人
<400>458
Thr Ala Gly Phe Pro Gly
1 5
<210>459
<211>6
<212>PRT
<213>人
<400>459
Glu Gly Gly Pro Pro Gly
1 5
<210>460
<211>6
<212>PRT
<213>人
<400>460
Pro Gln Gly Leu Pro Gly
1 5
<210>461
<211>6
<212>PRT
<213>人
<400>461
Ala Pro Gly Pro Leu Gly
1 5
<210>462
<211>6
<212>PRT
<213>人
<400>462
Gly Ser Pro Gly Pro Gln
1 5
<210>463
<211>6
<212>PRT
<213>人
<400>463
Gly Ala Ala Gly Ala Arg
1 5
<210>464
<211>6
<212>PRT
<213>人
<400>464
Gly Val Lys Gly Glu Arg
1 5
<210>465
<211>6
<212>PRT
<213>人
<400>465
Gly Asp Ala Gly Ala Pro
1 5
<210>466
<211>6
<212>PRT
<213>人
<400>466
Arg Gly Phe Asp Gly Arg
1 5
<210>467
<211>6
<212>PRT
<213>人
<400>467
Gly Leu Ser Gly Glu Arg
1 5
<210>468
<211>6
<212>PRT
<213>人
<400>468
Gly Ser Pro Gly Pro Gln
1 5
<210>469
<211>6
<212>PRT
<213>人
<400>469
Gly Val Lys Gly Glu Arg
1 5
<210>470
<211>6
<212>PRT
<213>人
<400>470
Leu Ala Gly Pro Pro Gly
1 5
<210>471
<211>6
<212>PRT
<213>人
<400>471
Thr Gly Ala Arg Gly Leu
1 5
<210>472
<211>6
<212>PRT
<213>人
<400>472
Lys Gly Asp Ala Gly Gln
1 5
<210>473
<211>6
<212>PRT
<213>人
<400>473
Leu Gln Gly Leu Pro Gly
1 5
<210>474
<211>6
<212>PRT
<213>人
<400>474
Ile Ala Gly Ile Thr Gly
1 5
<210>475
<211>6
<212>PRT
<213>人
<400>475
Ala Gly Gln Gln Gly Ala
1 5
<210>476
<211>6
<212>PRT
<213>人
<400>476
Leu Ala Gly Pro Pro Gly
1 5
<210>477
<211>6
<212>PRT
<213>人
<400>477
Gly Leu Ser Gly Glu Arg
1 5
<210>478
<211>6
<212>PRT
<213>人
<400>478
Val Lys Gly Glu Arg Gly
1 5
<210>479
<211>6
<212>PRT
<213>人
<400>479
Ile Lys Gly Pro Ala Gly
1 5
<210>480
<211>6
<212>PRT
<213>人
<400>480
Glu Arg Gly Leu Pro Gly
1 5
<210>481
<211>6
<212>PRT
<213>人
<400>481
Val Gly Gly Leu Ala Gly
1 5
<210>482
<211>6
<212>PRT
<213>人
<400>482
Gly Pro Pro Gly Glu Pro
1 5
<210>483
<211>6
<212>PRT
<213>人
<400>483
Ile Asn Gly Ser Pro Gly
1 5
<210>484
<211>6
<212>PRT
<213>人
<400>484
Leu Met Gly Ala Arg Gly
1 5
<210>485
<211>6
<212>PRT
<213>人
<400>485
Lys Asn Gly Glu Thr Gly
1 5
<210>486
<211>6
<212>PRT
<213>人
<400>486
Gly Glu Arg Gly Ala Pro
1 5
<210>487
<211>6
<212>PRT
<213>人
<400>487
Pro Gly Pro Pro Gly Pro
1 5
<210>488
<211>6
<212>PRT
<213>人
<400>488
Gly Gln Pro Gly Asp Lys
1 5
<210>489
<211>6
<212>PRT
<213>人
<400>489
Pro Gly Val Pro Gly Ala
1 5
<210>490
<211>6
<212>PRT
<213>人
<400>490
Gly Ala Arg Gly Asn Asp
1 5
<210>491
<211>6
<212>PRT
<213>人
<400>491
Pro Gly Ala Pro Gly Gln
1 5
<210>492
<211>6
<212>PRT
<213>人
<400>492
Gly Pro Pro Gly Pro Pro
1 5
<210>493
<211>6
<212>PRT
<213>人
<400>493
Ile Ala Gly Ile Thr Gly
1 5
<210>494
<211>6
<212>PRT
<213>人
<400>494
Gly Pro Ala Gly Ile Pro
1 5
<210>495
<211>6
<212>PRT
<213>人
<400>495
Gly Pro Pro Gly Pro Pro
1 5
<210>496
<211>6
<212>PRT
<213>人
<400>496
Arg Pro Gly Leu Pro Gly
1 5
<210>497
<211>6
<212>PRT
<213>人
<400>497
Gly Pro Pro Gly Ser Asn
1 5
<210>498
<211>6
<212>PRT
<213>人
<400>498
Pro Gly Phe Pro Gly Met
1 5
<210>499
<211>6
<212>PRT
<213>人
<400>499
Gly Pro Pro Gly Glu Asn
1 5
<210>500
<211>6
<212>PRT
<213>人
<400>500
Gly Leu Pro Gly Pro Pro
1 5
<210>501
<211>6
<212>PRT
<213>人
<400>501
Pro Gly Pro Pro Gly Ile
1 5
<210>502
<211>6
<212>PRT
<213>人
<400>502
Pro Gly Phe Arg Gly Pro
1 5
<210>503
<211>6
<212>PRT
<213>人
<400>503
Gly Ile Ala Gly Ile Thr
1 5
<210>504
<211>6
<212>PRT
<213>人
<400>504
Gly Ile Pro Gly Ala Pro
1 5
<210>505
<211>6
<212>PRT
<213>人
<400>505
Gly Ile Thr Gly Ala Arg
1 5
<210>506
<211>6
<212>PRT
<213>人
<400>506
Gly Ala Pro Gly Glu Lys
1 5
<210>507
<211>6
<212>PRT
<213>人
<400>507
Ser Pro Gly Pro Gln Gly
1 5
<210>508
<211>6
<212>PRT
<213>人
<400>508
Pro Pro Gly Pro Gln Gly
1 5
<210>509
<211>6
<212>PRT
<213>人
<400>509
Glu Arg Gly Pro Pro Gly
1 5
<210>510
<211>6
<212>PRT
<213>人
<400>510
Ala Pro Gly Leu Arg Gly
1 5
<210>511
<211>6
<212>PRT
<213>人
<400>511
Gly Pro Ala Gly Pro Pro
1 5
<210>512
<211>6
<212>PRT
<213>人
<400>512
Ser Pro Gly Pro Gln Gly
1 5
<210>513
<211>6
<212>PRT
<213>人
<400>513
Leu Ala Gly Pro Pro Gly
1 5
<210>514
<211>6
<212>PRT
<213>人
<400>514
Phe Pro Gly Pro Lys Gly
1 5
<210>515
<211>6
<212>PRT
<213>人
<400>515
Pro Pro Gly Pro Ala Gly
1 5
<210>516
<211>6
<212>PRT
<213>人
<400>516
Leu Pro Gly Ala Ala Gly
1 5
<210>517
<211>6
<212>PRT
<213>人
<400>517
Ile Pro Gly Gln Pro Gly
1 5
<210>518
<211>6
<212>PRT
<213>人
<400>518
Gly Ala Pro Gly Pro Ala
1 5
<210>519
<211>6
<212>PRT
<213>人
<400>519
Gly His Arg Gly Phe Asp
1 5
<210>520
<211>6
<212>PRT
<213>人
<400>520
Pro Gly Pro Lys Gly Asp
1 5
<210>521
<211>6
<212>PRT
<213>人
<400>521
Gly Pro Pro Gly Pro Ser
1 5
<210>522
<211>6
<212>PRT
<213>人
<400>522
Pro Pro Gly Ala Pro Gly
1 5
<210>523
<211>6
<212>PRT
<213>人
<400>523
Gly Glu Val Gly Pro Ala
1 5
<210>524
<211>6
<212>PRT
<213>人
<400>524
Gly Ala Pro Gly Leu Arg
1 5
<210>525
<211>6
<212>PRT
<213>人
<400>525
Gly Pro Gln Gly Val Lys
1 5
<210>526
<211>6
<212>PRT
<213>人
<400>526
Gly Met Pro Gly Pro Arg
1 5
<210>527
<211>6
<212>PRT
<213>人
<400>527
Gly Ala Ala Gly Ile Lys
1 5
<210>528
<211>6
<212>PRT
<213>人
<400>528
Pro Gly Ala Ala Gly Phe
1 5
<210>529
<211>6
<212>PRT
<213>人
<400>529
Gly Pro Ala Gly Glu Arg
1 5
<210>530
<211>6
<212>PRT
<213>人
<400>530
Gly Ile Ala Gly Pro Arg
1 5
<210>531
<211>6
<212>PRT
<213>人
<400>531
Thr Gly Ala Arg Gly Leu
1 5
<210>532
<211>6
<212>PRT
<213>人
<400>532
Val Lys Gly Glu Ser Gly
1 5
<210>533
<211>6
<212>PRT
<213>人
<400>533
Thr Gly Glu Arg Gly Ala
1 5
<210>534
<211>6
<212>PRT
<213>人
<400>534
Glu Arg Gly Leu Pro Gly
1 5
<210>535
<211>6
<212>PRT
<213>人
<400>535
Ile Thr Gly Ala Arg Gly
1 5
<210>536
<211>6
<212>PRT
<213>人
<400>536
Glu Arg Gly Leu Pro Gly
1 5
<210>537
<211>6
<212>PRT
<213>人
<400>537
Pro Gly Ala Pro Gly Gly
1 5
<210>538
<211>6
<212>PRT
<213>人
<400>538
Gly Pro Pro Gly Val Ala
1 5
<210>539
<211>6
<212>PRT
<213>人
<400>539
Gly Leu Ala Gly Pro Pro
1 5
<210>540
<211>6
<212>PRT
<213>人
<400>540
Val Gly Gly Leu Ala Gly
1 5
<210>541
<211>6
<212>PRT
<213>人
<400>541
Ser Pro Gly Ala Gln Gly
1 5
<210>542
<211>6
<212>PRT
<213>人
<400>542
Gln Pro Gly Val Met Gly
1 5
<210>543
<211>6
<212>PRT
<213>人
<400>543
Ile Pro Gly Ala Pro Gly
1 5
<210>544
<211>6
<212>PRT
<213>人
<400>544
Val Lys Gly Glu Arg Gly
1 5
<210>545
<211>6
<212>PRT
<213>人
<400>545
Gly Pro Pro Gly Ile Asn
1 5
<210>546
<211>6
<212>PRT
<213>人
<400>546
Gly Ile Asn Gly Ser Pro
1 5
<210>547
<211>6
<212>PRT
<213>人
<400>547
Leu Arg Gly Gly Ala Gly
1 5
<210>548
<211>6
<212>PRT
<213>人
<400>548
Tyr Gln Gly Pro Pro Gly
1 5
<210>549
<211>6
<212>PRT
<213>人
<400>549
Gly Ile Pro Gly Phe Pro
1 5
<210>550
<211>6
<212>PRT
<213>人
<400>550
Phe Pro Gly Met Lys Gly
1 5
<210>551
<211>6
<212>PRT
<213>人
<400>551
Gly Pro Pro Gly Glu Asn
1 5
<210>552
<211>6
<212>PRT
<213>人
<400>552
Ala Ala Gly Phe Pro Gly
1 5
<210>553
<211>6
<212>PRT
<213>人
<400>553
Pro Gly Val Ser Gly Pro
1 5
<210>554
<211>6
<212>PRT
<213>人
<400>554
Gly Phe Pro Gly Ala Pro
1 5
<210>555
<211>6
<212>PRT
<213>人
<400>555
Gly Leu Ser Gly Glu Arg
1 5
<210>556
<211>6
<212>PRT
<213>人
<400>556
Gly Gly Ala Gly Pro Pro
1 5
<210>557
<211>6
<212>PRT
<213>人
<400>557
Val Gly Gly Leu Ala Gly
1 5
<210>558
<211>6
<212>PRT
<213>人
<400>558
Gly Leu Ala Gly Pro Pro
1 5
<210>559
<211>6
<212>PRT
<213>人
<400>559
Pro Gly Pro Pro Gly Ile
1 5
<210>560
<211>6
<212>PRT
<213>人
<400>560
Gly Ala Pro Gly Pro Met
1 5
<210>561
<211>6
<212>PRT
<213>人
<400>561
Gly Ala Arg Gly Leu Ala
1 5
<210>562
<211>6
<212>PRT
<213>人
<400>562
Gly Leu Ala Gly Pro Pro
1 5
<210>563
<211>6
<212>PRT
<213>人
<400>563
Pro Gly Phe Arg Gly Pro
1 5
<210>564
<211>6
<212>PRT
<213>人
<400>564
Gly Pro Val Gly Pro Ser
1 5
<210>565
<211>6
<212>PRT
<213>人
<400>565
Ala Gly Gln Pro Gly Glu
1 5
<210>566
<211>6
<212>PRT
<213>人
<400>566
Gly Ala Pro Gly Phe Arg
1 5
<210>567
<211>6
<212>PRT
<213>人
<400>567
Pro Gly Phe Pro Gly Met
1 5
<210>568
<211>6
<212>PRT
<213>人
<400>568
Gly Leu Ala Gly Pro Pro
1 5
<210>569
<211>6
<212>PRT
<213>人
<400>569
Ser Gly Asp Arg Gly Glu
1 5
<210>570
<211>6
<212>PRT
<213>人
<400>570
Ala Gly Ile Pro Gly Phe
1 5
<210>571
<211>6
<212>PRT
<213>人
<400>571
Glu Arg Gly Ala Ala Gly
1 5
<210>572
<211>6
<212>PRT
<213>人
<400>572
Pro Gly Pro Pro Gly Thr
1 5
<210>573
<211>6
<212>PRT
<213>人
<400>573
His Pro Gly Ser Pro Gly
1 5
<210>574
<211>6
<212>PRT
<213>人
<400>574
Ser Pro Gly Pro Gln Gly
1 5
<210>575
<211>6
<212>PRT
<213>人
<400>575
Gly Leu Ala Gly Thr Ala
1 5
<210>576
<211>6
<212>PRT
<213>人
<400>576
Gly Pro Pro Gly Pro Gln
1 5
<210>577
<211>6
<212>PRT
<213>人
<400>577
Gly Phe Pro Gly Met Lys
1 5
<210>578
<211>6
<212>PRT
<213>人
<400>578
Glu Lys Gly Pro Ala Gly
1 5
<210>579
<211>6
<212>PRT
<213>人
<400>579
Pro Gly Pro Gln Gly Leu
1 5
<210>580
<211>6
<212>PRT
<213>人
<400>580
Phe Pro Gly Ala Pro Gly
1 5
<210>581
<211>6
<212>PRT
<213>人
<400>581
Ala Pro Gly Pro Leu Gly
1 5
<210>582
<211>6
<212>PRT
<213>人
<400>582
Gly Phe Pro Gly Met Lys
1 5
<210>583
<211>6
<212>PRT
<213>人
<400>583
Pro Gly Leu Pro Gly Ile
1 5
<210>584
<211>6
<212>PRT
<213>人
<400>584
Gly His Arg Gly Phe Asp
1 5
<210>585
<211>6
<212>PRT
<213>人
<400>585
