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Lecture15:MolecularStructureoftheCellMembrane 15.1. Introduction Welcometothislectureonmolecularstructureofthecellmembrane.Inthis lecture,wearegoingtolookatthemoleculesthatmakeupthecompositionof thecellmembrane.Wewilldiscussthefluid-mosaicmodelofthecellmembrane. Wewillalsolookatthedifferentarrangementsofthemembraneproteins. Finally,wewillendthislecturebylookingatthemajorfunctionsofthe membraneintegralproteins.Ihopethatyouwillenjoythelectureanditassists youinlearningaboutthecellmembrane. 15.2. Objectives Attheendofthislecture,youshouldbeableto 1.Explainwhythefluid-mosaicmodelofthecellmembraneis thewidelyacceptedmodelofthecellmembrane. 2.Describethearrangementsofperipheralandintegral membraneproteins. 3.Listthe5majorfunctionsofintegralproteins. 15.3. Fluid-MosaicModeloftheCellMembrane Inthissectionofthelecture,wewilldiscussthefluid-mosaicmodelofthecell membrane. Thefluid-mosaicmodel,isbasedonthepaperpublishedbySingerandNicolson in1972,inwhichtheyreviewedtheirstudiesaswellasotherstudiesonthe compositionandfunctionalpropertiesofthecellmembrane.Theyproposedthat theonlymodelofthecellmembrane,consistentwiththeexperimentalevidence wasafluid-mosaicmodel.Inthismodel,thelipidsformedthematrixofthecell membrane,withinwhichwereembeddedproteinmolecules.Inthis“sea”of lipids,therewereproteinsthateitherspannedtheentirecellmembraneorwere associatedeitherwiththeinnerorouterleafletofthephospholipidbilayerofthe cellmembrane.ThisshowninFigure15.1below. Figure15.1.Thelipid-globularmosaicmodelwiththelipidprovidingthe matrix.Source:SingerSJandNicolsonGL.TheFluidModeloftheStructureof CellMembranes.Science175:720-731(1972). 1 Aswecanseeinfigure15.1,thelarge“potato”shapedstructuresareprotein molecules.Thesecaneitherspanthewholecellmembraneorbeassociatedwith oneorotherleafletofthecellmembrane.Theroundballswithtailsarethe phospholipidmolecules. Thephospholipidsmakethemembranefluidandtheproteinsprovidethe mosaic,hencethetermFluid-MosaicModel. Question:Whichmoleculemakesthematrixofthecell membrane? 15.4. Structureandchemicalpropertiesofthephospholipids Sonowwewilllookatthelipidstounderstandhowthesemakethematrixofthe cellmembraneandarrangethemselvesinabilayerformation. Themajorityofthelipidsinthecellmembranearephospholipids.A phospholipidismadeupof3partsasshowninfigure15.2.(1)Ithasacentral backbonemadeupofaglycerolmolecule,whichismakeupof3carbonatoms. (2)Attachedto2ofthe3carbonsoftheglycerolmoleculeareacylchains(Acyl chainsaremadeupofchainsofcarbonatomslinkedbycovalentbonds).(3)The remaining3thirdcarbonhasaphosphategroupattached–thatiswhyitis calledaphospholipid.Nowtothephosphategroupdifferentmoleculescanbe linked.Ifwelookatfigure2,wecanseethataninositolsugargrouphasbeen attachedtothephosphategroupmakingaphospholipidcalled phosphatidylinositol.Similarly,otherphospholipidsarenamedaccordingtothe groupattachedtothephosphate. Figure15.2.Structureofaphospholipidmoleculeshowingtheglycerol backbone,theacylchains,thephosphatetowhichdifferentmoleculescanbe 2 attached.Inthiscase,itisaninositolmoleculemakingaphosphatidylinositol molecule. Question:Infigure15.2,whatpartofthephospholipidis shownasroundballsinfig15.1? Nowwehavetoconsiderhowphospholipidsbehaveinawateryenvironment, i.e.,anaqueoussolution.Phospholipidmoleculesarecalledamphipathic