Flow-induced elongation of von Willebrand factor precedes tension-dependent activation

Hongxia Fu, Yan Jiang, Darren Yang, Friedrich Scheiflinger, Wesley P. Wong () and Timothy A. Springer ()
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Hongxia Fu: Program in Cellular and Molecular Medicine, Boston Children’s Hospital
Yan Jiang: Program in Cellular and Molecular Medicine, Boston Children’s Hospital
Darren Yang: Program in Cellular and Molecular Medicine, Boston Children’s Hospital
Friedrich Scheiflinger: Shire
Wesley P. Wong: Program in Cellular and Molecular Medicine, Boston Children’s Hospital
Timothy A. Springer: Program in Cellular and Molecular Medicine, Boston Children’s Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Von Willebrand factor, an ultralarge concatemeric blood protein, must bind to platelet GPIbα during bleeding to mediate hemostasis, but not in the normal circulation to avoid thrombosis. Von Willebrand factor is proposed to be mechanically activated by flow, but the mechanism remains unclear. Using microfluidics with single-molecule imaging, we simultaneously monitored reversible Von Willebrand factor extension and binding to GPIbα under flow. We show that Von Willebrand factor is activated through a two-step conformational transition: first, elongation from compact to linear form, and subsequently, a tension-dependent local transition to a state with high affinity for GPIbα. High-affinity sites develop only in upstream regions of VWF where tension exceeds ~21 pN and depend upon electrostatic interactions. Re-compaction of Von Willebrand factor is accelerated by intramolecular interactions and increases GPIbα dissociation rate. This mechanism enables VWF to be locally activated by hydrodynamic force in hemorrhage and rapidly deactivated downstream, providing a paradigm for hierarchical mechano-regulation of receptor–ligand binding.

Date: 2017
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DOI: 10.1038/s41467-017-00230-2

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