6FWN

Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor

Summary for 6FWN

• Entry DOI: 10.2210/pdb6fwn/pdb
• NMR Information: BMRB: 34243
• Descriptor: von Willebrand factor (1 entity in total)
• Functional Keywords: von willebrand factor, vwc domain, blood clotting
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 9122.32

Authors

Xu, E.-R.,von Buelow, S.,Chen, P.-C.,Lenting, P.J.,Kolsek, K.,Aponte-Santamaria, C.,Simon, B.,Foot, J.,Obser, T.,Graeter, F.,Schneppenheim, R.,Denis, C.V.,Wilmanns, M.,Hennig, J. (deposition date: 2018-03-06, release date: 2018-10-24, Last modification date: 2024-10-23)

Primary citation

Xu, E.R.,von Bulow, S.,Chen, P.C.,Lenting, P.J.,Kolsek, K.,Aponte-Santamaria, C.,Simon, B.,Foot, J.,Obser, T.,Schneppenheim, R.,Grater, F.,Denis, C.V.,Wilmanns, M.,Hennig, J.
Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor.
Blood, 133:366-376, 2019

PubMed Abstract: Von Willebrand factor (VWF) is a key player in the regulation of hemostasis by promoting recruitment of platelets to sites of vascular injury. An array of 6 C domains forms the dimeric C-terminal VWF stem. Upon shear force activation, the stem adopts an open conformation allowing the adhesion of VWF to platelets and the vessel wall. To understand the underlying molecular mechanism and associated functional perturbations in disease-related variants, knowledge of high-resolution structures and dynamics of C domains is of paramount interest. Here, we present the solution structure of the VWF C4 domain, which binds to the platelet integrin and is therefore crucial for the VWF function. In the structure, we observed 5 intra- and inter-subdomain disulfide bridges, of which 1 is unique in the C4 domain. The structure further revealed an unusually hinged 2-subdomain arrangement. The hinge is confined to a very short segment around V2547 connecting the 2 subdomains. Together with 2 nearby inter-subdomain disulfide bridges, this hinge induces slow conformational changes and positional alternations of both subdomains with respect to each other. Furthermore, the structure demonstrates that a clinical gain-of-function VWF variant (Y2561) is more likely to have an effect on the arrangement of the C4 domain with neighboring domains rather than impairing platelet integrin binding.

PubMed: 30305279
DOI: 10.1182/blood-2018-04-843615

Experimental method

SOLUTION NMR