N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance
| العنوان: | N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance |
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| المؤلفون: | 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 |
| المساهمون: | British Heart Foundation |
| المصدر: | Europe PubMed Central |
| بيانات النشر: | American Society of Hematology, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1528-0020 0006-4971 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9a0edef87f40fc1cecc5eea23f4f1b6fTest https://doi.org/10.1182/blood-2016-04-709436Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9a0edef87f40fc1cecc5eea23f4f1b6f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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