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Lecture15:MolecularStructureoftheCellMembrane15.1. IntroductionWelcometothislectureonmolecularstructureofthecellmembrane.Inthislecture,wearegoingtolookatthemoleculesthatmakeupthecompositionofthecellmembrane.Wewilldiscussthefluid-mosaicmodelofthecellmembrane.Wewillalsolookatthedifferentarrangementsofthemembraneproteins.Finally,wewillendthislecturebylookingatthemajorfunctionsofthemembraneintegralproteins.Ihopethatyouwillenjoythelectureanditassistsyouinlearningaboutthecellmembrane.15.2. Objectives

Attheendofthislecture,youshouldbeableto

1.Explainwhythefluid-mosaicmodelofthecellmembraneisthewidelyacceptedmodelofthecellmembrane.2.Describethearrangementsofperipheralandintegralmembraneproteins.3.Listthe5majorfunctionsofintegralproteins.

15.3. Fluid-MosaicModeloftheCellMembraneInthissectionofthelecture,wewilldiscussthefluid-mosaicmodelofthecellmembrane.Thefluid-mosaicmodel,isbasedonthepaperpublishedbySingerandNicolsonin1972,inwhichtheyreviewedtheirstudiesaswellasotherstudiesonthecompositionandfunctionalpropertiesofthecellmembrane.Theyproposedthattheonlymodelofthecellmembrane,consistentwiththeexperimentalevidencewasafluid-mosaicmodel.Inthismodel,thelipidsformedthematrixofthecellmembrane,withinwhichwereembeddedproteinmolecules.Inthis“sea”oflipids,therewereproteinsthateitherspannedtheentirecellmembraneorwereassociatedeitherwiththeinnerorouterleafletofthephospholipidbilayerofthecellmembrane.ThisshowninFigure15.1below.

Figure15.1.Thelipid-globularmosaicmodelwiththelipidprovidingthematrix.Source:SingerSJandNicolsonGL.TheFluidModeloftheStructureofCellMembranes.Science175:720-731(1972).

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Aswecanseeinfigure15.1,thelarge“potato”shapedstructuresareproteinmolecules.Thesecaneitherspanthewholecellmembraneorbeassociatedwithoneorotherleafletofthecellmembrane.Theroundballswithtailsarethephospholipidmolecules.Thephospholipidsmakethemembranefluidandtheproteinsprovidethemosaic,hencethetermFluid-MosaicModel.

Question:Whichmoleculemakesthematrixofthecellmembrane?

15.4. StructureandchemicalpropertiesofthephospholipidsSonowwewilllookatthelipidstounderstandhowthesemakethematrixofthecellmembraneandarrangethemselvesinabilayerformation.Themajorityofthelipidsinthecellmembranearephospholipids.Aphospholipidismadeupof3partsasshowninfigure15.2.(1)Ithasacentralbackbonemadeupofaglycerolmolecule,whichismakeupof3carbonatoms.(2)Attachedto2ofthe3carbonsoftheglycerolmoleculeareacylchains(Acylchainsaremadeupofchainsofcarbonatomslinkedbycovalentbonds).(3)Theremaining3thirdcarbonhasaphosphategroupattached–thatiswhyitiscalledaphospholipid.Nowtothephosphategroupdifferentmoleculescanbelinked.Ifwelookatfigure2,wecanseethataninositolsugargrouphasbeenattachedtothephosphategroupmakingaphospholipidcalledphosphatidylinositol.Similarly,otherphospholipidsarenamedaccordingtothegroupattachedtothephosphate.

Figure15.2.Structureofaphospholipidmoleculeshowingtheglycerolbackbone,theacylchains,thephosphatetowhichdifferentmoleculescanbe

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attached.Inthiscase,itisaninositolmoleculemakingaphosphatidylinositolmolecule.

Question:Infigure15.2,whatpartofthephospholipidisshownasroundballsinfig15.1?

