UncoveringtheStructuralBasisofaNewTwistinProteinUbiquitinationKedarPuvar1,Zhao-QingLuo*,2,andChittaranjanDas*,11.DepartmentofChemistry,PurdueUniversity,560OvalDrive,WestLafayette,Indiana479062.PurdueInstituteofImmunology,Inflammation,andInfectiousDiseasesandtheDepartmentofBiologicalSciences,PurdueUniversity,915WestStateSt,WestLafayette,Indiana47906AbstractMembersoftheSidEeffectorfamilyfromLegionellapneumophilarepresentanewparadigmintheubiquitinworld.TheseenzymescatalyzeubiquitinationoftargetproteinsviaamechanismdifferentfromconventionalE1-E2-E3biochemistryandplayimportantrolesinL.pneumophilavirulence.Theycombinemono-ADP-ribosylationandphosphodiesteraseactivitiestoattachubiquitinontosubstrates,ingreatcontrasttotheorthodoxpathway.Aseriesofrecentstructuralandmechanisticstudieshaveshednewlightintotheactionoftheseenzymes.Hereinwesummarizethekeyinsightsintotheseproteins’structureandfunction,emphasizingtheirmodularnature,anddiscussthebiochemicalimplicationsoftheseproteinsaswellasareasoffurtherexploration.Keywordsubiquitination;bacteria;ADP-ribosylation;signaling;Legionella;effectorsUbiquitinationandtheSidEfamilyThepost-translationalmodificationknownasubiquitination,vitalforcellularfunctionandsignalingineukaryoticorganisms,isdefinedastheattachmentofthesmallproteinubiquitin(Ub)throughitsC-terminusontothelysineresidueofaproteinsubstrateviaanisopeptidebond[1].Ubiquitinisattachedtothesubstratebythecoordinated,ATP-drivenactionofthreeenzymestermedastheUbactivatingE1,UbconjugatingE2,andUbE3ligasethatcatalyzeacascadeofreactionsinvolvingactivationandsequentialtransferofUb,ultimatelyresultinginisopeptidelinkageofUbwithtargetLysresidues.AdditionofasingleUbviathisE1-E2-E3cascaderesultsinmonoubiquitination,whichisoftenfurtherelaboratedbysuccessiveadditionofmoreUbgroupstoproducepolyubiquitinchainsinwhichthemonomericUbunitsareisopeptidelinkedviaoneoftheseveninternalLysresidues,orthe*Correspondence:cdas@purdue.edu,luoz@purdue.edu.Publisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscri...
