Molecular bilogical studies on the assembly of the anticoagulant protein C pathway-Strucure-function relationship of the functional domains in the related molecules.

抗凝蛋白C通路组装-相关分子功能域的结构-功能关系的分子生物学研究。

• 批准号: 07458151
• 负责人: SUZUKI Koji
• 金额: $ 4.16万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07458151/
• 关键词: protein C pathway; protein C; protein S; thrombomodulin; factor V; prothrombin; prothrombinase complex; molecular interaction

The anticoagulant protein C pathway is one of the most important systems to maintain the vascular blood fluidity. The aim of this project is to clarify the structure-function relationship of the molecules assembling in the protein C pathway to understand the molecular mechanism of this pathway. Here we studied the following three subjects : (1) Molecular mechanism of the dysfunction of protein S-Tokushima (Lys^<155>*Glu) for the regulation of the blood coagulation system. The results obtained suggest that the dysfunction of protein S-Tokushima occurs because it fails to interact with activated protein C (APC), factor Xa and prothrombin. The molecular interactions between these proteins are required for the expression of the APC cofactor activity and for the inhibition of the prothrombinase complex activity. (2) The importance of the Gla^<26> residue of protein C in expression of the anticoagulant activity of protein C on the phospholipid membrane. The results obtained suggest that Gla^<26>-dependent conformation is required for the binding of protein C and APC to phospholipids, thrombomodulin and the surface of endothelial cell protein C/APC receptor, but not to protein S and factor Va. (3) The role of the kringle domains of prothrombin during the assembly of the prothrombinase complex which efficiently produces thrombin, a physiological activator of protein C.The results obtained suggest that the kringle 2 domain interacts with factor Xa and that both kringle 1 and 2 domains of prothrombin interact with factor Va during the assembly of the prothrombinase complex. These findings may highlight the molecular mechanism of the anticoagulant protein C pathway.

抗凝蛋白C途径是维持血管流动性的最重要系统之一。该项目的目的是阐明在蛋白质C途径中组装的分子的结构功能关系，以了解该途径的分子机制。在这里，我们研究了以下三个主题：（1）蛋白S-Tokushima（Lys^<155> GLU）功能障碍的分子机制，以调节血液凝结系统。获得的结果表明，蛋白S-Tokushima的功能障碍是因为它与活化的蛋白C（APC），因子XA和凝血酶原相互作用。这些蛋白质之间的分子相互作用是表达APC辅因子活性和抑制凝血酶激酶复合活性所必需的。 （2）GLA^<26>蛋白C残基在蛋白C上对磷脂膜上蛋白C抗凝活性的表达的重要性。获得的结果表明，蛋白C和APC与磷脂，血栓瘤蛋白和内皮细胞蛋白C/APC受体的结合是必需的，这是必需的蛋白质的生理活化剂C.获得的结果表明，Kringle 2结构域与因子XA相互作用，并且在凝血酶复合物组装过程中，凝血酶原蛋白的Kringle 1和2结构域都与因子VA相互作用。这些发现可能突出抗凝蛋白C途径的分子机制。

项目成果

Suzuki K.: "Molecular Basis of Thrombosis and Hemostasis(Protein C)" Marcel Dekker,Inc,New York(eds.Roberts HR & High KA), 688(31) (1995)

Suzuki K.：“血栓形成和止血的分子基础（蛋白质 C）”Marcel Dekker, Inc，纽约（Roberts HR 编辑）

Suzuki K.: "Molecular Basis of Thrombosis and Hemostasis(Protein S)" Marcel Dekker,Inc,New York(eds.Roberts HR & High KA), 688(19) (1995)

Suzuki K.：“血栓形成和止血的分子基础（蛋白质 S）”Marcel Dekker, Inc，纽约（Roberts HR 编辑）

Nishioka J,Ido M,Suzuki K,et al.: "The Gla^<26> residue of protein C is required for the binding of protein C to hrombomodulin and endothelial cell protein C receptor, but not to protein S and factor Va." Thromb.Haemostas.75. 275-282 (1996)

Nishioka J、Ido M、Suzuki K 等人：“蛋白 C 的 Gla^26 残基是蛋白 C 与血栓调节蛋白和内皮细胞蛋白 C 受体结合所必需的，但与蛋白 S 和因子 Va 的结合则不需要。

Gabazza EC,Takeya H,Suzuki K,et al.: "Protein C activation in NIDDM patients." Diabetologia. 39. 1455-1461 (1996)

Gabazza EC、Takeya H、Suzuki K 等人：“NIDDM 患者中的蛋白 C 激活。”

Gabazza EC, Takeya H, Suzuki K, et al.: "Acquired activated protein C resistance in patients with lupus anticoagulant and essential thrombocythemia." Clin. Appl. Thromb. Hemostas.(in press).

Gabazza EC、Takeya H、Suzuki K 等人：“狼疮抗凝剂和原发性血小板增多症患者获得性活化蛋白 C 抵抗。”