becauseonepartofit“fears”water(hydrophobic)andotherpart“likes”water (hydrophilic).Theacylchainsprovidethehydrophobiccharacterwhilethe phosphatepartprovidesthehydrophiliccharacter.Thesecharacteristicscausea conflictwhenaphospholipidisinanaqueousenvironment,i.e.,howcanthe “fear”ofand“like”ofwaterbothbesatisfied. Infigure15.3,wethatthatphospholipidmoleculewillarrangethemselvesonthe surfaceofthewaterbyhavingthehydrophilicpartinthewaterandhydrophobic partoutofthewater.Thisformsamonolayer. Figure15.3.Whenphospholipidsareaddedtowater,theywillformamonolayer onthewatersurfacewithhydrophobiclipidtailsoutofthewaterandthe hydrophilicheadgroupinthewater.Thissatisfiestheneedsofthehydrophobic andhydrophilicpartsofthephospholipids. Butwhathappenswhenthephospholipidsarecompletelysubmergedinan aqueoussolution.Inthissituation,the“conflict”isresolvedbyformingabilayer arrangement.Thismoleculararrangementisthermodynamicallystable,meaning noenergyinputisnecessarytomaintainitsconformation.Asweseeinfigure 15.4,bythisarrangement,theacylchain(lipidpart)formtheinteriorofthe bilayerwheretheycaninteractwithotheracylchains.Aswaterisnotwelcome inthisregion,thisregionmakesahydrophobicregion. 3 Figure15.4.Inanaqueousenvironment,thephospholipidswillformabilayer, withwateronbothsidesandwaterfreeareainthemiddle. Alsowecanseeinfigure15.4,theoutsideandinsidefaceofthemembraneisin contactwiththewatermolecules,whichiswhatthehydrophilicportionofthe phospholipidsliketodo.Sobythisarrangementtheconflictisresolved.Boththe “fears”ofand“likes”ofwaterofthephospholipidmoleculehavebeensatisfied. Inthenextlecture,whenwediscusshowionsandmoleculesmoveacrossthe cellmembrane,wewilllearnthatthishydrophobicinteriorofthecellmembrane formsaformidableenergybarrierforthemovementofions,chargedmolecules, andwater-solublemoleculestocrossthemembrane. Nowwemaybewonderingwhysomepartsofthephospholipidmoleculelike waterandanotherpartdonot?Theanswerliesinthecovalentbondsbetween theatoms.Theacylchainsofthephospholipidhavenon-polarcovalentbonds; hencethesecarbonchainscannotinteractwithwatermolecules,whichhave polarbonds.Ontheotherhand,thephosphateandgroupattachedtoithaspolar covalentbondsthatcaninteractwithpolarwatermolecules. Whatisthedifferencebetweenapolarandnon-polarcovalent bond?Betweenwhichatomsthatarelinkedbycovalentbonds cantheretherebepolarbondsandnon-polarbonds? Soinwater,thephospholipidmoleculehastofindawaysothatthehydrophilic partcaninteractwithwaterandthehydrophobicpartcanstayawayfromwater. Theresult,inawateryfluid,isaphospholipidbilayer,whichmakesthematrixof thecellmembrane. Question:Whycanoilsandfatnotdissolveinwater? Theaveragewidthofacellmembraneis7.5nmwiththetwolayersofthe phospholipidsmakingitswidth. 