ArticleBiophysical journal2015
Force-sensitive autoinhibition of the von Willebrand factor is mediated by interdomain interactions.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 76 citations in OpenAlex.
- Vicinal disulfide bond modulates A1-GPIbα interaction by altering the force-induced conformational changes of A2 domain.Communications biology · 2025Article
- Key residues regulating von Willebrand factor A1/A2 interactions: insights from molecular dynamics simulations and experimental validation.Research and practice in thrombosis and haemostasis · 2025Article
- Recent advances in vascular thiol isomerases: insights into structures, functions in thrombosis and antithrombotic inhibitor development.Thrombosis journal · 2025Review
- Article
- The interplay between adsorption and aggregation of von Willebrand factor chains in shear flows.Biophysical journal · 2023Article
- Molecular mechanisms of catch bonds and their implications for platelet hemostasis.Biophysical reviews · 2023Review
- Biomechanical activation of blood platelets via adhesion to von Willebrand factor studied with mesoscopic simulations.Biomechanics and modeling in mechanobiology · 2023Article
- Removal of the vicinal disulfide enhances the platelet-capturing function of von Willebrand factor.Blood · 2023Article
- The Power of Touch: Type 4 Pili, the von Willebrand A Domain, and Surface Sensing by Pseudomonas aeruginosa.Journal of bacteriology · 2022Review
- The N-terminal autoinhibitory module of the A1 domain in von Willebrand factor stabilizes the mechanosensor catch bond.RSC chemical biology · 2022Article
- Von Willebrand factor A1 domain stability and affinity for GPIbα are differentially regulated by itseLife · 2022Article
- Gain-of-Function Variant p.Pro2555Arg of von Willebrand Factor Increases Aggregate Size through Altering Stem Dynamics.Thrombosis and haemostasis · 2022Article
- Distribution and history of extensional stresses on vWF surrogate molecules in turbulent flow.Scientific reports · 2022Article
- Exposure of Von Willebrand Factor Cleavage Site in A1A2A3-Fragment under Extreme Hydrodynamic Shear.Polymers · 2021Article
- Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation in vitro.Haematologica · 2021Article
- Article
- Intradimer forces and their implication for conformations of von Willebrand factor multimers.Biophysical journal · 2021Article
- Article
- STED lithography in microfluidics for 3D thrombocyte aggregation testing.Journal of nanobiotechnology · 2021Article
- Article
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
Abstract
Von Willebrand factor (VWF) plays a central role in hemostasis. Triggered by shear-stress, it adheres to platelets at sites of vascular injury. Inactivation of VWF has been associated to the shielding of its adhesion sites and proteolytic cleavage. However, the molecular nature of this shielding and its coupling to cleavage under shear-forces in flowing blood remain unknown. In this study, we describe, to our knowledge, a new force-sensory mechanism for VWF-platelet binding, which addresses these questions, based on a combination of molecular dynamics (MD) simulations, atomic force microscopy (AFM), and microfluidic experiments. Our MD simulations demonstrate that the VWF A2 domain targets a specific region at the VWF A1 domain, corresponding to the binding site of the platelet glycoprotein Ibα (GPIbα) receptor, thereby causing its blockage. This implies autoinhibition of the VWF for the binding of platelets mediated by the A1-A2 protein-protein interaction. During force-probe MD simulations, a stretching force dissociated the A1A2 complex, thereby unblocking the GPIbα binding site. Dissociation was found to be coupled to the unfolding of the A2 domain, with dissociation predominantly occurring before exposure of the cleavage site in A2, an observation that is supported by our AFM experiments. This suggests that the A2 domain prevents platelet binding in a force-dependent manner, ensuring that VWF initiates hemostasis before inactivation by proteolytic cleavage. Microfluidic experiments with an A2-deletion VWF mutant resulted in increased platelet binding, corroborating the key autoinhibitory role of the A2 domain within VWF multimers. Overall, autoinhibition of VWF mediated by force-dependent interdomain interactions offers the molecular basis for the shear-sensitive growth of VWF-platelet aggregates, and might be similarly involved in shear-induced VWF self-aggregation and other force-sensing functions in hemostasis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.