免疫球蛋白的结构与功能的关系

免疫球蛋白的结构与功能的关系第一页，共五十二页，编辑于2023年，星期日SignallingantigenreceptorsonBcells-bifunctionalantigen-binding secretedmolecules（B细胞表面受体和分泌的抗体）Structuralconservationandinfinitevariability-domainstructure（结构上不仅保守而且无限可变的）.TheImmunoglobulinGeneSuperfamily（免疫球蛋白的超家族）Theimmunoglobulinfold（免疫球蛋白的折叠）Frameworkandcomplementaritydeterminingregions-hypervariable loops（框架结构和可变区）Modesofinteractionswithantigens（与抗原相互作用的模型）Effectormechanismsandisotype–roleoftheFc.（Fc区的作用）MultimericantibodiesandmultimerisationCharacteristicsandpropertiesofeachIgisotypeIgreceptorsandtheirfunctionsImmunoglobulinStructure-FunctionRelationship第二页，共五十二页，编辑于2023年，星期日CellsurfaceantigenreceptoronBcellsB细胞表面受体和分泌的抗体AllowsBcellstosensetheirantigenicenvironmentConnectsextracellularspacewithintracellularsignallingmachinerySecretedantibody（抗体） Neutralisation（中和作用） Arming/recruitingeffectorcells（激活或者诱导功能细胞） Complementfixation（帮助机体对抗原的清除）ImmunoglobulinStructure-FunctionRelationship第三页，共五十二页，编辑于2023年，星期日ImmunoglobulinsareBifunctionalProteinsImmunoglobulinsmustinteractwithasmallnumberof specialisedmolecules-（免疫球蛋白必须与特殊分子相互作用） Fcreceptorsoncells（细胞表面的Fc受体） Complementproteins（辅助蛋白） Intracellularcellsignallingmolecules（细胞内信号转导分子）whilstsimultaneouslyrecognisinganinfinitearrayof antigenicdeterminants.（同时能够识别无限抗原族）第四页，共五十二页，编辑于2023年，星期日Structuralconservationandacapacityforinfinitevariabilityina singlemoleculeisprovidedbyaDOMAINstructure.（结构上不仅保守而且无限可变的-抗体结构域）Igdomainsarederivedfromasingleancestralgenethathas duplicated,diversifiedandbeenmodifiedtoendowan assortmentoffunctionalqualitiesonacommonbasicstructure（Ig结构域源于一个原始基因，复制，多元化，修饰等）Igdomainsarenotrestrictedtoimmunoglobulins（Ig结构域不仅仅局限于免疫球蛋白）.ThemoststrikingcharacteristicoftheIgdomainisadisulphide bond-linkedstructureof110aminoacidslong（Ig结构域最明显的特点是其双硫键，连接了110个氨基酸）.Immunoglobulindomains第五页，共五十二页，编辑于2023年，星期日ThegenesencodingIgdomainsarenotrestrictedtoIggenes.Althoughfirstdiscoveredinimmunoglobulins,theyarefoundinasuperfamilyofrelatedgenes,particularlythoseencodingproteinscrucialtocell-cellinteractionsandmolecularrecognitionsystems.IgSFmoleculesarefoundinmostcelltypesandarepresentacrosstaxonomicboundariesIggenesuperfamily-IgSF第六页，共五十二页，编辑于2023年，星期日AntibodiesareProteinsthatRecognizeSpecificAntigens

抗体能够特异性的识别抗原第七页，共五十二页，编辑于2023年，星期日Epitopes（抗原决定簇）:AntigenRegionsthatInteractwithAntibodies第八页，共五十二页，编辑于2023年，星期日ConsequencesofAntibodyBinding