4 Whilesofar,wehavefocusedonthephospholipidsasthesemakeupthe majorityoflipidmoleculesfoundinthecellmembrane,thereareotherlipids.In figure15.5,wecanseethestructureoftheotherlipids:glycolipidsand cholesterol.Showninthesamefigureare3othermajortypesofphospholipids: phosphatidylinositols,phosphatidylserine,andphosphatidylcholine. (Phosphatidylethanolamine,the4thmajortypeismissinginthisfigure). Rememberinnamingphospholipids,thelongfirstpartofthe name(phosphatidyl-)isfortheacylchainpartandthesecond partisforthemoleculeattachedtoitsphosphategroup. Glycosphingolipid- Figure15.5.The6differenttypeslipidsthatarefoundinmostcellmembranes. (theimageforphosphatidylethanolamineisnotshownbutitisamajor phospholipidfoundinthecellmembrane) Thereisadifferenceincompositionoflipidsmakingtheouterleafletofthecell membrane,i.e.,theonefacingtheextracellularfluidandtheinnerleafletfacing theintracellularfluid.Theouterleafletismadeupmainlyofphosphatidylcholine withsphingomyelinandglycolipids.Theinnerleaflethas phosphatidylethanolamine,phosphatidylserineandphosphatidylinositol. Wewillcomeacrossthephospholipid,phosphatidylinositol,inlecturesonCell Signaling.Therewewilllearnthatthebondbetweenthecarbonoftheglycerol 5 backboneofthephospholipidandphosphateisbrokenbyanenzyme, phospholipaseC,toproduce2molecules:inositoltriphosphate(IP3)and diacylglyerol(DAG).Theseactassecondmessengers. Onafinalpointwithregardtophospholipids,theiracylchainscanbesaturated ornot.Wereadinnewspaperandmagazinearticlesaboutheartdiseaselinked towhetherthefatsweeataresaturatedornot.Itseemsthatsaturatedfatsare notgoodforourheart.(Fatsandoilscontainalotoftriglycerides,i.e.,glycerol moleculewith3acylchains).Sowhatisasaturatedfat?Itisafatwherethe bondsbetweenthecarbonatomsintheacylchainareallsingle.Inunsaturated fats,oneormorebondsintheacylcarbonchaincanhaveadoublebonds. Becausethesaturatedacylchainscaninteractcloselywitheachother,the membranefluidityisreduced.Forunsaturatedacylchains,thekinksorbendsin thecarbonchain,preventcloseinteractionsothemembraneismorefluid. Cholesterol,whichwehaveheardaboutalotaboutinrelationtoheartdisease, alsohasaneffectonthecellmembranefluidity.Duetoitsrigidplanarring structure,iteasilyslipsinbetweentheacylchainsofneighboringphospholipids. (seefigure15.5toreviewthestructure).Whenthecholesterolconcentrationis low,themembranefluidityisreducedbutathigherconcentrationcholesterol increasesmembranefluidity.Inthelecturesonreproductivephysiology,wewill alsocomeacrosscholesterolasitisaprecursormoleculeforthemajorsex steroidhormones:estrogen,progesterone,estradiol-17β,andtestosterone. Cholesterolwillalsobediscussedinlecturesongastrointestinalphysiologyand incardiovascularphysiology. Ithasnowbecomecommontohaveone’scholesterollevel measured.Why? 15.5. Permeabilityofaphospholipidbilayer Fromwhatwehavediscussedsofar,weknowthatthephospholipidbilayerhas amiddlepart,whichhasnowater–itisahydrophobicenvironment.Figure15.6 isanelectronmicroscopeoftwocellmembranes.Betweenthecellmembranesis theintracellularspace.Whenwelookcloselyatthecellmembranes,wecansee twodarklineswithalightlinebetweenthem.Thedarkthinoutsidelineisdueto thehydrophilicheadgroupsofthephospholipids,andtheregionbetweenthese lines,thelightarea,isduetotheacylchainsofthephospholipidmolecules;this ishydrophobicregionofthecellmembrane. 