Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module.
Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module.
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DOI：
10.1038/s41467-021-22634-x
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发表时间：
2021-04-21
影响因子：
16.6
通讯作者：
Li R
中科院分区：
文献类型：
--
作者：
Arce NA;Cao W;Brown AK;Legan ER;Wilson MS;Xu ER;Berndt MC;Emsley J;Zhang XF;Li R
血管性血友病因子(VWF)在剪切流的作用下被激活以启动止血，而异常激活可导致血栓形成。在临界剪切力以上，VWF的A1结构域被激活，并通过GPIB-IX复合体捕获血小板。在这里，我们证明了控制VWF激活的剪切响应元件位于A1两侧的不连续自抑制模块(AIM)中。在单分子环境中应用张力力诱导AIM的协同展开以暴露A1。通过截断N-端或C-端的AIM区域、2B型VWD突变或结合类似里斯托菌素的单抗，所有这些都可以激活A1，从而降低AIM去折叠力。此外，AIM由由caplacizumab组成的纳米体机械稳定，caplacizumab是FDA迄今批准的唯一针对VWF的抗血栓药物。因此，AIM是VWF活动的机械调节器。它的构象动力学可以定义VWF的自我抑制和随后在力作用下激活的程度。血管性血友病因子(von Willebrand factor，VWF)是血液中一种由血管内皮细胞分泌的大分子糖蛋白，它的激活可导致VWF-血小板复合体或血栓的形成。在这里，作者使用单分子力测量、X射线结晶学和功能测量来监测VWF通过自抑制模块(AIM)的机械展开而激活的情况。
Von Willebrand factor (VWF) activates in response to shear flow to initiate hemostasis, while aberrant activation could lead to thrombosis. Above a critical shear force, the A1 domain of VWF becomes activated and captures platelets via the GPIb-IX complex. Here we show that the shear-responsive element controlling VWF activation resides in the discontinuous autoinhibitory module (AIM) flanking A1. Application of tensile force in a single-molecule setting induces cooperative unfolding of the AIM to expose A1. The AIM-unfolding force is lowered by truncating either N- or C-terminal AIM region, type 2B VWD mutations, or binding of a ristocetin-mimicking monoclonal antibody, all of which could activate A1. Furthermore, the AIM is mechanically stabilized by the nanobody that comprises caplacizumab, the only FDA-approved anti-thrombotic drug to-date that targets VWF. Thus, the AIM is a mechano-regulator of VWF activity. Its conformational dynamics may define the extent of VWF autoinhibition and subsequent activation under force. Von Willebrand factor (VWF) is a large glycoprotein in the blood secreted from endothelial cells lining the blood vessel and activation of VWF leads to formation of VWF-platelet complexes or thrombi. Here authors use single-molecule force measurement, X-ray crystallography and functional measurements to monitor the activation of VWF via mechanical unfolding of the autoinhibitory module (AIM).
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DOI：
10.1111/jth.14962
发表时间：
2020-09
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Cao W;Cao W;Zhang W;Zheng XL;Zhang XF
通讯作者：
Zhang XF
影响因子：
3.7
作者：
Badirou, Idinath;Kurdi, Mohamad;Denis, Cecile V.
通讯作者：
Denis, Cecile V.
影响因子：
4.8
作者：
Emsley, J;Cruz, M;Liddington, R
通讯作者：
Liddington, R
影响因子：
3.4
作者：
Evans, E;Ritchie, K
通讯作者：
Ritchie, K
影响因子：
20.3
作者：
Flood, Veronica H.;Gill, Joan Cox;Montgomery, Robert R.
通讯作者：
Montgomery, Robert R.