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

Title data

Xu, Emma-Ruoqi ; von Bülow, Sören ; Chen, Po-Chia ; Lenting, Peter J. ; Kolšek, Katra ; Aponte-Santamaría, Camilo ; Simon, Bernd ; Foot, Jaelle ; Obser, Tobias ; Schneppenheim, Reinhard ; Gräter, Frauke ; Denis, Cécile V. ; Wilmanns, Matthias ; Hennig, Janosch:
Structure and dynamics of the platelet integrin-binding C4 domain of von Willebrand factor.
In: Blood. Vol. 133 (2019) Issue 4 . - pp. 366-376.
ISSN 1528-0020
DOI: https://doi.org/10.1182/blood-2018-04-843615

Abstract in another language

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.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry with an Emphasis on Biophysical Chemistry > Chair Biochemistry with an Emphasis on Biophysical Chemistry - Univ.-Prof. Dr. Janosch Hennig
Result of work at the UBT: No
DDC Subjects: 500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 06 Oct 2021 12:17
Last Modified: 06 Oct 2021 12:17
URI: https://eref.uni-bayreuth.de/id/eprint/67217