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dc.contributor.authorTilvawala, Ronak
dc.contributor.authorNemmara, Venkatesh V.
dc.contributor.authorReyes, Archie C.
dc.contributor.authorSorvillo, Nicoletta
dc.contributor.authorSalinger, Ari J.
dc.contributor.authorCherpokova, Deya
dc.contributor.authorFukui, Saeko
dc.contributor.authorGutch, Sarah
dc.contributor.authorWagner, Denisa
dc.contributor.authorThompson, Paul R
dc.date2022-08-11T08:08:28.000
dc.date.accessioned2022-08-23T15:56:15Z
dc.date.available2022-08-23T15:56:15Z
dc.date.issued2021-12-16
dc.date.submitted2022-01-02
dc.identifier.citation<p>Tilvawala R, Nemmara VV, Reyes AC, Sorvillo N, Salinger AJ, Cherpokova D, Fukui S, Gutch S, Wagner D, Thompson PR. The role of SERPIN citrullination in thrombosis. Cell Chem Biol. 2021 Dec 16;28(12):1728-1739.e5. doi: 10.1016/j.chembiol.2021.07.009. Epub 2021 Aug 4. PMID: 34352225; PMCID: PMC8688209. <a href="https://doi.org/10.1016/j.chembiol.2021.07.009">Link to article on publisher's site</a></p>
dc.identifier.issn2451-9448 (Linking)
dc.identifier.doi10.1016/j.chembiol.2021.07.009
dc.identifier.pmid34352225
dc.identifier.urihttp://hdl.handle.net/20.500.14038/29928
dc.description.abstractAberrant protein citrullination is associated with many pathologies; however, the specific effects of this modification remain unknown. We have previously demonstrated that serine protease inhibitors (SERPINs) are highly citrullinated in rheumatoid arthritis (RA) patients. These citrullinated SERPINs include antithrombin, antiplasmin, and t-PAI, which regulate the coagulation and fibrinolysis cascades. Notably, citrullination eliminates their inhibitory activity. Here, we demonstrate that citrullination of antithrombin and t-PAI impairs their binding to their cognate proteases. By contrast, citrullination converts antiplasmin into a substrate. We recapitulate the effects of SERPIN citrullination using in vitro plasma clotting and fibrinolysis assays. Moreover, we show that citrullinated antithrombin and antiplasmin are increased and decreased in a deep vein thrombosis (DVT) model, accounting for how SERPIN citrullination shifts the equilibrium toward thrombus formation. These data provide a direct link between increased citrullination and the risk of thrombosis in autoimmunity and indicate that aberrant SERPIN citrullination promotes pathological thrombus formation.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=34352225&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1016/j.chembiol.2021.07.009
dc.subjectcitrullination
dc.subjectdeep vein thrombosis
dc.subjectrheumatoid arthritis
dc.subjectserine protease inhibitors
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectCardiovascular Diseases
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal Chemistry and Pharmaceutics
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectMusculoskeletal Diseases
dc.titleThe role of SERPIN citrullination in thrombosis
dc.typeJournal Article
dc.source.journaltitleCell chemical biology
dc.source.volume28
dc.source.issue12
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2131
dc.identifier.contextkey27074122
html.description.abstract<p>Aberrant protein citrullination is associated with many pathologies; however, the specific effects of this modification remain unknown. We have previously demonstrated that serine protease inhibitors (SERPINs) are highly citrullinated in rheumatoid arthritis (RA) patients. These citrullinated SERPINs include antithrombin, antiplasmin, and t-PAI, which regulate the coagulation and fibrinolysis cascades. Notably, citrullination eliminates their inhibitory activity. Here, we demonstrate that citrullination of antithrombin and t-PAI impairs their binding to their cognate proteases. By contrast, citrullination converts antiplasmin into a substrate. We recapitulate the effects of SERPIN citrullination using in vitro plasma clotting and fibrinolysis assays. Moreover, we show that citrullinated antithrombin and antiplasmin are increased and decreased in a deep vein thrombosis (DVT) model, accounting for how SERPIN citrullination shifts the equilibrium toward thrombus formation. These data provide a direct link between increased citrullination and the risk of thrombosis in autoimmunity and indicate that aberrant SERPIN citrullination promotes pathological thrombus formation.</p>
dc.identifier.submissionpathfaculty_pubs/2131
dc.contributor.departmentThompson Lab
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages1728-1739.e5


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