神经营养素信号通路

NeurotrophinSignaling

(TrkSignalingPathway)1神经营养素信号通路5/9/2024NeurotrophinsTheneurotrophinsareafamilyofproteinsthatareessentialforthedevelopmentofthevertebratenervoussystem.NGF–NervegrowthfactorBDNF–Brain-derivedneurotrophicfactorNT3–Neurotrophin3NT4–Neurotrophin42神经营养素信号通路5/9/2024FunctionAclassofgrowthfactors,secretedproteinsthatarecapableofsignalingparticularcellstosurvive,differentiate,orgrow.Growthfactorssuchasneurotrophinsthatpromotethesurvivalofneuronsareknownasneurotrophicfactors.Secretedbytargettissueandactbypreventingtheassociatedneuronfrominitiatingprogrammedcelldeath(PCD)-thusallowingtheneuronstosurvive.Neurotrophinsalsoinducedifferentiationofprogenitorcells,toformneurons.PDB1SG13神经营养素信号通路5/9/2024Chao

MV.20044神经营养素信号通路5/9/2024BiogenesisTheneurotrophinsareinitiallysynthesizedasprecursorsorpro-neurotrophins,whicharecleavedtoproducethematureproteins.(ProNGF->NGF)Pro-neurotrophinsarecleavedintracellularlybyFURINorpro-convertasesatahighlyconserveddibasicamino-acidcleavagesitetoreleasecarboxy-terminalmatureproteins.Thematureproteins:about12kDainsize,formstable,non-covalentdimers,normallyexpressedatverylowlevelsduringdevelopment.Theamino-terminalhalf(orpro-domain)ofthepro-neurotrophinisbelievedtobeimportantfortheproperfoldingandintracellularsortingofneurotrophins.5神经营养素信号通路5/9/2024NeurotrophinReceptorsEachneurotrophincansignalthroughtwodifferenttypesofcellsurfacereceptorTrkreceptortyrosinekinasesp75neurotrophinreceptor(p75NTR).Transmembranereceptor,alsoknownasTNFRSF16.amemberofthetumournecrosisfactorreceptor(TNFR)death-receptorfamily.6神经营养素信号通路5/9/2024ModelsofTrkandp75receptorDifferentneurotrophinsshowbindingspecificityforparticularreceptors.Theseinteractionshavegenerallybeenconsideredtobeofhighaffinity.However,inreality,thebindingofNGFtoTrkA,andofBDNFtoTrkBisoflowaffinity,butitcanberegulatedbyreceptordimerization,structuralmodificationsorassociationwiththep75receptor.Chao

MV.20047神经营养素信号通路5/9/2024Thep75receptorcanbindtoeachneurotrophin,andalsoactsasaco-receptorforTrkreceptors.Expressionofp75canincreasetheaffinityofTrkAforNGFandcanenhanceitsspecificityforcognateneurotrophins.Asaresult,increasedligandselectivitycanbeconferredontheTrkreceptorsbythep75receptor.Chao

MV.20048神经营养素信号通路5/9/2024CrystalStructureoftheReceptorComplexbetweenTrkAandp75SecondarystructureSymmetry9神经营养素信号通路5/9/2024ModelsofTrkandp75receptorTrkreceptorscontainextracellularimmunoglobulinG(IgG)domainsforligandbindingandacatalytictyrosinekinasesequenceintheintracellulardomain.Theextracellularportionofp75containsfourcysteine-richrepeats,andtheintracellularpartcontainsadeathdomain.Neurotrophinbindingtothep75receptormediatessurvival,cellmigrationandmyelinationthroughseveralsignallingpathways.Chao

MV.200410神经营养素信号通路5/9/2024Theratioofreceptorsisimportantindictatingthenumbersofsurvivingcells.Interactionsbetweenp75andTrkreceptorsprovidegreaterdiscriminationbetweendifferentneurotrophins.11神经营养素信号通路5/9/2024112神经营养素信号通路5/9/2024Theinteractionofp75NTRwithTrkAenhancestheresponsivenessofTrkAtonervegrowthfactor(NGF)topromotesurvivalandgrowth.b,Incontrast,whenboundtounprocessedNGF(proNGF),acomplexofp75NTRandsortilininducescelldeath.Nykjaeretal.2004&200813神经营养素信号通路5/9/2024HowcouldNGFpromotesurvivalthroughTrkAanddeaththroughp75NTR—sometimesinthesamecelltype?

Nykjaeretal.2004&200814神经营养素信号通路5/9/2024Thefunctionofp75NTRdependsonthecellularcontext;activationofp75NTRpromotesdeathinnumerouscells,includinginjuredneurons,butpromotesmigration,growthandsurvivalinothercells.Inthenextdevelopment(2008),NGFwasfoundtoexistinbothunprocessed('pro')andmatureforms.OnsomecellsthematureNGFpreferentiallyactivatesTrkA,whereasproNGFonlyactivatesp75NTR.Importantly,proNGFismuchmoreefficientthanNGFatinducingthedeathofresponsivecells,leadingtospeculationthatthenatureoftheNGFitselfisakeydeterminantoftheultimateoutcomeofp75NTRactivation.Nykjaeretal.2004&200815神经营养素信号通路5/9/2024SometimesCREBphosphorylationrequiresactivationandendocytosisofTrKAlocatedattheaxonterminals.distalaxonsaresometimesmorethanonemeterawayfromthecellsoma;Totransmitthesignaloveralongdistance,neurotrophinsandactivatedTrksaretransportedtogetherinendocyticvesiclestothecellsoma.16神经营养素信号通路5/9/2024InternalizationandsignalingisregulatedbypolyubiquitinationofLys485ofTrkA.ThangiahGeetha,JianxiongJiang,MarieW.Wooten.2005TRAF6(TNFreceptorassociatedfactor)Ub(Ubiquitin)–Proteasomepathwayofproteindegradation17神经营养素信号通路5/9/2024Ubiquitinproperties(human)Lys-11orLys-48:

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