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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >Modeling ADAMTS13-von Willebrand Factor interaction: Implications for oxidative stress-related cardiovascular diseases and type 2A von Willebrand Disease
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Modeling ADAMTS13-von Willebrand Factor interaction: Implications for oxidative stress-related cardiovascular diseases and type 2A von Willebrand Disease

机译：模拟ADAMTS13-von Willebrand因子相互作用：对氧化应激相关的心血管疾病和2A型von Willebrand疾病的影响

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摘要

The haemostatic potential of von Willebrand factor, a glycoprotein expressed by endothelial cells as ultra-large polymers (UL-vWF) 1, increases with its length, which in turn is regulated proteolytically by ADAMTS13, a zinc-metalloprotease selectively cleaving vWF at the Tyr1605-Met1606 bond. We have recently shown that in vitro oxidation of Met1606, under conditions mimicking those found in diseases characterized by high oxidative stress, severely impairs proteolysis by ADAMTS13, with a resulting pro-thrombotic effect caused by the accumulation of UL-vWF species. Conversely, Val1607Asp mutation, found in vWF from patients with type 2A von Willebrand disease, accelerates proteolysis of vWF, with a final hemorrhagic effect. Considering the physio-pathological importance of ADAMTS13-vWF interaction and the absence of experimental structural data, here we produced by homology modeling techniques a three-dimensional model of ADAMTS13 metalloprotease domain (M13). Thereafter, the vWF(1604-1607) peptide, containing the cleavable Tyr1605-Met1606 bond, was manually docked into the protease active site and the resulting model complex provided us key information for interpreting on structural grounds the variable effects that chemical modifications/mutations in vWF have on proteolysis by ADAMTS13.
机译：血管性血友病因子（一种由内皮细胞表达为超大聚合物（UL-vWF）1）的糖蛋白的止血潜力随着其长度的增加而增加，而ADAMTS13则由蛋白水解调节，ADAMTS13是一种锌金属蛋白酶，可在Tyr1605处选择性裂解vWF。 -Met1606债券。我们最近发现，在模仿以高氧化应激为特征的疾病中发现的条件下，Met1606的体外氧化会严重损害ADAMTS13的蛋白水解作用，并导致由UL-vWF物种积累引起的促血栓形成作用。相反，从2A型von Willebrand病患者的vWF中发现的Val1607Asp突变会加速vWF的蛋白水解，最终产生出血效应。考虑到ADAMTS13-vWF相互作用的生理病理学重要性以及缺乏实验结构数据，在这里我们通过同源建模技术产生了ADAMTS13金属蛋白酶结构域（M13）的三维模型。此后，将包含可裂解的Tyr1605-Met1606键的vWF（1604-1607）肽手动对接到蛋白酶活性位点中，得到的模型复合物为我们提供了重要信息，可用于从结构基础上解释化学修饰/突变在vWF已通过ADAMTS13进行蛋白水解。

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