6 Figure15.6.Transmissionelectronmicroscopepictureofacellmembrane. BloomandFawcett,1994,Springer. Whilethecellmembraneisonly5-6nminwidth,itactsasaverylargeenergy barrierforions,chargedmolecules,andwater-solublemolecules. Forustounderstandwhythecellmembraneissuchalargeenergybarrier,we needtoknowhowionsandchargedmoleculesinteractwiththepolarwater molecules.Inwater,ionsandchargedmoleculesaswellaswater-soluble moleculeshavecloudorshieldofwatermoleculesattachedtothem.Iftheionor chargedmoleculeispasstothroughahydrophobicregion,thesewater moleculeshavetoberemovedduringtheirpassageacrossthecellmembrane. Thisrequiresaverylargeamountofenergy,whichisnotavailable.Soasanion orachargedmoleculeorawatersolublemoleculecannotsheditswater moleculestocrossalipidbilayer,itmakesalipidbilayerenergetically impermeabletoions,chargedmolecules,water-solublemolecules. Thelipidbilayerisalsoimpermeabletomanywater-solublemoleculessuch proteins,nucleiacids,sugars,andnucleotidesduetotheirlargesize.However, thecellmembraneispermeabletothesmall-unchargedwater-soluble molecules,e.g.,oxygen,carbondioxide,ammonia,urea,andwater. Whichtypesofmoleculescancrossthelipidbilayer?Whatare thechemicalpropertiesofthesemolecules? Ithasbeenmentionedinthepreviouslecturesthations,chargedmoleculesand largewater-solublemoleculesdocrossthecellmembrane.Afterall,cellsneedto takeinglucose,aminoacidsandothermaterialandexcretemetabolicwastein theinterstitialfluid.Themechanismbywhichthisisdonewillbeexplainedin detailinthenextlecture.Herewewilllookattheroleofintegralmembrane proteins,manyofwhichareinvolvedinregulationofthemovementofionsand moleculesacrossthecellmembrane. 15.6. Featuresofperipheralandintegralmembraneproteins Besidesthelipids,thecellmembranealsocontainsproteins.Theseare dividedinto2classes:peripheralandintegral. 7 Peripheralproteinscanbeeasilyremovedfromthemembraneandare notembeddedorcovalentlylinkedtothelipidbilayer.Instead,they interactandadheretoproteinsthatareembeddedinorspanthecell membrane,i.e.,integralproteins.Peripheralproteinscanbepresentboth ontheextracellularandintracellularfaceofthecellmembrane. Integralproteinsontheotherhandareembeddedinorspanthelipid bilayerandveryhardtoseparatefromthecellmembrane.Asyoucansee fromfigure15.7,integralproteinscanbefoundineithertheouteror innerleafletofthecellmembraneorspanningtheentirewidthofthecell membrane. Figure15.7.Differentarrangementsoftheperipheralandintegralmembrane proteinsinthelipidbilayerofacellmembrane. Infigure15.7,bluecoloredproteinsareperipheralproteinsthatadhereto integralproteinsshowninorange.Integralproteinscanhaveoneormore segmentsspanningthecellmembrane.Notealsothecovalentlinkageofproteins withmembranelipids(ontheright-sideofthefigure).Wealsoseethatintegral proteinshaveanextracellulardomainandanintracellulardomain.Alsothe segmentsoftheproteinpassingthroughthemembranehaveahelicalshape. Someproteinshaveonlyonesegmentwhileothershavemorethanoneprotein segmentpassingthroughthecellmembrane. Nowwemaywonderhowaproteinisabletointeractbothwithhydrophobic environmentintheinteriorofthemembraneandtheaqueoussolutiononeither sideofthecell.Wheredoesitsamphipathiccharactercomefrom? Proteinsaremadeupofaminoacidsandsomeaminoacidshavehydrophobic properties.Thesemakeupthesegmentthatspansthemembrane.Their hydrophobicpreferringsidechainscaninteractwiththeacylchainsofthecell 8 membranephospholipids.Theirhydrophilicaminoacidsarepositionedonthe insideofthehelixsotheycreateahydrophilicenvironment. Listtheaminoacidsthatarehydrophobicsidegroupsand thosethathavehydrophilicsidegroups? Likephospholipids,membraneproteinsarefreetodiffusealongtheplanofthe cellmembrane.Inanelegantexperimentalstudy,donein1970’s,Fryeand