1521-0081/72/2/380–413$35.00https://doi.org/10.1124/pr.118.015651PHARMACOLOGICALREVIEWSPharmacolRev72:380–413,April2020Copyright©2020byTheAuthor(s)ThisisanopenaccessarticledistributedundertheCCBY-NCAttribution4.0Internationallicense.ASSOCIATEEDITOR:RICHARDD.YEProteinEngineeringintheUbiquitinSystem:ToolsforDiscoveryandBeyondBoZhao,YienCheTsai,BoJin,BufanWang,YiyangWang,HanZhou,TomayaCarpenter,AllanM.Weissman,andJunYinEngineeringResearchCenterofCellandTherapeuticAntibody,MinistryofEducation,andSchoolofPharmacy,ShanghaiJiaoTongUniversity,Shanghai,China(B.Z.,B.J.,B.W.);DepartmentofPathophysiology,SchoolofMedicine,JinanUniversity,Guangzhou,China(Y.W.);LaboratoryofProteinDynamicsandSignaling,CenterforCancerResearch,NationalCancerInstitute,Frederick,Maryland(Y.C.T.,A.M.W.);andDepartmentofChemistry,CenterforDiagnosticsandTherapeutics,GeorgiaStateUniversity,Atlanta,Georgia(Y.W.,H.Z.,T.C.,J.Y.)Abstract.....................................................................................382SignificanceStatement......................................................................382I.Introduction.................................................................................382A.TheE1-E2-E3CascadeastheWriter,DeubiquitinatingEnzymeastheEditor,andUbiquitin-BindingDomainasReaderofProteinUbiquitinationSignals...................3841.E1:TheUbiquitin-ActivatingEnzyme.................................................3842.E2:TheUbiquitin-ConjugatingEnzyme...............................................3843.E3:TheUbiquitinLigase.............................................................3854.DeubiquitinatingEnzymes............................................................3855.Ubiquitin-BindingDomains...........................................................386B.PlatformsofProteinEngineering........................................................3861.DivergentVersusDirectedEvolution.................................................3862.ScreenVersusSelection...........................
