| UniProtSummary | FUNCTION:SwissProt:P05067#Thegamma-CTFpeptidesaswellasthecaspase-cleavedpeptides,includingC31,arepotentenhancersofneuronalapoptosis.
SIZE:770aminoacids;86943Da
SUBUNIT:Binds,viaitsC-terminus,tothePIDdomainofseveralcytoplasmicproteins,includingAPBBfamilymembers,theAPBAfamily,MAPK8IP1,SHC1and,NumbandDab1(Bysimilarity).BindingtoDab1inhibitsitsserinephosphorylation(Bysimilarity).AlsointeractswithGPCR-likeproteinBPP,FPRL1,APPBP1,IB1,KNS2(viaitsTPRdomains)(Bysimilarity),APPBP2(viaBaSS)andDDB1.Invitro,itbindsMAPTviatheMT-bindingdomains(Bysimilarity).AssociateswithmicrotubulesinthepresenceofATPandinakinesin-dependentmanner(Bysimilarity).Interacts,throughaC-terminaldomain,withGNAO1.Amyloidbeta-42bindsCHRNA7inhippocampalneurons.Beta-amyloidassociateswithHADH2.SolubleAPPbinds,viaitsN-terminalhead,toFBLN1.InteractswithCPEB1(Bysimilarity).
SUBCELLULARLOCATION:Membrane;Single-passtypeImembraneprotein.Note=Cellsurfaceproteinthatrapidlybecomesinternalizedviaclathrin-coatedpits.Duringmaturation,theimmatureAPP(N-glycosylatedintheendoplasmicreticulum)movestotheGolgicomplexwherecompletematurationoccurs(O-glycosylatedandsulfated).Afteralpha-secretasecleavage,solubleAPPisreleasedintotheextracellularspaceandtheC-terminalisinternalizedtoendosomesandlysosomes.SomeAPPaccumulatesinsecretorytransportvesiclesleavingthelateGolgicompartmentandreturnstothecellsurface.Gamma-CTF(59)peptideislocatedtoboththecytoplasmandnucleiofneurons.ItcanbetranslocatedtothenucleusthroughassociationwithFe65.Beta-APP42associateswithFRPL1atthecellsurfaceandthecomplexisthenrapidlyinternalized.APPsortstothebasolateralsurfaceinepithelialcells.Duringneuronaldifferentiation,theThr-743phosphorylatedformislocatedmainlyingrowthcones,moderatelyinneuritesandsparinglyinthecellbody.Caseinkinasephosphorylationcanoccureitheratthecellsurfaceorwithinapost-Golgicompartment.
TISSUESPECIFICITY:Expressedinallfetaltissuesexaminedwithhighestlevelsinbrain,kidney,heartandspleen.Weakexpressioninliver.Inadultbrain,highestexpressionfoundinthefrontallobeofthecortexandintheanteriorperisylviancortex-operculargyri.Moderateexpressioninthecerebellarcortex,theposteriorperisylviancortex-operculargyriandthetemporalassociatedcortex.Weakexpressionfoundinthestriate,extra-striateandmotorcortices.IsoformAPP695isthepredominantforminneuronaltissue,isoformAPP751andisoformAPP770arewidelyexpressedinnon-neuronalcells.IsoformAPP751isthemostabundantforminT-lymphocytes.Appicanisexpressedinastrocytes.
DOMAIN:SwissProt:P05067Thebasolateralsortingsignal(BaSS)isrequiredforsortingofmembraneproteinstothebasolateralsurfaceofepithelialcells.&TheNPXYsequencemotiffoundinmanytyrosine-phosphorylatedproteinsisrequiredforthespecificbindingofthePIDdomain.However,additionalaminoacidseitherN-orC-terminaltotheNPXYmotifareoftenrequiredforcompleteinteraction.ThePIDdomain-containingproteinswhichbindAPPrequiretheYENPTYmotifforfullinteraction.Theseinteractionsareindependentofphosphorylationontheterminaltyrosineresidue.TheNPXYsiteisalsoinvolvedinclathrin-mediatedendocytosis.
