信号分子与信号转导SignalingTransduction02课件

ClassificationofphosphataseaccordingtotheAminoacidsequenceinactivecenterSer/Thr

phosphatase

TyrphosphataseDualspecificity

Ⅱ.Gprotein/smallGproteinguaninenucleotidebindingprotein，Gprotein（鸟苷酸结合蛋白）亦称GTP结合蛋白

asignalmoleculeinvariouspathways,functioningdifferentlyindifferentcellsTwoformsofGproteinGproteinbindingwithGTP:itsactiveform

GTPhydrolysedtoGDP:inactiveform

2typesofGprotein：Hetero-trimerG

protein:（Gα）,β,γ(Gβγ)

bindingwithreceptorwith7transmembrane

dormains，SmallG

protein(21kD）

Theactivation/deactivationcycleforhormonallystimulatedadenylatecyclaseGprotein-coupledreceptors，GPCRs

Ligand-GPCRs–Gprotein-（AC,PLC…)-cellfunction

TheroleofPIP2inintracellularsignalingFactorscontrolsmallGproteinact.Factorincreasingact.：guaninenucleotideexchangefactor(GEF)

guaninenucleotidereleaseprotein(GNRP)Factordecreasingact.：guaninenucleotidedissociationinhibitor(GDI)

GTPaseactivationprotein(GAP)

RasactivationanditsregulatorsGTPGDPRasRasSOSGAPonoffSummaryofSection3ProteinsarethemaincomponentsofsignalingpathwaysProetin

kinasesandphosphotasesaretheswitchinsignalingpathways.GproteinandsmallGproteinarefunctionastheirbindingwithGTP/GDPⅠ.SignalingComplexanditscharacterProteinswon’tseparatedeachotherincells

butaggregated

Proteincomplex-functioninginlife1.Signalingcomplexensurestheefficiency,precision,varietyPriority:①directlycontact，efficency,precision②amplification③collaboration,variety④complex,multiple

2.SignalingcomplexexistsatmembraneandcytoskeletonstructureProteincomplex–

existedinmembranestructureorcellskeletoncompartmentation。3.ComponentsofcomplexchangesdependedonexogenoussignalsDynamicstate:thecomponentsandformationofsignalcomplexdependedonexogenoussignals

Significance:withdrewligand-stopsignaingimmediatelyreutilizationofsignalmolecules,saveenergyⅡ.Dt-protinteraction–mediatedbydomainsCharacterofproteininteractiondomain(PID)①onemoleculecontains≥twoPID②samedomainexistedinvariousproteins,butsequencearenotexactlysame

–bindingspecificity③PID

doesn’thaveenzymeactivity,justbindingPIDrecognizedmotifSrchomology2SH2Tyr-PiSrchomology3SH3ProrichpleckstrinhomologyPHPhospholipidderivationProteintyrosinebindingPTBTyr-PiWWWWProrichDomainanditsrecognizedmotif2.Srchomology2(SH2)domainSrchomology2domain:SH2domianFunction:therecognizedmotifisphosphorylatedtyrosineandneighboringaminoacids

DifferentproteincontainsdifferentSH2-selectivity3.SH3DomainSrchomology2domain:SH3domianFunction:therecognizedmotifisproline-rich(9-10Pro)sequenceⅢ.adaptorproteinsandscaffoldingproteinsadaptorproteinakindofmediatorprotein,Linkone,upstreamprot.,toanother,downstream

role：recruitandorganizethecomplex

Mostadaptorproteinscontaintwodomains,nootherspecialdomain

1.adaptorproteinAdaptorproteinNckSH2CNSH3SH3SH3HGFR,VEGFR,BCR-AblPDGFR,EphB1SLP-76,HPK1,p130casIRS-1,p62doc

CKIg2,WASP,IRS-1,DOCK180,NIKIRS-1,DOCK180,Sos,NIK,Pak1,Pak3,NAP4,WIP,dynamin,synaptojanin、Abl,c-CblAbl,c-Cbl,NAP1,Sam68Section5GeneralSignalPathwaysMediatedbyMembraneReceptors

膜受体介导的基本信号转导通路

3typesofmembraneboundreceptor：Ionchannelreceptor(ICR)G-proteincouplingreceptor(GPCR)Singletransmembranereceptor

(STMR)ICRGPCRSTMR内源性配体神经递质神经递质、激素、趋化因子、外源刺激（味，光）生长因子细胞因子结构寡聚体形成的孔道单体具有或不具有催化活性的单体跨膜区段数目4个7个1个功能离子通道激活G蛋白激活蛋白酪氨酸激酶细胞应答去极化与超极化去极化与超极化调节蛋白质功能和表达水平调节蛋白质的功能和表达水平，调节细胞分化和增殖Charactersof3typesreceptorsⅠ.IonChannelReceptorstructurallyachannel,openorclosepassthroughion,

ligand-gatedreceptorchannelLigand:neurotransmittermainly

AcetylcholinereceptorAcetylcholineBindingSiteIonchanneloverlooksidelook

TheroleofAcetylcholinIonchannelmemb.electricpotentialchangechemicalsignalformationcellfunctionIonchannel

Cationchannel:AcetylCholine,Glutamicacid,5-Hydroxytrypotamine

Anionchannel:Glycine，γ-aminobutylicacidⅡ.G-proteincouplingreceptor–secondmessenger-targetmoleculesGPCR:

bindingGproteinwithtri-subunitactivateGproteinGPCR

aserpentinereceptor,7transmembraneG蛋白偶联区1.G-proteinactivationinitiatessignalingModeloftransductionviaG-protein：①ligandreceptorbinding②receptoractivatesG-protein③G-proteinact.orinh.targetprtoein④changesecondmessengerlevelordistribution,⑤secondmessengeraffectsitstargetmoleculeconformationalchange

