Sliding-Rebinding Mechanism Governs Glycoprotein Ib/von Willebrand Factor Catch Bonds.

The interaction of platelet receptor Glycoprotein Ib (GPIb) and the plasma protein von Willebrand factor (VWF) initiates platelet adhesion and agglutination at the site of vascular injury. The binding sites of GPIb and vWF have been mapped to be the N-terminal domain of GPIb α subunit (GPIbαN) and the A1 domain of VWF respectively. The co-crystal structure of wild-type GPIbαN and VWF-A1 complex is solved and two separated binding interfaces have been identified. One is between the β-switch region of GPIbαN and the central β sheet of A1, another is between the β-finger region of GPIbαN and the loops on the bottom of A1. It has been demonstrated that flow enhances GPIb-VWF binding. Moreover, recent single-molecule experiments with atomic force microscopy (AFM) have shown that GPIb forms catch bonds with VWF. Using GPIbαN/VWF-A1 crystal structure, we studied the dissociation of GPIbαN from VWF-A1 with steered molecular dynamics (SMD) simulations. Our results show that the sliding-rebinding mechanism we proposed previously for selectin/ligand catch bonds also operates for the GPIb/VWF system. When force is applied to GPIbαN/VWF-A1 complex, the interactions between GPIbαN β switch and A1 central β sheet dissociate first, this may lead to the sliding of GPIbαN β finger on the A1 bottom surface to allow new interactions formation. The sliding and forming new interactions will in turn enhance the rebinding of GPIbαN β switch and A1 central β sheet and prolong bond lifetime. The N- and C- terminal flanking sequence of A1 serves as a flexible hinge to regulate catch bonds. As shown in the crystal structure, the A1 N-terminal residue D506 interacts with R543 and R687. The presence of these interactions favors the fast-dissociation pathway, while their dissociation signifies the transition to the sliding pathway. Our results have provided an explanation for the AFM experimental data showing that catch bonds were eliminated by two A1 gain-of-function mutants R543Q and R687E, because these single residue replacements eliminate their interaction with D506, making the transition to occur at much lower forces and prolonging bond lifetime at low forces. R543Q mutant naturally occurs in some patients with type 2B von Willebrand disease (VWD) and R687E mutant also exhibits type 2B VWD phenotype. Our results may provide an explanation for type 2B VWD based on the mechanically regulated nonequilibrium structure-function relationship of GPIb/VWF interaction.