Pro Gly Pro Lys Gly Asn
1 5
<210>586
<211>6
<212>PRT
<213>人
<400>586
Gly Glu Val Gly Pro Ala
1 5
<210>587
<211>6
<212>PRT
<213>人
<400>587
Gly Pro Pro Gly Pro Ser
1 5
<210>588
<211>6
<212>PRT
<213>人
<400>588
Gly Leu Pro Gly Leu Ala
1 5
<210>589
<211>6
<212>PRT
<213>人
<400>589
Gly Ser Pro Gly Tyr Gln
1 5
<210>590
<211>6
<212>PRT
<213>人
<400>590
Glu Met Gly Pro Ala Gly
1 5
<210>591
<211>6
<212>PRT
<213>人
<400>591
Gly Lys Pro Gly Ala Asn
1 5
<210>592
<211>6
<212>PRT
<213>人
<400>592
Gly Met Pro Gly Pro Arg
1 5
<210>593
<211>6
<212>PRT
<213>人
<400>593
Gly Ile Thr Gly Ala Arg
1 5
<210>594
<211>6
<212>PRT
<213>人
<400>594
Ala Gly Pro Arg Gly Ala
1 5
<210>595
<211>6
<212>PRT
<213>人
<400>595
Gly Pro Ala Gly Ala Asn
1 5
<210>596
<211>6
<212>PRT
<213>人
<400>596
Gly Lys Pro Gly Ala Asn
1 5
<210>597
<211>6
<212>PRT
<213>人
<400>597
Gly Phe Pro Gly Ala Arg
1 5
<210>598
<211>6
<212>PRT
<213>人
<400>598
Ile Ala Gly Ile Thr Gly
1 5
<210>599
<211>6
<212>PRT
<213>人
<400>599
Ile Thr Gly Ala Arg Gly
1 5
<210>600
<211>6
<212>PRT
<213>人
<400>600
Leu Arg Gly Gly Ala Gly
1 5
<210>601
<211>6
<212>PRT
<213>人
<400>601
Val Gly Gly Leu Ala Gly
1 5
<210>602
<211>6
<212>PRT
<213>人
<400>602
Ala Gly Pro Pro Gly Met
1 5
<210>603
<211>6
<212>PRT
<213>人
<400>603
Pro Gln Gly Pro Pro Gly
1 5
<210>604
<211>6
<212>PRT
<213>人
<400>604
Ser Pro Gly Gly Lys Gly
1 5
<210>605
<211>6
<212>PRT
<213>人
<400>605
Gly Ala Pro Gly Glu Lys
1 5
<210>606
<211>6
<212>PRT
<213>人
<400>606
Ile Lys Gly Pro Ala Gly
1 5
<210>607
<211>6
<212>PRT
<213>人
<400>607
Phe Arg Gly Pro Ala Gly
1 5
<210>608
<211>6
<212>PRT
<213>人
<400>608
Asp Ala Gly Ala Pro Gly
1 5
<210>609
<211>6
<212>PRT
<213>人
<400>609
Gly Leu Pro Gly Pro Pro
1 5
<210>610
<211>6
<212>PRT
<213>人
<400>610
Pro Gly Glu Asn Gly Lys
1 5
<210>611
<211>6
<212>PRT
<213>人
<400>611
Gln Gln Gly Ala Ile Gly
1 5
<210>612
<211>6
<212>PRT
<213>人
<400>612
Val Ala Gly Pro Pro Gly
1 5
<210>613
<211>6
<212>PRT
<213>人
<400>613
Pro Gly Met Lys Gly His
1 5
<210>614
<211>6
<212>PRT
<213>人
<400>614
Pro Gly Asp Lys Gly Glu
1 5
<210>615
<211>6
<212>PRT
<213>人
<400>615
Gly Ser Asp Gly Gln Pro
1 5
<210>616
<211>6
<212>PRT
<213>人
<400>616
Gly Ala Arg Gly Asn Asp
1 5
<210>617
<211>6
<212>PRT
<213>人
<400>617
Gly Ala Arg Gly Pro Pro
1 5
<210>618
<211>6
<212>PRT
<213>人
<400>618
Gly Pro Lys Gly Asp Ala
1 5
<210>619
<211>6
<212>PRT
<213>人
<400>619
Pro Gly Pro Gln Gly His
1 5
<210>620
<211>6
<212>PRT
<213>人
<400>620
Gly Ile Thr Gly Ala Arg
1 5
<210>621
<211>6
<212>PRT
<213>人
<400>621
Gly Ser Arg Gly Ala Pro
1 5
<210>622
<211>6
<212>PRT
<213>人
<400>622
Gly Ala Pro Gly Glu Lys
1 5
<210>623
<211>6
<212>PRT
<213>人
<400>623
Pro Gln Gly Leu Gln Gly
1 5
<210>624
<211>6
<212>PRT
<213>人
<400>624
Lys Gly Ser Pro Gly Ala
1 5
<210>625
<211>6
<212>PRT
<213>人
<400>625
Pro Gly Pro Gln Gly Pro
1 5
<210>626
<211>6
<212>PRT
<213>人
<400>626
Gly Pro Thr Gly Pro Ile
1 5
<210>627
<211>6
<212>PRT
<213>人
<400>627
Gly Ser Pro Gly Glu Arg
1 5
<210>628
<211>6
<212>PRT
<213>人
<400>628
Gly Ser Pro Gly Ala Gln
1 5
<210>629
<211>6
<212>PRT
<213>人
<400>629
Gly Leu Ala Gly Pro Pro
1 5
<210>630
<211>6
<212>PRT
<213>人
<400>630
Gly Ala Pro Gly Glu Lys
1 5
<210>631
<211>6
<212>PRT
<213>人
<400>631
Gly Met Pro Gly Pro Arg
1 5
<210>632
<211>6
<212>PRT
<213>人
<400>632
Pro Gly Pro Leu Gly Ile
1 5
<210>633
<211>6
<212>PRT
<213>人
<400>633
Gly Asn Arg Gly Glu Arg
1 5
<210>634
<211>6
<212>PRT
<213>人
<400>634
Pro Ser Gly Pro Pro Gly
1 5
<210>635
<211>6
<212>PRT
<213>人
<400>635
Gly Leu Pro Gly Leu Ala
1 5
<210>636
<211>6
<212>PRT
<213>人
<400>636
Pro Gly Pro Pro Gly Thr
1 5
<210>637
<211>6
<212>PRT
<213>人
<400>637
Gly Pro Pro Gly Pro Gln
1 5
<210>638
<211>6
<212>PRT
<213>人
<400>638
Phe Pro Gly Met Lys Gly
1 5
<210>639
<211>6
<212>PRT
<213>人
<400>639
Gly Pro Pro Gly Ile Cys
1 5
<210>640
<211>6
<212>PRT
<213>人
<400>640
Gly Pro Pro Gly Ile Cys
1 5
<210>641
<211>6
<212>PRT
<213>人
<400>641
Gly Ala Pro Gly Leu Met
1 5
<210>642
<211>6
<212>PRT
<213>人
<400>642
Glu Pro Gly Pro Arg Gly
1 5
<210>643
<211>6
<212>PRT
<213>人
<400>643
Gly His Arg Gly Phe Asp
1 5
<210>644
<211>6
<212>PRT
<213>人
<400>644
Gly Ala Ala Gly Ile Lys
1 5
<210>645
<211>6
<212>PRT
<213>人
<400>645
Gly Glu Pro Gly Pro Arg
1 5
<210>646
<211>6
<212>PRT
<213>人
<400>646
Gly Ile Pro Gly Ala Pro
1 5
<210>647
<211>6
<212>PRT
<213>人
<400>647
Gly Ala Pro Gly Leu Met
1 5
<210>648
<211>6
<212>PRT
<213>人
<400>648
Thr Gly Ala Arg Gly Leu
1 5
<210>649
<211>6
<212>PRT
<213>人
