ArticleBiophysical journal2015
Structural origins of misfolding propensity in the platelet adhesive von Willebrand factor A1 domain.
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 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Interpreting human genetic variation at atomic resolution.Nature genetics · 2026Review
- Structure-resolved dynamics of type 2M von Willebrand disease.Journal of thrombosis and haemostasis : JTH · 2025Article
- Advancing Deep Variant Phenotyping of Mitochondrial Enzyme Complexes For Precision Medicine in Allogeneic Hematopoietic Stem-Cell Transplantation.Transplantation reports · 2025Article
- Conformation-specific RNA aptamers for phenotypic distinction between normal von Willebrand factor and type 2B von Willebrand disease.NAR molecular medicine · 2024Article
- Removal of the vicinal disulfide enhances the platelet-capturing function of von Willebrand factor.Blood · 2023Article
- Structural bioinformatics enhances mechanistic interpretation of genomic variation, demonstrated through the analyses of 935 distinct RAS family mutations.Bioinformatics (Oxford, England) · 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
- Extant fold-switching proteins are widespread.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The Chaperonin GroEL: A Versatile Tool for Applied Biotechnology Platforms.Frontiers in molecular biosciences · 2018Article
- 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
- Untangling a Structurally Resolved Protein Folding Intermediate.Biophysical journal · 2016Article
- Mutational Constraints on Local Unfolding Inhibit the Rheological Adaptation of von Willebrand Factor.The Journal of biological chemistry · 2016Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The von Willebrand factor (VWF) A1 and A3 domains are structurally isomorphic yet exhibit distinct mechanisms of unfolding. The A1 domain, responsible for platelet adhesion to VWF in hemostasis, unfolds through a molten globule intermediate in an apparent three-state mechanism, while A3 unfolds by a classical two-state mechanism. Inspection of the sequences or structures alone does not elucidate the source of this thermodynamic conundrum; however, the three-state character of the A1 domain suggests that it has more than one cooperative substructure yielding two separate unfolding transitions not present in A3. We investigate the extent to which structural elements contributing to intermediate conformations can be identified using a residue-specific implementation of the structure-energy-equivalence-of-domains algorithm (SEED), which parses proteins of known structure into their constituent thermodynamically cooperative components using protein-group-specific, transfer free energies. The structural elements computed to contribute to the non-two-state character coincide with regions where Von Willebrand disease mutations induce misfolded molten globule conformations of the A1 domain. This suggests a mechanism for the regulation of rheological platelet adhesion to A1 based on cooperative flexibility of the α2 and α3 helices flanking the platelet GPIbα receptor binding interface.
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