Nucleocytoplasmic Shuttling Activity of Ataxin-3 英文参考文献.docVIP

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Nucleocytoplasmic Shuttling Activity of Ataxin-3 英文参考文献.doc

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Nucleocytoplasmic Shuttling Activity of Ataxin-3 英文参考文献

NucleocytoplasmicShuttlingActivityofAtaxin-3 SandraMacedo-Ribeiro1.*,Lu?′saCortes2.,Patr?′ciaMaciel3,AnaLu?′saCarvalho2,4* 1IBMC-InstitutodeBiologiaMoleculareCelular,UniversidadedoPorto,Porto,Portugal,2CenterforNeuroscienceandCellBiology(CNC),UniversityofCoimbra,Coimbra, Portugal,3LifeandHealth SciencesResearchInstitute (ICVS),SchoolofHealthSciences, UniversityofMinho,Braga,Portugal, 4Department ofZoology,University of Coimbra,Coimbra,Portugal Abstract Spinocerebellarataxiatype-3,alsoknownasMachado-JosephDisease(MJD),isoneofmanyinheritedneurodegenerative disorders caused by polyglutamine-encoding CAG repeat expansions in otherwise unrelated genes. Disease protein misfolding and aggregation, often within the nucleus of affected neurons, characterize polyglutamine disorders. Several evidenceshaveimplicatedthenucleusastheprimarysiteofpathogenesisforMJD.However,themoleculardeterminants forthenucleocytoplasmictransportofhumanataxin-3(Atx3),theproteinwhichismutatedinpatientswithMJD,arenot characterized. InordertocharacterizethenuclearshuttlingactivityofAtx3,weperformedyeastnuclearimportassaysandfoundthatAtx3 isactivelyimportedintothenucleus,bymeansofaclassicalnuclearlocalizingsequenceformedbyaclusteroflysineand arginineresidues.Ontheotherhand,whenactivenuclearexportwasinhibitedusingleptomycinB,aspecificinhibitorof thenuclearexportreceptorCRM1,bothendogenousAtx3andtransfectedGFP-Atx3accumulatedinsidethenucleusofa subpopulationofCOS-7cells,whereasbothproteinsarenormallypredominantinthecytoplasm. Additionally,usingaRev(1.4)-GFPnuclearexportassay,weperformedanextensiveanalysisofsixputativealiphaticnuclear exportmotifsidentifiedinAtx3aminoacidsequence.Althoughnoneofthetestedpeptidesequenceswerefoundtodrive nuclear export when isolated, we have successfully mapped the region of Atx3 responsible for its CRM1-independent nuclearexportactivity.Curiously,theN-terminal Josephindomainaloneis exportedintothecytoplasm,butthenuclear exportactivityofAtx3issignificantlyenhanc