血红蛋白和免疫球蛋白

血红蛋白和免疫球蛋白第一页，共八十九页，编辑于2023年，星期二本次作业（第三次作业）海拔高度调控别构效应子BPG浓度的分子基础（或可以理解为海拔高度如何决定代谢产物BPG的浓度）。免疫记忆的分子基础。第二页，共八十九页，编辑于2023年，星期二配基(ligand):Amoleculeboundreversiblybyaproteiniscalledaligand.Aligandmaybeanykindofmolecule,includinganotherprotein.Aligandbindsatasiteontheproteincalledthebindingsite,whichiscomplementarytotheligandinsize,shape,charge,andhydrophobicorhydrophiliccharacter.1、Concepts基本概念第三页，共八十九页，编辑于2023年，星期二Thebindingofaproteinandligandisoftencoupledtoaconformationalchangeintheproteinthatmakesthebindingsitemorecomplementarytotheligand,permittingtighterbinding.Thestructuraladaptationthatoccursbetweenproteinandligandiscalledinducedfit(诱导契合).第四页，共八十九页，编辑于2023年，星期二第五页，共八十九页，编辑于2023年，星期二第六页，共八十九页，编辑于2023年，星期二Inamultisubunitprotein,aconformationalchangeinonesubunitoftenaffectstheconformationofothersubunits.Intermolecularsignaltransduction

第七页，共八十九页，编辑于2023年，星期二结合常数第八页，共八十九页，编辑于2023年，星期二解离常数第九页，共八十九页，编辑于2023年，星期二低解离常数与亲和层析第十页，共八十九页，编辑于2023年，星期二Enzymesrepresentaspecialcaseofproteinfunction.Enzymesbindandchemicallytransformothermolecules--theycatalyzereactions.Themoleculesacteduponbyenzymesarecalledreactionsubstrates(底物)ratherthanligands,andthesubstrate-bindingsiteiscalledthecatalyticsite(催化位点)oractivesite(活性位点).底物和活性位点第十一页，共八十九页，编辑于2023年，星期二Interactionsbetweenligandsandproteinsmayberegulated,usuallythroughspecificinteractionswithoneormoreadditionalligands.Theseotherligandsmaycauseconformationalchangesintheproteinthataffectthebindingofthefirstligand.(forexample,thecaseofBPG)Allosteric(变构效应)-aneffectthataffectstheactivityofonepartofanenzyme(suchasanactivesite)bythebindingofamoleculeatadifferentsite(regulatorysite)atadifferentlocationontheenzyme.变构效应/别构效应第十二页，共八十九页，编辑于2023年，星期二Changesinconformationmaybesubtle,reflectingmolecularvibrationsandsmallmovementsofaminoacidresiduesthroughouttheprotein.Aproteinflexing(挠动)inthiswayissometimessaidto“breathe”

Grd19/SNX3β1β1β2β2β3β3α1α1α2α2α3α3α4α4α1’CNNCGrd19-PtdIn(3)P蛋白质的柔性(Proteinsareflexible)

第十三页，共八十九页，编辑于2023年，星期二Grd19/SNX31

33PXdomain158

162phosphatidylinositol-3-phosphatePtdIn(3)P磷脂酰肌醇-3-磷酸Kd=0.15~0.5µMActiveForm第十四页，共八十九页，编辑于2023年，星期二Changesinconformationmayalsobequitedramatic,withmajorsegmentsoftheproteinstructuremovingasmuchasseveralnanometers.Specificconformationalchangesarefrequentlyessentialtoaprotein’sfunction.LicTmutant(active)H207D/H269DLicTwt(inactive)H207/H269phosphorylation第十五页，共八十九页，编辑于2023年，星期二2、ReversibleBindingofaLigandtoaProtein:

