6FWN

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

6FWN の概要

• エントリーDOI: 10.2210/pdb6fwn/pdb
• NMR情報: BMRB: 34243
• 分子名称: von Willebrand factor (1 entity in total)
• 機能のキーワード: von willebrand factor, vwc domain, blood clotting
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 9122.32

構造登録者

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. (登録日: 2018-03-06, 公開日: 2018-10-24, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

SOLUTION NMR