血紅蛋白和免疫球蛋白第一頁(yè)，共八十九頁(yè)，2022年，8月28日本次作業(yè)（第三次作業(yè)）海拔高度調(diào)控別構(gòu)效應(yīng)子BPG濃度的分子基礎(chǔ)（或可以理解為海拔高度如何決定代謝產(chǎn)物BPG的濃度）。免疫記憶的分子基礎(chǔ)。第二頁(yè)，共八十九頁(yè)，2022年，8月28日配基(ligand):Amoleculeboundreversiblybyaproteiniscalledaligand.Aligandmaybeanykindofmolecule,includinganotherprotein.Aligandbindsatasiteontheproteincalledthebindingsite,whichiscomplementarytotheligandinsize,shape,charge,andhydrophobicorhydrophiliccharacter.1、Concepts基本概念第三頁(yè)，共八十九頁(yè)，2022年，8月28日Thebindingofaproteinandligandisoftencoupledtoaconformationalchangeintheproteinthatmakesthebindingsitemorecomplementarytotheligand,permittingtighterbinding.Thestructuraladaptationthatoccursbetweenproteinandligandiscalledinducedfit(誘導(dǎo)契合).第四頁(yè)，共八十九頁(yè)，2022年，8月28日第五頁(yè)，共八十九頁(yè)，2022年，8月28日第六頁(yè)，共八十九頁(yè)，2022年，8月28日Inamultisubunitprotein,aconformationalchangeinonesubunitoftenaffectstheconformationofothersubunits.Intermolecularsignaltransduction

第七頁(yè)，共八十九頁(yè)，2022年，8月28日結(jié)合常數(shù)第八頁(yè)，共八十九頁(yè)，2022年，8月28日解離常數(shù)第九頁(yè)，共八十九頁(yè)，2022年，8月28日低解離常數(shù)與親和層析第十頁(yè)，共八十九頁(yè)，2022年，8月28日Enzymesrepresentaspecialcaseofproteinfunction.Enzymesbindandchemicallytransformothermolecules--theycatalyzereactions.Themoleculesacteduponbyenzymesarecalledreactionsubstrates(底物)ratherthanligands,andthesubstrate-bindingsiteiscalledthecatalyticsite(催化位點(diǎn))oractivesite(活性位點(diǎn)).底物和活性位點(diǎn)第十一頁(yè)，共八十九頁(yè)，2022年，8月28日Interactionsbetweenligandsandproteinsmayberegulated,usuallythroughspecificinteractionswithoneormoreadditionalligands.Theseotherligandsmaycauseconformationalchangesintheproteinthataffectthebindingofthefirstligand.(forexample,thecaseofBPG)Allosteric(變構(gòu)效應(yīng))-aneffectthataffectstheactivityofonepartofanenzyme(suchasanactivesite)bythebindingofamoleculeatadifferentsite(regulatorysite)atadifferentlocationontheenzyme.變構(gòu)效應(yīng)/別構(gòu)效應(yīng)第十二頁(yè)，共八十九頁(yè)，2022年，8月28日Changesinconformationmaybesubtle,reflectingmolecularvibrationsandsmallmovementsofaminoacidresiduesthroughouttheprotein.Aproteinflexing(撓動(dòng))inthiswayissometimessaidto“breathe”

Grd19/SNX3β1β1β2β2β3β3α1α1α2α2α3α3α4α4α1’CNNCGrd19-PtdIn(3)P蛋白質(zhì)的柔性(Proteinsareflexible)

第十三頁(yè)，共八十九頁(yè)，2022年，8月28日Grd19/SNX31

33PXdomain158

162phosphatidylinositol-3-phosphatePtdIn(3)P磷脂酰肌醇-3-磷酸Kd=0.15~0.5μMActiveForm第十四頁(yè)，共八十九頁(yè)，2022年，8月28日Changesinconformationmayalsobequitedramatic,withmajorsegmentsoftheproteinstructuremovingasmuchasseveralnanometers.Specificconformationalchangesarefrequentlyessentialtoaprotein’sfunction.LicTmutant(active)H207D/H269DLicTwt(inactive)H207/H269phosphorylation第十五頁(yè)，共八十九頁(yè)，2022年，8月28日2、ReversibleBindingofaLigandtoaProtein:

