Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation.
Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation.
复制标题
凝血酶和血栓调节蛋白之间的复合物形成抑制凝血酶催化的纤维蛋白形成和因子V激活。
DOI：
10.1016/s0021-9258(18)34276-5
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发表时间：
1982
期刊：
影响因子：
--
通讯作者：
K. Harris
中科院分区：
文献类型：
--
作者：
C. Esmon;N. Esmon;K. Harris
当凝血酶与一种特定的细胞表面辅因子蛋白——凝血调节蛋白结合时，蛋白C被迅速激活。研究开始确定凝血酶-血栓调节蛋白复合物形成对凝血酶底物特异性的影响。当凝血酶与凝血调节蛋白结合时，合成的复合物保留了不到1%的游离凝血酶的纤维蛋白原凝血活性。不涉及凝血酶分子的永久性改变，因为充分的凝血活性是通过与过量的二异丙基磷酸凝血酶的复合物孵育而再生的。与依赖于Ca2+的凝血酶-血栓调节蛋白复合物对蛋白C的激活不同，纤维蛋白原凝血活性的抑制并不依赖于二价金属离子的存在。凝血酶-血栓调节蛋白复合物的形成也抑制凝血酶因子v的激活。尽管大分子亚状态特异性发生了这些变化，但在凝血酶-血栓调节蛋白复合物形成时，合成底物对甲酰基- l-精氨酸甲酯和N -苯甲酰- l-精氨酸乙酯的水解没有明显变化。这种复合物的形成导致凝血酶的Km（从9.0 +/- 0.4到10.2 +/- 0.6微米）和Vmax（从230 +/- 10到270 +/- 10 mol/s/mol）的轻微增加。这些研究表明，凝血调节蛋白具有两种不同的抗凝功能：1)抑制凝血酶对凝血纤维蛋白原和活化因子V的能力；2)加速抗凝血活性蛋白C的形成。
Protein C is activated rapidly when thrombin binds to a specific cell surface cofactor protein, thrombomodulin. Studies were initiated to determine the influence of thrombin-thrombomodulin complex formation on the substrate specificity of thrombin. When thrombin binds to thrombomodulin, the resultant complex retains less than 1% of the fibrinogen clotting activity of free thrombin. Permanent alteration of the thrombin molecule is not involved since full clotting activity is regenerated by incubation of the complex with excess diisopropyl phosphothrombin. Unlike the activation of protein C by the thrombin-thrombomodulin complex which is dependent on Ca2+, inhibition of fibrinogen clotting activity is not dependent on the presence of divalent metal ions. Formation of the thrombin-thrombomodulin complex also inhibits thrombin activation of factor V. Despite these changes in macromolecular substate specificity, no significant change in the hydrolysis of the synthetic substrates p-tosyl-L-arginine methyl ester and N alpha-benzoyl-L-arginine ethyl ester is detected upon formation of the thrombin-thrombomodulin complex. Formation of this complex results in a slight increase in the Km (from 9.0 +/- 0.4 to 10.2 +/- 0.6 microM) and Vmax (from 230 +/- 10 to 270 +/- 10 mol/s/mol of thrombin) for the specific thrombin substrate H-D-Phe-Pip-Arg-p-nitroanilide. These studies suggest that thrombomodulin has two distinct anticoagulant functions: 1) to inhibit the ability of thrombin to clot fibrinogen and to activate factor V; and 2) to accelerate the formation of the anticoagulant, activated protein C.