Nowwehavetoconsiderhowphospholipidsbehaveinawateryenvironment,i.e.,anaqueoussolution.Phospholipidmoleculesarecalledamphipathicbecauseonepartofit“fears”water(hydrophobic)andotherpart“likes”water(hydrophilic).Theacylchainsprovidethehydrophobiccharacterwhilethephosphatepartprovidesthehydrophiliccharacter.Thesecharacteristicscauseaconflictwhenaphospholipidisinanaqueousenvironment,i.e.,howcanthe“fear”ofand“like”ofwaterbothbesatisfied.Infigure15.3,wethatthatphospholipidmoleculewillarrangethemselvesonthesurfaceofthewaterbyhavingthehydrophilicpartinthewaterandhydrophobicpartoutofthewater.Thisformsamonolayer.

Figure15.3.Whenphospholipidsareaddedtowater,theywillformamonolayeronthewatersurfacewithhydrophobiclipidtailsoutofthewaterandthehydrophilicheadgroupinthewater.Thissatisfiestheneedsofthehydrophobicandhydrophilicpartsofthephospholipids.Butwhathappenswhenthephospholipidsarecompletelysubmergedinanaqueoussolution.Inthissituation,the“conflict”isresolvedbyformingabilayerarrangement.Thismoleculararrangementisthermodynamicallystable,meaningnoenergyinputisnecessarytomaintainitsconformation.Asweseeinfigure15.4,bythisarrangement,theacylchain(lipidpart)formtheinteriorofthebilayerwheretheycaninteractwithotheracylchains.Aswaterisnotwelcomeinthisregion,thisregionmakesahydrophobicregion.

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Figure15.4.Inanaqueousenvironment,thephospholipidswillformabilayer,withwateronbothsidesandwaterfreeareainthemiddle.Alsowecanseeinfigure15.4,theoutsideandinsidefaceofthemembraneisincontactwiththewatermolecules,whichiswhatthehydrophilicportionofthephospholipidsliketodo.Sobythisarrangementtheconflictisresolved.Boththe“fears”ofand“likes”ofwaterofthephospholipidmoleculehavebeensatisfied.Inthenextlecture,whenwediscusshowionsandmoleculesmoveacrossthecellmembrane,wewilllearnthatthishydrophobicinteriorofthecellmembraneformsaformidableenergybarrierforthemovementofions,chargedmolecules,andwater-solublemoleculestocrossthemembrane.Nowwemaybewonderingwhysomepartsofthephospholipidmoleculelikewaterandanotherpartdonot?Theanswerliesinthecovalentbondsbetweentheatoms.Theacylchainsofthephospholipidhavenon-polarcovalentbonds;hencethesecarbonchainscannotinteractwithwatermolecules,whichhavepolarbonds.Ontheotherhand,thephosphateandgroupattachedtoithaspolarcovalentbondsthatcaninteractwithpolarwatermolecules.

Whatisthedifferencebetweenapolarandnon-polarcovalentbond?Betweenwhichatomsthatarelinkedbycovalentbondscantheretherebepolarbondsandnon-polarbonds?

Soinwater,thephospholipidmoleculehastofindawaysothatthehydrophilicpartcaninteractwithwaterandthehydrophobicpartcanstayawayfromwater.Theresult,inawateryfluid,isaphospholipidbilayer,whichmakesthematrixofthecellmembrane.

Question:Whycanoilsandfatnotdissolveinwater?

Theaveragewidthofacellmembraneis7.5nmwiththetwolayersofthephospholipidsmakingitswidth.

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Whilesofar,wehavefocusedonthephospholipidsasthesemakeupthemajorityoflipidmoleculesfoundinthecellmembrane,thereareotherlipids.Infigure15.5,wecanseethestructureoftheotherlipids:glycolipidsandcholesterol.Showninthesamefigureare3othermajortypesofphospholipids:phosphatidylinositols,phosphatidylserine,andphosphatidylcholine.(Phosphatidylethanolamine,the4thmajortypeismissinginthisfigure).