肌红蛋白和血红蛋白第十六页，共八十九页，编辑于2023年，星期二血红蛋白:hemoglobin-oxygentransportprotein

(α2β2incomplexwith4hemes)肌红蛋白:myoglobin-oxygenstorageproteinMyoglobinandhemoglobinmaybethemost-studiedandbest-understoodproteins.Thesemoleculesillustratealmosteveryaspectofthatmostcentralofbiochemicalprocesses:thereversiblebindingofaligandtoaprotein.Thisclassicmodelofproteinfunctiontellsusagreatdealabouthowproteinswork.globin(珠蛋白)incomplexwithheme(血红素)

第十七页，共八十九页，编辑于2023年，星期二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第十八页，共八十九页，编辑于2023年，星期二1)Thesequencesofhemoglobinsdifferbetweenspecies.2)Evenwithinaspecies,differentvariantsofhemoglobinexist.3)Mutationsinthegenesforthehemoglobinproteininaspeciesresultinhemoglobinvariants,someofthesemutantformsofhemoglobincauseagroupofhereditarydiseasestermedthehemoglobinopathies.4)Thebestknownissickle-celldisease,whichwasthefirsthumandiseasewhosemechanismwasunderstoodatthemolecularlevel.5)A(mostly)separatesetofdiseasescalledthalassemiasinvolvesunderproductionofnormalandsometimesabnormalhemoglobins,throughproblemsandmutationsinglobingeneregulation.6)Allthesediseasesproduceanemia.Genetics第十九页，共八十九页，编辑于2023年，星期二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.第二十页，共八十九页，编辑于2023年，星期二Expressionofhumanglobingenesatdifferentstagesofdevelopment.第二十一页，共八十九页，编辑于2023年，星期二1)Hemoglobin(Hb)issynthesizedinacomplexseriesofsteps.2)Thehemepartissynthesizedinaseriesofstepsinthemitochondria(线粒体)andthecytosolofimmatureredbloodcells,whiletheglobinproteinpartsaresynthesizedbyribosomesinthecytosol.3)ProductionofHbcontinuesinthecellthroughoutitsearlydevelopmentfromtheproerythroblast(原成红细胞)tothereticulocyte(网织红细胞)inthebonemarrow(骨髓).4)Thenucleusislostinmammalian(哺乳动物)redbloodcells,butnotinbirdsandmanyotherspecies.Evenafterthelossofthenucleusinmammals,residualribosomalRNAallowsfurthersynthesisofHbuntilthereticulocytelosesitsRNAsoonafterenteringthevasculature(脉管系统).Synthesis第二十二页，共八十九页，编辑于2023年，星期二Roleoftheglobinsinoxygentransportandstorage.hemoglobinmyoglobin静脉动脉肺/腮第二十三页，共八十九页，编辑于2023年，星期二Theironatomofheme(亚铁血红素)hassixcoordinationbonds:fourintheplaneof,andbondedto,theflatporphyrinringsystem.Porphyrins(卟啉),ofwhichprotoporphyrin(原卟啉)IXisonlyoneexample,consistoffourpyrrole(吡咯)ringslinkedbymethene(亚甲基)bridges,withsubstitutionsatoneormoreofthepositionsdenotedX.Heme(亚铁血红素)第二十四页，共八十九页，编辑于2023年，星期二ThisviewshowsthetwocoordinationbondstoFe2＋

