Histidine protein kinases key signal transducers outside the animal kingdom.docx

Histidine protein kinases key signal transducers outside the animal kingdom.docx

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Histidineproteinkinaseskeysignaltransducersoutsidetheanimalkingdom

Proteinfamilyreview

Histidineproteinkinases:

keysignaltransducersoutsidetheanimalkingdom

PeterMWolanin1,PeterAThomason1andJeffryBStock12*

∙*Correspondingauthor:

JeffryBStockjstock@princeton.edu

AuthorAffiliations

1DepartmentofMolecularBiology,PrincetonUniversity,Princeton,NJ08544,USA

2DepartmentofChemistry,PrincetonUniversity,Princeton,NJ08544,USA

Forallauthoremails,pleaselogon.

GenomeBiology2002,3:

reviews3013-reviews3013.8 doi:

10.1186/gb-2002-3-10-reviews3013

Theelectronicversionofthisarticleisthecompleteoneandcanbefoundonlineat:

Published:

25September2002

©2002BioMedCentralLtd

Summary

Histidineproteinkinases（HPKs）arealargefamilyofsignal-transductionenzymesthatautophosphorylateonaconservedhistidineresidue.HPKsformtwo-componentsignalingsystemstogetherwiththeirdownstreamtargetproteins,theresponseregulators,whichhaveaconservedaspartateinaso-called'receiverdomain'thatisphosphorylatedbytheHPK.Two-componentsignaltransductionisprevalentinbacteriaandisalsowidelyusedbyeukaryotesoutsidetheanimalkingdom.ThetypicalHPKisatransmembranereceptorwithanamino-terminalextracellularsensingdomainandacarboxy-terminalcytosolicsignalingdomain;most,ifnotall,HPKsfunctionasdimers.Theyshowlittlesimilaritytoproteinkinasesthatphosphorylateserine,threonineortyrosineresidues,butmayshareadistantevolutionaryrelationshipwiththeseenzymes.InexcessofathousandknowngenesencodeHPKs,whichareimportantformultiplefunctionsinbacteria,includingchemotaxisandquorumsensing,andineukaryotes,includinghormone-dependentdevelopmentalprocesses.Theproteinsdivideintoatleast11subfamilies,onlyoneofwhichispresentineukaryotes,suggestingthatlateralgenetransfergaverisetotwo-componentsignalingintheseorganisms.

Geneorganizationandevolutionaryhistory

Histidineproteinkinases（HPKs）,togetherwiththeirpartnerresponseregulators,areundoubtedlythemostwidelyusedofallsignal-transductionenzymesinnature.Theyarepresentinallthreemajorkingdomsoflife（theBacteria,ArchaeaandEukarya）[1,2],andfunctioninthesensingofacell'sexternalenvironment[3].Forunicellularorganismsthisusuallyequatestosensingnutrients,chemoattractants,osmoticconditionsandsoon.HPKsarealsoresponsibleforcoordinatingthebehaviorofcellpopulations.Inbacteriathistakestheformofquorumsensing[4].InEukarya,whereHPKsappeartobeconfinedtoplantsandtofree-livingorganisms,suchasyeasts,fungiandprotozoa,HPKshaverolesinregulatinghormone-dependentdevelopmentalprocesses[5];forexample,HPKsareresponsiblefortransducingtheeffectsofthehormoneethyleneinplants[6],andforcoordinatingthedevelopmentofthefruitingbodyoftheslimemoldDictyosteliumdiscoideum[5].NoHPK（orresponseregulator）genesarepresentinthecompletedgenomesequencesofCaenorhabditiselegans[7],Drosophilamelanogaster[8],orHomosapiens[9],anditisthoughtthattheseenzymesareabsentfromtheanimalkingdomasawhole.

HPKs（andresponseregulators）probablyaroseinbacteriaand,withfewexceptions,arefoundinallbacterialspecies[2],whichhaveawidevariationofHPKgenenumbers:

forexample,theEscherichiacoliandBacillussubtilisgenomesbothcontainabout25HPKgenes;incontrast,HelicobacterpylorihasonlyfourHPKs,andthethreeMycoplasmaspecieswhosegenomeshavebeensequenced（M.genitalium,M.pneumoniae,andM.pulmonis）areamongtherareexceptionswithnoHPKgenes.TherearewelloverathousandHPKgenescurrentlyinsequencedatabases,andHPKgenesarefoundmuchlessfrequentlyinarchaeaandeukaryotesthaninbacteria.HPKproteinscanbedividedbysequenceanalysisinto11subfamilies,andvirtuallyalleukaryoticHPKsbelongtoasinglesubfamily[1].This,andtherelativescarcityofHPKgenesinarchaeaandeukaryotes,supportsthenotionthatHPK（andresponseregulator）genesarrivedineukaryotesandarchaeabylateralgenetransferfrombacteria.

Inprokaryotes,thegenesforcognatepairsofHPKsandresponseregulatorsaretypicallyfoundtogetherinasingleoperon,suchastheEnvZ-OmpRsystemthatcontrolsosmosensinginE.coli[3].Thefunctionalrelationshipbetweenthesesignalingpartnersisthereforereflectedintheirgeneorganization.Cross-regulationofaresponseregulatorbyadditionalhistidinekinasesdoesoccur,however.Forinstance,theOmpRresponseregulatorreceivesphosphateinvivonotonlyfromitscognateHPKEnvZ,butalsofromtheArcBhistidinekinase[10],althoughtheArcBandOmpRgenesarenotonthesameoperon.

