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

DOI: 10.1038/s41467-021-22634-x DOI Help

Authors: Nicholas A. Arce (Emory University School of Medicine) , Wenpeng Cao (Lehigh University) , Alexander K. Brown (University of Nottingham) , Emily R. Legan (Emory University School of Medicine) , Moriah S. Wilson (Emory University School of Medicine) , Emma-Ruoqi Xu (University of Nottingham) , Michael C. Berndt (Curtin University) , Jonas Emsley (University of Nottingham) , X. Frank Zhang (Lehigh University) , Renhao Li (Emory University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: April 2021
Diamond Proposal Number(s): 19880

Open Access Open Access

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.

Journal Keywords: Blood proteins; Single-molecule biophysics

Diamond Keywords: Thrombosis

Subject Areas: Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

Added On: 26/04/2021 11:49


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)