4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE RESEARCH
DOI: 10.1038/s41467-021-22634-x

Keywords

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Funding

  1. NIH [GM008602, GM008367, HL082808, HL143794, HL152348, HL154656, HL149357]
  2. British Heart Foundation [FS/18/70/33893]
  3. Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory
  4. AHA [20PRE34990025]

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The study reveals that the mechanism for activating Von Willebrand factor (VWF) in response to mechanical force is located in the autoinhibitory module, which can be unfolded by tensile force to activate VWF. Certain mutations or external factors can also affect the unfolding force of the module, thus influencing the activation of VWF. This research contributes to understanding the mechanical regulation of VWF and its potential applications.
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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