{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Atiq F"],"funding":["Science Foundation Ireland","NHLBI NIH HHS","ZonMw","NIH"],"pagination":["2752-2760"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11533894"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["22(10)"],"pubmed_abstract":["<h4>Background</h4>von Willebrand factor (VWF)-R1205H variant (Vicenza) results in markedly enhanced VWF clearance in humans that has been shown to be largely macrophage-mediated. However, the biological mechanisms underlying this enhanced clearance remain poorly understood.<h4>Objectives</h4>This study aimed to investigate the roles of (i) specific VWF domains and (ii) different macrophage receptors in regulating enhanced VWF-R1205H clearance.<h4>Methods</h4>In vivo clearance of full-length and truncated wild-type (WT)-VWF and VWF with R1205 substitutions was investigated in VWF<sup>-/-</sup> mice. Plate-binding assays were employed to characterize VWF binding to purified scavenger receptor class A member 1 (SR-AI), low-density lipoprotein receptor-related protein-1 (LRP1) cluster II or cluster IV receptors, and macrophage galactose-type lectin.<h4>Results</h4>In full-length VWF missing the A1 domain, introduction of R1205H led to significantly enhanced clearance in VWF<sup>-/-</sup> mice compared with WT-VWF missing the A1 domain. Importantly, R1205H in a truncated VWF-D'D3 fragment also triggered increased clearance compared with WT-VWF-D'D3. Additional in vivo studies demonstrated that VWF-R1205K (which preserves the positive charge at 1205) exhibited normal clearance, whereas VWF-R1205E (which results in loss of the positive charge) caused significantly enhanced clearance, pinpointing the importance of the positive charge at VWF-R1205. In vitro plate-binding studies confirmed increased VWF-R1205H interaction with SR-AI compared with WT-VWF. Furthermore, significantly enhanced VWF-R1205H binding to LRP1 cluster IV (P < .001) and less marked enhanced binding to LRP1 cluster II (P = .034) was observed. In contrast, VWF-R1205H and WT-VWF demonstrated no difference in binding affinity to macrophage galactose-type lectin.<h4>Conclusion</h4>Disruption of the positive charge at amino acid R1205 causes conformational changes in the VWF-D'D3 domains and triggers enhanced LRP1-mediated and SR-AI-mediated clearance."],"journal":["Journal of thrombosis and haemostasis : JTH"],"pubmed_title":["R1205H (Vicenza) causes conformational changes in the von Willebrand factor D'D3 domains and enhances von Willebrand factor binding to clearance receptors LRP1 and SR-AI."],"pmcid":["PMC11533894"],"funding_grant_id":["P01 HL144457","P01 HL081588"],"pubmed_authors":["Baci B","Aburawi HE","O'Donnell JS","Rawley O","O'Sullivan JM","Amin A","Chion A","Cooke N","Terraube V","Ozbil M","Byrne C","Lillicrap D","Hulshof AM","Doherty D","Atiq F"],"additional_accession":[]},"is_claimable":false,"name":"R1205H (Vicenza) causes conformational changes in the von Willebrand factor D'D3 domains and enhances von Willebrand factor binding to clearance receptors LRP1 and SR-AI.","description":"<h4>Background</h4>von Willebrand factor (VWF)-R1205H variant (Vicenza) results in markedly enhanced VWF clearance in humans that has been shown to be largely macrophage-mediated. However, the biological mechanisms underlying this enhanced clearance remain poorly understood.<h4>Objectives</h4>This study aimed to investigate the roles of (i) specific VWF domains and (ii) different macrophage receptors in regulating enhanced VWF-R1205H clearance.<h4>Methods</h4>In vivo clearance of full-length and truncated wild-type (WT)-VWF and VWF with R1205 substitutions was investigated in VWF<sup>-/-</sup> mice. Plate-binding assays were employed to characterize VWF binding to purified scavenger receptor class A member 1 (SR-AI), low-density lipoprotein receptor-related protein-1 (LRP1) cluster II or cluster IV receptors, and macrophage galactose-type lectin.<h4>Results</h4>In full-length VWF missing the A1 domain, introduction of R1205H led to significantly enhanced clearance in VWF<sup>-/-</sup> mice compared with WT-VWF missing the A1 domain. Importantly, R1205H in a truncated VWF-D'D3 fragment also triggered increased clearance compared with WT-VWF-D'D3. Additional in vivo studies demonstrated that VWF-R1205K (which preserves the positive charge at 1205) exhibited normal clearance, whereas VWF-R1205E (which results in loss of the positive charge) caused significantly enhanced clearance, pinpointing the importance of the positive charge at VWF-R1205. In vitro plate-binding studies confirmed increased VWF-R1205H interaction with SR-AI compared with WT-VWF. Furthermore, significantly enhanced VWF-R1205H binding to LRP1 cluster IV (P < .001) and less marked enhanced binding to LRP1 cluster II (P = .034) was observed. In contrast, VWF-R1205H and WT-VWF demonstrated no difference in binding affinity to macrophage galactose-type lectin.<h4>Conclusion</h4>Disruption of the positive charge at amino acid R1205 causes conformational changes in the VWF-D'D3 domains and triggers enhanced LRP1-mediated and SR-AI-mediated clearance.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Oct","modification":"2026-06-04T00:12:59.147Z","creation":"2026-05-03T03:12:11.547Z"},"accession":"S-EPMC11533894","cross_references":{"pubmed":["38996914"],"doi":["10.1016/j.jtha.2024.06.023"]}}