Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibα complex reveals conformation differences with a complex bearing von Willebrand disease mutations

Abstract

The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibα (GpIbα) and the A1 domain of the von Willebrand factor (VWF). Here we report the 2.6-Å crystal structure of a complex comprised of the extracellular domain of GpIbα and the wild-type A1 domain of VWF. A direct comparison of this structure to a GpIbα-A1 complex containing " gain-of-function" mutations, A1-R543Q and GpIbα-M239V, reveals specific structural differences between these complexes at sites near the two GpIbα-A1 binding interfaces. At the smaller interface, differences in interaction show that the α1-β2 loop of A1 serves as a conformational switch, alternating between an open α1-β2 isomer that allows faster dissociation of GpIbα-A1, as observed in the wild-type complex, and an extended isomer that favors tight association as seen in the complex containing A1 with a type 2B von Willebrand Disease (VWD) mutation associated with spontaneous binding to GpIbα. At the larger interface, differences in interaction associated with the GpIbα-M239V platelet-type VWD mutation are minor and localized but feature discrete γ-turn conformers at the loop end of the β-hairpin structure. The β-hairpin, stabilized by a strong classic γ-turn as seen in the mutant complex, relates to the increased affinity of A1 binding, and the β-hairpin with a weak inverse γ-turn observed in the wild-type complex corresponds to the lower affinity state of GpIbα. These findings provide important details that add to our understanding of how both type 2B and platelet-type VWD mutations affect GpIbα-A1 binding affinity.