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

perpendicular(垂直于)totheplane.第二十五页，共八十九页，编辑于2023年，星期二Evolutionoftheglobingenes

圆口鱼类多骨鱼类灵长类哺乳动物第二十六页，共八十九页，编辑于2023年，星期二Evolutionaryconservationoftheglobinfoldingpattern第二十七页，共八十九页，编辑于2023年，星期二ThestructureofmyoglobinMyoglobin第二十八页，共八十九页，编辑于2023年，星期二OxygenbindstohemewiththeO2axisatanangle,abindingconformationreadilyaccommodatedbymyoglobin.CarbonmonoxidebindstofreehemewiththeCOaxisperpendicular(垂直)totheplaneoftheporphyrin(卟啉)ring.Whenbindingtothehemeinmyoglobin,COisforcedtoadoptaslightanglebecausetheperpendiculararrangementisstericallyblockedbyHisE7,thedistalHis.ThiseffectweakensthebindingofCOtomyoglobin.Anotherview(derivedfromPDBID1MBO),showingthearrangementofkeyaminoacidresiduesaroundthehemeofmyoglobin.TheboundO2ishydrogen-bondedtothedistalHis,HisE7(His64),furtherfacilitatingthebindingofO2.Stericeffectsonthebindingofligandstothehemeofmyoglobin第二十九页，共八十九页，编辑于2023年，星期二DynamicsofoxygenreleasebymyoglobinTherate-limitingprocessinoxygenreleaseistheopeningofapathwayfortheO2moleculetoescapefromthehemepocket.Oxygenmayspendtime"rattlinginitscage"-andperhapsbeingrecaptured-beforethetertiarystructureofthemyoglobinshiftsenoughtoletitescape拨浪鼓第三十页，共八十九页，编辑于2023年，星期二Dominantinteractionsbetweenhemoglobinsubunits.Hemoglobin第三十一页，共八十九页，编辑于2023年，星期二Acomparisonofthestructuresofmyoglobin(PDBID1MBO)andthe

subunitofhemoglobin(derivedfromPDBID1HGA).第三十二页，共八十九页，编辑于2023年，星期二Thelooserconformationiscalledrelaxed(松弛的)(R).

Thetighterconformationiscalledtense(紧张的)(T).

TheenergypriceforthechangefromtheTstatetotheRstateispaidbythebindingofO2tothemolecule.OncetheO2hasdeparted,themoleculewillnaturallyfallbackintoitslower-energydeoxyconformation(T).第三十三页，共八十九页，编辑于2023年，星期二1)Inthetetramericformofnormaladulthemoglobin,thebindingofoxygenisacooperativeprocess.2)Thebindingaffinityofhemoglobinforoxygenisincreasedbytheoxygensaturationofthemolecule,withthefirstoxygensboundinfluencingtheshapeofthebindingsitesforthenextoxygens,inawayfavorableforbinding.3)Thispositivecooperativebindingisachievedthroughstericconformationalchangesofthehemoglobinproteincomplexasdiscussedabove,i.e.whenonesubunitproteininhemoglobinbecomesoxygenated,thisinducesaconformationalorstructuralchangeinthewholecomplex,causingtheothersubunitstogainanincreasedaffinityforoxygen.Asaconsequence,theoxygenbindingcurveofhemoglobinissigmoidal,orS-shaped,asopposedtothenormalhyperboliccurveassociatedwithnoncooperativebinding.Cooperative第三十四页，共八十九页，编辑于2023年，星期二Theligand-bindingsitesarecomposedofbothhigh-andlowstabilitysegments,soaffinityforligandisrelativelylow.(a)Intheabsenceofligand,theredsegmentsarequiteflexibleandtakeupavarietyofconformations,fewofwhichfacilitateligandbinding.Thegreensegmentsaremoststableinthelow-affinitystate.(b)Thebindingofligandtoonesubunitstabilizesahigh-affinityconformationofthenearbyredsegment(nowshowningreen),inducingaconformationalchangeintherestofthepolypeptide.Thisisaformofinducedfit.Theconformationalchangeistransmittedtotheothersubunitthroughprotein-proteininteractions,suchthatahigher-affinityconformationofthebindingsiteisstabilizedintheothersubunit.Asecondligandmoleculecannowbindtothesecondsubunit,withahigheraffinitythanthebindingofthefirst,givingrisetotheobservedpositivecooperativity.Structuralchangesinamultisubunitproteinundergoingcooperativebindingtoligand.第三十五页，共八十九页，编辑于2023年，星期二Forexample,intheupperleftofthefourhemesshown,oxygenbindscausestheironatomtomovebackwardintothehemetugingthehistidineresiduecloser