Rememberinnamingphospholipids,thelongfirstpartofthename(phosphatidyl-)isfortheacylchainpartandthesecondpartisforthemoleculeattachedtoitsphosphategroup.

Figure15.5.The6differenttypeslipidsthatarefoundinmostcellmembranes.(theimageforphosphatidylethanolamineisnotshownbutitisamajorphospholipidfoundinthecellmembrane)Thereisadifferenceincompositionoflipidsmakingtheouterleafletofthecellmembrane,i.e.,theonefacingtheextracellularfluidandtheinnerleafletfacingtheintracellularfluid.Theouterleafletismadeupmainlyofphosphatidylcholinewithsphingomyelinandglycolipids.Theinnerleaflethasphosphatidylethanolamine,phosphatidylserineandphosphatidylinositol.Wewillcomeacrossthephospholipid,phosphatidylinositol,inlecturesonCellSignaling.Therewewilllearnthatthebondbetweenthecarbonoftheglycerol

Glycosphingolipid-

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backboneofthephospholipidandphosphateisbrokenbyanenzyme,phospholipaseC,toproduce2molecules:inositoltriphosphate(IP3)anddiacylglyerol(DAG).Theseactassecondmessengers.Onafinalpointwithregardtophospholipids,theiracylchainscanbesaturatedornot.Wereadinnewspaperandmagazinearticlesaboutheartdiseaselinkedtowhetherthefatsweeataresaturatedornot.Itseemsthatsaturatedfatsarenotgoodforourheart.(Fatsandoilscontainalotoftriglycerides,i.e.,glycerolmoleculewith3acylchains).Sowhatisasaturatedfat?Itisafatwherethebondsbetweenthecarbonatomsintheacylchainareallsingle.Inunsaturatedfats,oneormorebondsintheacylcarbonchaincanhaveadoublebonds.Becausethesaturatedacylchainscaninteractcloselywitheachother,themembranefluidityisreduced.Forunsaturatedacylchains,thekinksorbendsinthecarbonchain,preventcloseinteractionsothemembraneismorefluid.Cholesterol,whichwehaveheardaboutalotaboutinrelationtoheartdisease,alsohasaneffectonthecellmembranefluidity.Duetoitsrigidplanarringstructure,iteasilyslipsinbetweentheacylchainsofneighboringphospholipids.(seefigure15.5toreviewthestructure).Whenthecholesterolconcentrationislow,themembranefluidityisreducedbutathigherconcentrationcholesterolincreasesmembranefluidity.Inthelecturesonreproductivephysiology,wewillalsocomeacrosscholesterolasitisaprecursormoleculeforthemajorsexsteroidhormones:estrogen,progesterone,estradiol-17β,andtestosterone.Cholesterolwillalsobediscussedinlecturesongastrointestinalphysiologyandincardiovascularphysiology.

Ithasnowbecomecommontohaveone’scholesterollevelmeasured.Why?

15.5. PermeabilityofaphospholipidbilayerFromwhatwehavediscussedsofar,weknowthatthephospholipidbilayerhasamiddlepart,whichhasnowater–itisahydrophobicenvironment.Figure15.6isanelectronmicroscopeoftwocellmembranes.Betweenthecellmembranesistheintracellularspace.Whenwelookcloselyatthecellmembranes,wecanseetwodarklineswithalightlinebetweenthem.Thedarkthinoutsidelineisduetothehydrophilicheadgroupsofthephospholipids,andtheregionbetweentheselines,thelightarea,isduetotheacylchainsofthephospholipidmolecules;thisishydrophobicregionofthecellmembrane.

