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The cell behaviors that we describe in this final section all rely on acoordinated deployment of the components and processes that we haveexplored in the first three sections of the chapter: the dynamic assembly and disassembly of cltoskeletal polymers, the regulation and modification of theirstructure by polymer-associated proteins, and the actions of motor proteinsmoving along the polymers. How does the cell coordinate all these activities todefine its shape, to enable it to crawl, or to divide it neatly into two at mitosis?These problems of cltoskeletal coordination will challenge scientists for manyyears to come.1026Chapter 16:The CytoskeletonTo provide a sense of our present understanding, we first discuss exampleswhere specialized cells build stable arrays of filaments and use highly orderedarrays of motor proteins sliding them relative to each other to generate thelarge-scale movements of muscle, cilia, and eucaryotic flagella.
Next, we consider two important instances where filament dynamics collude with motorprotein activity to generate complex, self-organized dynamic structures: themicrotubule-based mitotic spindle and the actin arrays involved in cell crawling. Finally, we consider the extraordinary organization and behavior of theneuronal c)'toskeleton.Slidingof Myosinll and ActinFilamentsCausesMusclestoContractMuscle contraction is the most familiar and the best understood form of movement in animals.
In vertebrates, running, walking, swimming, and flying alldepend on the rapid contraction of skeletal muscle on its scaffolding of bone,while involuntary movements such as heart pumping and gut peristalsis dependon the contraction of cardiac muscle and smooth muscle, respectively.All theseforms of muscle contraction depend on the ATP-driven sliding of highly organized arrays of actin filaments against arrays of myosin II filaments.Skeletalmuscle was a relatively late evolutionary development, and musclecells are highly specialized for rapid and efficient contracrion.
The long thinmuscle fibers of skeletal muscle are actually huge single cells that form duringdevelopment by the fusion of many separate cells, as discussed in Chapter 22.The large muscle cell retains the many nuclei of the contributing cells. Thesenuclei lie just beneath the plasma membrane (Figure f6-23). The bulk of thecltoplasm inside is made up of myofibrils, which is the name given to the basiccontractile elements of the muscle cell.
A myofibril is a cylindrical structure l-2pm in diameter that is often as long as the giant muscle cell itself. It consists of along repeated chain of tiny contractile units-called snrcomeres,each about 2.2pm long, which give the vertebrate myofibril its striated appearance (Figurero-7$.Each sarcomere is formed from a miniature, precisely ordered array of parallel and partly overlapping thin and thick filaments. Tlne thin fiIaments are composed of actin and associatedproteins, and they are attached at their plus endsto a Z disc at each end of the sarcomere.The capped minus ends of the actin filaments extend in toward the middle of the sarcomere, where they overlap withthick fiIamenfs, the bipolar assembliesformed from specific muscle isoforms ofmyosin II (see Figure 16-55). \Mhen this region of overlap is examined in crosssection by electron microscopy, the myosin filaments are seen to be arranged ina regular hexagonal lattice, with the actin filaments evenly spaced between them(Figure 16-75).
cardiac muscle and smooth muscle also contain sarcomeres,although the organization is not as regular as that in skeletal muscle.Sarcomere shortening is caused by the myosin filaments sliding past theactin thin filaments, with no change in the length of either type of filament (Figure 16-74 c and D). Bipolar thick filaments walk toward the plus ends of two setsof thin filaments of opposite orientations, driven by dozens of independentmyosin heads that are positioned to interact with each thin filament.
Becausethere is no coordination among the movements of the myosin heads, it is criticalFigure16-73 Skeletalmusclecells(alsocalledmusclefibers).(A)Thesehugemultinucleatedcellsform by the fusionofmanymusclecellprecursors,calledmyoblasts.In an adult human,a musclecellis typically50 pm in diameterand canbe up to severalcentimeterslong.(B)Fluorescencemicrographof rat muscle,showingthe peripherallylocatednuclei(blue)in thesegiant cells.Myofibrilsarestainedred;seealsoFigure23-468.(B,courtesyof NancyL. Kedersha.)myofibril50pm1027THECYTOSKELETONAND CELLBEHAVIORZ discdark band light band_dE--l)(B)IIIone sarcomeret h i c k f i l a m e n t( m y o s i n )t h i n f i l a m e n t( a c t i n l light band dark band light band2pmelectronFigure 16-74 Skeletalmusclemyofibrils,(A)Low-magnificationmicrographof a longitudinalsectionthrougha skeletalmusclecellof arabbit,showingthe regularpatternof cross-striations.Thecellcontainsmanymyofibrilsalignedin parallel(seeFigure16-73).(B)Detailof theskeletalmuscleshownin (A),showingportionsof two adjacentmyofibrilsand the definitionof a sarcomere(blackarrow).(C)Schematicdiagramof asinglesarcomere,showingthe originof the darkand light bandsseeninarethe electronmicrographs.TheZ discs,at eachend of the sarcomere,theattachmentsitesfor the plusendsof actinfilaments(thinfilaments);M line,or midline,isthe locationof proteinsthat linkadjacentmyosinllfilaments(thickfilaments)to one another.Thedarkbands,which markthetheylocationof the thickfilaments,aresometimescalledA bandsbecauseindexchangesappearanisotropicin polarizedlight (thatis,their refractivewith the planeof polarization).The light bands,whichcontainonly thinfilamentsand thereforehavea lowerdensityof protein,arerelativelyisotropicin polarizedlightand aresometimescalledI bands.(D)Whenthesarcomerecontracts,the actinand myosinfilamentsslidepastone another(A and B,courtesyof RogerCraig.)without shortening.that they operate with a low processivity, remaining tightly boundfilament for only a small fraction of each AIPase cycle so that theyone another back.