抗体结合效应第九页，共五十二页，编辑于2023年，星期日CLVLSSSSSSSSCH3CH2CH1VHFcFabF(ab)2Domainsarefolded,compact,proteaseresistantstructuresDomainStructureofImmunoglobulins免疫球蛋白的结构域Pepsincleavagesites-1x(Fab)2&1xFcPapaincleavagesites-2xFab1xFcLightchainCdomainskorlHeavychainCdomainsa,d,e,g,orm第十页，共五十二页，编辑于2023年，星期日CH3第十一页，共五十二页，编辑于2023年，星期日CH3CH2第十二页，共五十二页，编辑于2023年，星期日CH3CH2CH1第十三页，共五十二页，编辑于2023年，星期日CH3CH2CH1VH1第十四页，共五十二页，编辑于2023年，星期日CH3CH2CH1VH1VL第十五页，共五十二页，编辑于2023年，星期日CH3CH2CH1VH1CLVL第十六页，共五十二页，编辑于2023年，星期日CH3CH2CH1VH1CLVL第十七页，共五十二页，编辑于2023年，星期日HingeCH3CH2CH1VH1VLCLElbow第十八页，共五十二页，编辑于2023年，星期日CH3CH2FbFvFvFvFbFvHingeElbowCH3CH2FbFvFlexibilityandmotionofimmunoglobulins第十九页，共五十二页，编辑于2023年，星期日HingeFvFbFabCH3CH2CH1VH1VLCLFcElbowCarbohydrate第二十页，共五十二页，编辑于2023年，星期日TheImmunoglobulinFoldThecharacteristicstructuralmotifofallIgdomainsBarrelunderconstructionAbarrelmadeofasheetofstavesarrangedinafoldedoversheetAbbarrelof7(CL)or8(VL)polypeptidestrandsconnectedbyloopsandarrangedtoencloseahydrophobicinteriorSingleVLdomain第二十一页，共五十二页，编辑于2023年，星期日UnfoldedVLregionshowing8antiparallelb-pleatedsheetsconnectedbyloops.NH2COOHSSTheImmunoglobulinFold第二十二页，共五十二页，编辑于2023年，星期日Immunoglobulinsmustinteractwithafinitenumberof specialisedmolecules-EasilyexplainedbyacommonFcregionirrespectiveofspecificity-whilstsimultaneouslyrecognisinganinfinitearrayof antigenicdeterminants.Inimmunoglobulins,whatisthestructuralbasisfortheinfinitediversityneededtomatchtheantigenicuniverse?ImmunoglobulinsareBifunctionalProteins第二十三页，共五十二页，编辑于2023年，星期日AminoacidNo.Variability8010060402020406080100120CytochromesCVariabilityofaminoacidsinrelatedproteinsWu&Kabat1970AminoacidNo.Variability8010060402020406080100120HumanIgheavychains第二十四页，共五十二页，编辑于2023年，星期日FR1FR2FR3FR4CDR2CDR3CDR1Distinctregionsofhighvariabilityandconservationledtotheconcept ofaFRAMEWORK(FR),onwhichhypervariableregionswere suspended.FrameworkandHypervariableregionsAminoacidNo.Variability8010060402020406080100120Mosthypervariableregionscoincidedwithantigencontactpoints- theCOMPLEMENTARITYDETERMININGREGIONS(CDRs)第二十五页，共五十二页，编辑于2023年，星期日HypervariableregionsHypervariableCDRsarelocatedonloopsattheendoftheFvregions第二十六页，共五十二页，编辑于2023年，星期日Space-fillingmodelof(Fab)2,viewedfromabove,illustratingthesurfacelocationofCDRloopsLightchains GreenandbrownHeavychains CyanandblueCDRs Yellow第二十七页，共五十二页，编辑于2023年，星期日TheframeworksupportsthehypervariableloopsTheframeworkformsacompactbbarrel/sandwichwitha hydrophobiccoreThehypervariableloopsjoin,andaremoreflexiblethan,theb strandsThesequencesofthehypervariableloopsarehighlyvariable amongstantibodiesofdifferentspecificitiesThevariablesequencesofthehypervariableloopsinfluences theshape,hydrophobicityandchargeatthetipoftheantibodyVariableaminoacidsequenceinthehypervariableloops accountsforthediversityofantigensthatcanberecognisedby arepertoireofantibodiesHypervariableloopsandframework:Summary第二十八页，共五十二页，编辑于2023年，星期日AntigensvaryinsizeandcomplexityProtein:InfluenzahaemagglutininHapten:5-(para-nitrophenylphosphonate)-pentanoicacid.