<400>649
Met Pro Gly Pro Arg Gly
1 5
<210>650
<211>6
<212>PRT
<213>人
<400>650
Gly Met Lys Gly His Arg
1 5
<210>651
<211>6
<212>PRT
<213>人
<400>651
Gly Pro Gln Gly Val Lys
1 5
<210>652
<211>6
<212>PRT
<213>人
<400>652
Pro Gly Ala Asn Gly Leu
1 5
<210>653
<211>6
<212>PRT
<213>人
<400>653
Gly Thr Gly Gly Pro Pro
1 5
<210>654
<211>6
<212>PRT
<213>人
<400>654
Gly Pro Pro Gly Pro Arg
1 5
<210>655
<211>6
<212>PRT
<213>人
<400>655
Gly Gly Lys Gly Glu Arg
1 5
<210>656
<211>6
<212>PRT
<213>人
<400>656
Pro Gln Gly Val Lys Gly
1 5
<210>657
<211>6
<212>PRT
<213>人
<400>657
Pro Gly Ala Asn Gly Leu
1 5
<210>658
<211>161
<212>PRT
<213>人
<400>658
Met Glu Lys Leu Leu Cys Phe Leu Val Leu Thr Ser Leu Ser His Ala
1 5 10 15
Phe Gly Gln Thr Asp Met Ser Arg Lys Ala Phe Val Phe Pro Lys Glu
20 25 30
Ser Asp Thr Ser Tyr Val Ser Leu Lys Ala Pro Leu Thr Lys Pro Leu
35 40 45
Lys Ala Phe Thr Val Cys Leu His Phe Tyr Thr Glu Leu Ser Ser Thr
50 55 60
Arg Gly Thr Val Phe Ser Arg Met Pro Pro Arg Asp Lys Thr Met Arg
65 70 75 80
Phe Phe Ile Phe Trp Ser Lys Asp Ile Gly Tyr Ser Phe Thr Val Gly
85 90 95
Gly Ser Glu Ile Leu Phe Glu Val Pro Glu Val Thr Val Ala Pro Val
100 105 110
His Ile Cys Thr Ser Trp Glu Ser Ala Ser Gly Ile Val Glu Phe Trp
115 120 125
Val Asp Gly Lys Pro Arg Val Arg Lys Ser Leu Lys Lys Gly Tyr Thr
130 135 140
Val Gly Ala Glu Ala Ser Ile Ile Leu Gly Gln Glu Gln Asp Ser Phe
145 150 155 160
Gly
<210>659
<211>317
<212>PRT
<213>人
<400>659
Met Lys Val Leu Trp Ala Ala Leu Leu Val Thr Phe Leu Ala Gly Cys
1 5 10 15
Gln Ala Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu
20 25 30
Arg Gln Gln Thr Glu Trp Gln Ser Gly Gln Arg Trp Glu Leu Ala Leu
35 40 45
Gly Arg Phe Trp Asp Tyr Leu Arg Trp Val Gln Thr Leu Ser Glu Gln
50 55 60
Val Gln Glu Glu Leu Leu Ser Ser Gln Val Thr Gln Glu Leu Arg Ala
65 70 75 80
Leu Met Asp Glu Thr Met Lys Glu Leu Lys Ala Tyr Lys Ser Glu Leu
85 90 95
Glu Glu Gln Leu Thr Pro Val Ala Glu Glu Thr Arg Ala Arg Leu Ser
100 105 110
Lys Glu Leu Gln Ala Ala Gln Ala Arg Leu Gly Ala Asp Met Glu Asp
115 120 125
Val Cys Gly Arg Leu Val Gln Tyr Arg Gly Glu Val Gln Ala Met Leu
130 135 140
Gly Gln Ser Thr Glu Glu Leu Arg Val Arg Leu Ala Ser His Leu Arg
145 150 155 160
Lys Leu Arg Lys Arg Leu Leu Arg Asp Ala Asp Asp Leu Gln Lys Arg
165 170 175
Leu Ala Val Tyr Gln Ala Gly Ala Arg Glu Gly Ala Glu Arg Gly Leu
180 185 190
Ser Ala Ile Arg Glu Arg Leu Gly Pro Leu Val Glu Gln Gly Arg Val
195 200 205
Arg Ala Ala Thr Val Gly Ser Leu Ala Gly Gln Pro Leu Gln Glu Arg
210 215 220
Ala Gln Ala Trp Gly Glu Arg Leu Arg Ala Arg Met Glu Glu Met Gly
225 230 235 240
Ser Arg Thr Arg Asp Arg Leu Asp Glu Val Lys Glu Gln Val Ala Glu
245 250 255
Val Arg Ala Lys Leu Glu Glu Gln Ala Gln Gln Ile Arg Leu Gln Ala
260 265 270
Glu Ala Phe Gln Ala Arg Leu Lys Ser Trp Phe Glu Pro Leu Val Glu
275 280 285
Asp Met Gln Arg Gln Trp Ala Gly Leu Val Glu Lys Val Gln Ala Ala
290 295 300
Val Gly Thr Ser Ala Ala Pro Val Pro Ser Asp Asn His
305 310 315
<210>660
<211>17
<212>PRT
<213>人
<400>660
Ala Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu Arg
1 5 10 15
Gln
<210>661
<211>17
<212>PRT
<213>人
<400>661
Ala Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu Arg
1 5 10 15
Gln
<210>662
<211>16
<212>PRT
<213>人
<400>662
Val Ala Glu Val Arg Ala Lys Leu Glu Glu Gln Ala Gln Gln Ile Arg
1 5 10 15
<210>663
<211>17
<212>PRT
<213>人
<400>663
Ala Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu Arg
1 5 10 15
Gln
<210>664
<211>13
<212>PRT
<213>人
<400>664
Ala Met Leu Gly Gln Ser Thr Glu Glu Leu Arg Val Arg
1 5 10
<210>665
<211>14
<212>PRT
<213>人
<400>665
Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu Arg Gln
1 5 10
<210>666
<211>14
<212>PRT
<213>人
<400>666
Arg Gln Gln Thr Glu Trp Gln Ser Gly Gln Arg Trp Glu Leu
1 5 10
<210>667
<211>18
<212>PRT
<213>人
<400>667
Leu Ala Val Tyr Gln Ala Gly Ala Arg Glu Gly Ala Glu Arg Gly Leu
1 5 10 15
Ser Ala
<210>668
<211>13
<212>PRT
<213>人
<400>668
Arg Ala Lys Leu Glu Glu Gln Ala Gln Gln Ile Arg Leu
1 5 10
<210>669
<211>14
<212>PRT
<213>人
<400>669
Ala Lys Leu Glu Glu Gln Ala Gln Gln Ile Arg Leu Gln Ala
1 5 10
<210>670
<211>17
<212>PRT
<213>人
<400>670
Ala Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu Arg
1 5 10 15
Gln
<210>671
<211>16
<212>PRT
<213>人
<400>671
Lys Val Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu Arg Gln
1 5 10 15
<210>672
<211>14
<212>PRT
<213>人
<400>672
Glu Gln Ala Val Glu Thr Glu Pro Glu Pro Glu Leu Arg Gln
1 5 10
