Download 1 Lecture 15: Molecular Structure of the Cell Membrane 15.1

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).
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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
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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.
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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.
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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
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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.
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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.
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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
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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.
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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
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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
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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)
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