第二十九页，共五十二页，编辑于2023年，星期日AntibodiesinteractwithantigensinavarietyofwaysAntigeninsertsintoapocketintheantibodyAntigeninteractswithanextendedantibodysurfaceoragrooveintheantibodysurface第三十页，共五十二页，编辑于2023年，星期日CH3CH2FbFvFvFvFbFvHingeElbowCH3CH2FbFvFlexibilityandmotionofimmunoglobulins第三十一页，共五十二页，编辑于2023年，星期日30stronglyneutralisingMcAb60stronglyneutralisingMcAbFabregions60weaklyneutralisingMcAbFabregionsHumanRhinovirus14-acommoncoldvirus30nmModelsofHumanRhinovirus14neutralisedbymonoclonalantibodies第三十二页，共五十二页，编辑于2023年，星期日ElectronmicrographsofAntibodiesandcomplementopsonisingEpsteinBarrVirus(EBV)NegativelystainedEBVEBVcoatedwithacoronaofanti-EBVantibodiesEBVcoatedwithantibodiesandactivatedcomplementcomponents第三十三页，共五十二页，编辑于2023年，星期日Antibody+complement-mediateddamagetoE.coliHealthyE.coliElectronmicrographsoftheeffectofantibodiesandcomplementuponbacteria第三十四页，共五十二页，编辑于2023年，星期日Non-covalentforcesinantibody-antigeninteractionsElectrostaticforces AttractionbetweenoppositechargesHydrogenbonds HydrogenssharedbetweenelectronegativeatomsVanderWaal’sforces Fluctuationsinelectroncloudsaroundmolecules oppositelypolariseneighbouringatomsHydrophobicforces Hydrophobicgroupspacktogethertoexclude water(involvesVanderWaal’sforces)第三十五页，共五十二页，编辑于2023年，星期日WhydoantibodiesneedanFcregion?DetectantigenPrecipitateantigenBlocktheactivesitesoftoxinsorpathogen-associated moleculesBlockinteractionsbetweenhostandpathogen-associated moleculesThe(Fab)2fragmentcan-InflammatoryandeffectorfunctionsassociatedwithcellsInflammatoryandeffectorfunctionsofcomplementThetraffickingofantigensintotheantigenprocessing pathwaysbutcannotactivate第三十六页，共五十二页，编辑于2023年，星期日StructureandfunctionoftheFcregionCH3CH2IgAIgDIgGCH4CH3CH2IgEIgMThehingeregionisreplacedbyanadditionalIgdomainFcstructureiscommontoallspecificitiesofantibodywithinanISOTYPE(althoughthereareallotypes)Thestructureactsasareceptorforcomplementproteinsandaligandforcellularbindingsites第三十七页，共五十二页，编辑于2023年，星期日MonomericIgMIgMonlyexistsasamonomeronthesurfaceofBcellsCm4containsthetransmembraneandcytoplasmicregions.TheseareremovedbyRNAsplicingtoproducesecretedIgMMonomericIgMhasaverylowaffinityforantigenCm4Cm3Cm2Cm1N.B.Onlyconstantheavychaindomainsareshown第三十八页，共五十二页，编辑于2023年，星期日Cm3bindsC1qtoinitiateactivationoftheclassicalcomplementpathwayCm1bindsC3btofacilitateuptakeofopsonisedantigensbymacrophagesCm4mediatesmultimerisation(Cm3mayalsobeinvolved)Cm4Cm3Cm2Cm1N.B.OnlyconstantheavychaindomainsareshownPolymericIgMIgMformspentamersandhexamers第三十九页，共五十二页，编辑于2023年，星期日CCCCCCMultimerisationofIgMCm4Cm3Cm2CCCm4Cm3Cm2CCCm4Cm3Cm2CCCm4Cm3Cm2CCCm4Cm3Cm2CCssssssCCss1.TwoIgMmonomersintheER (Fcregionsonlyshown)2.CysteinesintheJchainformdisulphidebondswithcysteinesfromeachmonomertoformadimer3.AJchaindetachesleavingthedimerdisulphidebonded.4.AJchaincapturesanotherIgMmonomerandjoinsittothedimer.5.Thecycleisrepeatedtwicemore6.TheJchainremainsattachedtotheIgMpentamer.第四十页，共五十二页，编辑于2023年，星期日Antigen-inducedconformationalchangesinIgMPlanaror‘Starfish’conformationfoundinsolution.DoesnotfixcomplementStapleor‘crab’conformationofIgMConformationchangeinducedbybindingtoantigen.Efficientatfixingcomplement第四十一页，共五十二页，编辑于2023年，星期日IgMfactsandfiguresHeavychain:

