Esmon C T
Oklahoma Medical Research Foundation, Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
FASEB J. 1995 Jul;9(10):946-55. doi: 10.1096/fasebj.9.10.7615164.
The protein C anticoagulant system generates an "on demand" physiologic anticoagulant response. The pathway is initiated when thrombin binds to the endothelial cell thrombin binding protein, thrombomodulin. The complex exhibits dramatically altered macromolecular specificity. It rapidly cleaves the protein C zymogen to form the anticoagulant, activated protein C. Complex formation between thrombin and thrombomodulin also prevents thrombin, the enzyme responsible for clot formation and a potent platelet activator, from being able to clot fibrinogen or to activate platelets. Structural, kinetic, and competition studies suggest that thrombomodulin blocks these clotting reactions by masking the binding sites for fibrinogen and the platelet thrombin receptor. Stimulation of protein C activation appears to occur through conformational changes in the extended binding pocket of thrombin. This prevents repulsive interactions with protein C that exist when the free enzyme attempts to dock with this substrate. In addition to protein-protein interactions, thrombomodulin has a covalently associated chondroitin sulfate moiety. Chondroitin sulfate binds to a basic surface on thrombin that is also involved in heparin interaction. The chondroitin sulfate enhances the affinity of thrombin for thrombomodulin approximately 10- to 20-fold, making thrombomodulin a more potent inhibitor of coagulation, altering thrombin's conformation and specificity, and accelerating thrombin inhibition by the serpin, antithrombin. These properties make thrombomodulin a molecular switch ideally suited to trigger an anticoagulant response when too much thrombin is generated. The importance of the system is documented by the clinical observation that patients deficient in protein C often die of massive thrombotic complications that can be reversed or prevented by infusion of protein C.
蛋白C抗凝系统产生一种“按需”的生理性抗凝反应。当凝血酶与内皮细胞凝血酶结合蛋白血栓调节蛋白结合时，该途径被启动。该复合物表现出显著改变的大分子特异性。它迅速切割蛋白C酶原以形成抗凝剂活化蛋白C。凝血酶与血栓调节蛋白之间的复合物形成还可防止负责凝血的酶及强效血小板激活剂凝血酶使纤维蛋白原凝固或激活血小板。结构、动力学和竞争研究表明，血栓调节蛋白通过掩盖纤维蛋白原和血小板凝血酶受体的结合位点来阻断这些凝血反应。蛋白C活化的刺激似乎是通过凝血酶延伸结合口袋中的构象变化而发生的。这可防止与游离酶试图与该底物对接时存在的蛋白C发生排斥性相互作用。除了蛋白质-蛋白质相互作用外，血栓调节蛋白还具有共价结合的硫酸软骨素部分。硫酸软骨素与凝血酶上也参与肝素相互作用的碱性表面结合。硫酸软骨素使凝血酶对血栓调节蛋白的亲和力提高约10至20倍，使血栓调节蛋白成为更有效的凝血抑制剂，改变凝血酶的构象和特异性，并加速丝氨酸蛋白酶抑制剂抗凝血酶对凝血酶的抑制作用。这些特性使血栓调节蛋白成为一种分子开关，非常适合在产生过多凝血酶时触发抗凝反应。该系统的重要性通过临床观察得到证明，即蛋白C缺乏的患者常死于大量血栓形成并发症，输注蛋白C可逆转或预防这些并发症。
