(69)--医学细胞生物学Chapter18MechanicalMolecules.pdf

《(69)--医学细胞生物学Chapter18MechanicalMolecules.pdf》由会员分享，可在线阅读，更多相关《(69)--医学细胞生物学Chapter18MechanicalMolecules.pdf（20页珍藏版）》请在淘文阁 - 分享文档赚钱的网站上搜索。

1、P1:GIGWY001-18WY001-Bolsover-v2.clsSeptember 4,200313:5818MECHANICAL MOLECULESTHE CYTOSKELETON IS BOTH STRONG AND MOTILEEukaryotic cells are supported by a network of struts and cables called the cytoskeleton.Inanimal cells,which lack a rigid cell wall,it is the cytoskeleton that determines cell sha

2、pe.In addition the cytoskeleton is responsible for cell locomotion,for moving componentsfrom place to place within the cell,and for cell division.The cytoskeleton is composedof three cytoplasmic filament networks:microtubules,microfilaments,and intermediatefilaments(Fig.18.1).Although all three are

3、physically strong,microtubules and microfila-mentshavetheadditionalroleoforganizingmovement,bothofentirecellsandofstructureswithin them.The term cytoskeleton implies a rigid set of“bones”within the cell.Nothingcould be further from the truth,and all three filament systems are highly dynamic,altering

4、their organization in response to the needs of the cell.The molecules that make up thethree filament systems have been highly conserved throughout evolution;the cytoskeletalproteins present in the cells of complex organisms such as humans are much the same asthoseinasimpleorganismsuchasayeast.Althou

5、ghtheindividualmoleculesmakingupthecytoskeletonarebelowthelimitofresolutionofthelightmicroscope,thecytoskeletonitselfcan be readily observed within the cell by using fluorescence microscopy(e.g.,page 6).MICROTUBULESMicrotubules possess a combination of physical properties that allows them to partici

6、patein multiple cellular functions.They can form bundles of rigid fibers that make excellentCell Biology:A Short Course,Second Edition,by Stephen R.Bolsover,Jeremy S.Hyams,Elizabeth A.Shephard,Hugh A.White,Claudia G.WiedemannISBN 0-471-26393-1 CopyrightC?2004 by John Wiley&Sons,Inc.381P1:GIGWY001-18

7、WY001-Bolsover-v2.clsSeptember 4,200313:58382MECHANICAL MOLECULESmicrotubulesnucleuscentrosomemicrofilaments(stress fibers)intermediate filaments Figure 18.1.Typical spatial organization of microtubules,stress fibers(one form of microfila-ments),and intermediate filaments.structural scaffolds and he

8、nce serve an important role in the determination of cell shape.They have an inherent structural polarity that defines a polarity(front vs.back)to the cell.Theyprovideasystemofintracellularhighwaysthatsupportsatwo-waytrafficoforganellesand small vesicles powered by enzymes that interact with the micr

9、otubule surface.Theycan be rapidly formed and broken down,a property that allows the cell to respond to subtleenvironmental changes.Finally,they play a role in one of the most exquisite and preciseof all movements within the cell,the segregation of chromosomes at mitosis and meiosis(Chapter 19).Anim

10、alcellscontainanetworkofseveralthousandmicrotubules,each25nmindiame-ter.Allthecellsmicrotubulescanbetracedbacktoasinglestructurecalledthecentrosome,which is tightly attached to the surface of the nucleus at the cell centre(Fig.18.1).Thecentrosome is the microtubule organizing center of the cell and

11、consists of amorphous ma-terial enclosing a pair of centrioles(Fig.18.2).Centrioles have a characteristic nine-waypattern that we will meet again in cilia and flagella(page 386).Microtubules in plant cellshave a quite different organization,lying immediately beneath the cell membrane,orientedat righ

12、t angles to the direction of cell expansion.The role of microtubules in plants is todirect the deposition of cellulose fibers on the outside of the cell membrane.Cellulosesynthase,a multiprotein enzyme complex that spans the cell membrane,is thought to movealong microtubules forming new parallel tra

13、cks of cellulose microfibrils on the cell surface(Fig.18.3).As a consequence of the position of the microtubules beneath the membrane,cellulose is laid down in hoops that encase the plant cell in a rigid corset and allow it toexpand only in one direction.Plant cells do not contain centrioles,and it

14、remains unclearwhether their microtubules arise from a defined organizing center.Microtubules are composed of a protein called tubulin that consists of two dissimilarsubunits designated and.In the human genome there are about five-tubulin genes androughly the same number for tubulin.There is a third

15、 member of the tubulin superfamily,tubulin,which does not itself contribute to microtubule structure but which is found atthe centrosome and plays a role in initiating microtubule assembly.-Tubulin/-tubulindimers assemble into chains called protofilaments,13 of which make up the microtubulewall(Fig.

