Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module

被引:44
作者
Arce, Nicholas A. [1 ]
Cao, Wenpeng [2 ]
Brown, Alexander K. [3 ]
Legan, Emily R. [1 ]
Wilson, Moriah S. [1 ]
Xu, Emma-Ruoqi [3 ]
Berndt, Michael C. [4 ]
Emsley, Jonas [3 ]
Zhang, X. Frank [2 ]
Li, Renhao [1 ]
机构
[1] Emory Univ, Sch Med, Dept Pediat, Aflac Canc & Blood Disorders Ctr,Childrens Health, Atlanta, GA USA
[2] Lehigh Univ, Dept Mech Engn & Mech, Dept Bioengn, Bethlehem, PA 18015 USA
[3] Univ Nottingham, Biodiscovery Inst, Sch Pharm, Nottingham, England
[4] Curtin Univ, Fac Hlth Sci, Perth, WA, Australia
关键词
PLATELET GLYCOPROTEIN-IB; TERMINAL FLANKING REGION; FACTOR A1 DOMAIN; IX-V COMPLEX; VONWILLEBRAND-FACTOR; FACTOR BINDING; MONOCLONAL-ANTIBODY; CRYSTAL-STRUCTURE; SINGLE-MOLECULE; A2; DOMAIN;
D O I
10.1038/s41467-021-22634-x
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:14
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