肌紅蛋白和血紅蛋白第十六頁(yè)，共八十九頁(yè)，2022年，8月28日血紅蛋白:hemoglobin-oxygentransportprotein

(α2β2incomplexwith4hemes)肌紅蛋白:myoglobin-oxygenstorageproteinMyoglobinandhemoglobinmaybethemost-studiedandbest-understoodproteins.Thesemoleculesillustratealmosteveryaspectofthatmostcentralofbiochemicalprocesses:thereversiblebindingofaligandtoaprotein.Thisclassicmodelofproteinfunctiontellsusagreatdealabouthowproteinswork.globin(珠蛋白)incomplexwithheme(血紅素)

第十七頁(yè)，共八十九頁(yè)，2022年，8月28日In1840,theoxygen-carryingproteinhaemoglobinwasdiscoveredbyHünefeld.In1851,OttoFunkepublishedaseriesofarticlesinwhichhedescribedgrowinghemoglobincrystalsbysuccessivelydilutingredbloodcellswithasolventsuchaspurewater,alcoholorether,followedbyslowevaporationofthesolventfromtheresultingproteinsolution.In1958,JohnKendrewandassociatessuccessfullydeterminedthestructureofmyoglobinbyhigh-resolutionX-raycrystallography.In1959,MaxPerutzdeterminedthemolecularstructureofhemoglobinbyX-raycrystallography.Forthisdiscovery,JohnKendrewsharedthe1962NobelPrizeinchemistrywithMaxPerutz.1)Kendrew,JC.Bodo,G.Dintzis,HM.Parrish,RG.Wyckoff,H.andPhillipsDC.(1958)."AThree-DimensionalModeloftheMyoglobinMoleculeObtainedbyX-RayAnalysis".Nature181(4610):662–666.2)Perutz,M.F.;Rossmann,M.G.;Cullis,A.F.;Muirhead,H.;Will,G.;North,A.C.T.(1960)."StructureofH".Nature185(4711):416–422.3)PerutzMF(November1960)."Structureofhemoglobin".Brookhavensymposiainbiology13:165–83.Researchhistory第十八頁(yè)，共八十九頁(yè)，2022年，8月28日1)Thesequencesofhemoglobinsdifferbetweenspecies.2)Evenwithinaspecies,differentvariantsofhemoglobinexist.3)Mutationsinthegenesforthehemoglobinproteininaspeciesresultinhemoglobinvariants,someofthesemutantformsofhemoglobincauseagroupofhereditarydiseasestermedthehemoglobinopathies.4)Thebestknownissickle-celldisease,whichwasthefirsthumandiseasewhosemechanismwasunderstoodatthemolecularlevel.5)A(mostly)separatesetofdiseasescalledthalassemiasinvolvesunderproductionofnormalandsometimesabnormalhemoglobins,throughproblemsandmutationsinglobingeneregulation.6)Allthesediseasesproduceanemia.Genetics第十九頁(yè)，共八十九頁(yè)，2022年，8月28日TypesinhumansHemoglobinvariantsareapartofthenormalembryonicandfetaldevelopment,butmayalsobepathologicmutantformsofhemoglobininapopulation,causedbyvariationsingenetics.Somevariantssuchassickle-cellanemiaareresponsiblefordiseases(hemoglobinopathies).Othervariantscausenodetectablepathology(non-pathologicalvariants).Intheembryo:Gower1(ζ2ε2)Gower2(α2ε2)(PDB1A9W)HemoglobinPortland(ζ2γ2)Inthefetus:HemoglobinF(α2γ2)(PDB1FDH)Inadults:HemoglobinA(α2β2)(PDB1BZ0)-Themostcommonwithanormalamountover95%HemoglobinA2(α2δ2)-δchainsynthesisbeginslateinthethirdtrimesterandinadults,ithasanormalrangeof1.5-3.5%HemoglobinF(α2γ2)-InadultsHemoglobinFisrestrictedtoalimitedpopulationofredcellscalledF-cells.However,thelevelofHbFcanbeelevatedinpersonswithsickle-celldisease.第二十頁(yè)，共八十九頁(yè)，2022年，8月28日Expressionofhumanglobingenesatdifferentstagesofdevelopment.第二十一頁(yè)，共八十九頁(yè)，2022年，8月28日1)Hemoglobin(Hb)issynthesizedinacomplexseriesofsteps.2)Thehemepartissynthesizedinaseriesofstepsinthemitochondria(線粒體)andthecytosolofimmatureredbloodcells,whiletheglobinproteinpartsaresynthesizedbyribosomesinthecytosol.3)ProductionofHbcontinuesinthecellthroughoutitsearlydevelopmentfromtheproerythroblast(原成紅細(xì)胞)tothereticulocyte(網(wǎng)織紅細(xì)胞)inthebonemarrow(骨髓).4)Thenucleusislostinmammalian(哺乳動(dòng)物)redbloodcells,butnotinbirdsandmanyotherspecies.Evenafterthelossofthenucleusinmammals,residualribosomalRNAallowsfurthersynthesisofHbuntilthereticulocytelosesitsRNAsoonafterenteringthevasculature(脈管系統(tǒng)).Synthesis第二十二頁(yè)，共八十九頁(yè)，2022年，8月28日Roleoftheglobinsinoxygentransportandstorage.hemoglobinmyoglobin靜脈動(dòng)脈肺/腮第二十三頁(yè)，共八十九頁(yè)，2022年，8月28日Theironatomofheme(亞鐵血紅素)hassixcoordinationbonds:fourintheplaneof,andbondedto,theflatporphyrinringsystem.Porphyrins(卟啉),ofwhichprotoporphyrin(原卟啉)IXisonlyoneexample,consistoffourpyrrole(吡咯)ringslinkedbymethene(亞甲基)bridges,withsubstitutionsatoneormoreofthepositionsdenotedX.Heme(亞鐵血紅素)第二十四頁(yè)，共八十九頁(yè)，2022年，8月28日ThisviewshowsthetwocoordinationbondstoFe2＋