G-proteincycle2.ActivatedG-proteinaltersactivityoftargetmole.活化的G蛋白的α亚基主要作用于生成或水解细胞内第二信使的酶，如AC、PLC等效应分子（effector），改变它们的活性，从而改变细胞内第二信使的浓度。可以激活AC的G蛋白的亚基称为s（s代表stimulate）；反之，称为i（i代表inhibit）。GáEffectivemole.Messengeincyto.Targetmole.asAC↑cAMP↑PKA↑aiAC↓cAMP↓PKA↓aqPLC↑Ca2+、IP3、DAG↑PKC↑atcGMP-PDE↑cGMP↓Na+Chan.↓Gasubunitanditseffect

3.Glucagonreceptor-AC-cAMP-PKApathwaysAdrenocorticotrophin(ACTH)Melanotrophin(MSH)Corticoliberin(CRH)OlfactionmoleculeDopamineParathyrinAdrenalineProstaglandinE1,E2Glucagon5-HT（1a）、5-HT（2）Histamine（H2receptor）SomatostadinLutropin(LH)TastemoleculeSignalsactsbyAC-cAMP-PKApathways4.AngiotensinIIreceptor-PLC-IP3/DAG-PKCAngiotensinIIreceptorisaGCPR

q

→

PLC-IP3/DAG-PKC

pathwayAcetylCholine[M1]light(fruitfly)5-HT（1c）ATPGastrinreleasingpeptideThyrotropinreleasinghormone(TRH)AdrenergicagonistGlutaminevasopressin-antidiuretichormoneAngiotensinIIgonadotrophinreleasainghormone(GRH)histamine[H1receptor]SignalsactsbyPLC-IP3/DG-PKC此外，由于G蛋白亚型的不同，形成多种其他通路和效应，如PDE-cGMP-Na+通道信号转导通路、PLC-IP3-Ca2+/CaM-PK信号转导通路等。Ⅲ.Enzymecouplingreceptor-proteinkinasekinase–proteinkinase–targetmole酶偶联受体指那些自身具有酶活性，或者自身没有酶活性，但与酶分子结合存在的一类受体。这些受体大多为只有1个跨膜区段的糖蛋白，亦称为单跨膜受体。酶偶联受体种类繁多，但是以具有PTK活性和与PTK偶联的受体居多。常见的酶偶联受体：受体型蛋白酪氨酸激酶（receptorstyrosinekinases，RTKs）蛋白酪氨酸激酶偶联受体（tyrosinekinase-coupledreceptors，TKCRs）受体型蛋白酪氨酸磷酸酶（receptorstyrosinephosphatases，RTPs）受体型蛋白丝/苏氨酸激酶（receptorsserine/threonine

kinase，RSTK）受体型鸟苷酸环化酶（receptorsguanylate

cyclases，RGCs）酶偶联受体大部分是生长因子和细胞因子的受体，它们所介导的信号转导通路主要是那些调节蛋白质的功能和表达水平、调节细胞增殖和分化。1.PTKcouplingreceptor:similarmodelPTKcouplingreceptor主要通过蛋白质相互作用激活自身或细胞内其他的PTK或丝/苏氨酸激酶来转导信号。PTK偶联受体介导的信号转导途径的基本模式：①结合配体后受体形成二聚体或寡聚体；②第一个蛋白激酶被激活。对于具有蛋白激酶活性的受体来说，此步骤是激活受体胞内结构域的蛋白激酶活性；对于没有蛋白激酶活性的受体来说，此步骤是受体通过蛋白质-蛋白质相互作用激活与它紧密偶联的蛋白激酶；③通过蛋白质-蛋白质相互作用或蛋白激酶的磷酸化修饰激活下游信号转导分子，通常是继续活化下游的一些蛋白激酶；④蛋白激酶通过磷酸化修饰激活代谢途径中的关键酶、反式作用因子等，影响代谢途径、基因表达、细胞运动、细胞增殖等。表皮生长因子受体作用机制：2.EGFRsignalingpathway:Ras→MAPK表皮生长因子受体（epidermalgrowthfactorreceptor,EGFR）是一个典型的受体型PTK。Ras→MAPK途径是EGFR的主要信号通路之一。EGFR介导的信号转导过程3.OtherspathwaysthanenzymecoupingreceptorT细胞抗原受体、B细胞抗原受体、肥大细胞表面的IgE受体属于酶偶联受体，它们自身不具备蛋白酪氨酸激酶活性；非受体型的Src家族蛋白酪氨酸激酶和ZAP70家族蛋白酪氨酸激酶是这一类受体的直接信号转导分子。下游分子包括PLCγ、MAPK家族的活化，并有多种衔接蛋白参与。大部分白细胞介素（interlukin,IL）受体属于酶偶联受体。通过JAK（JanusKinase）-STAT（signaltransducerandactivatoroftranscription）通路转导信号。细胞内有数种JAK和数种STAT的亚型存在，分别转导不同的白细胞介素的信号。白介素介导的信号转导途径转化生长因子β（transformgrowthfactorβ,TGFβ）受体属于单次跨膜受体，自身具有蛋白丝氨酸激酶催化结构域。受体活化后通过信号分子Smad介导的途径调节靶基因转录，影响细胞的分化。细胞内有数种Smad存在，参与