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

Emma-Ruoqi Xu, Sören von Bülow, Po-Chia Chen, Peter J. Lenting, Katra Kolšek, Camilo Aponte-Santamaría, Bernd Simon, Jaelle Foot, Tobias Obser, Reinhard Schneppenheim, Frauke Gräter, Cecile V. Denis, Matthias Wilmanns and Janosch Hennig

Key points

  • The high-resolution structure and associated dynamics of the platelet integrin-binding VWF C4 domain is presented.

  • A possible mechanism of gain-of-function variant affecting the arrangement with neighboring domains is proposed.


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 six 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 five intra- and inter-subdomain disulfide bridges, of which one is unique in the C4 domain. The structure further revealed an unusually hinged two-subdomain arrangement. The hinge is confined to a very short segment around V2547 connecting the two subdomains. Together with two 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) (Schneppenheim et al., submitted) is more likely to have an effect on the arrangement of the C4 domain with neighboring domains rather than impairing platelet integrin binding.

  • Submitted April 6, 2018.
  • Accepted September 24, 2018.