perpendiculartotheporphyrin(卟啉)ringsystem.OneofthesetwobondsisoccupiedbyaHisresidue,sometimescalledtheproximalHis.Theotherbondisthebindingsiteforoxygen.Theremainingfourcoordinationbondsareintheplaneof,andbondedto,theflatporphyrinringsystem.Thehemegroupviewedfromtheside.Twocoordinationbonds

perpendicular(垂直于)totheplane.第二十五頁(yè)，共八十九頁(yè)，2022年，8月28日Evolutionoftheglobingenes

圓口魚類多骨魚類靈長(zhǎng)類哺乳動(dòng)物第二十六頁(yè)，共八十九頁(yè)，2022年，8月28日Evolutionaryconservationoftheglobinfoldingpattern第二十七頁(yè)，共八十九頁(yè)，2022年，8月28日ThestructureofmyoglobinMyoglobin第二十八頁(yè)，共八十九頁(yè)，2022年，8月28日OxygenbindstohemewiththeO2axisatanangle,abindingconformationreadilyaccommodatedbymyoglobin.CarbonmonoxidebindstofreehemewiththeCOaxisperpendicular(垂直)totheplaneoftheporphyrin(卟啉)ring.Whenbindingtothehemeinmyoglobin,COisforcedtoadoptaslightanglebecausetheperpendiculararrangementisstericallyblockedbyHisE7,thedistalHis.ThiseffectweakensthebindingofCOtomyoglobin.Anotherview(derivedfromPDBID1MBO),showingthearrangementofkeyaminoacidresiduesaroundthehemeofmyoglobin.TheboundO2ishydrogen-bondedtothedistalHis,HisE7(His64),furtherfacilitatingthebindingofO2.Stericeffectsonthebindingofligandstothehemeofmyoglobin第二十九頁(yè)，共八十九頁(yè)，2022年，8月28日DynamicsofoxygenreleasebymyoglobinTherate-limitingprocessinoxygenreleaseistheopeningofapathwayfortheO2moleculetoescapefromthehemepocket.Oxygenmayspendtime"rattlinginitscage"-andperhapsbeingrecaptured-beforethetertiarystructureofthemyoglobinshiftsenoughtoletitescape撥浪鼓第三十頁(yè)，共八十九頁(yè)，2022年，8月28日Dominantinteractionsbetweenhemoglobinsubunits.Hemoglobin第三十一頁(yè)，共八十九頁(yè)，2022年，8月28日Acomparisonofthestructuresofmyoglobin(PDBID1MBO)andthe

subunitofhemoglobin(derivedfromPDBID1HGA).第三十二頁(yè)，共八十九頁(yè)，2022年，8月28日Thelooserconformationiscalledrelaxed(松弛的)(R).

