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Article Dans Une Revue Blood Année : 2019

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

Emma-Ruoqi Xu
Sören von Bülow
Po-Chia Chen
Katra Kolšek
  • Fonction : Auteur
Camilo Aponte-Santamaría
  • Fonction : Auteur
Bernd Simon
  • Fonction : Auteur
Jaelle Foot
  • Fonction : Auteur
Tobias Obser
  • Fonction : Auteur
Reinhard Schneppenheim
  • Fonction : Auteur
Frauke Gräter
  • Fonction : Auteur
Cécile Denis
Matthias Wilmanns
  • Fonction : Auteur
Janosch Hennig

Résumé

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.

Domaines

Hématologie

Dates et versions

hal-04456916 , version 1 (14-02-2024)

Identifiants

Citer

Emma-Ruoqi Xu, Sören von Bülow, Po-Chia Chen, Peter Lenting, Katra Kolšek, et al.. Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor. Blood, 2019, 133 (4), pp.366-376. ⟨10.1182/blood-2018-04-843615⟩. ⟨hal-04456916⟩
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