<210>673
<211>16
<212>PRT
<213>人
<400>673
Asp Glu Val Lys Glu Gln Val Ala Glu Val Arg Ala Lys Leu Glu Glu
1 5 10 15
<210>674
<211>16
<212>PRT
<213>人
<400>674
Lys Glu Ser Asp Thr Ser Tyr Val Ser Leu Lys Ala Pro Leu Thr Lys
1 5 10 15
<210>675
<211>16
<212>PRT
<213>人
<400>675
Gly Gly Asn Phe Glu Gly Ser Gln Ser Leu Val Gly Asp Ile Gly Asn
1 5 10 15
<210>676
<211>16
<212>PRT
<213>人
<400>676
Ala Leu Lys Tyr Glu Val Gln Gly Glu Val Phe Thr Lys Pro Gln Leu
1 5 10 15
<210>677
<211>14
<212>PRT
<213>人
<400>677
Gly Ile Val Glu Phe Trp Val Asp Gly Lys Pro Arg Val Arg
1 5 10
<210>678
<211>10
<212>PRT
<213>人
<400>678
Arg Lys Ala Phe Val Phe Pro Lys Glu Ser
1 5 10
<210>679
<211>16
<212>PRT
<213>人
<400>679
Lys Tyr Glu Val Gln Gly Glu Val Phe Thr Lys Pro Gln Leu Trp Pro
1 5 10 15
<210>680
<211>13
<212>PRT
<213>人
<400>680
Asp Ser Phe Gly Gly Asn Phe Glu Gly Ser Gln Ser Leu
1 5 10
<210>681
<211>12
<212>PRT
<213>人
<400>681
Asp Phe Val Leu Ser Pro Asp Glu Ile Asn Thr Ile
1 5 10
<210>682
<211>13
<212>PRT
<213>人
<400>682
Ser Leu Lys Lys Gly Tyr Thr Val Gly Ala Glu Ala Ser
1 5 10
<210>683
<211>12
<212>PRT
<213>人
<400>683
Ala Phe Gly Gln Thr Asp Met Ser Arg Lys Ala Phe
1 5 10
<210>684
<211>14
<212>PRT
<213>人
<400>684
Ser Leu Lys Lys Gly Tyr Thr Val Gly Ala Glu Ala Ser Ile
1 5 10
<210>685
<211>11
<212>PRT
<213>人
<400>685
Gly Glu Val Phe Thr Lys Pro Gln Leu Trp Pro
1 5 10
<210>686
<211>15
<212>PRT
<213>人
<400>686
Ser Ile Ile Leu Gly Gln Glu Gln Asp Ser Phe Gly Gly Asn Phe
1 5 10 15
<210>687
<211>14
<212>PRT
<213>人
<400>687
Lys Tyr Glu Val Gln Gly Glu Val Phe Thr Lys Pro Gln Leu
1 5 10
<210>688
<211>6
<212>PRT
<213>人
<400>688
Lys Val Glu Gln Ala Val
1 5
<210>689
<211>6
<212>PRT
<213>人
<400>689
Ala Glu Val Arg Ala Lys
1 5
<210>690
<211>6
<212>PRT
<213>人
<400>690
Met Leu Gly Gln Ser Thr
1 5
<210>691
<211>6
<212>PRT
<213>人
<400>691
Gln Ala Val Glu Thr Glu
1 5
<210>692
<211>6
<212>PRT
<213>人
<400>692
Gln Gln Thr Glu Trp Gln
1 5
<210>693
<211>6
<212>PRT
<213>人
<400>693
Ala Val Tyr Gln Ala Gly
1 5
<210>694
<211>6
<212>PRT
<213>人
<400>694
Ala Lys Leu Glu Glu Gln
1 5
<210>695
<211>6
<212>PRT
<213>人
<400>695
Lys Leu Glu Glu Gln Ala
1 5
<210>696
<211>6
<212>PRT
<213>人
<400>696
Val Glu Gln Ala Val Glu
1 5
<210>697
<211>6
<212>PRT
<213>人
<400>697
Gln Ala Val Glu Thr Glu
1 5
<210>698
<211>6
<212>PRT
<213>人
<400>698
Glu Val Lys Glu Gln Val
1 5
<210>699
<211>6
<212>PRT
<213>人
<400>699
Ala Phe Val Phe Pro Lys
1 5
<210>700
<211>6
<212>PRT
<213>人
<400>700
Tyr Glu Val Gln Gly Glu
1 5
<210>701
<211>6
<212>PRT
<213>人
<400>701
Lys Ala Phe Val Phe Pro
1 5
<210>702
<211>6
<212>PRT
<213>人
<400>702
Ser Phe Gly Gly Asn Phe
1 5
<210>703
<211>6
<212>PRT
<213>人
<400>703
Phe Val Leu Ser Pro Asp
1 5
<210>704
<211>6
<212>PRT
<213>人
<400>704
Leu Lys Lys Gly Tyr Thr
1 5
<210>705
<211>6
<212>PRT
<213>人
<400>705
Phe Gly Gln Thr Asp Met
1 5
<210>706
<211>6
<212>PRT
<213>人
<400>706
Leu Lys Lys Gly Tyr Thr
1 5
<210>707
<211>6
<212>PRT
<213>人
<400>707
Ile Ile Leu Gly Gln Glu
1 5
<210>708
<211>6
<212>PRT
<213>人
<400>708
Tyr Glu Val Gln Gly Glu
1 5
<210>709
<211>6
<212>PRT
<213>人
<400>709
Leu Lys Tyr Glu Val Gln
1 5
<210>710
<211>6
<212>PRT
<213>人
<400>710
Ile Val Glu Phe Trp Val
1 5
<210>711
<211>6
<212>PRT
<213>人
<400>711
Glu Ser Asp Thr Ser Tyr
1 5
<210>712
<211>6
<212>PRT
<213>人
<400>712
Gly Asn Phe Glu Gly Ser
1 5
<210>713
<211>6
<212>PRT
<213>人
<400>713
Thr Glu Pro Glu Pro Glu
1 5
<210>714
<211>6
<212>PRT
<213>人
<400>714
Thr Glu Pro Glu Pro Glu
1 5
<210>715
<211>6
<212>PRT
<213>人
<400>715
Glu Gln Ala Gln Gln Ile
1 5
<210>716
<211>6
<212>PRT
<213>人
<400>716
Thr Glu Glu Leu Arg Val
1 5
<210>717
<211>6
<212>PRT
<213>人
<400>717
Pro Glu Pro Glu Leu Arg
1 5
<210>718
<211>6
<212>PRT
<213>人
<400>718
Ser Gly Gln Arg Trp Glu
1 5
<210>719
<211>6
<212>PRT
<213>人
<400>719
Glu Gly Ala Glu Arg Gly
1 5
<210>720
<211>6
<212>PRT
<213>人
<400>720
Gln Ala Gln Gln Ile Arg
1 5
<210>721
<211>6
<212>PRT
<213>人
<400>721
Gln Gln Ile Arg Leu Gln
1 5
<210>722
<211>6
<212>PRT
<213>人
<400>722
Glu Pro Glu Pro Glu Leu
1 5
<210>723
<211>6
<212>PRT
<213>人
<400>723
Pro Glu Pro Glu Leu Arg
1 5
<210>724
<211>6
<212>PRT
<213>人
<400>724
Glu Val Arg Ala Lys Leu
1 5
<210>725
<211>7
<212>PRT
<213>人
<400>725
Lys Ala Phe Val Phe Pro Lys
1 5
<210>726
<211>6
<212>PRT
<213>人
<400>726
Ala Phe Val Phe Pro Lys
1 5
<210>727
<211>6
<212>PRT
<213>人
<400>727
Lys Pro Gln Leu Trp Pro
1 5
<210>728
<211>6
<212>PRT
<213>人
<400>728