pullsontheproteinchainholdingthehistidine.Aschematicvisualmodelofoxygenbindingprocess第三十六页，共八十九页，编辑于2023年，星期二Thebindingandreleaseofoxygen(shownnowingreen)illustratesthestructuraldifferencesbetweenoxy-anddeoxyhemoglobin,respectively.Thehistidinewhichispulledbymotionoftheironatom,isshownhereinyellow.Anotherviewofhowbindingandreleaseofligandsinducesaconformational(structural)changeinhemoglobin.Onlyoneofthefourhemegroupsisshown,第三十七页，共八十九页，编辑于2023年，星期二MechanismoftheT-Rtransitioninhemoglobin第三十八页，共八十九页，编辑于2023年，星期二SomeionpairsthatstabilizetheTstateofdeoxyhemoglobin第三十九页，共八十九页，编辑于2023年，星期二Severaltheorieshavebeendevelopedtodescribeallosterictransitions.Theymaybegenerallygroupedintothefollowingthreeclasses:第四十页，共八十九页，编辑于2023年，星期二characterizedbytheco-existenceofmoleculeswithsomesubunitsintheweak-bindingstateandsomeinthestrongSequentialmodel,theprototypeforthemodelsthatdescribeallosterictransitionsKoshland,Nemethy,andFilmer(KNFmodel)第四十一页，共八十九页，编辑于2023年，星期二Theshiftisaconcerted(协同的)oneConcertedmodelMonod,Wyman,andChangeux(MWCmodel)第四十二页，共八十九页，编辑于2023年，星期二AdaptedfromG.K.Ackersetal.,Science(1992)255:54-63.thechangesintertiarystructurethataccompanyoxygenbindingcanbetolerateduptoacertainpointbeforetheT-Rswitchoccurs.Specifically,wheneveronesiteisoccupiedoneachofthetwoα-βdimers,themoleculeasawholeadoptstheRquaternarystructureMultistatemodel第四十三页，共八十九页，编辑于2023年，星期二HemoglobinbindingO2inlung(high[O2])andleaseitintissue(low[O2])Asigmoid(cooperative)bindingcurve.CooperativebindingrendershemoglobinmoresensitivetothesmalldifferencesinO2concentrationbetweenthetissuesandthelungs,allowinghemoglobintobindoxygeninthelungs(wherepO2ishigh)andreleaseitinthetissues(wherepO2islow).AllostericEffecter:O2第四十四页，共八十九页，编辑于2023年，星期二Aplotoflog[θ/(1-θ)]versuslog[L]iscalledaHillplotTheslope(斜率)ofaHillplotisdenotedbynH,theHillcoefficient(希尔系数)Hillequation(希尔方程)希尔方程和希尔系数第四十五页，共八十九页，编辑于2023年，星期二TheoreticallynH=4WhennH＝1,thereisnoevidentcooperativity.ThemaximumdegreeofcooperativityobservedforhemoglobincorrespondsapproximatelytonH＝3.Notethatwhilethisindicatesahighlevelofcooperativity,nHislessthann,thenumberofO2-bindingsitesinhemoglobin.Thisisnormalforaproteinthatexhibitsallostericbindingbehavior.Hillplotsforthebindingofoxygentomyoglobinandhemoglobin.第四十六页，共八十九页，编辑于2023年，星期二OtherAllostericEffectorsbesidesO2:1,H+

2,CO3,CO24,BPG第四十七页，共八十九页，编辑于2023年，星期二ApHdropinthebloodinthecapillarieslowerstheoxygenaffinityofhemoglobin,allowingevenmoreefficientreleaseofthelasttracesofoxygen.TheresponseofhemoglobintochangesinpHiscalledtheBohreffect.TheoverallreactionmaybewrittenHb-4O2

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

(wheren>2)

