The role of FYVEfinger proteins in vesicle transport

Eukaryoticcellstakeupconstituentsoftheextra-cellularenvironmentandregulatethecell-surfacelevelofmembraneproteinsviaarecyclingsystemofmembranevesiclescalledendosomes.Whencellsaretakingupelementsfromthecell-surfaceitiscalledendocytosis,andwhentheyaredeliveredtothecell-surfaceitiscalledexocytosis.Thetransferrinreceptor(TfR)isoftenemployedasamodelproteinforstudyingthisprocess.Thetransferrinreceptormediatesuptakeofironbybindingdiferrictransferrin(Tf-2Fe++)fromtheplasma.Endocytosisofthereceptorisinitiatedbytheformationofaclathrin-coatedpitinthecellmembrane,whichsubsequentlyformstheprimaryendosomeandthenfuseswiththeearlyendosome.ThelumenofanearlyendosomehasaslightlyacidicpH,whichenablestheionstobereleased.Theionsmovetothecytosolandthereceptor-apotransferrin(Tf)complexissortedforrecyclingbacktothecellmembraneinrecyclingendosomes.Atthecellsurfacetheapotransferrinisreplacedwithdiferrictransferrinandthecyclerepeats(1;2).Whetheraendocytosedproteinisrecycledornotisdeterminedbyasortingprocessinitiatedintheearlyendosome.Theearlyendosomeisthefirstorganellealongtheendo-lysosomalpathwayanditisthemajorsortingstation.Internalizedmembraneproteinscaneitherbesortedforrecyclingfromtheearlyendosomebyafastroute(e.g.TfR(3))ormakeittothelateendosomeandrecyclebyaslowroute(e.g.angiotensinreceptor,AT1R(4))orberetainedinthelateendosomeanddirectedtothelysosomefordegradation(e.g.epidermalgrowthfactorreceptor,EGFR(5)).Theearlyendosomehasbeensuggestedtoturnintoamulti-vesicularlateendosomethroughamaturationprocessthatchangesitsbiochemicalcompositionandmorphology.Thelateendosomeisfollowedbythelysosome,whichistheterminalorganelleontheendocyticpathwayandisdevoidofrecyclingreceptors.Thelysosomehasaveryacidicenvironmentandcontainsproteases(1;6).Vesiculartraffickingandpropersortingofinternalizedproteinsrequiretherecruitmentofcytosolicproteinstoaspecificendosomalmembraneinareversibleandregulatedmanner.Manyproteinsbecomereversiblylocalizedtomembranesthroughinteractionwithspecificlipidheadgroups.Phosphatidylinositol3-phosphate(PI3P)isaminorPI3Kproductthatisconstitutivelyproducedandspecificallylocalizetoearlyendosomesandseveralproteinsbindspecificallytoitsheadgroup(7;8).TheseproteinsallhaveadomaincalledaFYVE-fingerwhichbindstoPI3P(9-11).Itisacysteine-richdomainreminiscentofazincfingerwitheightconservedcysteines,whichcoordinatetwoZincions,andseveralotherconservedresidues,(SchwabeandKlug,1994;Stenmarketal.,1996).ThemotifisnamedFYVE-fingeraftertheproteinsinwhichitoriginallywasfoundnamely,Fab1p,YOTB,Vac1pandEEA1(12).TwoFYVEfingerproteinsimportantinvesicletransportareillustratedinthispathway.Thefirstandmostwellstudiedistheearlyendosomalautoantigen(EEA1).Itisaproteininvolvedinfusionofprimaryendosomeswithearlyendosomes(13).EEA1isalargecoiled-coilproteinthatcontainsaC-terminalFYVE-fingerandtwodomainsthatbindtotheactive,GTP-boundformoftheearly-endosomalGTPaseRab5(14).OneofthesedomainsisadjacenttotheFYVE-finger,whereastheother,aC2H2-typezincfinger,isfoundattheNterminus(13;15).TheCterminusofEEA1,containingoneRab5-bindingdomainandtheFYVE-finger,isnecessaryandsufficientforspecifictargetingofEEA1toearlyendosomes,andthemembranebindingrequiresbothPI3KactivityandRab5:GTP(14;16).TherelativelylowaffinitiesoftheC-terminalRab5-bindingdomainforRab5:GTPandoftheFYVE-fingerforPI3Psecurethatunderphysiologicalconditions,EEA1isonlyrecruitedtomembranesthatcontainbothofthesecomponentsandRab5isrequiredonbothmembranesinorderforthefusiontotakeplace(17).ThesecondFYVEfingerproteininthispathwayisHRS.Itisalsopresentinearlyendosomalmembranesandisinvolvedinsortingofendocytosedproteins.Itbindsubiquitinatedproteinsandsortsthemintoclathrin-coatedmicrodomainsoftheearlyendosomes.HRShasadomainstructurewithaFYVEdomain,anN-terminalVHS-domain,anubiquitininteractingmotif(UIM),aproline-richdomain,twocoiled-coildomains(thesecondbindstotheSNAREproteinSNAP-25),andaC-terminalclathrininteractingdomain.Therearetwodifferentformsofclathrincoatsinendosomeswithdistinctlocalization,onethatisinvolvedinbuddingtoformrecyclingvesiclesandonewithaflatmorphology.HRSbindstotheflatclathrin,whichcausesitsspecificlocalizationinthesepartsoftheearlyendosome.HRSispreventingreceptorrecyclingbyrecruitingandconcentratingubiquitinatedproteinssuchastheEGFRintheearlyendosomes.Theubiquitinatedproteinsareretainedinthelateendosomeandpolyubiquitinatedproteinsaresubsequentlytransportedtothelysosomefordegradation(18).

Contributor:CharlottaGranas

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