16、18.4).Within each protofilament the tubulin dimers are arranged in a“head-to-tail”manner,and so on.This gives the microtubule an built-in molecular polaritythat is reflected in the way it grows.Tubulin subunits are added to,and lost from,one endmuch more rapidly than the other.By convention,the fast

17、 growing end is referred to as the(+)end and the slow growing end as the()end.P1:GIGWY001-18WY001-Bolsover-v2.clsSeptember 4,200313:58pericentriolarmaterialcentriolesmicrotubulescrosssectionFigure 18.2.The microtubule organizing center or centrosome consists of amorphous material enclosing a pair of

18、 centrioles.383P1:GIGWY001-18WY001-Bolsover-v2.clsSeptember 4,200313:58384MECHANICAL MOLECULEScellulose microfibrilmicrotubulecellulosesynthaseplasmamembrane(a)(b)cellulosemicrofibrilDirection of cellexpansionFigure 18.3.Cellulose synthase runs on microtubule tracks.In cells,the minus end of each mi

19、crotubule is embedded in the centrosome so that onlythe plus ends are free to grow or shrink.This process is surprisingly complex.Individualmicrotubules undergo periods of slow growth followed by rapid shrinkage,sometimesdisappearingcompletely.Thisphenomenonisreferredtoasdynamicinstability.Bychance,

20、thegrowingendsofcertainmicrotubulesmaybecapturedbysitesatthecellmembraneandstabilized,so that they are protected from shrinkage.Their further growth influences theshape of the cell(Fig.18.5).Groups of microtubules having a common orientation makean excellent structural framework.Because microtubules

21、 are dynamic,the framework canbe continually remodeled as the needs of the cell change.One of the most important tools in establishing microtubule function in cells has beenthe plant alkaloid colchicine.Extracted from the corms of the autumn crocus,ColchicumP1:GIGWY001-18WY001-Bolsover-v2.clsSeptemb

22、er 4,200313:58MICROTUBULES385microtubuleprotofilament(+)()-tubulin/-tubulin dimerFigure 18.4.Microtubule structure.autumnale,colchicine has been used since Roman times as a treatment for gout.Cellsexposedtocolchicinelosetheirshape,andthemovementoforganelleswithinthecytoplasmceases.When the drug is w

23、ashed away,microtubules reassemble from the centrosome andnormal functions are resumed(Fig.18.6).Another drug,taxol,obtained from the bark ofthe Pacific yew,Taxus brevifolia,has the opposite effect,causing large numbers of verystable microtubules to form in the cell,an effect that is difficult to re

24、verse.Unlike animal cells,plant cells do not use their cytoskeletons to define their cell shape,but instead use their extracellular cell walls.The direction in which a growing plant cellextends is determined in the first instance by the direction in which the cellulose micro-filaments run.However,th

25、ese are laid down by cellulose synthase following microtubuletracks so in fact the cytoskeleton has defined the direction of cell growth,but indirectlyrather than by itself acting as a load-bearing component.dynamic instability,microtubules grow and shrink,sensing their environmentthe ends of these

26、two microtubules have been captured and stabilized.Now,they do not shrink but only grow,altering the cell shapecentrosomenucleusFigure 18.5.Microtubules show dynamic instability.P1:GIGWY001-18WY001-Bolsover-v2.clsSeptember 4,200313:58386MECHANICAL MOLECULEScolchicinetaxolFigure 18.6.Effects of taxol

27、 and colchicine on microtubules.MICROTUBULE-BASED MOTILITYCells move for a variety of reasons.Human spermatozoa in their millions swim franticallytoward an ovum;the soil amoeba,Acanthamoeba(said to be the most abundant organismon Earth),crawls over and between soil particles,engulfing bacteria and s

28、mall organicparticles as it does so.Cells in the early human embryo show similar crawling movementas they reorganize to form tissues and organs;the invasive properties of some cancer cellsis due to their reverting to this highly motile embryonic state.Of course,not all cellsshow these obvious forms

29、of motility,but careful observation of even the most sedentaryeukaryotic cells often reveals a remarkable repertoire of intracellular movements.Bothmicrotubules and actin filaments play important roles in cell motility.We will describemicrotubule-based motility first;actin-based motility will be cov

30、ered following the sectionon microfilaments.Cilia and FlagellaCiliaandflagellaappearedveryearlyintheevolutionofeukaryoticcellsandhaveremainedessentially unchanged to the present day.The terms cilium(meaning an eyelash)andflagellum(meaning a whip)are often used arbitrarily.Generally,cilia are shorter

31、 thanflagella(40m)and are present on the surface of the cell in muchgreater numbers(ciliated cells often have hundreds of cilia but flagellated cells usuallyhave a single flagellum).The real difference,however,lies in the nature of their movement(Fig.18.7).Cilia row like oars.The movement is biphasi

32、c,consisting of an effective strokein which the cilium is held rigid and bends only at its base and a recovery stroke in whichthe bend formed at the base passes out to the tip.Flagella wriggle like eels.They generatewaves that pass along their length,usually from base to tip at constant amplitude.Th

33、usthe movement of water by a flagellum is parallel to its axis while a cilium moves waterperpendicular to its axis and,hence,perpendicular to the surface of the cell.Cilia are such a conspicuous feature of some protists that they are called ciliates.Theswimmingofaparamecium(Fig.18.8),forexample,isge