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Figure15.6.Transmissionelectronmicroscopepictureofacellmembrane.BloomandFawcett,1994,Springer.Whilethecellmembraneisonly5-6nminwidth,itactsasaverylargeenergybarrierforions,chargedmolecules,andwater-solublemolecules.Forustounderstandwhythecellmembraneissuchalargeenergybarrier,weneedtoknowhowionsandchargedmoleculesinteractwiththepolarwatermolecules.Inwater,ionsandchargedmoleculesaswellaswater-solublemoleculeshavecloudorshieldofwatermoleculesattachedtothem.Iftheionorchargedmoleculeispasstothroughahydrophobicregion,thesewatermoleculeshavetoberemovedduringtheirpassageacrossthecellmembrane.Thisrequiresaverylargeamountofenergy,whichisnotavailable.Soasanionorachargedmoleculeorawatersolublemoleculecannotsheditswatermoleculestocrossalipidbilayer,itmakesalipidbilayerenergeticallyimpermeabletoions,chargedmolecules,water-solublemolecules.Thelipidbilayerisalsoimpermeabletomanywater-solublemoleculessuchproteins,nucleiacids,sugars,andnucleotidesduetotheirlargesize.However,thecellmembraneispermeabletothesmall-unchargedwater-solublemolecules,e.g.,oxygen,carbondioxide,ammonia,urea,andwater.

Whichtypesofmoleculescancrossthelipidbilayer?Whatarethechemicalpropertiesofthesemolecules?

Ithasbeenmentionedinthepreviouslecturesthations,chargedmoleculesandlargewater-solublemoleculesdocrossthecellmembrane.Afterall,cellsneedtotakeinglucose,aminoacidsandothermaterialandexcretemetabolicwasteintheinterstitialfluid.Themechanismbywhichthisisdonewillbeexplainedindetailinthenextlecture.Herewewilllookattheroleofintegralmembraneproteins,manyofwhichareinvolvedinregulationofthemovementofionsandmoleculesacrossthecellmembrane.15.6. Featuresofperipheralandintegralmembraneproteins

Besidesthelipids,thecellmembranealsocontainsproteins.Thesearedividedinto2classes:peripheralandintegral.

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Peripheralproteinscanbeeasilyremovedfromthemembraneandarenotembeddedorcovalentlylinkedtothelipidbilayer.Instead,theyinteractandadheretoproteinsthatareembeddedinorspanthecellmembrane,i.e.,integralproteins.Peripheralproteinscanbepresentbothontheextracellularandintracellularfaceofthecellmembrane.

Integralproteinsontheotherhandareembeddedinorspanthelipidbilayerandveryhardtoseparatefromthecellmembrane.Asyoucanseefromfigure15.7,integralproteinscanbefoundineithertheouterorinnerleafletofthecellmembraneorspanningtheentirewidthofthecellmembrane.

Figure15.7.Differentarrangementsoftheperipheralandintegralmembraneproteinsinthelipidbilayerofacellmembrane.Infigure15.7,bluecoloredproteinsareperipheralproteinsthatadheretointegralproteinsshowninorange.Integralproteinscanhaveoneormoresegmentsspanningthecellmembrane.Notealsothecovalentlinkageofproteinswithmembranelipids(ontheright-sideofthefigure).Wealsoseethatintegralproteinshaveanextracellulardomainandanintracellulardomain.Alsothesegmentsoftheproteinpassingthroughthemembranehaveahelicalshape.Someproteinshaveonlyonesegmentwhileothershavemorethanoneproteinsegmentpassingthroughthecellmembrane.Nowwemaywonderhowaproteinisabletointeractbothwithhydrophobicenvironmentintheinteriorofthemembraneandtheaqueoussolutiononeithersideofthecell.Wheredoesitsamphipathiccharactercomefrom?Proteinsaremadeupofaminoacidsandsomeaminoacidshavehydrophobicproperties.Thesemakeupthesegmentthatspansthemembrane.Theirhydrophobicpreferringsidechainscaninteractwiththeacylchainsofthecell

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membranephospholipids.Theirhydrophilicaminoacidsarepositionedontheinsideofthehelixsotheycreateahydrophilicenvironment.

Listtheaminoacidsthatarehydrophobicsidegroupsandthosethathavehydrophilicsidegroups?

