MOBILE REACTIVE CENTER OF SERPINS AND THE CONTROL OF THROMBOSIS
MOBILE REACTIVE CENTER OF SERPINS AND THE CONTROL OF THROMBOSIS
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DOI：
10.1038/353576a0
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发表时间：
1991-10-10
期刊：
影响因子：
64.8
通讯作者：
STEIN, PE
中科院分区：
文献类型：
--
作者：
CARRELL, RW;EVANS, DL;STEIN, PE
人血浆中的两种蛋白酶抑制剂在控制血栓形成中发挥着关键作用：抗凝血酶抑制凝血，纤溶酶原激活剂抑制剂 PAI-1 抑制纤维蛋白溶解（血栓溶解）。 两种抑制剂都是丝氨酸蛋白酶抑制剂家族的成员，并且都以潜在或非活性形式存在于血浆中。 我们在此表明，丝氨酸蛋白酶抑制剂的反应中心可以采用不同的构象，并且反应中心的移动性对于抗凝血酶的功能及其与肝素的结合和激活是必要的；新锁定构象的识别解释了 PAI-1 的潜在非活性状态。 这种改变构象的能力不仅可以调节抑制活性，还可以保护循环抑制剂免受蛋白水解攻击。 这些发现共同解释了与其他丝氨酸蛋白酶抑制剂家族的小固定肽环相比，丝氨酸蛋白酶抑制剂保留了大且不受约束的反应中心。
TWO protease inhibitors in human plasma play a key part in the control of thrombosis: antithrombin inhibits coagulation and the plasminogen activator inhibitor PAI-1 inhibits fibrinolysis, the dissolving of clots. Both inhibitors are members of the serpin family and both exist in the plasma in latent or inactive forms. We show here that the reactive centre of the serpins can adopt varying conformations and that mobility of the reactive centre is necessary for the function of antithrombin and its binding and activation by heparin; the identification of a new locked conformation explains the latent inactive state of PAI-1. This ability to vary conformation not only allows the modulation of inhibitory activity but also protects the circulating inhibitor against proteolytic attack. Together these findings explain the retention by the serpins of a large and unconstrained reactive centre as compared to the small fixed peptide loop of other families of serine protease inhibitors.