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.

血管内的血液流动性是通过血管内表面多种抗凝系统的激活来维持的，如抗凝蛋白C途径系统、抗凝血酶III-肝素系统等。遗传性异常患者，缺乏抗血栓因子或分子异常，常患有血栓性疾病。因此，研究抗凝系统中正常和异常因子（蛋白质）的遗传分析和结构与功能关系的分析对于诊断和治疗具有重要意义。在这项研究中，我们分析了几个因素的结构-功能关系；血栓调节蛋白、蛋白C和蛋白S，它们是蛋白C途径的主要成分。其中，发现含有血栓调节蛋白中的六个表皮生长因子(EGF)结构域中的第四至第六结构域的区域在与血栓调节蛋白复合的凝血酶激活C蛋白的过程中充当凝血酶和C蛋白的结合位点。我们还发现，蛋白 S 的四个 EGF 结构域中的第二个结构域作为活化蛋白 C 的结合位点，在活化蛋白 C 的辅因子活性表达中发挥着至关重要的作用。这些结果表明，功能结构域在活化蛋白 C 的辅因子活性表达中发挥着至关重要的作用。与抗血栓系统中靶蛋白的相互作用。

项目成果

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。”

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。”

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。”

Ogawa,H.,Ido,M.and Suzuki,K.: "The thrombin receptor transmits signals through a 33-kDa protein kinase in human platelets." Biochem.Biophys.Res.Commun.203. 907-913 (1994)

Okawa,H.、Ido,M. 和 Suzuki,K.：“凝血酶受体通过人血小板中的 33 kDa 蛋白激酶传递信号。”

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。”