دورية أكاديمية
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: | Chion A; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., O'Sullivan JM; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., Drakeford C; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., Bergsson G; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., Dalton N; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., Aguila S; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., Ward S; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., Fallon PG; Inflammation and Immunity Research Group, Institute of Molecular Medicine, and., Brophy TM; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital., Preston RJ; Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland., Brady L; Department of Histopathology, Sir Patrick Dun Research Laboratory, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Sheils O; Department of Histopathology, Sir Patrick Dun Research Laboratory, St. James's Hospital, Trinity College Dublin, Dublin, Ireland., Laffan M; Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom., McKinnon TA; Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom., O'Donnell JS; Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital, National Centre for Hereditary Coagulation Disorders, St. James's Hospital, Dublin, Ireland; and Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland. |
| المصدر: | Blood [Blood] 2016 Oct 13; Vol. 128 (15), pp. 1959-1968. Date of Electronic Publication: 2016 Aug 23. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York] : Elsevier Original Publication: New York, Grune & Stratton [etc.] |
| مواضيع طبية MeSH: | Macrophages/*metabolism , Polysaccharides/*metabolism , von Willebrand Factor/*metabolism, Amino Acid Substitution ; Animals ; Cell Line, Tumor ; Humans ; Macrophages/cytology ; Mice ; Mice, Knockout ; Mutation, Missense ; Polysaccharides/chemistry ; Polysaccharides/genetics ; Protein Domains ; von Willebrand Factor/chemistry ; von Willebrand Factor/genetics |
| مستخلص: | 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 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 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. (© 2016 by The American Society of Hematology.) |
| معلومات مُعتمدة: | FS/11/3/28632 United Kingdom BHF_ British Heart Foundation; PG/11/50/28984 United Kingdom BHF_ British Heart Foundation; PG/14/91/31222 United Kingdom BHF_ British Heart Foundation |
| المشرفين على المادة: | 0 (Polysaccharides) 0 (von Willebrand Factor) |
| تواريخ الأحداث: | Date Created: 20160825 Date Completed: 20170804 Latest Revision: 20220129 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1182/blood-2016-04-709436 |
| PMID: | 27554083 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1528-0020 |
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| DOI: | 10.1182/blood-2016-04-709436 |