Structure and dynamics of the von Willebrand Factor C6 domain.

Autor: Chen PC; Structural and Computational Biology Unit, EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany., Kutzki F; Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany., Mojzisch A; Dermatology and Venereology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany., Simon B; Structural and Computational Biology Unit, EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany., Xu ER; European Molecular Biology Laboratory, Hamburg Unit, Notkestraße 85, 22607 Hamburg, Germany., Aponte-Santamaría C; Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany., Horny K; Structural and Computational Biology Unit, EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany., Jeffries C; European Molecular Biology Laboratory, Hamburg Unit, Notkestraße 85, 22607 Hamburg, Germany., Schneppenheim R; Pediatric Hematology and Oncology, University Medical Centre Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany., Wilmanns M; European Molecular Biology Laboratory, Hamburg Unit, Notkestraße 85, 22607 Hamburg, Germany; University Medical Centre Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany., Brehm MA; Department of Digital Health Sciences and Biomedicine, School of Life Sciences, University of Siegen, Am Eichenhang 50, 57076 Siegen, Germany., Gräter F; Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany; Interdisciplinary Center for Scientific Computing, Heidelberg University, INF 305, 69120 Heidelberg, Germany. Electronic address: frauke.graeter@h-its.org., Hennig J; Structural and Computational Biology Unit, EMBL Heidelberg, Meyerhofstrasse 1, 69117 Heidelberg, Germany; Chair of Biochemistry IV, Biophysical Chemistry, University of Bayreuth, 95447 Bayreuth, Germany. Electronic address: janosch.hennig@embl.de.
Jazyk: angličtina
Zdroj: Journal of structural biology [J Struct Biol] 2022 Dec; Vol. 214 (4), pp. 107923. Date of Electronic Publication: 2022 Nov 18.
DOI: 10.1016/j.jsb.2022.107923
Abstrakt: Von Willebrand disease (VWD) is a bleeding disorder with different levels of severity. VWD-associated mutations are located in the von Willebrand factor (VWF) gene, coding for the large multidomain plasma protein VWF with essential roles in hemostasis and thrombosis. On the one hand, a variety of mutations in the C-domains of VWF are associated with increased bleeding upon vascular injury. On the other hand, VWF gain-of-function (GOF) mutations in the C4 domain have recently been identified, which induce an increased risk of myocardial infarction. Mechanistic insights into how these mutations affect the molecular behavior of VWF are scarce and holistic approaches are challenging due to the multidomain and multimeric character of this large protein. Here, we determine the structure and dynamics of the C6 domain and the single nucleotide polymorphism (SNP) variant G2705R in C6 by combining nuclear magnetic resonance spectroscopy, molecular dynamics simulations and aggregometry. Our findings indicate that this mutation mostly destabilizes VWF by leading to a more pronounced hinging between both subdomains of C6. Hemostatic parameters of variant G2705R are close to normal under static conditions, but the missense mutation results in a gain-of-function under flow conditions, due to decreased VWF stem stability. Together with the fact that two C4 variants also exhibit GOF characteristics, our data underline the importance of the VWF stem region in VWF's hemostatic activity and the risk of mutation-associated prothrombotic properties in VWF C-domain variants due to altered stem dynamics.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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