Thetighterconformationiscalledtense(緊張的)(T).

TheenergypriceforthechangefromtheTstatetotheRstateispaidbythebindingofO2tothemolecule.OncetheO2hasdeparted,themoleculewillnaturallyfallbackintoitslower-energydeoxyconformation(T).第三十三頁(yè)，共八十九頁(yè)，2022年，8月28日1)Inthetetramericformofnormaladulthemoglobin,thebindingofoxygenisacooperativeprocess.2)Thebindingaffinityofhemoglobinforoxygenisincreasedbytheoxygensaturationofthemolecule,withthefirstoxygensboundinfluencingtheshapeofthebindingsitesforthenextoxygens,inawayfavorableforbinding.3)Thispositivecooperativebindingisachievedthroughstericconformationalchangesofthehemoglobinproteincomplexasdiscussedabove,i.e.whenonesubunitproteininhemoglobinbecomesoxygenated,thisinducesaconformationalorstructuralchangeinthewholecomplex,causingtheothersubunitstogainanincreasedaffinityforoxygen.Asaconsequence,theoxygenbindingcurveofhemoglobinissigmoidal,orS-shaped,asopposedtothenormalhyperboliccurveassociatedwithnoncooperativebinding.Cooperative第三十四頁(yè)，共八十九頁(yè)，2022年，8月28日Theligand-bindingsitesarecomposedofbothhigh-andlowstabilitysegments,soaffinityforligandisrelativelylow.(a)Intheabsenceofligand,theredsegmentsarequiteflexibleandtakeupavarietyofconformations,fewofwhichfacilitateligandbinding.Thegreensegmentsaremoststableinthelow-affinitystate.(b)Thebindingofligandtoonesubunitstabilizesahigh-affinityconformationofthenearbyredsegment(nowshowningreen),inducingaconformationalchangeintherestofthepolypeptide.Thisisaformofinducedfit.Theconformationalchangeistransmittedtotheothersubunitthroughprotein-proteininteractions,suchthatahigher-affinityconformationofthebindingsiteisstabilizedintheothersubunit.Asecondligandmoleculecannowbindtothesecondsubunit,withahigheraffinitythanthebindingofthefirst,givingrisetotheobservedpositivecooperativity.Structuralchangesinamultisubunitproteinundergoingcooperativebindingtoligand.第三十五頁(yè)，共八十九頁(yè)，2022年，8月28日Forexample,intheupperleftofthefourhemesshown,oxygenbindscausestheironatomtomovebackwardintothehemetugingthehistidineresiduecloser

