SHSOSOOUbHNSubstrateHOOATPAMPSHSHSHUBIQUITINATIONRINGE3sSOOHN~600inhumansUbiquitintransferHECTE3sHECTE3SOOHNSOSOOHNSOUbiquitintransferUbiquitintransferOHNOHNOHNUbiquitinactivatingenzyme(E1)Ubiquitinconjugatingenzyme(E2)Ubiquitinligase(E3)CharacteristicdomainsRING(ReallyInterestingNewGene):Znbindingdomain,recruitstheUb-chargedE2U-box:samefoldasRINGwithoutZncoordinationHECT(homologoustoE6-APcarboxylterminus)MonomericRINGExample:c-CBLHomodimericRINGExamples:cIAP,RNF4,BIRC7,IDOL,TRIM5αCullin-RINGligasesMonomericU-boxExample:E4BHeterodimericRINGExamples:BRCA1–BARD1,Mdm2–MdmX,RING1B–Bmi1HomodimericU-boxExamples:CHIP,Prp19OthermultisubunitE3sTheanaphasepromotingcomplex/cyclosome(APC/C)Composedof:Substratereceptor(SR)-example:F-boxproteinSkp2Adaptorprotein-example:Skp1Cullin-example:Cul1Ring-boxprotein(Rbx)-example:Rbx1RecruitstheUb-chargedE2ContainsacatalyticcysteineFlexibletetherallowschangesinrelativeorientationsofthetwolobes~30inhumansExamplesofknownregulationmechanismsAutoinhibitionthroughintramolecularinteractionsreleasedby:phosphorylation(e.g.,Itch),neddylation(e.g.,Smurf1),proteininteraction(e.g.,Smurf1,Smurf2)ExamplesofknownregulationmechanismsAutoinhibitionthroughintramolecularinteractionsreleasedby:phosphorylation/phosphoubiquitininteraction(Parkin),bindingtoneddylatedCRLs(e.g.,HHARI),proteininteractions(e.g.,HOIP)ExamplesofknownregulationmechanismsNeddylation(e.g.,CRLs)Phosphorylation(e.g.,c-CBL,APC,Mdm2)Smallmolecule:E3interaction(e.g.,TRAF-2:sphingosine-1-phosphate)NEDD4familyWWWWWWWWC2Examples:Smurf1(2WWmotifs),Smurf2(3WWmotifs),Itch(4WWmotifs)HERCfamilyHECTHECTRLDRLDWD40SPRYRLDOtherHECTsHECTFamiliesSmallHERCsLargeHERCsRBRParkinParcRNF144(A/B)HOIPHHARIRING0UblCullinDOCRBRAriadneUBAPUBLDDUBANZFB-box1000AANCRRBSHRING1,recruitstheUb-chargedE2RING2orRcat,containsacatalyticcysteineIBR(InBetweenRING)orBRcatNlobeClobeSHRINGE3CullinSRAdaptorRING-boxproteinE3Example:E6AP2211Proteindegradationbytheproteasome,cell-cycleprogression,transcriptionalregulation,DNArep...