Physiologically,thisreactionhastwoconsequences:First,inthecapillaries,hydrogenionspromotethereleaseofO2bydrivingthereactiontotheright.Then,whenthevenous(静脉)bloodrecirculatestothelungsorgills(腮),theoxygenationhastheeffectofreleasingtheH+byshiftingtheequilibriumtotheleft.This,inturn,tendstoreleaseCO2fromthebicarbonatedissolvedinthebloodbythereversalofthebicarbonatereaction:CO2+H2O<=>HCO3-+H+ThefreeCO2canthenbeexpired.theBohreffect第四十八页，共八十九页，编辑于2023年，星期二第四十九页，共八十九页，编辑于2023年，星期二Hemoglobin'soxygen-bindingcapacityisdecreasedinthepresenceofcarbonmonoxidebecausebothgasescompeteforthesamebindingsitesonhemoglobin,carbonmonoxidebindingpreferentiallyinplaceofoxygen.Thebindingofoxygenisaffectedbymoleculessuchascarbonmonoxide(CO)(forexamplefromtobaccosmoking抽烟,carexhaust汽车尾气

andincompletecombustioninfurnaces壁炉中的不充分燃烧).COcompeteswithoxygenatthehemebindingsite.HemoglobinbindingaffinityforCOis200timesgreaterthanitsaffinityforoxygen,meaningthatsmallamountsofCOdramaticallyreducehemoglobin'sabilitytotransportoxygen.WhenhemoglobincombineswithCO,itformsaverybrightredcompoundcalledcarboxyhemoglobin,whichmaycausetheskinofCOpoisoningvictimstoappearpinkindeath,insteadofwhiteorblue.WheninspiredaircontainsCOlevelsaslowas0.02%,headacheandnauseaoccur;iftheCOconcentrationisincreasedto0.1%,unconsciousnesswillfollow.Inheavysmokers,upto20%oftheoxygen-activesitescanbeblockedbyCO.AllostericEffecter:CO,Competitive第五十页，共八十九页，编辑于2023年，星期二Hemoglobinalsohascompetitivebindingaffinityforcyanide(CN-),sulfurmonoxide(SO),nitrogendioxide(NO2),andsulfide(S2-),includinghydrogensulfide(H2S).Allofthesebindtoironinhemewithoutchangingitsoxidationstate,buttheyneverthelessinhibitoxygen-binding,causinggravetoxicity.第五十一页，共八十九页，编辑于2023年，星期二CO第五十二页，共八十九页，编辑于2023年，星期二1)normalhemoglobin,2)hemoglobinfromananemic(贫血的)individualwithonly50%ofherhemoglobinfunctional,and3)hemoglobinfromanindividualwith50%ofhishemoglobinsubunitscomplexedwithCO.Severaloxygen-bindingcurves第五十三页，共八十九页，编辑于2023年，星期二Carbondioxideoccupiesadifferentbindingsiteonthehemoglobin.Carbondioxideismorereadilydissolvedindeoxygenatedblood,facilitatingitsremovalfromthebodyaftertheoxygenhasbeenreleasedtotissuesundergoingmetabolism.Thisincreasedaffinityforcarbondioxidebythevenous(静脉)bloodisknownastheHaldaneeffect.Throughtheenzymecarbonicanhydrase,carbondioxidereactswithwatertogivecarbonicacid,whichdecomposesintobicarbonateandprotons:CO2+H2O→H2CO3→HCO3-+H+