pullsontheproteinchainholdingthehistidine.Aschematicvisualmodelofoxygenbindingprocess第三十六頁(yè)，共八十九頁(yè)，2022年，8月28日Thebindingandreleaseofoxygen(shownnowingreen)illustratesthestructuraldifferencesbetweenoxy-anddeoxyhemoglobin,respectively.Thehistidinewhichispulledbymotionoftheironatom,isshownhereinyellow.Anotherviewofhowbindingandreleaseofligandsinducesaconformational(structural)changeinhemoglobin.Onlyoneofthefourhemegroupsisshown,第三十七頁(yè)，共八十九頁(yè)，2022年，8月28日MechanismoftheT-Rtransitioninhemoglobin第三十八頁(yè)，共八十九頁(yè)，2022年，8月28日SomeionpairsthatstabilizetheTstateofdeoxyhemoglobin第三十九頁(yè)，共八十九頁(yè)，2022年，8月28日Severaltheorieshavebeendevelopedtodescribeallosterictransitions.Theymaybegenerallygroupedintothefollowingthreeclasses:第四十頁(yè)，共八十九頁(yè)，2022年，8月28日characterizedbytheco-existenceofmoleculeswithsomesubunitsintheweak-bindingstateandsomeinthestrongSequentialmodel,theprototypeforthemodelsthatdescribeallosterictransitionsKoshland,Nemethy,andFilmer(KNFmodel)第四十一頁(yè)，共八十九頁(yè)，2022年，8月28日Theshiftisaconcerted(協(xié)同的)oneConcertedmodelMonod,Wyman,andChangeux(MWCmodel)第四十二頁(yè)，共八十九頁(yè)，2022年，8月28日AdaptedfromG.K.Ackersetal.,Science(1992)255:54-63.thechangesintertiarystructurethataccompanyoxygenbindingcanbetolerateduptoacertainpointbeforetheT-Rswitchoccurs.Specifically,wheneveronesiteisoccupiedoneachofthetwoα-βdimers,themoleculeasawholeadoptstheRquaternarystructureMultistatemodel第四十三頁(yè)，共八十九頁(yè)，2022年，8月28日HemoglobinbindingO2inlung(high[O2])andleaseitintissue(low[O2])Asigmoid(cooperative)bindingcurve.CooperativebindingrendershemoglobinmoresensitivetothesmalldifferencesinO2concentrationbetweenthetissuesandthelungs,allowinghemoglobintobindoxygeninthelungs(wherepO2ishigh)andreleaseitinthetissues(wherepO2islow).AllostericEffecter:O2第四十四頁(yè)，共八十九頁(yè)，2022年，8月28日Aplotoflog[θ/(1-θ)]versuslog[L]iscalledaHillplotTheslope(斜率)ofaHillplotisdenotedbynH,theHillcoefficient(希爾系數(shù))Hillequation(希爾方程)希爾方程和希爾系數(shù)第四十五頁(yè)，共八十九頁(yè)，2022年，8月28日TheoreticallynH=4WhennH＝1,thereisnoevidentcooperativity.ThemaximumdegreeofcooperativityobservedforhemoglobincorrespondsapproximatelytonH＝3.Notethatwhilethisindicatesahighlevelofcooperativity,nHislessthann,thenumberofO2-bindingsitesinhemoglobin.Thisisnormalforaproteinthatexhibitsallostericbindingbehavior.Hillplotsforthebindingofoxygentomyoglobinandhemoglobin.第四十六頁(yè)，共八十九頁(yè)，2022年，8月28日OtherAllostericEffectorsbesidesO2:1,H+

2,CO3,CO24,BPG第四十七頁(yè)，共八十九頁(yè)，2022年，8月28日ApHdropinthebloodinthecapillarieslowerstheoxygenaffinityofhemoglobin,allowingevenmoreefficientreleaseofthelasttracesofoxygen.TheresponseofhemoglobintochangesinpHiscalledtheBohreffect.TheoverallreactionmaybewrittenHb-4O2

+nH+<=>Hb-nH++4O2

(wheren>2)

Physiologically,thisreactionhastwoconsequences:First,inthecapillaries,hydrogenionspromotethereleaseofO2bydrivingthereactiontotheright.Then,whenthevenous(靜脈)bloodrecirculatestothelungsorgills(腮),theoxygenationhastheeffectofreleasingtheH+byshiftingtheequilibriumtotheleft.This,inturn,tendstoreleaseCO2fromthebicarbonatedissolvedinthebloodbythereversalofthebicarbonatereaction:CO2+H2O<=>HCO3-+H+ThefreeCO2canthenbeexpired.theBohreffect第四十八頁(yè)，共八十九頁(yè)，2022年，8月28日第四十九頁(yè)，共八十九頁(yè)，2022年，8月28日Hemoglobin'soxygen-bindingcapacityisdecreasedinthepresenceofcarbonmonoxidebecausebothgasescompeteforthesamebindingsitesonhemoglobin,carbonmonoxidebindingpreferentiallyinplaceofoxygen.Thebindingofoxygenisaffectedbymoleculessuchascarbonmonoxide(CO)(forexamplefromtobaccosmoking抽煙,carexhaust汽車尾氣

