Adhesive Forces between A1 Domain of von Willebrand Factor and N-terminus Domain of Glycoprotein Ibα Measured by Atomic Force Microscopy.

Platelet interaction with von Willebrand factor is enhanced by shear-induced clustering of glycoprotein Ibα.

Initial platelet arrest at the exposed arterial vessel wall is mediated through glycoprotein Ibα binding to the A1 domain of von Willebrand factor. This interaction occurs at sites of elevated shear force, and strengthens upon increasing hydrodynamic drag. The increased interaction requires shear-dependent exposure of the von Willebrand factor A1 domain, but the contribution of glycoprotein Ibα...

Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions.

Von Willebrand factor (VWF) plays a central role in hemostasis. Triggered by shear-stress, it adheres to platelets at sites of vascular injury. Inactivation of VWF has been associated to the shielding of its adhesion sites and proteolytic cleavage. However, the molecular nature of this shielding and its coupling to cleavage under shear-forces in flowing blood remain unknown. In this study, we d...

Simultaneous exposure of sites in von Willebrand factor for glycoprotein Ib binding and ADAMTS13 cleavage: studies with ristocetin.

OBJECTIVE Platelet-bound von Willebrand factor (VWF) was recently demonstrated to be a better substrate for ADAMTS13, suggesting that 1 conformational change exposes both the glycoprotein Ibα binding site in the A1 domain and the ADAMTS13 cleavage site in the A2 domain. Because ristocetin induces VWF to bind glycoprotein Ibα in the absence of shear stress, we evaluated whether it could also enh...

Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases.

Mutations in the ultralong vascular protein von Willebrand factor (VWF) cause the common human bleeding disorder, von Willebrand disease (VWD). The A1 domain in VWF binds to glycoprotein Ibα (GPIbα) on platelets, in a reaction triggered, in part, by alterations in flow during bleeding. Gain-of-function mutations in A1 and GPIbα in VWD suggest conformational regulation. We report that force appl...

Shielding the front strand β3 of the von Willebrand factor A1 domain inhibits its binding to platelet glycoprotein Ibα