Studies on The Role of Functional Domains in Factors Playing in The Regulation of Thrombus Formation

功能域在血栓形成调节因子中的作用研究

• 批准号: 05454622
• 负责人: SUZUKI Koji
• 金额: $ 4.35万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454622/
• 关键词: Anticoagulant protein C pathway; Thrombomodulin; Protein C; Protein S; Factor X; Functional domain; EGF domain; 組換え蛋白質; 分子間相互作用; トロンビン; EGF様ドメイン; 血管内皮細胞; ホモシステイン; 遺伝子発現機構

The blood fluidity in the vessel is maintained by the activation of several anticoagulant systems on the surface of intravascule, such as anticoagulant protein C pathway system and antithrombin III-heparin system.Hereditary abnormal patients, who are lacking antithrombotic factor or have abnormal molecule, are often suffered from the thrombotic diseases. Thus it is very important for diagnosis and medical treatments to study the genetic analysis and the analysis on the structure-function relationship of the normal and abnormal factors (proteins) in the anticoagulant systems. In this study, we analyzed the structure-function relationship of several factors ; thrombomodulin, protein C and protein S,which are major components in the protein C pathway. In which, a region containing the fourth to the sixth domains of the six epidermal growth factor (EGF) domains in thrombomodulin was found to serve the binding sites for thrombin and protein C during the activation of protein C by thrombin complexed with thrombomodulin. We also found that the second domain of the four EGF domains of protein S plays a crucial role as a binding site of activated protein C in the expression of the cofactor activity for activated protein C.These results suggest that the functional domains play roles in the interactions with the target proteins in the antithrombotic system.

血管中的血液流动性通过激活肺活腔表面的几个抗凝系统的激活，例如抗凝蛋白C途径系统和抗凝血酶III-Heparin System.Herepordardormal患者，这些患者缺乏抗肉质因子或缺乏异常分子的患者。因此，对于诊断和医疗治疗，研究抗凝系统正常因素和异常因子（蛋白质）的结构功能关系的分析非常重要。在这项研究中，我们分析了几个因素的结构 - 功能关系。血小板蛋白，蛋白C和蛋白质S，它们是蛋白C途径中的主要成分。其中，在血小板蛋白中，含有六个表皮生长因子（EGF）结构域的第四至第六域的区域被发现在与血栓蛋白复合的凝血酶激活期间，在蛋白C激活过程中为凝血酶和蛋白质C提供结合位点。我们还发现，蛋白质的四个EGF结构域的第二个结构域在激活蛋白C的表达中起着至关重要的作用，作为活化蛋白的辅因子活性的结合位点。这些结果表明，这些功能结构域在与抗强化系统中与靶蛋白的相互作用中起着作用。

项目成果

Iino.M.,Takeya,H.,Suzuki,K.,et al.: "The role of human factor X activation peptide in activation of factor X by factor IXa." J.Biochem.116. 335-340 (1994)

Iino.M.、Takeya,H.、Suzuki,K.,et al.：“人 X 因子激活肽在 IXa 因子激活 X 因子中的作用。”

Wada,H.,Mori,Y.,Suzuki,K.,et al.: "Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia." Am.J.Hematol.44. 112-116 (1993)

Wada,H.,Mori,Y.,Suzuki,K.,et al.：“高胆固醇血症患者血管内皮细胞标志物血浆水平升高。”

Ito,T.,Hiraiwa,J.,Nishioka,J.,Suzuki,K.: "Characterization of functionally important regions of tissue factor by using monoclonal antibodies." J.Biochem.114. 691-696 (1993)

Ito,T.、Hiraiwa,J.、Nishioka,J.、Suzuki,K.：“使用单克隆抗体表征组织因子的功能重要区域。”

Suzuki,K.: "Molecular Bilogy of Thrombosis and Hemostasis.(Protein C.)" Marcel Dekker,Inc,New York(eds.by Roberts,H.R.and High,K.A.), 688(32) (1995)

Suzuki,K.：“血栓形成和止血的分子生物学。（蛋白质 C.）”Marcel Dekker, Inc，纽约（Roberts, H.R. 和 High, K.A. 编辑），688(32) (1995)

Hayashi,T.Nishioka,J.,Suzuki,K.,et al.: "Protein S Tokushima:abnormal molecule with a substitution of Glu for Lys-155 in the second epidermal growth factor -like domain of protein S." Blood. 83. 683-690 (1994)

Hayashi,T.Nishioka,J.,Suzuki,K.,et al.：“蛋白质 S 德岛：蛋白质 S 的第二个表皮生长因子样结构域中的 Lys-155 被 Glu 取代的异常分子。”