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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系数互动：对氧化应激相关心血管疾病的影响和2A型von Willebrand病

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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：Von Willebrand因子的止血势，一种由内皮细胞表达的糖蛋白为超大型聚合物（UL-VWF）1，其长度增加，其长度随着AdamTs13，锌金属蛋白酶选择性地切割Tyr1605的锌金属蛋白酶释放地调节-met1606键。最近，我们已经表明，MET1606的体外氧化，在模拟中的疾病中的疾病的条件下，由Adamts13严重损害蛋白水解，得到了由UL-VWF物种的积累引起的促血栓形成效应。相反，Val1607ASP突变，在VWF中发现，来自2A型von Willebrand疾病的患者，加速VWF的蛋白水解，最终出血效果。考虑到ADAMTS13-VWF相互作用的生理病理学意义和实验结构数据的缺失，在这里我们通过同源性建模技术产生了ADAMTS13金属蛋白酶域的三维模型（M13）。此后，含有可切割的Tyr1605-Met1606键的VWF（1604-1607）肽被手动停靠在蛋白酶活性位点，并得到的模型复合物为美国关键信息提供了用于解释结构地面的可变效应，即化学修饰/突变VWF对Adamts13进行了蛋白水解。

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