Interrogation of structure-function relationships in network formation of von Willebrand Factor domains by X-ray crystallography
Final Report Abstract
Von Willebrand factor (VWF) is a key player in the regulation of haemostasis by promoting recruitment of platelets to sites of vascular injury. An array of six C domains that is rich in disulfide bonds 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. During the funding period of SHENC, we determined two novel solution structures of two of the six VWF C domains. C4 binds to platelet integrin, and is therefore crucial for the VWF functional regulation. In the C4 structure, we observed five intra- and inter-subdomain disulfide bridges, of which one is unique in the C4 domain. However, only the four canonical disulfide bridges are found in the C6 domain. Structural dynamics of both C4 and C6 revealed an unusually hinged two-subdomain arrangement, confined to a very short segment connecting the two subdomains. Together with two nearby intersubdomain disulfide bridges, this hinge induces slow conformational changes and positional alternations of both subdomains with respect to each other. Taken together, our data provide clues why external forces are required in the context of full-length VWF to bind platelet integrin. Furthermore, the structures demonstrate how clinical gain-of-function VWF variants (Schneppenheim et al.) are more likely to have an effect on the arrangement of the C4 domain with neighbouring domains rather than impairing platelet integrin binding.
Publications
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Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor. Blood
E-R Xu, S von Bülow, P-C Chen, P J Lenting, K Kolšek, C Aponte-Santamaría, B Simon, J Foot, T Obser, R Schneppenheim, F Graeter, C V Denis, M Wilmanns , and J Hennig
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The von Willebrand factor Tyr2561 allele is a gain-of-function variant and a risk factor for early myocardial infarction. Blood. 2019 Jan 24;133(4):356-365
R Schneppenheim, N Hellermann, M A Brehm, U Klemm, T Obser, V Huck, S Schneider, C V Denis, A Tischer, M Auton, W März, E-R Xu, M Wilmanns, and R B Zotz