PTM:Proteolyticallyprocessedundernormalcellularconditions.Cleavagebyalpha-secretaseoralternativelybybeta-secretaseleadstogenerationandextracellularreleaseofsolubleAPPpeptides,S-APP-alphaandS-APP-beta,respectively,andtheretentionofcorrespondingmembrane-anchoredC-terminalfragments,C83andC99.SubsequentprocessingofC83bygamma-secretaseyieldsP3peptides.Thisisthemajorsecretorypathwayandisnon-amyloidogenic.Alternatively,presenilin/nicastrin-mediatedgamma-secretaseprocessingofC99releasestheamyloidbetaproteins,amyloid-beta40(Abeta40)andamyloid-beta42(Abeta42),majorcomponentsofamyloidplaques,andthecytotoxicC-terminalfragments,gamma-CTF(50),gamma-CTF(57)andgamma-CTF(59).&Proteolyticallycleavedbycaspasesduringneuronalapoptosis.CleavageatAsp-739byeithercaspase-6,-8or-9resultsintheproductionoftheneurotoxicC31peptideandtheincreasedproductionofbeta-amyloidpeptides.&N-andO-glycosylated.O-linkageofchondroitinsulfatetotheL-APPisoformsproducestheAPPproteoglycancoreproteins,theappicans.Thechondroitinsulfatechainofappicanscontains4-O-sulfatedgalactoseinthelinkageregionandchondroitinsulfateEintherepeateddisaccharideregion(Bysimilarity).&PhosphorylationintheC-terminalontyrosine,threonineandserineresiduesisneuron-specific.PhosphorylationcanaffectAPPprocessing,neuronaldifferentiationandinteractionwithotherproteins.PhosphorylatedonThr-743inneuronalcellsbyCdc5kinaseandMapk10,individingcellsbyCdc2kinaseinacell-cycledependentmannerwithmaximallevelsattheG2/Mphaseand,invitro,byGSK-3-beta.TheThr-743phosphorylatedformcausesaconformationalchangewhichreducesbindingofFe65familymembers.PhosphorylationonTyr-757isrequiredforSHCbinding.Phosphorylatedintheextracellulardomainbycaseinkinasesonbothsolubleandmembrane-boundAPP.Thisphosphorylationisinhibitedbyheparin.&Extracellularbindingandreductionofcopper,resultsinacorrespondingoxidationofCys-144andCys-158,andtheformationofadisulfidebond.Invitro,theAPP-Cu(+)complexinthepresenceofhydrogenperoxideresultsinanincreasedproductionofbeta-amyloid-containingpeptides.
DISEASE:SwissProt:P05067#DefectsinAPPareacauseofautosomaldominantAlzheimerdisease(AD)[MIM:104300].ADisthemostprevelantformofdementia,characterizedbyneurofibrillarytanglesandamyloidplaquesdepositioninthebrain.IdenticallesionsoccurintheneuronsofagedDownsyndromebutatanearlieragethaninAD.Themajorconstituentoftheseneuriticplaquesistheneurotoxicamyloid-beta-APP40-42peptide(s),derivedproteolyticallyfromthetransmembraneprecursorproteinAPPbysequentialsecretaseprocessing.Mutationsoccurringatthebeta-amyloidN-terminal,suchastheSwedishdoublemutation,appeartoincreaselevelsofbeta-amyloidbyfacilitatingbeta-secretasecleavageresultinginelevatedlevelsofbothbeta-APP42andbeta-APP40.ThecytotoxicC-terminalfragments(CTFs)andthecaspase-cleavedproductssuchasC31,arealsoimplicatedinADneuronaldeath.AlzheimerdiseasecausedbymutationsinAPPisarareoccurrenceandusuallycausesthefamilialorearly-onsetformofthedisease(FAD).Flemish-typeADischaracterizedby,inadditiontopreseniledementia,cerebralhemorrhagingduetocerebralamyloidangiopathywhichissimilarto,butdistinctfrom,cerebroarterialamyloidosisDutchtype.Onlyabout5%ofallcasesofAlzheimerdiseasearecausedbyFADmutations,therestaresporADIc.&DefectsinAPParethecauseofhereditarycerebralhemorrhagewithamyloidosisDutchtype(HCHWAD)[MIM:609065].HCHWADischaracterizedbyamyloiddepositsincerebralvessels.Theprincipalclinicalcharacteristicsarerecurringcerebralhemorrhages,sometimesprecededbymigrainousheadachesormentalcleavage.Beta-APP40isthepredominantformofcerebrovascularamyloid.&DefectsinAPParethecauseofhereditarycerebroarterialamyloidosisIowatype[MIM:605714].HereditarycerebroarterialamyloidosisIowatypeisanautosomaldominantdementiabeginninginthesixthorseventhdecadeoflife.Thepatientshaveprogressiveaphasicdementia,leukoencephalopathy,andoccipitalcalcifications.Theydonotpresentcerebralhemorrhaging.
SIMILARITY:BelongstotheAPPfamily.&Contains1BPTI/Kunitzinhibitordomain.
MISCELLANEOUS:Chelationofmetalions,notablycopper,ironandzinc,caninducehistidine-bridgingbetweenbeta-amyloidmoleculesresultinginbeta-amyloid-metalaggregates.Theaffinityforcopperismuchhigherthanforothertransientmetalsandisincreasedunderacidicconditions.Extracellularzinc-bindingincreasesbindingofheparintoAPPandinhibitscollagen-binding. |
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