m-MuHalf-life:

5to10days%ofIginserum: 10Serumlevel(mgml-1):

0.25-3.1Complementactivation:

++++byclassicalpathwayInteractionswithcells:

PhagocytesviaC3breceptors

EpithelialcellsviapolymericIgreceptorTransplacentaltransfer:

NoAffinityforantigen:

MonomericIgM-lowaffinity-valencyof2

PentamericIgM-highavidity-valencyof10第四十二页，共五十二页，编辑于2023年，星期日IgDfactsandfiguresIgDisco-expressedwithIgMonBcellsduetodifferentialRNAsplicingLevelofexpressionexceedsIgMonnaïveBcellsIgDplasmacellsarefoundinthenasalmucosa-howeverthefunctionofIgDinhostdefenceisunknown-knockoutmiceinconclusiveLigationofIgDwithantigencanactivate,deleteoranergiseBcellsExtendedhingeregionconferssusceptibilitytoproteolyticdegradationHeavychain:

d-DeltaHalf-life:

2to8days%ofIginserum: 0.2Serumlevel(mgml-1):

0.03-0.4Complementactivation:

NoInteractionswithcells:

TcellsvialectinlikeIgDreceptorTransplacentaltransfer:

No第四十三页，共五十二页，编辑于2023年，星期日IgAdimerisationandsecretionIgAisthemajorisotypeofantibodysecretedatmucosalsufacesExistsinserumasamonomer,butmoreusuallyasaJchain-linkeddimer,thatisformedinasimilarmannertoIgMpentamers.JCCSSSSCCSSSSCCssIgAexistsintwosubclassesIgA1ismostlyfoundinserumandmadebybonemarrowBcellsIgA2ismostlyfoundinmucosalsecretions,colostrumandmilkandismadebyBcellslocatedinthemucosae第四十四页，共五十二页，编辑于2023年，星期日EpithelialcellJCCSSSSCCSSSSCCssSecretoryIgAandtranscytosisBJCCSSSSCCSSSSCCssJCCSSSSCCSSSSCCssJCCSSSSCCSSSSCCsspIgR&IgAareinternalised‘Stalk’ofthepIgRisdegradedtoreleaseIgAcontainingpartofthepIgR-thesecretorycomponentJCCSSSSCCSSSSCCssIgAandpIgRaretransportedtotheapicalsurfaceinvesiclesBcellslocatedinthesubmucosaproducedimericIgAPolymericIgreceptorsareexpressedonthebasolateralsurfaceofepithelialcellstocaptureIgAproducedinthemucosa第四十五页，共五十二页，编辑于2023年，星期日IgAfactsandfiguresHeavychains:

a1

ora2-Alpha1or2Half-life:

IgA15-7days

IgA24-6daysSerumlevels(mgml-1):

IgA11.4-4.2

IgA20.2-0.5%ofIginserum: IgA111-14

IgA21-4Complementactivation:

IgA1-byalternativeandlectinpathway

IgA2-NoInteractionswithcells:

EpithelialcellsbypIgR

PhagocytesbyIgAreceptorTransplacentaltransfer:

NoToreducevulnerabilitytomicrobialproteasesthehingeregionofIgA2istruncated,andinIgA1thehingeisheavilyglycosylated.IgAisinefficientatcausinginflammationandelicitsprotectionbyexcluding,binding,cross-linkingmicroorganismsandfacilitatingphagocytosis第四十六页，共五十二页，编辑于2023年，星期日IgEfactsandfiguresIgEappearslateinevolutioninaccordancewithitsroleinprotectingagainstparasiteinfectionsMostIgEisabsorbedontothehighaffinityIgEreceptorsofeffectorcellsIgEisalsocloselylinkedwithallergicdiseasesHeavychain: e-EpsilonHalf-life:

1-5daysSerumlevel(mgml-1):

0.0001-0.0002%ofIginserum: 0.004Complementactivation:

NoInteractionswithcells:

ViahighaffinityIgEreceptorsexpressed bymastcells,eosinophils,basophils andLangerhanscells

VialowaffinityIgEreceptoronBcells andmonocytesTransplacentaltransfer:

No第四十七页，共五十二页，编辑于2023年，星期日ThehighaffinityIgEreceptor(FceRI)achainbchaing2SSSSSSCe1Ce1Ce2Ce2Ce3Ce3Ce4Ce4Ce1Ce1Ce2Ce2Ce3Ce3Ce4Ce4TheIgE-FceRIinteractionisthehighestaffinityofanyFcreceptorwithanextremelylowdissociationrate.BindingofIgEtoFceRIincreasesthehalflifeofIgECe3ofIgEinteractswiththeachainofFceRIcausingaconformationalchange.第四十八页，共五十二页，编辑于2023年，星期日IgGfactsandfiguresHeavychains:

g1g2g3g4-Gamma1-4Half-life:

IgG1 21-24days IgG2 21-24days

IgG3 7-8days IgG4 21-24daysSerumlevel(mgml-1):

IgG1 5-12 IgG2 2-6

IgG3 0.5-1 IgG4 0.2-1%ofIginserum: IgG1 45-53 IgG2 11-15