How unique structural adaptations support and coordinate the complex function of von Willebrand factor.

von Willebrand factor (VWF) is a multimeric protein consisting of covalently linked monomers, which share an identical domain architecture.

Although involved in processes such as inflammation, angiogenesis, and cancer metastasis, VWF is mostly known for its role in hemostasis, by acting as a chaperone protein for coagulation factor VIII (FVIII) and by contributing to the recruitment of platelets during thrombus formation.

To serve its role in hemostasis, VWF needs to bind a variety of ligands, including FVIII, platelet-receptor glycoprotein Ib-α, VWF-cleaving protease ADAMTS13, subendothelial collagen, and integrin α-IIb/β-3. Importantly, interactions are differently regulated for each of these ligands.

How are these binding events accomplished and coordinated? The basic structures of the domains that constitute the VWF protein are found in hundreds of other proteins of prokaryotic and eukaryotic organisms.

However, the determination of the 3-dimensional structures of these domains within the VWF context and especially in complex with its ligands reveals that exclusive, VWF-specific structural adaptations have been incorporated in its domains.

They provide an explanation of how VWF binds its ligands in a synchronized and timely fashion.

In this review, we have focused on the domains that interact with the main ligands of VWF and discuss how elucidating the 3-dimensional structures of these domains has contributed to our understanding of how VWF function is controlled.

We further detail how mutations in these domains that are associated with von Willebrand disease modulate the interaction between VWF and its ligands.