DisorderedProteinKinaseRegionsinRegulationofKinaseDomainCoresGergőGógl1,AlexandrP.Kornev2,AttilaReményi1,*,andSusanS.Taylor2,3,*1InstituteofEnzymology,ResearchCenterforNaturalSciences,HungarianAcademyofSciences,Budapest,Hungary2DepartmentofPharmacology,UniversityofCaliforniaSanDiego,9500GilmanDrive,LaJolla,SanDiego,CA92093-0654,USA3DepartmentofChemistryandBiochemistry,UniversityofCaliforniaSanDiego,9500GilmanDrive,LaJolla,SanDiego,CA92093-0654,USAAbstractSincepublicationofthecrystalstructureofproteinkinase(PK)Athreedecadesago,astructuralportraitoftheconservedkinasecorehasbeendrawn.Thenextchallengeistoelucidatestructuresoffull-lengthkinasesandtoaddresstheintrinsicallydisorderedregions(IDRs)thattypicallyflankthecoreaswellasthesmalllinearmotifs(SLiMs)thatareembeddedwithintheIDRs.Itisincreasinglyapparentthatunstructuredregionsintegratethekinasecatalyticchassisintomultienzyme-basedregulatorynetworks.Theextracellularsignal-regulatedkinase-ribosomalS6PK-phosphoinositide-dependentkinase(ERK-RSK-PDK)complexisanexcellentexampletodemonstratehowIDRsandSLiMsgoverncommunicationbetweenfourdifferentkinasecatalyticcorestomediateactivationandhowinmoleculartermsthesepromotetheformationofkinaseheterodimersinacontextdependentfashion.KinaseDomainCoresversusIntrinsicallyDisorderedLinkersProteinkinases(PKs)aremetabolicswitchesthatregulatecellularsignaling.TheycatalyzephosphoryltransferfromATPtoaminoacidsidechainsoftheirproteinsubstrates.Incontrasttometabolicenzymes,whichevolvedtobeefficientcatalysts,PKshaveevolvedtobesensitivemolecularswitches[1].Inmostcases,theyareactivatedbyphosphorylation,andthenphosphorylatedownstreamsubstrateproteins.PKsrarelyactalone,astheyarepartofhierarchicallyorganizedcascadesormoreintertwinedkinasenetworks.Althoughweknowlittleabouthowkinasesareactivatedbyotherkinases,itcannotbeoverstatedhowimportantkinase-kinasecomplexesareincontrollingcellularphysiology.Welackstructuralinformationonhowkinaseheterodimersassemble,asthesecomplexesarehighlydynamicandaretypical...