AllostericEffecter:CO2第五十四页，共八十九页，编辑于2023年，星期二ThisreactionproducesH+,contributingtotheBohreffectCO2第五十五页，共八十九页，编辑于2023年，星期二OxygenBindingtoHemoglobinIsRegulatedby2,3-Bisphosphoglycerate(BPG)2,3-二磷酸甘油酸AllostericEffecter:BPG第五十六页，共八十九页，编辑于2023年，星期二Bindingof2,3-bisphosphoglyceratetodeoxyhemoglobinBPGbindsatasitedistantfromtheoxygen-bindingsiteandregulatestheO2-bindingaffinityofhemoglobininrelationtothepO2inthelungs.第五十七页，共八十九页，编辑于2023年，星期二EffectofBPGonthebindingofoxygentohemoglobin.1)HemoglobinbindstooxygenquitetightlywhenBPGisentirelyabsent,andthebindingcurveappearstobehyperbolic.2)Atsealevel,hemoglobinisnearlysaturatedwithO2inthelungs,butonly60%saturatedinthetissues,sotheamountofoxygenreleasedinthetissuesiscloseto40%ofthemaximumthatcanbecarriedintheblood.3)Athighaltitudes,O2deliverydeclinesbyaboutone-fourth,to30%ofmaximum.AnincreaseinBPGconcentration,however,decreasestheaffinityofhemoglobinforO2,sonearly40%ofwhatcanbecarriedisagaindeliveredtothetissues.TheBPGconcentrationinnormalhumanbloodis:about5mMatsealevelandabout8mMathighaltitudes.第五十八页，共八十九页，编辑于2023年，星期二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第五十九页，共八十九页，编辑于2023年，星期二第六十页，共八十九页，编辑于2023年，星期二Distributionofmutationsinhumanhemoglobins.第六十一页，共八十九页，编辑于2023年，星期二uniform,cup-shaped,normalerythrocytesthevariablyshapederythrocytesseeninsickle-cellanemiawhichrangefromnormaltospinyorsickle-shaped.Sickle-CellHemoglobinSickle-cellhemoglobinhasgaineditsnamebecauseitcausesredbloodcellstoadoptanelongated,sickleshapeatlowoxygenconcentrations,duetothetendencyofthemutanthemoglobin,initsdeoxygenatedstate,toaggregateintolong,rodlikestructures.Theelongatedcellstendtoblockcapillaries,causinginflammationandconsiderablepain.Evenmoreseriousisthatthesickledcellsarefragile.Theirbreakdownleadstoananemiathatleavesthevictimsusceptibletoinfectionsanddiseases.Individualswhoarehomozygousforthesickle-cellmutationoftendonotsurviveintoadulthood,andthosewhodoareseriouslydebilitated.第六十二页，共八十九页，编辑于2023年，星期二Insicklecellhemoglobin(HbS)glutamateinposition6(inbetachain)ismutatedtovaline.Thischangeallowsthedeoxygenatedformofthehemoglobintosticktoeachother.第六十三页，共八十九页，编辑于2023年，星期二Asaresultofthischange,deoxyhemoglobinShasahydrophobicpatchonitssurface,whichcausesthemoleculestoaggregateintostrandsthatalignintoinsolublefibers.第六十四页，共八十九页，编辑于2023年，星期二SickleCellAdvantageIndividualsheterozygousforsickle-cellhemoglobinhaveahigherresistancetomalaria(疟疾)thanthosewhodonotcarrythesickle-cellmutation.Themalarialparasitespendsaportionofitslifecycleinhumanredcells,andtheincreasedfragilityofthesickledcells,eveninheterozygousindividuals,tendstointerruptthiscycle.Heterozygous(杂合的)individualshaveahighersurvivalrate-andthereforeabetterchanceofpassingontheirgenes-inmalaria-infested(滋生)regions.However,thehighincidenceofthesegenesinthepopulationleadstothebirthofmanypeoplewhoarehomozygous(纯合子)forthemutanttrait.