andincompletecombustioninfurnaces壁爐中的不充分燃燒).COcompeteswithoxygenatthehemebindingsite.HemoglobinbindingaffinityforCOis200timesgreaterthanitsaffinityforoxygen,meaningthatsmallamountsofCOdramaticallyreducehemoglobin'sabilitytotransportoxygen.WhenhemoglobincombineswithCO,itformsaverybrightredcompoundcalledcarboxyhemoglobin,whichmaycausetheskinofCOpoisoningvictimstoappearpinkindeath,insteadofwhiteorblue.WheninspiredaircontainsCOlevelsaslowas0.02%,headacheandnauseaoccur;iftheCOconcentrationisincreasedto0.1%,unconsciousnesswillfollow.Inheavysmokers,upto20%oftheoxygen-activesitescanbeblockedbyCO.AllostericEffecter:CO,Competitive第五十頁(yè)，共八十九頁(yè)，2022年，8月28日Hemoglobinalsohascompetitivebindingaffinityforcyanide(CN-),sulfurmonoxide(SO),nitrogendioxide(NO2),andsulfide(S2-),includinghydrogensulfide(H2S).Allofthesebindtoironinhemewithoutchangingitsoxidationstate,buttheyneverthelessinhibitoxygen-binding,causinggravetoxicity.第五十一頁(yè)，共八十九頁(yè)，2022年，8月28日CO第五十二頁(yè)，共八十九頁(yè)，2022年，8月28日1)normalhemoglobin,2)hemoglobinfromananemic(貧血的)individualwithonly50%ofherhemoglobinfunctional,and3)hemoglobinfromanindividualwith50%ofhishemoglobinsubunitscomplexedwithCO.Severaloxygen-bindingcurves第五十三頁(yè)，共八十九頁(yè)，2022年，8月28日Carbondioxideoccupiesadifferentbindingsiteonthehemoglobin.Carbondioxideismorereadilydissolvedindeoxygenatedblood,facilitatingitsremovalfromthebodyaftertheoxygenhasbeenreleasedtotissuesundergoingmetabolism.Thisincreasedaffinityforcarbondioxidebythevenous(靜脈)bloodisknownastheHaldaneeffect.Throughtheenzymecarbonicanhydrase,carbondioxidereactswithwatertogivecarbonicacid,whichdecomposesintobicarbonateandprotons:CO2+H2O→H2CO3→HCO3-+H+

