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

TY - JOUR

T1 - Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor

AU - Xu, Emma-Ruoqi

AU - von Bülow, Sören

AU - Chen, Po-Chia

AU - Lenting, Peter J

AU - Kolšek, Katra

AU - Aponte-Santamaría, Camilo

AU - Simon, Bernd

AU - Foot, Jaelle

AU - Obser, Tobias

AU - Schneppenheim, Reinhard

AU - Gräter, Frauke

AU - Denis, Cecile V

AU - Wilmanns, Matthias

AU - Hennig, Janosch

N1 - © 2019 by The American Society of Hematology.

PY - 2019/1/24

Y1 - 2019/1/24

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1182/blood-2018-04-843615

DO - 10.1182/blood-2018-04-843615

M3 - SCORING: Journal article

C2 - 30305279

VL - 133

SP - 366

EP - 376

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 4

ER -