Edidinlabeledcellmembraneproteinsofmousecellswithonecoloredmarker andhumancellswithanothercoloredmarker.Thentheyfusedthecellstogether andobservedthatafter30-40mins,themembraneproteinsofmouseand humancellsweremixed.TheprocessoftheexperimentisshowninFigure15.8. Ifthemembraneproteinswerenotfreetodiffuseinthecellmembrane,the colorswouldnothavemixed. Thisexperimentandothershaveshownthat,ingeneral,membraneproteinsare notanchorednortieddowntoparticularareaofthecellmembrane.When neededtheproteincanbeanchoredtoaparticularsiteonthecellsurface,e.g., thelocalizationofacetylcholinereceptors(AchR)atthepost-synapticregionof theneuromuscularjunction.WewilllearnalotmoreaboutAchRinlectureson synapticphysiology. Figure15.8.SchematicrepresentationofFryeandEdidinexperiment.Theytook twomiceandhumancellsandmarkedtheproteinsinthecellmembranewitha colouredtag.Afterfusionofthetwocells,theyfoundthatthecolouredtagswere intermixed.Theonlylogicalconclusionofthisresultwasthatproteinsarefreeto diffusealongtheplaneofthecellmembrane. 9 LookingatFigure15.8,whatresultwouldhavebeenexpected ifmembraneproteinswerenotfreetodiffusealongtheplane ofthecellmembrane? Manyimportantproteinsinthecellmembranearenotsingleproteinmolecules butaremadeupofmultipleproteinmoleculescalledsub-units.Theseform multimericproteincomplexes.Thesemultimericproteinscanbemadeupof onlyasingletypesofproteinmoleculeorcanbeamixtureof2ormoredifferent proteinmolecules.Byhavingsubunits,amulitmericproteincanhavethe differentsubunitscarryoutdifferentfunctions,e.g.,oneproteinsub-unitcanbe abindingsiteforaligandwhileanothercanactasanenzyme,whichisactivated whentheligandbindstotheothersub-unit.Whenwelearnaboutcellsignaling andorganfunction,wewillcomeacrossmanyexamplesofmultimericproteins inphysiologicalprocesses. 15.7. FiveMajorfunctionscarriedoutbymembraneproteins Inthefollowinglist,themajorclassesoffunctionthatarecarriedoutby membraneproteinsislisted.Thefunctionsareonlyexplainedbrieflyasinlater lectures,wewilldiscussinmoredetailthemechanismoftheirfunctionandthe roletheirfunctionplaysintheoverallworkingofphysiologicalsystems. 15.7.1.Roleincell-to-cellcommunication Aswearemulticellularorganisms,communicationbetweenourcellsis crucialforcoordinatingresponseandchangesinfunctionneededtomaintain homeostasis.Ourcellscommunicatewitheachotherpredominantlywith chemicalsignals.Exceptforsteroidandthyroidhormones,andotherlipid solublesignalingmoleculesthatcancrossthelipidbilayer,otherchemical signalsneedtohavereceptorproteininthecellmembranewithwhichthey caninteracttoinfluencethecellularactivity. 15.7.2Receptors Thesearemembraneproteinsthatbindthechemicalmessengers(signals). Theyformaveryimportantclassofmembraneproteins.Theyconveythe “information”intothecellbymodificationsoftheirproteinstructure.The bindingofthesignalmoleculetotheextracellulardomaincauses conformationalchangesoftheproteinarrangementthatextendthroughthe cellmembranetotheintracellulardomainofthereceptor.Theintracellular domaincanbecomeenzymaticallyactiveorinteractwithothercytoplasmic proteins.Wewilllearnalotmoreaboutthiswhenwestarttolearnaboutcell signalingandsecondmessengers,topicsoflaterlectures. 