UbiquitinLigases:Structure,Function,andRegulationNingZhengandNitzanShabekHowardHughesMedicalInstituteandDepartmentofPharmacology,UniversityofWashington,Seattle,Washington98195;email:nzheng@uw.edu,nshabek@uw.eduAnnu.Rev.Biochem.2017.86:129–57FirstpublishedasaReviewinAdvanceonMarch27,2017TheAnnualReviewofBiochemistryisonlineatbiochem.annualreviews.orghttps://doi.org/10.1146/annurev-biochem-060815-014922Copyrightc⃝2017byAnnualReviews.AllrightsreservedKeywordsubiquitinligase,ubiquitination,PTM,posttranslationalmodification,degron,agonistAbstractUbiquitinE3ligasescontroleveryaspectofeukaryoticbiologybypromotingproteinubiquitinationanddegradation.Attheendofathree-enzymecas-cade,ubiquitinligasesmediatethetransferofubiquitinfromanE2ubiquitin-conjugatingenzymetospecificsubstrateproteins.EarlyinvestigationsofE3softheRING(reallyinterestingnewgene)andHECT(homologoustotheE6APcarboxylterminus)typesshedlightontheirenzymaticac-tivities,generalarchitectures,andsubstratedegron-bindingmodes.Recentstudieshaveprovideddeepermechanisticinsightsintotheircatalysis,acti-vation,andregulation.Inthisreview,wesummarizethecurrentprogressinstructure–functionstudiesofubiquitinligasesaswellasexcitingnewdiscov-eriesofnovelclassesofE3sanddiversesubstraterecognitionmechanisms.OurincreasedunderstandingofubiquitinligasefunctionandregulationhasprovidedtherationalefordevelopingE3-targetingtherapeuticsforthetreatmentofhumandiseases.129Clickheretoviewthisarticle'sonlinefeatures:•DownloadfiguresasPPTslides•Navigatelinkedreferences•Downloadcitations•Explorerelatedarticles•SearchkeywordsANNUALREVIEWSFurtherAnnu.Rev.Biochem.2017.86:129-157.Downloadedfromwww.annualreviews.orgAccessprovidedbyUniversityofCalifornia-SantaBarbaraon03/14/18.Forpersonaluseonly.ContentsINTRODUCTION...............................................................130PROGRESSINUNDERSTANDINGCATALYTICMECHANISMS.............131MechanismofE2∼UbActivationbyRINGE3s..................................131MechanismsofChainElongationbyRINGE3...