Ineukaryotes,HPKandreceiverdomains,containingtheaspartatethatisphosphorylatedbytheHPK,aregenerallyencodedwithinasinglegene,whereasinbacteriathereceiverdomainispartoftheresponseregulator.EukaryoticHPKproteinsthereforecontainbothelementsofthetraditionaltwo-componentpathway,andarereferredtoas'hybridkinases'.Suchhybridkinases,whilepredominatingineukaryotes,areonlyasmallminorityamongprokaryoticHPKs;allhybridHPKs（botheukaryoticandprokaryotic）belongtoasubdivisionoftheHPK1genefamily,oneofthe11HPKfamilies（Figure1）[1].

Figure1.Conservedsequencemotifsinthe11histidineproteinkinasesubfamilies.（a）MotifsrepresentativeofconservedsequencesintheHPK1family,whichincludesamajorityofallHPKs,includingalleukaryoticHPKs[1].（b）TherelativepositionsoftheconservedmotifsinarepresentativeHPK（E.coliEnvZ）.Regionsknownorpredictedtobeαhelicalareshownasrectangles,andβsheetsasarrows[14,21].TheconservedregionsthatmakeuptheHPKcore,designatedtheH,N,D,FandGboxes（showninblue）,typicallyspanapproximately200residuesintotal[1,19].HAMPisalinkerdomain,andTM1andTM2aretransmembranehelices.Sequencealignmentsof（c）theHbox,（d）theNbox,（e）theDandFboxes,and（f）theGboxforonerepresentativememberofeachofthe11HPKsubfamilies（exceptfortheHPK1family,whereonememberofHPK1aandonememberofHPK1bareshown）.Theproteinsusedtomakethisalignmentwere:

HPK1a,PseudomonasaeruginosaKinB（595aminoacidsintotal）;HPK1b,E.coliTorS（914aminoacids）;HPK2,E.coliEnvZ（450aminoacids）;HPK3,E.coliPhoQ（486aminoacids）;HPK4,E.coliNtrB（349aminoacids）;HPK5,E.coliDcuS（543aminoacids）;HPK6,Archaeoglobusfulgidusg2648416（607aminoacids）;HPK7,E.coliNarQ（566aminoacids）;HPK8,E.coliYehU（561aminoacids）;HPK9,E.coliCheA（654aminoacids）;HPK10,StreptococcuspneumoniaeComD（441aminoacids）;HPK11,Methanobacteriummth292（564aminoacids）.Theregionschosenforthesealignmentsweretakenfromsubfamily-specificalignmentscarriedoutinoneofourpreviousstudies[1],andareindicatedinparentheses.SequenceswerealignedusingClustalW.Tosimplifythealignment,a25amino-acidregionofHPK9wasremovedintheD-boxregion（indicatedbyanopensquare）,anda3amino-acidregionofHPK8wasremovedintheG-boxregion（indicatedbyafilledsquare）.HPK9doesnotcontainanHboxinitsdimerizationdomain,soHPK9wasleftoutoftheH-boxalignment.HPK7andHPK8donotcontainanFbox.TheHPK11subfamilycontainsapartiallyconservedFbox,buttheexampleusedforthisalignmentdoesnot.Highlyconservedresidues（thosepresentinamajorityofthesubfamilies）areshownboxedindarkblue,andaconsensussequenceispresentedbelowthealignedsequences;positionscontainingchemicallysimilarresiduesareshownboxedinlightblueandindicatedbyadotintheconsensussequence.

Characteristicstructuralfeatures

HPKscatalyzethetransferofphosphatefromATPtoauniquehistidineresidue,andallHPKshaveaconservedATP-bindingcatalyticdomainthatisrequiredforkinaseactivity.Thiscatalyticdomain,togetherwithadimerizationdomain,formsthekinasecore.TheHPKsareclassifiedinto11subfamiliesonthebasisofthesequencesofthesetwocoredomains[1].Figure1showsasequencealignmentofthecoredomainswitharepresentativeofeachsubfamily.

Thecoredomains

Histidinekinaseactivitydependsonhomodimerformation,withthedimerizationdomains,whichhavetwo-strandedcoiled-coils,comingtogethertoformafour-helixbundle[11,12].ItcanbeseeninFigure1that,exceptforthehpk9family（theCheAfamily）,thedimerizationdomainincludesamotif,knownastheH-box,whichcontainsthesiteofautophosphorylation.Asinthecaseoftyrosineproteinkinases,suchastheinsulinreceptor,HPK-mediatedautophosphorylationappearstooccurintrans,withthecatalyticdomainofonesubunitinadimerphosphorylatingtheH-boxhistidineintheopposingsubunit[3].ManyHPKsalsohavephosphataseactivitywhichdephosphorylatestheresponseregulatorandopposeskinasefunction[3,13]（fordetailsseetheMechanismsection）;phosphataseactivityismediatedbythedimerizationdomainintheseHPKs.

ThecatalyticdomainofHPKshasclearsequenceandstructuralhomologytotheATP-bindingdomainsoftypeIItopoisomerases（suchasGyrB）,themismatchrepairproteinMutL,andtheheat-shockproteinHsp90[14,15,16].Thesedomainsformafamilywithaconservedstructureofseveralαhelicespackedoveronefaceofalarge,mostlyantiparallel,βsheet,formingaloopthatclosesovertheboundATP（the'ATPlid'）.TheATPlidandtheentireATP-bindingsitearepoorlyorganizedintheabsenceofATPorATPanalogs[14,15,17].Asubstantialorderingofstructureandotherconformat