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

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 () and Renhao Li ()
Additional contact information
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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-22634-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22634-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-22634-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().