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

Author

Listed:
  • Nicholas A. Arce

    (Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine)

  • Wenpeng Cao

    (Lehigh University)

  • Alexander K. Brown

    (Biodiscovery Institute, School of Pharmacy, University of Nottingham)

  • Emily R. Legan

    (Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine)

  • Moriah S. Wilson

    (Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine)

  • Emma-Ruoqi Xu

    (Biodiscovery Institute, School of Pharmacy, University of Nottingham)

  • Michael C. Berndt

    (Faculty of Health Sciences, Curtin University)

  • Jonas Emsley

    (Biodiscovery Institute, School of Pharmacy, University of Nottingham)

  • X. Frank Zhang

    (Lehigh University)

  • Renhao Li

    (Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine)

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.

Suggested Citation

  • Nicholas A. Arce & Wenpeng Cao & Alexander K. Brown & Emily R. Legan & Moriah S. Wilson & Emma-Ruoqi Xu & Michael C. Berndt & Jonas Emsley & X. Frank Zhang & Renhao Li, 2021. "Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22634-x
    DOI: 10.1038/s41467-021-22634-x
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