AllostericEffecter:CO2第五十四頁(yè)，共八十九頁(yè)，2022年，8月28日ThisreactionproducesH+,contributingtotheBohreffectCO2第五十五頁(yè)，共八十九頁(yè)，2022年，8月28日OxygenBindingtoHemoglobinIsRegulatedby2,3-Bisphosphoglycerate(BPG)2,3-二磷酸甘油酸AllostericEffecter:BPG第五十六頁(yè)，共八十九頁(yè)，2022年，8月28日Bindingof2,3-bisphosphoglyceratetodeoxyhemoglobinBPGbindsatasitedistantfromtheoxygen-bindingsiteandregulatestheO2-bindingaffinityofhemoglobininrelationtothepO2inthelungs.第五十七頁(yè)，共八十九頁(yè)，2022年，8月28日EffectofBPGonthebindingofoxygentohemoglobin.1)HemoglobinbindstooxygenquitetightlywhenBPGisentirelyabsent,andthebindingcurveappearstobehyperbolic.2)Atsealevel,hemoglobinisnearlysaturatedwithO2inthelungs,butonly60%saturatedinthetissues,sotheamountofoxygenreleasedinthetissuesiscloseto40%ofthemaximumthatcanbecarriedintheblood.3)Athighaltitudes,O2deliverydeclinesbyaboutone-fourth,to30%ofmaximum.AnincreaseinBPGconcentration,however,decreasestheaffinityofhemoglobinforO2,sonearly40%ofwhatcanbecarriedisagaindeliveredtothetissues.TheBPGconcentrationinnormalhumanbloodis:about5mMatsealevelandabout8mMathighaltitudes.第五十八頁(yè)，共八十九頁(yè)，2022年，8月28日HemoglobinH(β4)-Avariantformofhemoglobin,formedbyatetramerofβchains,whichmaybepresentinvariantsofαthalassemia.HemoglobinBarts(γ4)-Avariantformofhemoglobin,formedbyatetramerofγchains,whichmaybepresentinvariantsofαthalassemia.HemoglobinS(α2βS2)-Avariantformofhemoglobinfoundinpeoplewithsicklecelldisease.Thereisavariationintheβ-chaingene,causingachangeinthepropertiesofhemoglobinwhichresultsinsicklingofredbloodcells.HemoglobinC(α2βC2)-Anothervariantduetoavariationintheβ-chaingene.Thisvariantcausesamildchronichemolyticanemia.HemoglobinAS-AheterozygousformcausingSicklecelltraitwithoneadultgeneandonesicklecelldiseasegeneHemoglobinSCdisease-AnotherheterozygousformwithonesicklegeneandanotherencodingHemoglobinC.Hemoglobinanddiseases第五十九頁(yè)，共八十九頁(yè)，2022年，8月28日第六十頁(yè)，共八十九頁(yè)，2022年，8月28日Distributionofmutationsinhumanhemoglobins.第六十一頁(yè)，共八十九頁(yè)，2022年，8月28日uniform,cup-shaped,normalerythrocytesthevariablyshapederythrocytesseeninsickle-cellanemiawhichrangefromnormaltospinyorsickle-shaped.Sickle-CellHemoglobinSickle-cellhemoglobinhasgaineditsnamebecauseitcausesredbloodcellstoadoptanelongated,sickleshapeatlowoxygenconcentrations,duetothetendencyofthemutanthemoglobin,initsdeoxygenatedstate,toaggregateintolong,rodlikestructures.Theelongatedcellstendtoblockcapillaries,causinginflammationandconsiderablepain.Evenmoreseriousisthatthesickledcellsarefragile.Theirbreakdownleadstoananemiathatleavesthevictimsusceptibletoinfectionsanddiseases.Individualswhoarehomozygousforthesickle-cellmutationoftendonotsurviveintoadulthood,andthosewhodoareseriouslydebilitated.第六十二頁(yè)，共八十九頁(yè)，2022年，8月28日Insicklecellhemoglobin(HbS)glutamateinposition6(inbetachain)ismutatedtovaline.Thischangeallowsthedeoxygenatedformofthehemoglobintosticktoeachother.第六十三頁(yè)，共八十九頁(yè)，2022年，8月28日Asaresultofthischange,deoxyhemoglobinShasahydrophobicpatchonitssurface,whichcausesthemoleculestoaggregateintostrandsthatalignintoinsolublefibers.第六十四頁(yè)，共八十九頁(yè)，2022年，8月28日SickleCellAdvantageIndividualsheterozygousforsickle-cellhemoglobinhaveahigherresistancetomalaria(瘧疾)thanthosewhodonotcarrythesickle-cellmutation.Themalarialparasitespendsaportionofitslifecycleinhumanredcells,andtheincreasedfragilityofthesickledcells,eveninheterozygousindividuals,tendstointerruptthiscycle.Heterozygous(雜合的)individualshaveahighersurvivalrate-andthereforeabetterchanceofpassingontheirgenes-inmalaria-infested(滋生)regions.However,thehighincidenceofthesegenesinthepopulationleadstothebirthofmanypeoplewhoarehomozygous(純合子)forthemutanttrait.第六十五頁(yè)，共八十九頁(yè)，2022年，8月28日Whenredcellsreachtheendoftheirlifeduetoagingordefects,theyarebrokendown,thehemoglobinmoleculeisbrokenupandtheirongetsrecycled.Whentheporphyrinringisbrokenup,thefragmentsarenormallysecretedinthebilebytheliver.Thisprocessalsoproducesonemoleculeofcarbonmonoxideforeverymoleculeofhemedegraded.Thisisoneofthefewnaturalsourcesofcarbonmonoxide(CO)productioninthehumanbody,andisresponsibleforthenormalbloodlevelsofcarbonmonoxideeveninpeoplebreathingpureair.Theothermajorfinalproductofhemedegradationisbilirubin(膽紅素).Increasedlevelsofthischemicalaredetectedinthebloodifredcellsarebeingdestroyedmorerapidlythanusual.Improperlydegradedhemoglobinproteinorhemoglobinthathasbeenreleasedfromthebloodcellstoorapidlycanclogsmallbloodvessels,especiallythedelicatebloodfilteringvesselsofthekidneys(腎臟),causingkidneydamage.Degradationinvertebrateanimals第六十六頁(yè)，共八十九頁(yè)，2022年，8月28日Hemoglobinconcentrationmeasurementisamongthemostcommonlyperformedbloodtests,usuallyaspartofacompletebloodcount.Forexampleitistypicallytestedbeforeblooddonation.Resultsarereporteding/L,g/dLormol/L.1g/dL=0.6206

