Protein Arginine Deiminase 2 Binds Calcium in an Ordered Fashion: Implications for Inhibitor Design

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dc.contributor.authorSlade, Daniel J.en
dc.contributor.authorFang, Pengfeien
dc.contributor.authorDreyton, Christina J.en
dc.contributor.authorZhang, Yingen
dc.contributor.authorFuhrmann, Jakoben
dc.contributor.authorRempel, Donen
dc.contributor.authorBax, Benjamin D.en
dc.contributor.authorCoonrod, Scott A.en
dc.contributor.authorLewis, Huw D.en
dc.contributor.authorGuo, Minen
dc.contributor.authorGross, Michael L.en
dc.contributor.authorThompson, Paul R.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2016-11-09T02:59:58Zen
dc.date.available2016-11-09T02:59:58Zen
dc.date.issued2015-04-01en
dc.description.abstractProtein arginine deiminases (PADs) are calcium-dependent histone-modifying enzymes whose activity is dysregulated in inflammatory diseases and cancer. PAD2 functions as an Estrogen Receptor (ER) coactivator in breast cancer cells via the citrullination of histone tail arginine residues at ER binding sites. Although an attractive therapeutic target, the mechanisms that regulate PAD2 activity are largely unknown, especially the detailed role of how calcium facilitates enzyme activation. To gain insights into these regulatory processes, we determined the first structures of PAD2 (27 in total), and through calcium-titrations by X-ray crystallography, determined the order of binding and affinity for the six calcium ions that bind and activate this enzyme. These structures also identified several PAD2 regulatory elements, including a calcium switch that controls proper positioning of the catalytic cysteine residue, and a novel active site shielding mechanism. Additional biochemical and mass-spectrometry-based hydrogen/deuterium exchange studies support these structural findings. The identification of multiple intermediate calcium-bound structures along the PAD2 activation pathway provides critical insights that will aid the development of allosteric inhibitors targeting the PADs.en
dc.description.versionPublished versionen
dc.format.extent1043 - 1053 (11) page(s)en
dc.identifier.doihttps://doi.org/10.1021/cb500933jen
dc.identifier.issn1554-8929en
dc.identifier.issue4en
dc.identifier.urihttp://hdl.handle.net/10919/73405en
dc.identifier.volume10en
dc.language.isoenen
dc.publisherAmerican Chemical Societyen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000353315100017&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectBiochemistry & Molecular Biologyen
dc.subjectPEPTIDYLARGININE DEIMINASEen
dc.subjectRHEUMATOID-ARTHRITISen
dc.subjectBREAST-CANCERen
dc.subjectCITRULLINATIONen
dc.subjectDISEASEen
dc.subjectSYSTEMen
dc.subjectCELLSen
dc.subjectIDENTIFICATIONen
dc.subjectACTIVATIONen
dc.subjectCHROMATINen
dc.titleProtein Arginine Deiminase 2 Binds Calcium in an Ordered Fashion: Implications for Inhibitor Designen
dc.title.serialACS Chemical Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen

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