N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance
| Autor: | Clive Drakeford, James S. O’Donnell, Lauren Brady, Padraic G. Fallon, Jamie M. O’Sullivan, Alain Chion, Orla Sheils, Thomas A. J. McKinnon, Sonia Aguila, Roger J. S. Preston, Michael Laffan, Niall Dalton, Teresa M. Brophy, Gudmundur Bergsson, Soracha E. Ward |
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| Přispěvatelé: | British Heart Foundation |
| Rok vydání: | 2016 |
| Předmět: |
030204 cardiovascular system & hematology
Biochemistry Mice chemistry.chemical_compound 0302 clinical medicine HUMAN VONWILLEBRAND-FACTOR hemic and lymphatic diseases 1114 Paediatrics And Reproductive Medicine Macrophage IN-VIVO Mice Knockout SHEAR-STRESS biology medicine.diagnostic_test MOUSE MODEL Hematology ADAMTS13 Cell biology VWF PROPEPTIDE cardiovascular system Life Sciences & Biomedicine HUMAN FACTOR-VIII circulatory and respiratory physiology congenital hereditary and neonatal diseases and abnormalities Glycan Proteolysis Immunology Protein domain Mutation Missense 1102 Cardiovascular Medicine And Haematology DOMINANT MODIFIER 03 medical and health sciences Protein Domains Von Willebrand factor Polysaccharides Cell Line Tumor von Willebrand Factor Von Willebrand disease medicine Animals Humans PLASMA-LEVELS Ristocetin Science & Technology Macrophages ABO BLOOD-GROUP 1103 Clinical Sciences Cell Biology medicine.disease Amino Acid Substitution chemistry biology.protein FACTOR SURVIVAL 030215 immunology |
| Zdroj: | Europe PubMed Central |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2016-04-709436 |
| Popis: | Enhanced von Willebrand factor (VWF) clearance is important in the etiology of von Willebrand disease. However the molecular mechanisms underlying VWF clearance remain poorly understood. In this study, we have investigated the role of VWF domains and specific glycan moieties in regulating in vivo clearance. Our findings demonstrate that the A1 domain of VWF contains a receptor-recognition site that plays a key role in regulating the interaction of VWF with macrophages. In A1-A2-A3 and full-length VWF, this macrophage-binding site is cryptic but becomes exposed following exposure to shear or ristocetin. Previous studies have demonstrated that the N-linked glycans within the A2 domain play an important role in modulating susceptibility to ADAMTS13 proteolysis. We further demonstrate that these glycans presented at N1515 and N1574 also play a critical role in protecting VWF against macrophage-binding and clearance. Indeed, loss of the N-glycan at N1515 resulted in markedly enhanced VWF clearance that was significantly faster than that observed with any previously described VWF mutations. In addition, A1-A2-A3 fragments containing the N1515Q or N1574Q substitutions also demonstrated significantly enhanced clearance. Importantly, clodronate-induced macrophage depletion significantly attenuated the increased clearance observed with N1515Q and N1574Q in both full-length VWF and in A1-A2-A3. Finally, we further demonstrate that loss of these N-linked glycans does not enhance clearance in VWF in the presence of a structurally constrained A2 domain. Collectively, these novel findings support the hypothesis that conformation of the VWF A domains plays a critical role in modulating macrophage-mediated clearance of VWF in vivo. |
| Databáze: | OpenAIRE |
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