mM.Normallevelsare:Men:13.8to17.2g/dLWomen:12.1to15.1g/dLChildren:11to16g/dLPregnantwomen:11to12g/dLDiagnosticuses第六十七頁(yè)，共八十九頁(yè)，2022年，8月28日3、ComplementaryInteractionsbetweenProteinsandLigands:免疫系統(tǒng)和免疫球蛋白第六十八頁(yè)，共八十九頁(yè)，2022年，8月28日December27,1822–September28,1895LouisPasteur第六十九頁(yè)，共八十九頁(yè)，2022年，8月28日Whenaforeignsubstance-avirus,abacterium,orevenaforeignprotein-invadesthetissuesofahighervertebrate(脊椎動(dòng)物)(likeahuman),theorganismdefendsitselfbywhatiscalledtheimmuneresponse(免疫應(yīng)答，免疫反應(yīng)).Theimmuneresponseisafirstlineofdefenseagainstinfectionandprobablyagainstcancercellsaswell.第七十頁(yè)，共八十九頁(yè)，2022年，8月28日Theimmuneresponsehastwofacets(形式):1.Humoralimmuneresponse(體液免疫應(yīng)答)-Lymphaticcells(淋巴細(xì)胞)calledBlymphocytessynthesizespecificimmunoglobulin(免疫球蛋白)moleculesthatareexcreted(分泌)fromthecellandbindtotheinvadingsubstance.Bindingeitherprecipitatestheforeignsubstanceormarksitfordestructionbycellscalledmacrophages(巨噬細(xì)胞).2.Cellularimmuneresponse(細(xì)胞免疫應(yīng)答)-LymphaticcellscalledTlymphocytes,bearingimmunoglobulin-likemoleculesontheirsurfaces,recognizeandkillforeignoraberrant(異常的)cells.第七十一頁(yè)，共八十九頁(yè)，2022年，8月28日AntigensandAntibodies:Theforeignsubstancethatelicits(引起)animmuneresponseiscalledtheantigen(抗原).Aspecificimmunoglobulinthatbindstotheantigeniscalledtheantibody(抗體).Iftheinvadingparticleislarge,likeacell,avirus,oraprotein,manydifferentantibodiesmaybeelicited,eachtypebindingspecificallytoanantigenicdeterminant(orepitope,抗原決定簇)onthesurfaceoftheparticle.第七十二頁(yè)，共八十九頁(yè)，2022年，8月28日ImmunoglobulinStructure–Eachimmunoglobulinmonomerconsistsoffourchains,twoheavychains(M=53,000each)andtwolightchains(M=23,000each),heldtogetherbydisulfidebonds.Ineachchainareconstantdomains(identicalinallantibodiesofagivenclass)andavariabledomain.Variationsintheaminoacidsequence(andthereforethetertiarystructure)ofthevariabledomainsofthelightandheavychainsconfer(賦予)themultitudinous(多種多樣的)specificitiesofantigenstodifferentdeterminants.第七十三頁(yè)，共八十九頁(yè)，2022年，8月28日Antigenicdeterminants(抗原決定簇)PrecipitatingAntigens-Alargeprotein,avirus,orabacterialcellhasmanydifferentpotentialantigenicdeterminantsonitssurfacethatantibodymoleculescanbind,therebyprecipitatingtheantigen.Antigenswithonlyonedeterminant,willbindtoanantibody,butnotprecipitate.Precipitationalsorequirestheantibodytobebivalent(tohavetwobindingsites).第七十四頁(yè)，共八十九頁(yè)，2022年，8月28日SchematicmodelsofanantibodymoleculeandaFabfragmentBycarefulproteolysis(蛋白酶水解),itispossibletocleaveantibodiesatthehingeregiontoproduceFabfragmentswithonlyonebindingsiteeach.Suchfragmentswillbind,butnotprecipitateantigen.FabFabFc第七十五頁(yè)，共八十九頁(yè)，2022年，8月28日CDR:complementaritydeterminingregions第七十六頁(yè)，共八十九頁(yè)，2022年，8月28日HumanshavefiveclassesofimmunoglobulinsTheJChain'smolecularweightisapproximately15kDa.Itexhibitsasta