An Acidic Loop and Cognate Phosphorylation Sites Define a Molecular Switch That Modulates Ubiquitin Charging Activity in Cdc34-Like Enzymes 英文参考文献.docVIP
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An Acidic Loop and Cognate Phosphorylation Sites Define a Molecular Switch That Modulates Ubiquitin Charging Activity in Cdc34-Like Enzymes 英文参考文献
AnAcidicLoopandCognatePhosphorylationSites
DefineaMolecularSwitchThatModulatesUbiquitin
ChargingActivityinCdc34-LikeEnzymes
ElenaPapaleo*,ValeriaRanzani,FaridaTripodi,AlessandroVitriolo,ClaudiaCirulli,PiercarloFantucci,
LiliaAlberghina,MarcoVanoni,LucaDeGioia,PaolaCoccetti*
DepartmentofBiotechnologyandBiosciences,UniversityofMilano-Bicocca,Milan,Italy
Abstract
E2ubiquitin-conjugatingenzymesarecrucialmediatorsofproteinubiquitination,whichstronglyinfluencetheultimatefate
ofthetargetsubstrates.Recently,ithasbeenshownthattheactivityofseveralenzymesoftheubiquitinationpathwayis
finelytunedbyphosphorylation,anubiquitousmechanismforcellularregulation,whichmodulatesproteinconformation.
Inthiscontribution,weprovidethefirstrationale,atthemolecularlevel,oftheregulatorymechanismmediatedbycasein
kinase2(CK2)phosphorylationofE2Cdc34-likeenzymes.Inparticular,weidentifytwoco-evolvingsignatureelementsin
oneofthelargerfamiliesofE2enzymes:anacidicinsertioninb4a2loopintheproximityofthecatalyticcysteineandtwo
conservedkeyserineresidueswithinthecatalyticdomain,whicharephosphorylatedbyCK2.Ourinvestigations,usingyeast
Cdc34asamodel,through2.5msmoleculardynamicssimulationsandbiochemicalassays,definethesetwoelementsasan
importantphosphorylation-controlledswitchthatmodulateopeningandclosingofthecatalyticcleft.Themechanismrelies
onelectrostaticrepulsionsbetweenaconservedserinephosphorylatedbyCK2andtheacidicresiduesoftheb4a 2loop,
promotingE2ubiquitinchargingactivity.Ourinvestigationidentifiesanewandunexpectedpivotalrolefortheacidicloop,
providingthefirstevidencethatthisloopiscrucialnotonlyfordownstreameventsrelatedtoubiquitinchainassembly,but
isalsomandatoryforthemodulationofanupstreamcrucialstepoftheubiquitinpathway:theubiquitinchargingintheE2
catalyticcleft.
Citation:PapaleoE,RanzaniV,TripodiF,VitrioloA,CirulliC,etal.(2011)AnAcidicLoopandCognatePhosphorylationSitesDefineaMolecularSwitchThat
ModulatesUbiquitinChargingActivityinCdc34-LikeEnzymes.PLoSComputBiol7(5):e1002056.doi:10.1371/journal
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