Regulation of the protein C anticoagulant and antiinflammatory pathways.
Regulation of the protein C anticoagulant and antiinflammatory pathways.
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DOI：
10.2174/092986710791233706
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发表时间：
2010
影响因子：
4.1
通讯作者：
Rezaie AR
中科院分区：
文献类型：
--
作者：
Rezaie AR
蛋白C是血浆中的维生素K依赖性抗凝丝氨酸蛋白酶酶原，其在被凝血酶-血栓调节蛋白复合物激活后通过有限的蛋白水解降解辅因子Va和VIIIa来下调凝血级联。除了其抗凝血功能之外，活化蛋白C（APC）还结合脂筏/小窝区室中的内皮蛋白C受体（EPCR）以活化蛋白酶活化受体1（PAR-1），从而引发内皮细胞中的抗凝血和细胞保护信号应答。这些特性导致FDA批准重组APC作为严重脓毒症的治疗药物。APC在抗凝剂和抗凝血剂途径中选择其底物的机制尚不清楚。最近的结构和诱变数据表明，三个暴露的表面环（称为39环）的碱性残基（Lys-37、Lys-38和Lys-39），60环（Lys-62、Lys-63和Arg-67）和70-80-环（Arg-74，Arg-75，和Lys-78）（胰凝乳蛋白酶编号）构成APC中的阴离子结合外部位点，其在抗凝剂途径中与促凝血辅因子Va和VIIIa相互作用。此外，两个带负电荷的残基上的螺旋结构上的APC的活性位点的相对侧已被证明，以确定在细胞保护途径中的PAR-1识别的特异性。本文将回顾APC发挥其蛋白水解功能的机制，在两个生理上相互关联的途径，以及如何结构-功能的见解APC与其底物相互作用的特异性的决定因素，在两个途径可以利用修补分子的结构，以获得APC衍生物具有潜在的改善治疗概况。
Protein C is a vitamin K-dependent anticoagulant serine protease zymogen in plasma which upon activation by the thrombin-thrombomodulin complex down-regulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. In addition to its anticoagulant function, activated protein C (APC) also binds to endothelial protein C receptor (EPCR) in lipid-rafts/caveolar compartments to activate protease- activated receptor 1 (PAR-1) thereby eliciting antiinflammatory and cytoprotective signaling responses in endothelial cells. These properties have led to FDA approval of recombinant APC as a therapeutic drug for severe sepsis. The mechanism by which APC selects its substrates in the anticoagulant and antiinflammatory pathways is not well understood. Recent structural and mutagenesis data have indicated that basic residues of three exposed surface loops known as 39-loop (Lys-37, Lys-38, and Lys-39), 60-loop (Lys-62, Lys-63, and Arg-67), and 70-80-loop (Arg-74, Arg-75, and Lys-78) (chymotrypsin numbering) constitute an anion binding exosite in APC that interacts with the procoagulant cofactors Va and VIIIa in the anticoagulant pathway. Furthermore, two negatively charged residues on the opposite side of the active-site of APC on a helical structure have been demonstrated to determine the specificity of the PAR-1 recognition in the cytoprotective pathway. This article will review the mechanism by which APC exerts its proteolytic function in two physiologically inter-related pathways and how the structure-function insights into determinants of the specificity of APC interaction with its substrates in two pathways can be utilized to tinker with the structure of the molecule to obtain APC derivatives with potentially improved therapeutic profiles.
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