Likephospholipids,membraneproteinsarefreetodiffusealongtheplanofthecellmembrane.Inanelegantexperimentalstudy,donein1970’s,FryeandEdidinlabeledcellmembraneproteinsofmousecellswithonecoloredmarkerandhumancellswithanothercoloredmarker.Thentheyfusedthecellstogetherandobservedthatafter30-40mins,themembraneproteinsofmouseandhumancellsweremixed.TheprocessoftheexperimentisshowninFigure15.8.Ifthemembraneproteinswerenotfreetodiffuseinthecellmembrane,thecolorswouldnothavemixed.Thisexperimentandothershaveshownthat,ingeneral,membraneproteinsarenotanchorednortieddowntoparticularareaofthecellmembrane.Whenneededtheproteincanbeanchoredtoaparticularsiteonthecellsurface,e.g.,thelocalizationofacetylcholinereceptors(AchR)atthepost-synapticregionoftheneuromuscularjunction.WewilllearnalotmoreaboutAchRinlecturesonsynapticphysiology.

Figure15.8.SchematicrepresentationofFryeandEdidinexperiment.Theytooktwomiceandhumancellsandmarkedtheproteinsinthecellmembranewithacolouredtag.Afterfusionofthetwocells,theyfoundthatthecolouredtagswereintermixed.Theonlylogicalconclusionofthisresultwasthatproteinsarefreetodiffusealongtheplaneofthecellmembrane.

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LookingatFigure15.8,whatresultwouldhavebeenexpectedifmembraneproteinswerenotfreetodiffusealongtheplaneofthecellmembrane?

Manyimportantproteinsinthecellmembranearenotsingleproteinmoleculesbutaremadeupofmultipleproteinmoleculescalledsub-units.Theseformmultimericproteincomplexes.Thesemultimericproteinscanbemadeupofonlyasingletypesofproteinmoleculeorcanbeamixtureof2ormoredifferentproteinmolecules.Byhavingsubunits,amulitmericproteincanhavethedifferentsubunitscarryoutdifferentfunctions,e.g.,oneproteinsub-unitcanbeabindingsiteforaligandwhileanothercanactasanenzyme,whichisactivatedwhentheligandbindstotheothersub-unit.Whenwelearnaboutcellsignalingandorganfunction,wewillcomeacrossmanyexamplesofmultimericproteinsinphysiologicalprocesses.15.7. FiveMajorfunctionscarriedoutbymembraneproteinsInthefollowinglist,themajorclassesoffunctionthatarecarriedoutbymembraneproteinsislisted.Thefunctionsareonlyexplainedbrieflyasinlaterlectures,wewilldiscussinmoredetailthemechanismoftheirfunctionandtheroletheirfunctionplaysintheoverallworkingofphysiologicalsystems.

15.7.1.Roleincell-to-cellcommunicationAswearemulticellularorganisms,communicationbetweenourcellsiscrucialforcoordinatingresponseandchangesinfunctionneededtomaintainhomeostasis.Ourcellscommunicatewitheachotherpredominantlywithchemicalsignals.Exceptforsteroidandthyroidhormones,andotherlipidsolublesignalingmoleculesthatcancrossthelipidbilayer,otherchemicalsignalsneedtohavereceptorproteininthecellmembranewithwhichtheycaninteracttoinfluencethecellularactivity.15.7.2ReceptorsThesearemembraneproteinsthatbindthechemicalmessengers(signals).Theyformaveryimportantclassofmembraneproteins.Theyconveythe“information”intothecellbymodificationsoftheirproteinstructure.Thebindingofthesignalmoleculetotheextracellulardomaincausesconformationalchangesoftheproteinarrangementthatextendthroughthecellmembranetotheintracellulardomainofthereceptor.Theintracellulardomaincanbecomeenzymaticallyactiveorinteractwithothercytoplasmicproteins.Wewilllearnalotmoreaboutthiswhenwestarttolearnaboutcellsignalingandsecondmessengers,topicsoflaterlectures.15.7.3.AdhesionmoleculesAnotherimportantclassofmembraneproteinsareadhesionmolecules.Theseareinvolvedinanumberofdifferentprocessessuchasdirectingmigrationofimmunecells,axonalguidanceinthedevelopingnervous

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system,regulationofcellshape,andgrowth.Theymakephysicalconnectionswiththeextracellularmatrixandwithothercells.Likeproteinreceptormolecules,adhesionmoleculescansendsignalsintothecell.

