ArticleThe Journal of biological chemistry2016
Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Flow molecular dynamics simulations reveal mechano-presentation of von Willebrand factor through glycan-modulated autoinhibitory modules.APL bioengineering · 2026Article
- Structure-resolved dynamics of type 2M von Willebrand disease.Journal of thrombosis and haemostasis : JTH · 2025Article
- The epitope of the antibody used in the REAADS VWF activity assay is quaternary.Thrombosis journal · 2025Article
- Conformation-specific RNA aptamers for phenotypic distinction between normal von Willebrand factor and type 2B von Willebrand disease.NAR molecular medicine · 2024Article
- Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module.Blood · 2024Article
- Molecular mechanisms of catch bonds and their implications for platelet hemostasis.Biophysical reviews · 2023Review
- Removal of the vicinal disulfide enhances the platelet-capturing function of von Willebrand factor.Blood · 2023Article
- Activation of von Willebrand factor via mechanical unfolding of its discontinuous autoinhibitory module.Nature communications · 2021Article
- Evidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease.Journal of molecular biology · 2020Article
- Glycosylation sterically inhibits platelet adhesion to von Willebrand factor without altering intrinsic conformational dynamics.Journal of thrombosis and haemostasis : JTH · 2020Article
- Platelet-type von Willebrand disease: Local disorder of the platelet GPIbα β-switch drives high-affinity binding to von Willebrand factor.Journal of thrombosis and haemostasis : JTH · 2019Article
- Delimiting the autoinhibitory module of von Willebrand factor.Journal of thrombosis and haemostasis : JTH · 2018Article
- The physical spacing between the von Willebrand factor D'D3 and A1 domains regulates platelet adhesion in vitro and in vivo.Journal of thrombosis and haemostasis : JTH · 2018Article
- Combined effects of two mutations in von Willebrand disease 2M phenotype.Research and practice in thrombosis and haemostasis · 2018Article
- A discontinuous autoinhibitory module masks the A1 domain of von Willebrand factor.Journal of thrombosis and haemostasis : JTH · 2017Article
- Clinical and laboratory phenotype variability in type 2M von Willebrand disease.Journal of thrombosis and haemostasis : JTH · 2017Article
- Enhanced Local Disorder in a Clinically Elusive von Willebrand Factor Provokes High-Affinity Platelet Clumping.Journal of molecular biology · 2017Article
- The Von Willebrand Factor A1-Collagen III Interaction Is Independent of Conformation and Type 2 Von Willebrand Disease Phenotype.Journal of molecular biology · 2017Article
- Data on the purification and crystallization of the loss-of-function von Willebrand disease variant (p.Gly1324Ser) of the von Willebrand factor A1 domain.Data in brief · 2016Article
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8 authors.
Funding
Abstract
Unusually large von Willebrand factor (VWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease, two rare mutations (G1324A and G1324S) within the platelet GPIbα binding interface of the VWF A1 domain impair the hemostatic function of VWF. We investigate structural and conformational effects of these mutations on the A1 domain's efficacy to bind collagen and adhere platelets under shear flow. These mutations enhance the thermodynamic stability, reduce the rate of unfolding, and enhance the A1 domain's resistance to limited proteolysis. Collagen binding affinity is not significantly affected indicating that the primary stabilizing effect of these mutations is to diminish the platelet binding efficiency under shear flow. The enhanced stability stems from the steric consequences of adding a side chain (G1324A) and additionally a hydrogen bond (G1324S) to His(1322) across the β2-β3 hairpin in the GPIbα binding interface, which restrains the conformational degrees of freedom and the overall flexibility of the native state. These studies reveal a novel rheological strategy in which the incorporation of a single glycine within the GPIbα binding interface of normal VWF enhances the probability of local unfolding that enables the A1 domain to conformationally adapt to shear flow while maintaining its overall native structure.
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