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

• Type of Material: Article
• Authors: Nicholas A Arce, Emory University; Wenpeng Cao, Lehigh University; Alexander K Brown, University of Nottingham; Emily R Legan, Emory University; Moriah S Wilson, Emory University; Emma-Ruoqi Xu, University of Nottingham; Michael C Berndt, Curtin University; Jonas Emsley, University of Nottingham; Frank X Zhang, Lehigh University; Renhao Li, Emory University
• Language: English
• Date: 2021-04-21
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-021-22634-x
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 12
• Issue: 1
• Start Page: 2360
• End Page: 2360
• Grant/Funding Information: This work was supported in part by NIH research grants (HL082808, HL143794, and HL152348), NIH training grants (GM008602 and GM008367), a studentship grant from the British Heart Foundation (FS/18/70/33893) awarded to J.E./A.K.B., and an infrastructure grant from Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory. N.A.A. was supported in part by AHA grant 20PRE34990025 and NIH fellowship HL154656. E.R.L. was supported in part by NIH fellowship HL149357.
• Keywords: PLATELET GLYCOPROTEIN-IB; CRYSTAL-STRUCTURE; IX-V COMPLEX; Science & Technology; FACTOR BINDING; VONWILLEBRAND-FACTOR; FACTOR A1 DOMAIN; Multidisciplinary Sciences; TERMINAL FLANKING REGION; SINGLE-MOLECULE; A2 DOMAIN; Science & Technology - Other Topics; MONOCLONAL-ANTIBODY
• Research Categories: Engineering, Mechanical; Health Sciences, Pharmacy

Abstract

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.