Each myosin thick filament has about 300 headsmuscle), and each head cycles about five times per second in thee;'1um' -.to the actindo not hold(294 in frogcourse of aFigure16-75 Electronmicrographsof aninsectflight muscleviewed in crosssection.The myosinand actinfilamentsarepackedtogetherwith almostcrystallineUnliketheirvertebrateregularity.counterparts,thesemyosinfilamentshavea hollow center,as seenin theon the right.Thegeometryofenlargementthe hexagonallatticeis slightlydifferentinvertebratemuscle.(FromJ.
Auber,J. deMicrosc.8:197-232, 1969.With permissionfrom Societ6frangaisede microscopie6lectronique.)1028Chapter16:TheCytoskeletonZ discCap Zm y o s i n( t h i c kf i l a m e n t )tropomodulin4!g!'llLlD'.:t.ra!i!rrtl,:)b l u se n dof actinf ilamentm t n u se n oa c t i n( t h i n f i l a m e n t )rapid contraction-sliding the myosin and actin filaments past one another atrates of up to 15 pm/sec and enabling the sarcomere to shorten by l0% of itslength in less than 1/50th ofa second.
The rapid synchronized shortening ofthethousands of sarcomeres lying end-to-end in each myofibril enables skeletalmuscle to contract rapidly enough for running and flying, or for playing thepiano.Accessory proteins produce the remarkable uniformity in filament organizalion,length, and spacing in the sarcomere (Figure f 6-76). The actin filamentplus ends are anchored in the Z disc, which is built fromcapzand o-actinin; theZ disc caps the filaments (preventing depolymerization), while holding themtogether in a regularly spaced bundle.
The preciselength of each thin filament isdetermined by a template protein of enormous size, called nebulin, which consists almost entirely of a repeating 35-amino-acid actin-binding motif. Nebulinstretches from the Z disc to the minus end of each thin filament and acts as a"molecular ruler" to dictate the length of the filament. The minus ends of thethin filaments are capped and stabilized by tropomodulin. Although there issome slow exchange of actin subunits at both ends of the muscle thin filament,such that the components of the thin filament turn over with a half-life of several days, the actin filaments in sarcomeresare remarkably stable compared tothe dynamic actin filaments characteristic of most other cell t!?es that turn overwith half-lives of a few minutes or less.Opposing pairs of an even longer template protein, called titin, position thethick filaments midway between the Z discs.
Titin acts as a molecular spring,with a long series of immunoglobulin-like domains that can unfold one by oneas stressis applied to the protein. A springlike unfolding and refolding of thesedomains keeps the thick filaments poised in the middle of the sarcomere andallows the muscle fiber to recover after being overstretched.In c. elegans,whosesarcomeres are longer than those in vertebrates, titin is also longer, suggestingthat it too servesas a molecular ruler, determining in this casethe overall lengthof each sarcomere (seeFigure 3-33).A SuddenRisein CytosolicCa2+ConcentrationInitiatesMuscleContraction<crcc>The force-generatingmolecular interaction between myosin thick filaments andactin thin filaments takes place only when a signal passesto the skeletal musclefrom its motor nerve.
Immediately upon arrival of the signal, the muscle cellact in rapid successionon the same thin filament without interfering with oneanother. second, a specialized membrane system relays the incoming signalrapidly throughout the entire cell. The signal from the nerve triggers an actionpotential in the muscle cell plasma membrane (discussedin Chapter ll), andFigureI 6-76 Organizationof accessoryproteins in a sarcomere.<CTGC>Eachgianttitin moleculeextendsfrom theZ discto the M line-a distanceof over1 pm.
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