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N-linked glycan sites within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance

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Title: N-linked glycan sites within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance
Authors: Chion, A
O'Sullivan, JM
Drakeford, C
Bergsson, G
Dalton, N
Aguila, S
Ward, S
Fallon, PG
Brophy, TM
Preston, RJ
Brady, L
Sheils, O
Laffan, M
McKinnon, TA
O'Donnell, JS
Item Type: Journal Article
Abstract: 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.
Issue Date: 13-Oct-2016
Date of Acceptance: 16-Aug-2016
URI: http://hdl.handle.net/10044/1/46259
DOI: https://dx.doi.org/10.1182/blood-2016-04-709436
ISSN: 0006-4971
Publisher: American Society of Hematology
Start Page: 1959
End Page: 1968
Journal / Book Title: Blood
Volume: 128
Issue: 15
Copyright Statement: © 2016 by The American Society of Hematology
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: FS/11/3/28632
Keywords: Science & Technology
Life Sciences & Biomedicine
Hematology
HUMAN VONWILLEBRAND-FACTOR
HUMAN FACTOR-VIII
ABO BLOOD-GROUP
FACTOR SURVIVAL
IN-VIVO
DOMINANT MODIFIER
VWF PROPEPTIDE
PLASMA-LEVELS
SHEAR-STRESS
MOUSE MODEL
Immunology
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
1114 Paediatrics And Reproductive Medicine
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)