Extracellular-signal regulated kinase 8 of Trypanosoma brucei uniquely phosphorylates its proliferating cell nuclear antigen homolog and reveals exploitable properties

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dc.contributor.authorValenciano Murillo, Ana L.en
dc.contributor.authorKnudsen, Giselle M.en
dc.contributor.authorMackey, Zachary B.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2018-06-01T19:03:21Zen
dc.date.available2018-06-01T19:03:21Zen
dc.date.issued2016-01-01en
dc.description.abstractThe Trypanosoma brucei subspecies T. brucei gambiense and T. brucei rhodesiense are vector-borne pathogens that cause sleeping sickness also known as Human African Trypanosomiasis (HAT), which is fatal if left untreated. The drugs that treat HAT are ineffective and cause toxic side effects. One strategy for identifying safer and more effective HAT drugs is to therapeutically exploit essential gene targets in T. brucei. Genes that make up a basic mitogen-activated protein kinase (MAPK) network are present in T. brucei. Tb927.10.5140 encodes an essential MAPK that is homologous to the human extracellular-signal regulated kinase 8 (HsERK8) which forms a tight complex with the replication factor proliferating cell nuclear antigen (PCNA) to stabilize intracellular PCNA levels. Here we demonstrate that (TbPCNA) is uniquely phosphorylated on serine (S) and threonine (T) residues in T. brucei and that TbERK8 phosphorylates TbPCNA at each of these residues. The ability of an ERK8 homolog to phosphorylate a PCNA homolog is a novel biochemical property that is first demonstrated here in T. brucei and may be unique to this pathogen. We demonstrate that the potent HsERK8 inhibitor Ro318220, has an IC50 for TbERK8 that is several hundred times higher than its reported IC50 for HsERK8. This indicated that the active sites of TbERK8 and HsERK8 can be selectively inhibited, which provides a rational basis for discovering inhibitors that specifically target this essential parasite MAPK to kill the parasite.en
dc.description.versionPublished versionen
dc.format.extent2827 - 2841 (15) page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1080/15384101.2016.1222340en
dc.identifier.eissn1551-4005en
dc.identifier.issn1538-4101en
dc.identifier.issue20en
dc.identifier.orcidMackey, ZB [0000-0002-4533-0973]en
dc.identifier.urihttp://hdl.handle.net/10919/83435en
dc.identifier.volume15en
dc.language.isoenen
dc.publisherTaylor & Francisen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000385379200021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution-NonCommercial 3.0 Unporteden
dc.rights.holderThe Author(s)en
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/en
dc.subjectCell Biologyen
dc.subjectevolutionen
dc.subjectextracellular-signal regulated kinase (ERK)en
dc.subjecthomology modelingen
dc.subjectinhibitorsen
dc.subjectmitogen-activated protein kinase (MAPK)en
dc.subjectproliferating cell nuclear antigen (PCNA)en
dc.subjectTrypanosoma bruceien
dc.subjectwestern bloten
dc.subjectACTIVATED PROTEIN-KINASEen
dc.subjectBLOOD-STREAM FORMSen
dc.subjectMASS-SPECTROMETRYen
dc.subjectPCNAen
dc.subjectEXPRESSIONen
dc.subjectERK8en
dc.subjectSPECIFICITYen
dc.subjectINHIBITORSen
dc.subjectSTABILITYen
dc.subjectPATHWAYen
dc.titleExtracellular-signal regulated kinase 8 of Trypanosoma brucei uniquely phosphorylates its proliferating cell nuclear antigen homolog and reveals exploitable propertiesen
dc.title.serialCell Cycleen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
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/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Fralin Affiliated Facultyen

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