Autoinhibitory module underlies species difference in shear activation of von Willebrand factor.
Autoinhibitory module underlies species difference in shear activation of von Willebrand factor.
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DOI：
10.1111/jth.15837
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发表时间：
2022-11
影响因子：
10.4
通讯作者：
Li, Renhao
中科院分区：
文献类型：
--
作者：
Arce, Nicholas A.;Liu, Yi;Chen, Wenchun;Zhang, X. Frank;Li, Renhao
血管性血液病因子（VWF）是一种多聚体血浆蛋白，在血管损伤和高剪切速率的血小板捕获之间架起桥梁。在高剪切或张力下，VWF可以通过其自抑制模块（AIM）的展开而被激活。AIM展开暴露A1结构域，允许与血小板糖蛋白（GP）Ibα结合，以启动原发性止血。AIM的特性及其在小鼠VWF中的抑制作用尚不清楚。目的：测定和表征小鼠VWF的自身抑制特性。重组小鼠VWF A1片段含有或缺乏A1结构域周围的侧翼区域。我们测试了这些片段与人或小鼠GPIbα和血小板结合的能力。我们用单分子力谱法比较了小鼠AIM-A1和人AIM-A1的展开。重组小鼠AIM-A1与GPIbα的结合具有比人更高的亲和力。缺乏部分AIM的重组小鼠蛋白与GPIbα的结合增加。缺乏AIM的活化A1片段可以有效地跨越物种屏障凝集血小板。利用单分子力谱，我们确定小鼠AIM在类似于人类AIM的力下展开。此外，人类AIM与小鼠A1配对在很大程度上再现了人类AIM-A1的行为。我们的研究结果表明，VWF-GPIbα结合的调节已经被专门调整为在不同的流变结构中发挥最佳作用。AIM序列的差异可能导致人和小鼠VWF剪切反应的差异。
Von Willebrand factor (VWF) is a multimeric plasma protein that bridges the gap between vessel injury and platelet capture at high shear rates. Under high shear or tension, VWF can become activated upon the unfolding of its autoinhibitory module (AIM). AIM unfolding exposes the A1 domain, allowing for binding to platelet glycoprotein (GP)Ibα to initiate primary hemostasis. The characteristics of the AIM and its inhibitory properties within mouse VWF are unknown. To determine and characterize the autoinhibitory properties of mouse VWF. Recombinant mouse VWF A1 fragments containing or lacking the flanking regions around the A1 domain were generated. We tested the ability of these fragments to bind to human or mouse GPIbα and platelets. We compared the unfolding of mouse AIM-A1 to human AIM-A1 by single-molecule force spectroscopy. Recombinant mouse AIM-A1 binds with higher affinity to GPIbα than its human counterpart. Recombinant mouse proteins lacking part of the AIM show increased binding to GPIbα. Activated A1 fragments lacking the AIM can effectively agglutinate platelets across the species barrier. Using single-molecule force spectroscopy, we determined that the mouse AIM unfolds under forces similar to the human AIM. Additionally, the human AIM paired with mouse A1 largely recapitulates the behavior of human AIM-A1. Our results suggest that the regulation of VWF-GPIbα binding has been specifically tuned to work optimally in different rheological architectures. Differences in the AIM sequence may contribute to the difference in VWF shear response between human and mice.
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DOI：
10.1111/jth.15702
发表时间：
2022-06
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
通讯作者：
--
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：
3.4
作者：
Evans, E;Ritchie, K
通讯作者：
Ritchie, K
DOI：
10.1161/atvbaha.117.310062
发表时间：
2017-12
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Chen W;Druzak SA;Wang Y;Josephson CD;Hoffmeister KM;Ware J;Li R
通讯作者：
Li R
DOI：
10.1111/jth.12425
发表时间：
2013-12
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Liang X;Russell SR;Estelle S;Jones LH;Cho S;Kahn ML;Berndt MC;Bunting ST;Ware J;Li R
通讯作者：
Li R