Phe Val Phe Pro Lys Glu
1 5
<210>729
<211>6
<212>PRT
<213>人
<400>729
Pro Asp Glu Ile Asn Thr
1 5
<210>730
<211>6
<212>PRT
<213>人
<400>730
Asp Met Ser Arg Lys Ala
1 5
<210>731
<211>6
<212>PRT
<213>人
<400>731
Val Gly Ala Glu Ala Ser
1 5
<210>732
<211>6
<212>PRT
<213>人
<400>732
Lys Pro Gln Leu Trp Pro
1 5
<210>733
<211>6
<212>PRT
<213>人
<400>733
Asp Ser Phe Gly Gly Asn
1 5
<210>734
<211>6
<212>PRT
<213>人
<400>734
Val Phe Thr Lys Pro Gln
1 5
<210>735
<211>757
<212>PRT
<213>人
<400>735
Met Ala Gly Leu Thr Ala Ala Ala Pro Arg Pro Gly Val Leu Leu Leu
1 5 10 15
Leu Leu Ser Ile Leu His Pro Ser Arg Pro Gly Gly Val Pro Gly Ala
20 25 30
Ile Pro Gly Gly Val Pro Gly Gly Val Phe Tyr Pro Gly Ala Gly Leu
35 40 45
Gly Ala Leu Gly Gly Gly Ala Leu Gly Pro Gly Gly Lys Pro Leu Lys
50 55 60
Pro Val Pro Gly Gly Leu Ala Gly Ala Gly Leu Gly Ala Gly Leu Gly
65 70 75 80
Ala Phe Pro Ala Val Thr Phe Pro Gly Ala Leu Val Pro Gly Gly Val
85 90 95
Ala Asp Ala Ala Ala Ala Tyr Lys Ala Ala Lys Ala Gly Ala Gly Leu
100 105 110
Gly Gly Val Pro Gly Val Gly Gly Leu Gly Val Ser Ala Gly Ala Val
115 120 125
Val Pro Gln Pro Gly Ala Gly Val Lys Pro Gly Lys Val Pro Gly Val
130 135 140
Gly Leu Pro Gly Val Tyr Pro Gly Gly Val Leu Pro Gly Ala Arg Phe
145 150 155 160
Pro Gly Val Gly Val Leu Pro Gly Val Pro Thr Gly Ala Gly Val Lys
165 170 175
Pro Lys Ala Pro Gly Val Gly Gly Ala Phe Ala Gly Ile Pro Gly Val
180 185 190
Gly Pro Phe Gly Gly Pro Gln Pro Gly Val Pro Leu Gly Tyr Pro Ile
195 200 205
Lys Ala Pro Lys Leu Pro Gly Gly Tyr Gly Leu Pro Tyr Thr Thr Gly
210 215 220
Lys Leu Pro Tyr Gly Tyr Gly Pro Gly Gly Val Ala Gly Ala Ala Gly
225 230 235 240
Lys Ala Gly Tyr Pro Thr Gly Thr Gly Val Gly Pro Gln Ala Ala Ala
245 250 255
Ala Ala Ala Ala Lys Ala Ala Ala Lys Phe Gly Ala Gly Ala Ala Gly
260 265 270
Val Leu Pro Gly Val Gly Gly Ala Gly Val Pro Gly Val Pro Gly Ala
275 280 285
Ile Pro Gly Ile Gly Gly Ile Ala Gly Val Gly Thr Pro Ala Ala Ala
290 295 300
Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Ala
305 310 315 320
Gly Leu Val Pro Gly Gly Pro Gly Phe Gly Pro Gly Val Val Gly Val
325 330 335
Pro Gly Ala Gly Val Pro Gly Val Gly Val Pro Gly Ala Gly Ile Pro
340 345 350
Val Val Pro Gly Ala Gly Ile Pro Gly Ala Ala Val Pro Gly Val Val
355 360 365
Ser Pro Glu Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Lys Tyr Gly
370 375 380
Ala Arg Pro Gly Val Gly Val Gly Gly Ile Pro Thr Tyr Gly Val Gly
385 390 395 400
Ala Gly Gly Phe Pro Gly Phe Gly Val Gly Val Gly Gly Ile Pro Gly
405 410 415
Val Ala Gly Val Pro Ser Val Gly Gly Val Pro Gly Val Gly Gly Val
420 425 430
Pro Gly Val Gly Ile Ser Pro Glu Ala Gln Ala Ala Ala Ala Ala Lys
435 440 445
Ala Ala Lys Tyr Gly Val Gly Thr Pro Ala Ala Ala Ala Ala Lys Ala
450 455 460
Ala Ala Lys Ala Ala Gln Phe Gly Leu Val Pro Gly Val Gly Val Ala
465 470 475 480
Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly
485 490 495
Leu Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly
500 505 510
Val Gly Val Ala Pro Gly Ile Gly Pro Gly Gly Val Ala Ala Ala Ala
515 520 525
Lys Ser Ala Ala Lys Val Ala Ala Lys Ala Gln Leu Arg Ala Ala Ala
530 535 540
Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly Val Gly Val Gly Val Pro
545 550 555 560
Gly Leu Gly Val Gly Ala Gly Val Pro Gly Leu Gly Val Gly Ala Gly
565 570 575
Val Pro Gly Phe Gly Ala Gly Ala Asp Glu Gly Val Arg Arg Ser Leu
580 585 590
Ser Pro Glu Leu Arg Glu Gly Asp Pro Ser Ser Ser Gln His Leu Pro
595 600 605
Ser Thr Pro Ser Ser Pro Arg Val Pro Gly Ala Leu Ala Ala Ala Lys
610 615 620
Ala Ala Lys Tyr Gly Ala Ala Val Pro Gly Val Leu Gly Gly Leu Gly
625 630 635 640
Ala Leu Gly Gly Val Gly Ile Pro Gly Gly Val Val Gly Ala Gly Pro
645 650 655
Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe
660 665 670
Gly Leu Val Gly Ala Ala Gly Leu Gly Gly Leu Gly Val Gly Gly Leu
675 680 685
Gly Val Pro Gly Val Gly Gly Leu Gly Gly Ile Pro Pro Ala Ala Ala
690 695 700
Ala Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu Gly Gly Val Leu Gly
705 710 715 720
Gly Ala Gly Gln Phe Pro Leu Gly Gly Val Ala Ala Arg Pro Gly Phe
725 730 735
Gly Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys Leu Gly Lys Ala Cys
740 745 750
Gly Arg Lys Arg Lys
755
<210>736
<211>20
<212>PRT
<213>人
<400>736
Ala Arg Pro Gly Val Gly Val Gly Gly Ile Pro Thr Tyr Gly Val Gly
1 5 10 15
Ala Gly Gly Phe
20
<210>737
<211>17
<212>PRT
<213>人
<400>737
Gly Leu Pro Tyr Thr Thr Gly Lys Leu Pro Tyr Gly Tyr Gly Pro Gly
1 5 10 15
Gly
<210>738
