ArticleScience advances2018
Autoregulation of von Willebrand factor function by a disulfide bond switch.
Article in Science advances, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 92 citations in OpenAlex.
- Hyperadhesive von Willebrand Factor Contributes to Pathogenesis of Preeclampsia.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- Multiple disulfide-bonded states confer extensive conformational diversity in fibrinogen.Protein science : a publication of the Protein Society · 2026Article
- Quantification of the Redox State of Protein Disulfide Bonds.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Genetic Diversity, Predictive Protein Structures, and Interaction Networks of Cysteine-Rich Receptor-Like Kinases inComputational and structural biotechnology journal · 2026Article
- Polyclonal Antibody Selection of Partially Disulfide-Bonded Protein States.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Determining the Redox Potential of a Protein Disulfide Bond.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Classification of Protein Disulfide Bonds.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Estimate of Numbers of Disulfide-Bonded Protein States.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Dynamic Force Spectroscopy for Analysis of Multiple Disulfide-Bonded Protein States.Methods in molecular biology (Clifton, N.J.) · 2026Article
- 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
- Patient anti-FVIII drug antibodies bind preferentially to a subset of FVIII covalent states.Blood advances · 2025Article
- Recent advances in vascular thiol isomerases: insights into structures, functions in thrombosis and antithrombotic inhibitor development.Thrombosis journal · 2025Review
- A novel role for protein disulfide isomerase ERp18 in venous thrombosis.Thrombosis journal · 2024Article
- Recent advances in vascular thiol isomerases and redox systems in platelet function and thrombosis.Journal of thrombosis and haemostasis : JTH · 2024Review
- Genome-Wide Comparative Analysis of SRCR Gene Superfamily in Invertebrates Reveals Massive and Independent Gene Expansions in the Sponge and Sea Urchin.International journal of molecular sciences · 2024Article
- Water-Assisted Programmable Assembly of Flexible and Self-Standing Janus Membranes.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- 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
- Mechano-covalent protection of coagulation factor VIII by von Willebrand factor.Blood advances · 2023Article
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Authors and funding
16 authors at 11 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Force-dependent binding of platelet glycoprotein Ib (GPIb) receptors to plasma von Willebrand factor (VWF) plays a key role in hemostasis and thrombosis. Previous studies have suggested that VWF activation requires force-induced exposure of the GPIb binding site in the A1 domain that is autoinhibited by the neighboring A2 domain. However, the biochemical basis of this "mechanopresentation" remains elusive. From a combination of protein chemical, biophysical, and functional studies, we find that the autoinhibition is controlled by the redox state of an unusual disulfide bond near the carboxyl terminus of the A2 domain that links adjacent cysteine residues to form an eight-membered ring. Only when the bond is cleaved does the A2 domain bind to the A1 domain and block platelet GPIb binding. Molecular dynamics simulations indicate that cleavage of the disulfide bond modifies the structure and molecular stresses of the A2 domain in a long-range allosteric manner, which provides a structural explanation for redox control of the autoinhibition. Significantly, the A2 disulfide bond is cleaved in ~75% of VWF subunits in healthy human donor plasma but in just ~25% of plasma VWF subunits from heart failure patients who have received extracorporeal membrane oxygenation support. This suggests that the majority of plasma VWF binding sites for platelet GPIb are autoinhibited in healthy donors but are mostly available in heart failure patients. These findings demonstrate that a disulfide bond switch regulates mechanopresentation of VWF.
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Registered trials
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.