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The molecular basis of VWF mechano-sensoring: Structure and interactions of VWF domains as the basis for regulation and aggregation

Fachliche Zuordnung Bioinformatik und Theoretische Biologie
Biophysik
Förderung Förderung von 2011 bis 2017
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 172540668
 
Erstellungsjahr 2018

Zusammenfassung der Projektergebnisse

The function of von Willebrand factor, including adhesion and network formation, is tightly regulated by mechanical force, the molecular mechanism of which has remained elusive to a large extent. In this project, we successfully moved forward our understanding on how building blocks of the VWF, domains and domain combinations, perform their function in an atomistic level, in general biochemical terms as well as in shear flow conditions, in health as well as in disease. Most importantly, we have successfully put forward a new mechanism for the force-dependence of the VWF-platelet interaction. In this scenario, which has been validated by experiments within SHENC, VWF A1-GPIb binding is inhibited by a specific A1-A2 interaction, which is relieved by force due to shear flow. In the second funding period, we extended our approach combining molecular modeling and Molecular Dynamics simulations to the dynamics of A1 with binding partners, and of A2 in presence/absence of disease mutants and the vicinal disulfide bond it carries. Secondly, as a major step towards a comprehensive understanding of the force-sensing function of VWF, we obtained structural models and dynamic data under force of the C domains of VWF, most importantly the C4 and C6 domain. We believe these simulations to help to explain on a molecular level the observed increased aggregation of VWF carrying polymorphism in the C4 domain. Finally, we have made progress on developing a Molecular Dynamics scheme, in which disulfide bonds can be reversibly broken and formed, in order to decipher mechanisms of forcedependent disulfide bond shuffling in C-domains (and maybe later D-domains, which carry protein disulfide isomerase motifs). Our work has profoundly contributed to the molecular-level understanding of how collective networks of wild-type and mutant VWF map to clinical presentation.

Projektbezogene Publikationen (Auswahl)

 
 

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