ArticleJournal of molecular biology2020
Evidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease.
Article in Journal of molecular biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Article
- State-of-the-Art and Future Directions in Structural Proteomics.Molecular & cellular proteomics : MCP · 2025Review
- 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
- Examining DNA Structures with In-droplet Hydrogen/Deuterium Exchange Mass Spectrometry.International journal of mass spectrometry · 2024Article
- Clinical and laboratory presentation of von Willebrand disease: Experience from a single center in Saudi Arabia.Journal of Taibah University Medical Sciences · 2023Article
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Camelid-derived single-chain antibodies in hemostasis: Mechanistic, diagnostic, and therapeutic applications.Research and practice in thrombosis and haemostasis · 2020Review
- Glycosylation sterically inhibits platelet adhesion to von Willebrand factor without altering intrinsic conformational dynamics.Journal of thrombosis and haemostasis : JTH · 2020Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 2 countries.
Funding
Abstract
Von Willebrand factor (VWF), an exceptionally large multimeric plasma glycoprotein, functions to initiate coagulation by agglutinating platelets in the blood stream to sites of vascular injury. This primary hemostatic function is perturbed in type 2 dysfunctional subtypes of von Willebrand disease (VWD) by mutations that alter the structure and function of the platelet GPIbα adhesive VWF A1 domains. The resulting amino acid substitutions cause local disorder and misfold the native structure of the isolated platelet GPIbα-adhesive A1 domain of VWF in both gain-of-function (type 2B) and loss-of-function (type 2M) phenotypes. These structural effects have not been explicitly observed in A1 domains of VWF multimers native to blood plasma. New mass spectrometry strategies are applied to resolve the structural effects of 2B and 2M mutations in VWF to verify the presence of A1 domain structural disorder in multimeric VWF harboring type 2 VWD mutations. Limited trypsinolysis mass spectrometry (LTMS) and hydrogen-deuterium exchange mass spectrometry (HXMS) are applied to wild-type and VWD variants of the single A1, A2, and A3 domains, an A1A2A3 tridomain fragment of VWF, plasmin-cleaved dimers of VWF, multimeric recombinant VWF, and normal VWF plasma concentrates. Comparatively, these methods show that mutations known to misfold the isolated A1 domain increase the rate of trypsinolysis and the extent of hydrogen-deuterium exchange in local secondary structures of A1 within multimeric VWF. VWD mutation effects are localized to the A1 domain without appreciably affecting the structure and dynamics of other VWF domains. The intrinsic dynamics of A1 observed in recombinant fragments of VWF are conserved in plasma-derived VWF. These studies reveal that structural disorder does occur in VWD variants of the A1 domain within multimeric VWF and provides strong support for VWF misfolding as a result of some, but not all, type 2 VWD variants.
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