Destabilization of the von Willebrand factor A2 domain under oxidizing conditions investigated by molecular dynamics simulations.
Destabilization of the von Willebrand factor A2 domain under oxidizing conditions investigated by molecular dynamics simulations.
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DOI：
10.1371/journal.pone.0203675
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Interlandi G
中科院分区：
文献类型：
--
作者：
Interlandi G
血管性血友病因子（vonWillebrand factor，VWF）是血小板粘附于血管损伤部位的关键。最近的研究表明，炎症过程中氧化剂的释放增加了VWF的血小板拴系活性，导致血栓形成前状态。这与VWF的A1、A2和A3结构域中甲硫氨酸残基的氧化有关。A1结构域与血小板表面受体糖蛋白Ib α（GpIbα）结合。这种相互作用已被证明是抑制在静态条件下由相邻的A2结构域。由血流施加的张力展开A2结构域，通常导致其被金属蛋白酶ADAMTS 13切割，从而防止病理性血栓形成。然而，氧化条件通过ADAMTS 13抑制蛋白水解。在这里，分子动力学模拟测试的假设是否甲硫氨酸氧化诱导的炎症条件下有利于展开的A2结构域有助于实验观察到的VWF的激活。结果表明，位于A2结构域的C-末端螺旋附近的甲硫氨酸残基的氧化降低了启动解折叠所需的力。此外，甲硫氨酸残基的氧化使A2结构域折叠的热力学平衡向变性状态移动。这项工作提出了一种机制，即氧化降低了A2结构域的动力学和热力学稳定性，消除了其对A1结构域与GpIbα结合的抑制功能。
The protein von Willebrand factor (VWF) is key for the adhesion of blood platelets to sites of vascular injury. Recent studies have shown that the release of oxidative agents during inflammation increases the platelet-tethering activity of VWF contributing to a pro-thrombotic state. This has been linked to the oxidation of methionine residues in the A1, A2 and A3 domains of VWF. The A1 domain binds to platelet surface receptors glycoprotein Ib α (GpIbα). This interaction has been shown to be inhibited under static conditions by the neighboring A2 domain. Tensile force exerted by blood flow unfolds the A2 domain normally leading to its cleavage by the metalloprotease ADAMTS13 preventing pathological thrombus formation. However, oxidizing conditions inhibit proteolysis through ADAMTS13. Here, molecular dynamics simulations tested the hypothesis whether methionine oxidation induced by inflammatory conditions favors unfolding of the A2 domain contributing to the experimentally observed activation of VWF. The results indicate that oxidation of methionine residues located near the C-terminal helix of the A2 domain reduce the force necessary to initiate unfolding. Furthermore, oxidation of methionine residues shifts the thermodynamic equilibrium of the A2 domain fold towards the denatured state. This work suggests a mechanism whereby oxidation reduces the kinetic and thermodynamic stability of the A2 domain removing its inhibitory function on the binding of the A1 domain to GpIbα.
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