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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Flow induces Ioop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα
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Flow induces Ioop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα

机译：血流在血小板糖蛋白Ibα的β开关上诱导从Ioop到β的发夹转变

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摘要

Interaction of glycoprotein lbα (GPIbα) with von Willebrand factor (VWF) initiates platelet adhesion to injured vascular wall to stop bleeding. A major contact between GPIba and VWF involves the β-switch region, which is a loop in the unliganded GPIba but switches to a β-hairpin in the complex structure. Paradoxically, flow enhances rather than impedes GPIba-VWF binding. Gain-of-function mutations (e.g., M239V) in the β-switch reduce the flow requirement for VWF binding, whereas loss-of-function mutations (e.g., A238V) increase the flow requirement. These phenomena cannot be explained by crystal structures or energy calculations. Herein we demonstrate that the β-hairpin is unstable without contacting VWF, in that it switches to a loop in free molecular dynamics simulations. Simulations with a novel flow molecular dynamics algorithm show that the loop conformation is unstable in the presence of flow, as it switches to β-hairpin even without contacting VWF. Compared with the wild-type, it is easier for the M239V mutant but harder for the A238V mutant to switch to β-hairpin in the presence of flow. These results elucidate the structural basis for the two mutants and suggest a regulatory mechanism by which flow activates GPIba via inducing a loop-to-β-hairpin conformational transition on the β-switch, thereby promoting VWF binding.
机译：糖蛋白lbα（GPIbα）与von Willebrand因子（VWF）的相互作用可启动血小板与受损血管壁的粘附，从而止血。 GPIba和VWF之间的主要接触涉及β-开关区域，该区域是未配体的GPIba中的一个环，但在复杂结构中转换为β-发夹。矛盾的是，流动增强而不是阻碍了GPIba-VWF的结合。 β-开关中的功能获得突变（例如M239V）减少了VWF结合的流量需求，而功能丧失突变（例如A238V）增加了流量需求。这些现象不能用晶体结构或能量计算来解释。在本文中，我们证明了β-发夹在不接触VWF的情况下是不稳定的，因为它在自由分子动力学模拟中切换为环。用新型流动分子动力学算法进行的仿真表明，在存在流动的情况下，环构象是不稳定的，因为即使不与VWF接触，环构象也会切换为β-发夹。与野生型相比，M239V突变体在存在流动的情况下更易于转换为β-发夹结构，而A238V突变体则更难。这些结果阐明了这两个突变体的结构基础，并提出了一种调节机制，该流动通过诱导β-开关上的环到β-发夹构象转变来激活GPIba，从而促进VWF结合。

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