Tissue Factor De-encryption, Thrombus Formation, and Thiol-disulfide Exchange
Tissue Factor De-encryption, Thrombus Formation, and Thiol-disulfide Exchange
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DOI：
10.1055/s-0032-1333311
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发表时间：
2013-02-01
影响因子：
5.7
通讯作者：
Chen, Vivien M. Y.
中科院分区：
文献类型：
--
作者：
Chen, Vivien M. Y.
组织因子（TF）通过与VIIa因子（FVIIa）形成复合物而启动血液凝固。传统上认为，循环中FVIIa与内皮下TF的分离是防止血栓形成的主要控制因素，健康个体的循环细胞和内皮在静止状态下不表达TF蛋白。然而，在健康的人血浆和血栓动物模型中检测到TF，这表明循环中的TF可以在激活事件后促进凝血酶的生成和纤维蛋白的形成。循环中的TF——事实上，细胞表面的大部分TF——是“加密的”或不凝血的。解密步骤涉及暴露于磷脂酰丝氨酸（PS），但单独暴露于磷脂酰丝氨酸不足以充分发挥TF活性。变构二硫键通过二硫键的形成和断裂介导适形变化来控制蛋白质的功能。TF在膜近端纤维连接蛋白III型结构域含有一个典型的表面暴露的变构键。涉及该二硫化物的硫-二硫化物交换涉及TF活化，形成与TF活性构象相对应的二硫化物键和与加密相对应的游离硫醇或巯基修饰形式。虽然TF解加密发生的确切机制仍然是一个争论的主题，但硫醇阻断和氧化还原酶的抑制在体外和体内不依赖血小板的凝血途径中对硫醇-二硫反应起着重要作用。特别是，氧化还原活性细胞外蛋白二硫异构酶参与血栓起始的早期阶段，并已被证明是抗血栓药物开发的潜在靶点。
Tissue factor (TF) by forming a complex with factor VIIa (FVIIa) initiates blood coagulation. It was traditionally believed that the separation of FVIIa in circulation from subendothelial TF was the main control that was preventing spontaneous initiation of thrombosis and that circulating cells and endothelium did not express TF protein at rest in healthy individuals. However, TF has been detected in healthy human plasma and animal models of thrombosis, which indicate that TF in circulation can contribute to thrombin generation and fibrin formation after an activation event. Circulating TF-and indeed, most of the TF on the cell surface-is "encrypted" or coagulation inactive. The de-encryption step involves exposure of phosphatidylserine (PS), but PS exposure alone is insufficient for full TF activity. Allosteric disulfide bonds control protein function by mediating conformal change through the formation and breaking of disulfide bonds. TF contains a typical surface exposed allosteric bond in the membrane proximal fibronectin type III domain. Thiol-disulfide exchange involving this disulfide is implicated in TF activation with the formation of the disulfide bond corresponding with the active conformation of TF and free thiol or thiol-modified forms corresponding with encryption. Although the exact mechanism by which TF de-encryption occurs remains a subject of debate, thiol blockade and inhibition of oxidoreductases show an important role for thiol-disulfide reactions in platelet-independent pathways of coagulation in vitro and in vivo. In particular, redox active extracellular protein disulfide isomerase is involved in the earliest stages of thrombus initiation and has proven to be a potential target for antithrombotic drug development.