Thesemoleculesarealsomedicallyimportantaslossofcell-cellandcell-matrixadhesionisahallmarkofmetastatictumorcells.Integrinsorcellmatrixadhesionmoleculesarealargefamilyoftransmembraneproteinsthatlinkcellstocomponentsoftheextracellularmatrix,e.g.,fibronectinandlaminin.Thereareseveralsuperfamiliesofadhesionmolecules:Cadherins-Ca2+-dependentcelladhesionmoleculeswhichhavealargeextracellulardomainthatbindsCa2+,Ca2+-independentneuralcelladhesionmolecules(N-CAMs)whicharemembersoftheimmunoglobulinsuperfamily.

Whatmakesmetastaticcancercellssuchaterrorforapersonwithcancer?

Ifthecancercellsdidnotlosstheircell-to-cellconnections,wouldthetumorbelocalizedordispersed?

15.7.4.Pores,Channels,Carriers,andPumps.

Poresandchannelsaretransmembraneproteinsthatprovidepassagewayforwater,specificions,andothermoleculestoflowpassivelydowntheirelectrochemicalgradienteitherintooroutofthecell.Carrierscaneitherfacilitatethetransportofaspecificmoleculeacrossthemembraneorcouplethetransportofamoleculetothatofothersolutes.Pumpsareenzymesthatusetheenergyderivedfromadenosinetriphosphate(ATP)totransportsubstancesintooroutofcellsagainsttheirelectrochemicalgradients.Youwillfindthattherearemanykindsofpumpswhicharedescribedinthenextlecture.Somepumps,liketheNa/KATPase,arevitalforcellsurvivalastheseareimportantfortheregulationofcellvolume.

15.7.5.IntegralsignalingproteinslocatedinthecytoplasmicfaceofthecellmembraneTheseproteins,whicharesoluble,arelinkedtolipidsinthemembrane.Theyplayanimportantroleincellsignaling.Examplesincludeguanosinetriphosphate(GTP)–bindingproteins(G-proteins),kinases,andoncogene.

15.8. Summary

Inthislecture,wewereexplainedsomeofthechemistryandphysicsunderlyingthebilayerorganizationofthecellmembraneandwhyfluid-mosaicmodelisthebestmodelwehaveofacellmembrane.Wealsolearntthelipidbilayeris

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impermeabletoions,chargedmolecules,andlargewater-solublemolecules,thereforehastobepathwaysandmechanismformovingthesesubstancesintoandoutofthecell.Thisisdonebyintegralmembraneproteins.Wealsolearntthatintegralproteinshaveotherfunctionsbesidestransport.Inthenextlecture,wewillgointomoredetaileddiscussionofhowthemembraneproteinscarrytransportfunctionformovementofsubstancesacrossthecellmembrane,andwhythisisimportantforustoknow,asthiswillbeveryusefulforuswhenwestudythefunctionoforgansystemsofthebodyintheothermodulesonmedicalphysiology.Figurenicelysummariesthestructureandcompositionofacellmembrane.

Figure15.9.Aschematicdiagramofthecellmembraneshowingthelipidbilayermatrixwithinwhicharetheproteinmoleculesthateitherspanthewidthofthecellmembraneorformperipheralattachments.(http://www.rsc.org/Education/Teachers/Resources/cfb/cells.htm

15.9. ReadingandReferences

WalterF.BoronandEmileL.Boulpaep.MedicalPhysiology:ACellularandMolecularApproach.(2012).Chapter2.SaundersElsevierSingerSJandNicolsonGL.TheFluidMosaicModeloftheStructureofCellMembranes.Science175(4023):720-731(1972)