<211>25
<212>PRT
<213>人
<400>738
Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro
1 5 10 15
Gly Ile Gly Pro Gly Gly Val Ala Ala
20 25
<210>739
<211>23
<212>PRT
<213>人
<400>739
Gly Gly Ala Gly Val Pro Gly Val Pro Gly Ala Ile Pro Gly Ile Gly
1 5 10 15
Gly Ile Ala Gly Val Gly Thr
20
<210>740
<211>23
<212>PRT
<213>人
<400>740
Gly Gly Ala Gly Val Pro Gly Val Pro Gly Ala Ile Pro Gly Ile Gly
1 5 10 15
Gly Ile Ala Gly Val Gly Thr
20
<210>741
<211>16
<212>PRT
<213>人
<400>741
Gly Val Gly Ile Ser Pro Glu Ala Gln Ala Ala Ala Ala Ala Lys Ala
1 5 10 15
<210>742
<211>16
<212>PRT
<213>人
<400>742
Gly Val Gly Ile Ser Pro Glu Ala Gln Ala Ala Ala Ala Ala Lys Ala
1 5 10 15
<210>743
<211>6
<212>PRT
<213>人
<400>743
Arg Pro Gly Val Gly Val
1 5
<210>744
<211>6
<212>PRT
<213>人
<400>744
Leu Pro Tyr Thr Thr Gly
1 5
<210>745
<211>6
<212>PRT
<213>人
<400>745
Val Ala Pro Gly Val Gly
1 5
<210>746
<211>6
<212>PRT
<213>人
<400>746
Gly Ala Gly Val Pro Gly
1 5
<210>747
<211>6
<212>PRT
<213>人
<400>747
Val Gly Ile Ser Pro Glu
1 5
<210>748
<211>6
<212>PRT
<213>人
<400>748
Arg Pro Gly Val Gly Val
1 5
<210>749
<211>6
<212>PRT
<213>人
<400>749
Leu Pro Tyr Thr Thr Gly
1 5
<210>750
<211>6
<212>PRT
<213>人
<400>750
Gly Val Gly Ala Gly Gly
1 5
<210>751
<211>6
<212>PRT
<213>人
<400>751
Tyr Gly Tyr Gly Pro Gly
1 5
<210>752
<211>6
<212>PRT
<213>人
<400>752
Gly Pro Gly Gly Val Ala
1 5
<210>753
<211>6
<212>PRT
<213>人
<400>753
Gly Ile Ala Gly Val Gly
1 5
<210>754
<211>13
<212>PRT
<213>人
<400>754
Lys Asn Gly Glu Thr Gly Pro Gln Gly Pro Gly Gly Cys
1 5 10
<210>755
<211>13
<212>PRT
<213>人
<400>755
Lys Asn Gly Glu Thr Gly Pro Gln Gly Pro Pro Gly Lys
1 5 10
<210>756
<211>13
<212>PRT
<213>人
<400>756
Lys Asp Gly Glu Thr Gly Ala Ala Gly Pro Pro Gly Lys
1 5 10
<210>757
<211>13
<212>PRT
<213>人
<400>757
Lys Asp Gly Glu Ala Gly Ala Gln Gly Pro Pro Gly Lys
1 5 10
<210>758
<211>14
<212>PRT
<213>人
<400>758
Pro Gly Lys Asn Gly Glu Thr Pro Gly Pro Gln Gly Pro Lys
1 5 10
<210>759
<211>13
<212>PRT
<213>人
<400>759
Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Gly Gly Cys
1 5 10
<210>760
<211>13
<212>PRT
<213>人
<400>760
Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Lys
1 5 10
<210>761
<211>13
<212>PRT
<213>人
<400>761
Ile Ala Gly Leu Thr Gly Ala Arg Gly Leu Ala Gly Lys
1 5 10
<210>762
<211>15
<212>PRT
<213>人
<400>762
Leu Gly Ile Ala Gly Ile Thr Gly Ala Arg Gly Leu Ala Gly Lys
1 5 10 15
<210>763
<211>6
<212>PRT
<213>人
<400>763
Lys Asp Gly Thr Ser Gly
1 5
<210>764
<211>13
<212>PRT
<213>人
<400>764
Lys Asp Gly Thr Ser Gly His Pro Gly Pro Gly Gly Cys
1 5 10
<210>765
<211>13
<212>PRT
<213>人
<400>765
Lys Asp Gly Thr Ser Gly His Pro Gly Pro Ile Gly Lys
1 5 10
<210>766
<211>13
<212>PRT
<213>人
<400>766
Lys Asp Gly Ser Ser Gly His Pro Gly Pro Ile Gly Lys
1 5 10
<210>767
<211>13
<212>PRT
<213>人
<400>767
Pro Gly Lys Asp Gly Thr Ser Gly His Pro Gly Pro Lys
1 5 10
<210>768
<211>13
<212>PRT
<213>人
<400>768
Cys Gly Gly Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly
1 5 10
<210>769
<211>12
<212>PRT
<213>人
<400>769
Ala Gln Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly
1 5 10
<210>770
<211>12
<212>PRT
<213>人
<400>770
Ala Gln Gly Pro Pro Gly Ser Pro Gly Pro Leu Gly
1 5 10
<210>771
<211>12
<212>PRT
<213>人
<400>771
Asp Asp Gly Pro Ser Gly Ala Glu Gly Pro Pro Gly
1 5 10
<210>772
<211>12
<212>PRT
<213>人
<400>772
Gly Pro Pro Gly Ala Pro Gly Pro Leu Gly Ile Ala
1 5 10
<210>773
<211>13
<212>PRT
<213>人
<400>773
Asn Thr Gly Ala Pro Gly Ser Pro Gly Val Cys Gly Gly
1 5 10
<210>774
<211>13
<212>PRT
<213>人
<400>774
Asn Thr Gly Ala Pro Gly Ser Pro Gly Val Ser Gly Lys
1 5 10
<210>775
<211>13
<212>PRT
<213>人
<400>775
Asn Ser Gly Ser Pro Gly Asn Pro Gly Val Ala Gly Lys
1 5 10
<210>776
<211>12
<212>PRT
<213>人
<400>776
Ala Gly Asn Thr Gly Ala Pro Gly Ser Pro Gly Val
1 5 10
<210>777
<211>13
<212>PRT
<213>人
<400>777
Ala Ile Gly Pro Ser Gly Pro Ala Gly Lys Gly Gly Cys
1 5 10
<210>778
<211>13
<212>PRT
<213>人
<400>778
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Claims (30)
1.用于对包含新表位的肽片段进行定量的生物测定方法，所述新表位是由蛋白酶对动脉粥样硬化斑块的蛋白质进行切割而形成的，所述方法包括将包含所述肽片段的样品与对所述新表位具有特异性结合亲和力的免疫结合配偶体相接触，以及测定所述免疫结合配偶体与所述样品中肽片段的结合水平。
2.根据权利要求1的方法，其中所述免疫结合配偶体对包含C端新表位的肽片段具有特异性结合亲和力。
3.根据权利要求1的方法，其中所述免疫结合配偶体对包含N端新表位的肽片段具有特异性结合亲和力。
4.根据前述任一项权利要求的方法，其中所述免疫结合配偶体对包含新表位的肽片段具有特异性结合亲和力，所述新表位是由蛋白酶在CRP的下列任一部分序列中对CRP进行切割而形成的：
。
5.根据权利要求1-3中任一项的方法，其中所述免疫结合配偶体对包含新表位的肽片段具有特异性结合亲和力，所述新表位是由蛋白酶在ApoE的下列任一部分序列中对ApoE进行切割而形成的：
。
