Structures of Glycoprotein Ibα and Its Complex with von Willebrand Factor A1 Domain

TLDR

Transient interactions between platelet receptor GpIbα and plasma protein von Willebrand factor reduce platelet velocity at vascular injury sites and contribute to haemostasis and thrombosis. The authors aim to present the crystal structures of the GpIbα amino‑terminal domain and its complex with the VWF A1 domain. They determined these structures to elucidate the molecular interface between GpIbα and VWF A1. The structures show GpIbα wrapping around one side of A1, forming two contact areas bridged by a solvated charge interaction, explain gain‑of‑function mutations associated with bleeding disorders, and provide a model for shear‑induced activation that informs antithrombotic drug development.

Abstract

Transient interactions of platelet-receptor glycoprotein Ibα (GpIbα) and the plasma protein von Willebrand factor (VWF) reduce platelet velocity at sites of vascular damage and play a role in haemostasis and thrombosis. Here we present structures of the GpIbα amino-terminal domain and its complex with the VWF domain A1. In the complex, GpIbα wraps around one side of A1, providing two contact areas bridged by an area of solvated charge interaction. The structures explain the effects of gain-of-function mutations related to bleeding disorders and provide a model for shear-induced activation. These detailed insights into the initial interactions in platelet adhesion are relevant to the development of antithrombotic drugs.