The N-terminal flanking region of the A1 domain regulates the force-dependent binding of von Willebrand factor to platelet glycoprotein Ib?.

ABSTRACT: Binding of platelet glycoprotein Ib? (GPIb?) to von Willebrand factor (VWF) initiates platelet adhesion to disrupted vascular surface under arterial blood flow. Flow exerts forces on the platelet that are transmitted to VWF-GPIb? bonds, which regulate their dissociation. Mutations in VWF and/or GPIb? may alter the mechanical regulation of platelet adhesion to cause hemostatic defects as found in patients with von Willebrand disease (VWD). Using a biomembrane force probe, we observed biphasic force-decelerated (catch) and force-accelerated (slip) dissociation of GPIb? from VWF. The VWF A1 domain that contains the N-terminal flanking sequence Gln(1238)-Glu(1260) (1238-A1) formed triphasic slip-catch-slip bonds with GPIb?. By comparison, using a short form of A1 that deletes this sequence (1261-A1) abolished the catch bond, destabilizing its binding to GPIb? at high forces. Importantly, shear-dependent platelet rolling velocities on these VWF ligands in a flow chamber system mirrored the force-dependent single-bond lifetimes. Adding the Gln(1238)-Glu(1260) peptide, which interacted with GPIb? and 1261-A1 but not 1238-A1, to whole blood decreased platelet attachment under shear stress. Soluble Gln(1238)-Glu(1260) reduced the lifetimes of GPIb? bonds with VWF and 1238-A1 but rescued the catch bond of GPIb? with 1261-A1. A type 2B VWD 1238-A1 mutation eliminated the catch bond by prolonging lifetimes at low forces, a type 2M VWD 1238-A1 mutation shifted the respective slip-catch and catch-slip transition points to higher forces, whereas a platelet type VWD GPIb? mutation enhanced the bond lifetime in the entire force regime. These data reveal the structural determinants of VWF activation by hemodynamic force of the circulation.

SUBMITTER: Ju L 

PROVIDER: S-EPMC3820866 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature