Oxidation shuts down an auto-inhibitory mechanism of von Willebrand factor.
Oxidation shuts down an auto-inhibitory mechanism of von Willebrand factor.
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氧化关闭了血管性血友病因子的一种自身抑制机制。
DOI：
10.1002/prot.26055
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发表时间：
2021-06
期刊：
影响因子：
2.9
通讯作者：
Interlandi G
中科院分区：
文献类型：
--
作者：
Tsai R;Interlandi G
血管性血友病因子（vonWillebrand factor，VWF）是炎症和病理性血栓形成之间的关键环节。特别是，由于炎症条件下氧化剂的释放，VWF特定结构域中甲硫氨酸残基的氧化与血小板结合活性增加有关。然而，蛋氨酸氧化如何激活VWF的原子细节至今尚未阐明。然而，了解VWF在氧化条件下的活化机制可以导致在炎症条件下选择性靶向VWF的新疗法的开发，以降低其血栓形成活性，同时保持其止血功能。在这篇手稿中，我们使用了一个动态流动试验和分子动力学（MD）模拟相结合，以研究如何蛋氨酸氧化去除VWF的自抑制机制。动态流动试验的结果显示，氧化不会直接激活A1结构域，A1结构域是VWF中含有血小板表面受体糖蛋白Ibα（GpIbα）结合位点的结构域，而是去除了相邻A2和A3结构域的抑制功能。此外，结合自由能微扰计算的MD模拟表明，甲硫氨酸氧化可能会破坏A1和A2结构域之间的结合界面，导致A1结构域中GpIbα结合位点的暴露。
The blood protein von Willebrand factor (VWF) is a key link between inflammation and pathological thrombus formation. In particular, oxidation of methionine residues in specific domains of VWF due to the release of oxidants in inflammatory conditions has been linked to an increased platelet-binding activity. However, the atomistic details of how methionine oxidation activates VWF have not been elucidated to date. Yet understanding the activation mechanism of VWF under oxidizing conditions can lead to the development of novel therapeutics that target VWF selectively under inflammatory conditions in order to reduce its thrombotic activity while maintaining its haemostatic function. In this manuscript, we used a combination of a dynamic flow assay and molecular dynamics (MD) simulations to investigate how methionine oxidation removes an auto-inhibitory mechanism of VWF. Results from the dynamic flow assay revealed that oxidation does not directly activate the A1 domain, which is the domain in VWF that contains the binding site to the platelet surface receptor glycoprotein Ibα (GpIbα), but rather removes the inhibitory function of the neighboring A2 and A3 domains. Furthermore, the MD simulations combined with free energy perturbation calculations suggested that methionine oxidation may destabilize the binding interface between the A1 and A2 domains leading to unmasking of the GpIbα-binding site in the A1 domain.
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