ArticleJournal of thrombosis and haemostasis : JTH2022
Desialylation of O-glycans activates von Willebrand factor by destabilizing its autoinhibitory module.
Article in Journal of thrombosis and haemostasis : JTH, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Flow molecular dynamics simulations reveal mechano-presentation of von Willebrand factor through glycan-modulated autoinhibitory modules.APL bioengineering · 2026Article
- Unraveling antibody-induced structural dynamics in the ADAMTS13 CUB1-2 domains via HDX-MS.Blood advances · 2025Article
- O-glycan determinants regulate VWF trafficking to Weibel-Palade bodies.Blood advances · 2024Article
- Conformational activation and inhibition of von Willebrand factor by targeting its autoinhibitory module.Blood · 2024Article
- The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome.Biomolecules · 2023Review
- Type 2B von Willebrand disease mutations differentially perturb autoinhibition of the A1 domain.Blood · 2023Article
- Autoinhibitory module underlies species difference in shear activation of von Willebrand factor.Journal of thrombosis and haemostasis : JTH · 2022Article
- Review
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Authors and funding
10 authors.
Funding
Abstract
backgroundThe binding of the A1 domain of von Willebrand factor (VWF) to platelet receptor glycoprotein (GP)Ibα defines the VWF activity in hemostasis. Recent studies suggest that sequences flanking A1 form cooperatively an autoinhibitory module (AIM) that reduces the accessibility of the GPIbα binding site on A1. Application of a tensile force induces unfolding of the AIM. Desialylation induces spontaneous binding of plasma VWF to platelets. Most O-glycans in VWF are located around the A1 domain. Removing certain O-glycans in the flanking sequences by site-directed mutagenesis enhances A1 binding to GPIbα and produces an effect similar to type 2B von Willebrand disease in animals.
objectivesTo understand if and how desialylation of O-glycans in the flanking sequences increases A1 activity.
methodsA recombinant AIM-A1 fragment encompassing VWF residues 1238-1493 and only O-glycans was treated with neuraminidase to produce desialylated protein. The glycan structure, dynamics, stability, and function of the desialylated protein was characterized by biochemical and biophysical methods and compared to the sialylated fragment.
resultsAsialo-AIM-A1 exhibited increased binding activity and induced more apparent platelet aggregation than its sialylated counterpart. It exhibited a lower melting temperature, and increased hydrogen-deuterium exchange rates at residues near the secondary GPIbα binding site and the N-terminal flanking sequence. Asialo-AIM-A1 is less mechanically stable than sialo-AIM-A1, with its unstressed unfolding rate approximately 3-fold greater than the latter.
conclusionsDesialylation of O-glycans around A1 increases its activity by destabilizing the AIM.
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