Mechanoenzymatic Cleavage of the Ultralarge Vascular Protein von Willebrand Factor

Abstract

Dissecting VWF's Thrombogenic Potential Von Willebrand factor (VWF) is secreted from cells in an ultralarge form (ULVWF) in response to thrombogenic stimuli. Shear forces expose a binding site for platelets, enabling formation of a hemostatic plug. The thrombogenic potential of VWF correlates with its length and is regulated by proteolytic cleavage of the A2 domain. Zhang et al. (p. 1330 ; see the Perspective by Gebhardt and Rief ) now combine single molecule data and polymer dynamics theory to show that shear forces in the circulation are sufficient to unfold the A2 domain and allow cleavage of multimers with more than about 200 monomers. The A2 domain may thus represent the “shear bolt” of VWF, unfolding when multimers experience high forces to allow cleavage and down-regulation of thrombogenic potential.