Flow induces loop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα
Flow induces loop-to-β-hairpin transition on the β-switch of platelet glycoprotein Ibα
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DOI：
10.1073/pnas.0801965105
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发表时间：
2008-09-16
影响因子：
11.1
通讯作者：
Zhu, Cheng
中科院分区：
文献类型：
--
作者：
Lou, Jizhong;Zhu, Cheng
糖蛋白Ibα(GPIBα)与血管性假血友病因子(VWF)相互作用，启动血小板与受损血管壁的黏附，从而止血。GPIBα和VWF之间的主要接触涉及贝塔开关区，这是未连接的GPIBα中的一个环，但在复杂结构中切换为贝塔发夹。矛盾的是，FLOW增强了而不是阻碍了GPIBα-VWF的结合。β开关中的功能获得突变(例如M239V)降低了VWF结合的流动需求，而功能丧失突变(例如A238V)增加了流动需求。这些现象不能用晶体结构或能量计算来解释。在这里，我们证明了在没有接触VWF的情况下，β-发夹是不稳定的，因为在自由分子动力学模拟中，它切换到一个环。用一种新的流动分子动力学算法进行的模拟表明，在流动的存在下，环状构象是不稳定的，因为它在没有接触VWF的情况下也会切换到β-发夹结构。与野生型相比，M239V突变体更容易在Flow的存在下转换为β-发夹，而A238V突变体则更难转换为β-发夹。这些结果阐明了这两个突变体的结构基础，并表明了一种调节机制，即FLOW通过诱导β开关上的环到β发夹的构象转变来激活GPIBα，从而促进VWF结合。
Interaction of glycoprotein Ib alpha (GPIb alpha) with von Willebrand factor (VWF) initiates platelet adhesion to injured vascular wall to stop bleeding. A major contact between GPIb alpha and VWF involves the beta-switch region, which is a loop in the unliganded GPIb alpha but switches to a beta-hairpin in the complex structure. Paradoxically, flow enhances rather than impedes GPIb alpha-VWF binding. Gain-of-function mutations (e.g., M239V) in the beta-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 beta-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 beta-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 beta-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 GPIb alpha via inducing a loop-to-beta-hairpin conformational transition on the beta-switch, thereby promoting VWF binding.