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凝血因子xi的二硫键在蛋白合成、分泌与功能的研究
首发时间：2024-07-26
摘要：凝血系统的激活是血栓形成过程中的关键步骤。目前市面上常见的传统抗凝剂多以凝血系统中的凝血因子vii、ix和x作为作用靶点，这些抗凝剂虽然有着一定的抗凝作用，但也存在导致出血风险增加的副作用。近年来凝血因子xi（fxi）抗凝剂在临床试验中展现出相较于传统抗凝剂的显著优势。同时已有研究表明c362-c482二硫键对fxi功能存在重要作用。为深入阐明fxi上所有二硫键的作用机制，我们构建了fxi野生型及其半胱氨酸突变型质粒并转染进293t细胞中并进行蛋白表达，应用western blotting、蛋白酶活性分析以及凝血酶生成检测来检测不同的二硫键断裂之后对fxi的合成、分泌及功能的影响。结果表明，fxi的合成过程不受二硫键断裂的影响；有15对二硫键断裂时会影响fxi的分泌；c362-c482和c553-c581二硫键直接调控fxi的蛋白酶活性；同时也发现蛋白质二硫键异构酶家族成员之一的pdir能够通过还原fxi上的二硫键来抑制其蛋白酶活性。
关键词： 凝血因子xi 二硫键 蛋白合成 蛋白分泌 蛋白功能 二硫键异构酶pdir
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characterization of the disulfide bonds on factor xi for protein synthesis, secretion and function
abstract：the activation of the coagulation system is a key step in the process of thrombosis. the traditional anticoagulants available on the market mostly target coagulation factors vii, ix, and x in the coagulation system. although these anticoagulants have certain anticoagulant effects, they also have the side effect of increasing the bleeding risk. in recent years, coagulation factor xi (fxi) anticoagulants have shown significant advantages over traditional anticoagulants in clinical trials. meanwhile, studies have shown that the c362-c482 disulfide bond plays an important role in fxi function. to further elucidate the mechanism of all disulfide bonds on fxi, we constructed fxi wild-type and its cysteine mutant plasmids and transfected them into 293t cells. western blotting, protein activity analysis, and thrombin generation assays were used to detect the effects of different disulfide bond on the synthesis, secretion, and function of fxi. the results show that the fxi synthesis do not affected by the ablations of disulfide bonds; the ablations of 15 disulfide bonds affect the fxi secretion; the c362-c482 and c553-c581 disulfide bonds regulate the protease activity of fxi; and the pdir, a member of the protein disulfide isomerase family, can inhibit the protease activity of fxi by reducing the disulfide bonds on it.
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