第六十五页，共八十九页，编辑于2023年，星期二Whenredcellsreachtheendoftheirlifeduetoagingordefects,theyarebrokendown,thehemoglobinmoleculeisbrokenupandtheirongetsrecycled.Whentheporphyrinringisbrokenup,thefragmentsarenormallysecretedinthebilebytheliver.Thisprocessalsoproducesonemoleculeofcarbonmonoxideforeverymoleculeofhemedegraded.Thisisoneofthefewnaturalsourcesofcarbonmonoxide(CO)productioninthehumanbody,andisresponsibleforthenormalbloodlevelsofcarbonmonoxideeveninpeoplebreathingpureair.Theothermajorfinalproductofhemedegradationisbilirubin(胆红素).Increasedlevelsofthischemicalaredetectedinthebloodifredcellsarebeingdestroyedmorerapidlythanusual.Improperlydegradedhemoglobinproteinorhemoglobinthathasbeenreleasedfromthebloodcellstoorapidlycanclogsmallbloodvessels,especiallythedelicatebloodfilteringvesselsofthekidneys(肾脏),causingkidneydamage.Degradationinvertebrateanimals第六十六页，共八十九页，编辑于2023年，星期二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第六十七页，共八十九页，编辑于2023年，星期二3、ComplementaryInteractionsbetweenProteinsandLigands:免疫系统和免疫球蛋白第六十八页，共八十九页，编辑于2023年，星期二December27,1822–September28,1895LouisPasteur第六十九页，共八十九页，编辑于2023年，星期二Whenaforeignsubstance-avirus,abacterium,orevenaforeignprotein-invadesthetissuesofahighervertebrate(脊椎动物)(likeahuman),theorganismdefendsitselfbywhatiscalledtheimmuneresponse(免疫应答，免疫反应).Theimmuneresponseisafirstlineofdefenseagainstinfectionandprobablyagainstcancercellsaswell.第七十页，共八十九页，编辑于2023年，星期二Theimmuneresponsehastwofacets(形式):1.Humoralimmuneresponse(体液免疫应答)-Lymphaticcells(淋巴细胞)calledBlymphocytessynthesizespecificimmunoglobulin(免疫球蛋白)moleculesthatareexcreted(分泌)fromthecellandbindtotheinvadingsubstance.Bindingeitherprecipitatestheforeignsubstanceormarksitfordestructionbycellscalledmacrophages(巨噬细胞).2.Cellularimmuneresponse(细胞免疫应答)-LymphaticcellscalledTlymphocytes,bearingimmunoglobulin-likemoleculesontheirsurfaces,recognizeandkillforeignoraberrant(异常的)cells.第七十一页，共八十九页，编辑于2023年，星期二AntigensandAntibodies:Theforeignsubstancethatelicits(引起)animmuneresponseiscalledtheantigen(抗原).Aspecificimmunoglobulinthatbindstotheantigeniscalledtheantibody(抗体).Iftheinvadingparticleislarge,likeacell,avirus,oraprotein,manydifferentantibodiesmaybeelicited,eachtypebindingspecificallytoanantigenicdeterminant(orepitope,抗原决定簇)onthesurfaceoftheparticle.第七十二页，共八十九页，编辑于2023年，星期二ImmunoglobulinStructure–Eachimmunoglobulinmonomerconsistsoffourchains,twoheavychains(M=53,000each)andtwolightchains(M=23,000each),heldtogetherbydisulfidebonds.Ineachchainareconstantdomains(identicalinallantibodiesofagivenclass)andavariabledomain.Variationsintheaminoacidsequence(andthereforethetertiarystructure)ofthevariabledomainsofthelightandheavychainsconfer(赋予)themultitudinous(多种多样的)specificitiesofantigenstodifferentdeterminants.第七十三页，共八十九页，编辑于2023年，星期二Antigenicdeterminants(抗原决定簇)PrecipitatingAntigens-Alargeprotein,avirus,orabacterialcellhasmanydifferentpotentialantigenicdeterminantsonitssurfacethatantibodymoleculescanbind,therebyprecipitatingtheantigen.Antigenswithonlyonedeterminant,willbindtoanantibody,butnotprecipitate.Precipitationalsorequirestheantibodytobebivalent(tohavetwobindingsites).第七十四页，共八十九页，编辑于2023年，星期二SchematicmodelsofanantibodymoleculeandaFabfragmentBycarefulproteolysis(蛋白酶水解),itispossibletocleaveantibodiesatthehingeregiontoproduceFabfragmentswithonlyonebindingsiteeach.Suchfragmentswillbind,butnotprecipitateantigen.FabFabFc第七十五页，共八十九页，编辑于2023年，星期二CDR:complementaritydeterminingregions第七十六页，共八十九页，编辑于2023年，星期二Humanshavefiveclassesofimmunoglobuli