6.根据权利要求4或5的方法，其中所述免疫结合配偶体对肽N端的下列任一序列具有特异性结合亲和力：
或者对肽C端的下列任一序列具有特异性结合亲和力：
7.根据权利要求1-3中任一项的方法，其中所述肽片段是光亮蛋白聚糖、多功能蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖、双糖链蛋白聚糖的片段。
8.根据权利要求7的方法，其中所述免疫结合配偶体对包含新表位的肽片段具有特异性结合亲和力，所述新表位是由蛋白酶在光亮蛋白聚糖、多功能蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖和双糖链蛋白聚糖的下列任一部分序列中切割光亮蛋白聚糖、多功能蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖或双糖链蛋白聚糖而形成的：
。
9.根据权利要求8的方法，其中所述免疫结合配偶体对肽N端的下列任一序列具有特异性结合亲和力：
。
10.根据权利要求8的方法，其中所述免疫结合配偶体对肽C端的下列任一序列具有特异性结合亲和力：
。
11.根据权利要求1-3中任一项的方法，其中所述免疫结合配偶体对包含新表位的肽片段具有特异性结合亲和力，所述新表位是由蛋白酶在III型胶原蛋白的下列任一部分序列中在符号＊标记的位点处对III型胶原蛋白进行切割而形成的：
。
12.根据权利要求11的方法，其中所述免疫结合配偶体对肽N端的下列任一序列具有特异性结合亲和力：
或者对肽C端的下列任一序列具有特异性结合亲和力：
13.根据权利要求1-3中任一项的方法，其中所述免疫结合配偶体对包含新表位的肽片段具有特异性结合亲和力，所述新表位是由蛋白酶在弹性蛋白的下列任一部分序列中对弹性蛋白进行切割而形成的：
14.根据权利要求13的方法，其中所述免疫结合配偶体对肽N端的下列任一序列具有特异性结合亲和力：
，
或者对肽C端的下列任一序列具有特异性结合亲和力：
15.根据上述任一权利要求的方法，其中所述免疫结合配偶体不与作为所述新表位序列之来源的完整蛋白特异性结合。
16.根据上述任一权利要求的方法，其中所述免疫结合配偶体是单克隆抗体或者具有特异性结合亲和力的单克隆抗体片段。
17.根据前述任一项权利要求的方法，其中所述方法以竞争性免疫测定的形式进行，其中将所述免疫结合配偶体和竞争剂在所述样品存在下孵育，所述竞争剂与所述样品中的肽片段竞争结合所述免疫结合配偶体。
18.根据权利要求17的方法，其中所述竞争剂是合成肽，或者是切割所述表位的来源蛋白以显露所述新表位而形成的纯化天然肽。
19.根据上述任一权利要求的方法，其中所述样品是尿、血清、血或血浆的样品。
20.根据前述任一权利要求的方法，其中所述样品是来自患者的样品，所述方法还包括将所测定的所述肽片段的结合水平与下列特征值进行比较：(a)相当的健康个体和/或(b)病理动脉粥样硬化状况。
21.针对C端或N端新表位的免疫结合配偶体，所述新表位是由蛋白酶切割光亮蛋白聚糖、多功能蛋白聚糖、基底膜蛋白聚糖、核心蛋白聚糖、双糖链蛋白聚糖、III型胶原蛋白、ApoE、CRP或弹性蛋白而形成的。
22.根据权利要求21的免疫结合配偶体，其对新表位具有特异性免疫反应性，所述新表位是由蛋白酶在权利要求5至14中任一项所述蛋白质的任一部分序列中切割所述蛋白质而形成的。
23.根据权利要求21或22的免疫结合配偶体，其为单克隆抗体或其结合片段。
24.产生权利要求23所述单克隆抗体的细胞系。
25.包含C端或N端新表位的肽，所述新表位是由蛋白酶在权利要求5至14中任一项所述蛋白质的任一部分序列中切割所述蛋白质而形成的。
26.根据权利要求25的肽，其作为半抗原与载体缀合以产生针对所述肽的免疫应答，或者固定于固体表面或者与检测标记缀合以用于免疫测定中。
27.编码包含C端或N端新表位的肽的分离核酸分子，所述新表位是由蛋白酶在权利要求5至14中任一项所述蛋白质的任一部分序列中切割所述蛋白质而形成的。
28.包含核酸序列的载体，所述核酸序列包含表达信号和编码序列，所述编码序列编码表达包含C端或N端新表位的肽，所述新表位是由蛋白酶在权利要求5至14中任一项所述蛋白质的任一部分序列中切割所述蛋白质而形成的。
29.转化有权利要求28所述载体并表达所述肽的宿主细胞。
30.免疫测定试剂盒，其包含权利要求21至23中任一项的免疫结合配偶体以及与所述免疫结合配偶体结合的竞争剂，并任选地包含以下一种或多种：洗涤试剂、缓冲剂、终止试剂、酶标记、酶标记底物、校准标准品、抗小鼠抗体和使用所述试剂盒进行测定的说明书。
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| US9404932B2 (en) * | 2007-11-05 | 2016-08-02 | Nordic Bioscience A/S | Pathology biomarker assay |
| EP2538222B1 (en) | 2007-11-05 | 2021-08-25 | Nordic Bioscience A/S | Biochemical markers for CVD risk assessment |
| ES2635494T3 (es) * | 2009-03-30 | 2017-10-04 | Nordic Bioscience A/S | Ensayo de biomarcador de fibrosis |
| GB201107922D0 (en) * | 2011-05-12 | 2011-06-22 | Nordic Bioscience As | Biochemical markers for CVD risk assessment |
| KR101968779B1 (ko) * | 2011-05-27 | 2019-04-12 | 노르딕 바이오사이언스 에이/에스 | 진단용 펩티드의 검출 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103238071A (zh) * | 2009-03-30 | 2013-08-07 | 北欧生物科技公司 | 纤维化生物标志物的测定 |
| CN106831980A (zh) * | 2011-11-04 | 2017-06-13 | 株式会社日皮 | Dpp‑4抑制剂 |
| CN106866814A (zh) * | 2011-11-04 | 2017-06-20 | 株式会社日皮 | Dpp‑4抑制剂 |
| CN106866814B (zh) * | 2011-11-04 | 2020-06-23 | 株式会社日皮 | Dpp-4抑制剂 |
| CN106831980B (zh) * | 2011-11-04 | 2020-09-15 | 株式会社日皮 | Dpp-4抑制剂 |
| CN102565418A (zh) * | 2011-12-25 | 2012-07-11 | 复旦大学附属中山医院 | 一种主动脉疾病早期诊断标志物及其应用 |
| CN109791143A (zh) * | 2016-09-29 | 2019-05-21 | 梅蒂克斯生物化学有限公司 | 确定与心血管疾病相关的风险的方法 |
| CN113631183A (zh) * | 2019-01-22 | 2021-11-09 | 克莱姆森大学研究基金会 | 抗弹性蛋白抗体及使用方法 |
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| JP2015007638A (ja) | 2015-01-15 |
| EP2538222B1 (en) | 2021-08-25 |
| EP2538223A2 (en) | 2012-12-26 |
| DK2208073T3 (da) | 2020-03-30 |
| CN105510601B (zh) | 2018-04-10 |
| EP2538218A2 (en) | 2012-12-26 |
| EP2538218A8 (en) | 2013-02-27 |
| US20100323377A1 (en) | 2010-12-23 |
| ES2777948T3 (es) | 2020-08-06 |
| JP2017181509A (ja) | 2017-10-05 |
| EP2538221A2 (en) | 2012-12-26 |
| US20160282362A1 (en) | 2016-09-29 |
| EP2538223A8 (en) | 2013-02-27 |
| EP2538222A2 (en) | 2012-12-26 |
| JP2011503564A (ja) | 2011-01-27 |
| EP2538221A3 (en) | 2013-04-24 |
| EP2538222A8 (en) | 2013-02-27 |
| WO2009059972A2 (en) | 2009-05-14 |
| EP2538222A3 (en) | 2013-04-24 |
| CN108196072A (zh) | 2018-06-22 |
| EP2208073A2 (en) | 2010-07-21 |
| EP2538218A3 (en) | 2013-04-24 |
| US9359633B2 (en) | 2016-06-07 |
| CN105510601A (zh) | 2016-04-20 |
| ES2897492T3 (es) | 2022-03-01 |
| JP6039879B2 (ja) | 2016-12-07 |
| EP2538223A3 (en) | 2013-04-24 |
| US10267809B2 (en) | 2019-04-23 |
| EP2208073B1 (en) | 2020-01-15 |
| DK2538222T3 (da) | 2021-11-15 |
| WO2009059972A3 (en) | 2009-09-17 |
| JP6309669B2 (ja) | 2018-04-11 |
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