ThalidomideBifunctionalthalidomideHarmfulproteinProteasomaleliminationC)DirectingE3ligasestodesiredsubstratesCRL4(CRBN)E3ligaseCRL4(CRBN)E3ligaseCRL4(CRBN)E3ligaseCRL4(CRBN)E3ligaseCRL4(CRBN)E3ligaseCRL4(CRBN)E3ligaseB)InhibitingtheproteasomeE3ligaseBortezomib(Velcade®)D)InhibitingUbcoderecognitionSignalpropagationSignalpropagationA)InhibitingE1,E2,E3orDUBsSubstraterecognitionActivecentersDUBNewsubstrateDNArepairK6,K27,K33,K63Substrate:H1-typehistoneUb-receptor:Rnf186,Rap80,BRCA1,53BP1EndocytosisMultimonoUb,K63Substrates:EndocyticcargoUbreceptors:Eps15,Epsin,Sts-1/2,Hrs,Stam2MitophagyK6,K11,K63,pS65-K63pS65-monoUbSubstrates:MOMproteinsUbreceptors:autophagyadaptorsp62,NBR1,optineurinNF-kBsignalingK63andM1Substrates:RIP,NemoUbreceptors:Nemo,Tab2/3ProteasomaldegradationK48,K11,K29,(K63)Substrates:ProteinsdestinedfordegradationReceptors:Rpn10,Rpn13,Dss1,Rad23,Dsk2,andDdi1Cell-cycleregulationK11/48branchedSubstrate:Nek2AReceptors:ProteasomeERADK11andK48Substrates:MisfoldedproteinsUbreceptor:ProteasomeXenophagyK63Substrates:ProteinssurroundingpathogenUbreceptors:autophagyreceptorsp62,NBR1,optineurinPost-golgitraffickingK33Substrate:Cm7Ubreceptor:Eps15I36patchI36,L71,L73I44patchL8,I44,H68,V70F4patchQ2,F4,T14TEK-boxK6,K11,T12,T14,E34C-terminaltailUb-bindingdomains(UBDs)recognizedifferentsurfacepatchesonUb,linkerregions,orthe(free)C-terminaltailUbreceptorUBDLinktopathway-specificeffectorsSubstrateSubstrateSubstrateSubstrateUbUbUbUbUbUbSubstrateSubstrateSubstrateSubstrateSubstrateSubstrateSubstrateSubstrateSubstrateSubstrateE1/E2enzymesE3ligases(enzymaticHECT-type;non-enzymaticU-BoxorRING-type)NHODUBsMulti-monoubiquitination“Writers”“Erasers”Poly-ubiquitinationK11-linkageHomotypicchains(8distincttypes)Heterotypicchains(numerousvariations)S65-phosphorylatedAcetylatedBranchedMixedK27-linkageK29-linkageK33-linkageK48-linkageK63-linkageM1-linkageK6-linkagePost-translationallymodifiedubiquitin...NH2SubstrateUbSubstrateSubstrateUbUbUbUbUbUbUbUbUbUbUbUbUbUbUbUbUbSubstrateUbU...