15.7.3.Adhesionmolecules Anotherimportantclassofmembraneproteinsareadhesionmolecules. Theseareinvolvedinanumberofdifferentprocessessuchasdirecting migrationofimmunecells,axonalguidanceinthedevelopingnervous 10 system,regulationofcellshape,andgrowth.Theymakephysicalconnections withtheextracellularmatrixandwithothercells.Likeproteinreceptor molecules,adhesionmoleculescansendsignalsintothecell. Thesemoleculesarealsomedicallyimportantaslossofcell-cellandcellmatrixadhesionisahallmarkofmetastatictumorcells.Integrinsorcell matrixadhesionmoleculesarealargefamilyoftransmembraneproteins thatlinkcellstocomponentsoftheextracellularmatrix,e.g.,fibronectinand laminin.Thereareseveralsuperfamiliesofadhesionmolecules:Cadherins- Ca2+-dependentcelladhesionmoleculeswhichhavealargeextracellular domainthatbindsCa2+,Ca2+-independentneuralcelladhesionmolecules (N-CAMs)whicharemembersoftheimmunoglobulinsuperfamily. Whatmakesmetastaticcancercellssuchaterrorfora personwithcancer? Ifthecancercellsdidnotlosstheircell-to-cell connections,wouldthetumorbelocalizedor dispersed? 15.7.4.Pores,Channels,Carriers,andPumps. Poresandchannelsaretransmembraneproteinsthatprovidepassage wayforwater,specificions,andothermoleculestoflowpassivelydown theirelectrochemicalgradienteitherintooroutofthecell.Carrierscan eitherfacilitatethetransportofaspecificmoleculeacrossthemembrane orcouplethetransportofamoleculetothatofothersolutes.Pumpsare enzymesthatusetheenergyderivedfromadenosinetriphosphate(ATP) totransportsubstancesintooroutofcellsagainsttheirelectrochemical gradients.Youwillfindthattherearemanykindsofpumpswhichare describedinthenextlecture.Somepumps,liketheNa/KATPase,arevital forcellsurvivalastheseareimportantfortheregulationofcellvolume. 15.7.5.Integralsignalingproteinslocatedinthecytoplasmicfaceofthe cellmembrane Theseproteins,whicharesoluble,arelinkedtolipidsinthemembrane.They playanimportantroleincellsignaling.Examplesincludeguanosine triphosphate(GTP)–bindingproteins(G-proteins),kinases,and oncogene. 15.8. Summary Inthislecture,wewereexplainedsomeofthechemistryand physicsunderlyingthebilayerorganizationofthecell membraneandwhyfluid-mosaicmodelisthebestmodelwe haveofacellmembrane.Wealsolearntthelipidbilayeris 11 impermeabletoions,chargedmolecules,andlargewatersolublemolecules,thereforehastobepathwaysandmechanism formovingthesesubstancesintoandoutofthecell.Thisisdone byintegralmembraneproteins.Wealsolearntthatintegral proteinshaveotherfunctionsbesidestransport.Inthenext lecture,wewillgointomoredetaileddiscussionofhowthe membraneproteinscarrytransportfunctionformovementof substancesacrossthecellmembrane,andwhythisisimportant forustoknow,asthiswillbeveryusefulforuswhenwestudy thefunctionoforgansystemsofthebodyintheothermodules onmedicalphysiology. Figurenicelysummariesthestructureandcompositionofacell membrane. Figure15.9.Aschematicdiagramofthecellmembraneshowingthe lipidbilayermatrixwithinwhicharetheproteinmoleculesthateither spanthewidthofthecellmembraneorformperipheralattachments. (http://www.rsc.org/Education/Teachers/Resources/cfb/cells.htm 15.9. ReadingandReferences WalterF.BoronandEmileL.Boulpaep.MedicalPhysiology:A CellularandMolecularApproach.(2012).Chapter2.Saunders Elsevier SingerSJandNicolsonGL.TheFluidMosaicModelofthe StructureofCellMembranes.Science175(4023):720-731 (1972) 12