34、neratedbythecoordinatedmotionof several thousand cilia on the cell surface.Cilia also play a number of important roles inthe human body.The respiratory tract,for example,is lined with about 0.5m2of ciliatedepithelium,bearing something like 1012cilia.The beating of these cilia moves a belt ofmucus co

35、ntaining inhaled particles and microorganisms away from the lungs.This activityis paralyzed by cigarette smoke,causing mucus to accumulate in the smokers lung andcausing the typical cough.P1:GIGWY001-18WY001-Bolsover-v2.clsSeptember 4,200313:58MICROTUBULE-BASED MOTILITY38718765432basal body123basal

36、bodyciliumflagellummedium pushed this waycell pushed this waycell pushedthis waymedium pushed this wayFigure 18.7.How cilia and flagella bend.P1:GIGWY001-18WY001-Bolsover-v2.clsSeptember 4,200313:58388MECHANICAL MOLECULESParamecium(cilia)sea urchin spermatozoon(flagellum)cross section B microtubuleA

37、 microtubuleouter dynein arminner dynein armcentral pair projectionsmembranecentral pair microtubulesradial spokeinterdoublet linktubulin subunitFigure 18.8.Cilia and flagella have identical structure.Despite their different pattern of beating,cilia and flagella are indistinguishable struc-turally(F

38、ig.18.8).Both consist of a regular arrangement of microtubules and associatedproteins with the nine-way pattern we have also seen in centrioles.Unlike centrioles,ciliaand flagella have a central pair of microtubules,so that the overall structure is called the9+2 axoneme.The axoneme is enclosed by an

39、 extension of the cell membrane.Attachedtothenineouterdoubletmicrotubulesareprojections,orarms,composedofamotorproteincalleddynein.DyneinisanATPasethatconvertstheenergyreleasedbyATPhydrolysisintothe mechanical work of ciliary and flagellar beating.Using ATP produced by mitochondrianear the base of t

40、he cilium or flagellum as fuel,the dynein arms push on the adjacent outerdoublets,forcing a sliding movement to occur between adjacent outer doublets.Becausethe arms are activated in a strict sequence both around and along the axoneme and becausethe amount of sliding is restricted by the radial spok

41、es and interdoublet links,sliding isconverted into bending.Bacterial flagella(page 264)use a fundamentally different mechanism.Like the pro-pellor of a boat,the motion of the bacterial flagellum is entirely driven by the rotary motorat its base.The bacterial flagellum itself is a specialized piece o

42、f extracellular cell wall,P1:GIGWY001-18WY001-Bolsover-v2.clsSeptember 4,200313:58MICROTUBULE-BASED MOTILITY389made of one protein(flagellin)that has no similarity to tubulin or dynein.Cilia and flagellaare full of cytosol all the way to their tips,and use the ATP in that cytosol to generate forceal

43、l the way along their length.fIN DEPTH 18.1 Calcium and Paramecium SwimmingParamecium,although it is a single-celled organism,is a fast-swimming predator.Its surface is covered with hundreds of cilia that are arranged in rows that lieobliquely to the cell axis.Cilia beat with their effective stroke

44、oriented toward therear,propelling the cell forward in a spiral motion.The beating of the individualcilia is coordinated to produce“metachronal waves”that pass from the front ofthe animal to the rear,rather like the wind passing across a corn field.Parameciumneeds millisecond-to-millisecond control

45、of its cilia as it swims through pondweedin search of prey.One reflex,the“avoiding reaction,”was first described almost acentury ago.When a Paramecium is swimming forward,the internal calcium con-centration is kept low,at about 100 nmol liter1.When the front of the animalbumps into an object,the pla

46、sma membrane depolarizes,opening voltage-gatedcalcium channels in the cilia all the way down the animal as a calcium actionpotential is generated.The influx of calcium ions raises the intracellular calciumconcentration,and this in turn causes the cilia to swing through 180so that theeffective stroke

47、 is now directed toward the anterior.This causes the Parameciumto reverse a few body lengths,taking it out of contact from the object with whichit collided.Calcium is now pumped out of the cell and the internal calcium con-centration falls back to 100 nmol liter1.The cilia now swing back to their or

48、iginalposition and forward swimming is resumed.?MedicalRelevance18.1A Sinister ComplaintA small number of men seeking the help of fertility clinics turn out to have notonly nonswimming sperm but a failure of all the cilia and flagella in their bodies.On questioning,they are often found to suffer fro

49、m chronic respiratory disease because the cilialining their airways are also immobile.Most surprising is the fact that half of these individualsalso exhibit Kartegeners syndrome,a condition in which the internal organs have the reversedorientation from normal,that is,the heart is on the right,the ap

50、pendix on the left,and so on.Itturns out that cilia set up a flow from right to left across the early embryo.Transmitters carried inthis flow tell the left-hand side to develop its characteristic organs,and vice versa.If a mutationrenders the cilia immobile,the leftright gradient of transmitter does