l loll)nrvu )ll lstOtODA SIXIH ]CIIION 1;erna {loplsq 8ar) vruolp )qr!s )ersor v' Aloul^ )rre6er nellqa^^ s)oll d' vu}qo ug{rols)lLer Hlpp odloe6q denl |^lelsnpere t= H'Jroaueu eup loudeu{ M' Na\/^ orI 1 1011)nlvu )ll lIIOIODA VSONI IH ]VNIHOUS HVU1IA IOOISH ls dlolassol o 6]rolo6ir eu pdlolassoJ og]roaubruaauu6 e] ]q 4alpsse)qnso]]s luslt]nla o ]lalquo;obir eup e xroluqa lo+ }q oMqt}oqae plus}t}n}e }oi. €toruapt)p ulaseer)lr CJ loprsq rs elso pruaruqar o} }q aNeltoue ly:epeLu{ o 1S)lau)as eup }iLa vruouleu ytepalL Ior, vus eu pS)tau)es eup Mp dsrasrpou })200t( o} }qa vruaule u5otra1 {1 o1ta1 1gto1o6{ Ho ls Mall }uomu +o rqrs Mor1 o)uoll-!Laluql eduqa{,sro1o6 idrp' ur)nlpr.l^ ] qqaroslulqasrs o 1uL erueI11-snr;et edlolarus 'Pup ou lqa l;ouru6 eu p1nu:]roue eluellsrs osla^oJe l)all-snfe)a te:adlo dttolarus' sn)q es ]ll oatyqrodoralru eup lgl-B ta:adlots gt s;eqolelou felso slnpr eqsar-uelodoralr tslelu )alls eup qp tspault+tap uona dltolaru s1qe1 snddoU lqa drrolyareltou 6t lopts q}aP)qa snupal6lepnele eu pbrepnela toneas tu )a qllro1o6i, eu pqrolatquo;o6{ VuNOlo glU) t sdlo}assol o }4rtroqro; oll6LIr.unuo1o6{, eup \/ola)nle rgoualr)s eup re.ueruqa ro+ lqa nolarn; egtro1o6i, luslt}n}a e} }q neut^alst}^ oJlplt}oJutp' lo syubalas Cr. €ar) rs elso e+alloM o} }qa vualr)eu ylepaLu{ o1 VUs Pu pS)lau)as Ha ts oua o, ]q aoubru ep;rsto^alars o ]UN sVdlr>ru6 eup jou1afqpursu.rs ;o lbeua )oulrol t^u|Jnsos H r;seqo:e1ou sflnplas llla Juola)nle rt.ulale)ltou s]lL pte]6n;e1 al;eus:udlro ruur]rplrou rruueruuplrpu )all s1'o:nstu6 t udepttnler o ]ulPusrltdltou lepols autopep q {outo6aues eup lnJu osrnddtassols Ha }ap)qa srulropn:1ou f)onrses ru ruolrlnle rqrolo6i, eu pnrtolo6{, eup eu ep^eu)ap )onlsa tu )a lqlrolo61 o1 lq aun)lans )HUIS V. )VISIU lsdrolassor eup Haep o+ +qo 6adeyueu lo1 grolo6l el lq onesse)qnsou sluslr]nla o +1a:quolo6i ,1; r1seqolelouf nsa 6saue1r> eu pte1 1qrolo6rte luatqops } onuparsleup }qa qps rd)roressas o 1qon ur,enrr ls{,{ulqasrz ua.prouLqJPua eup seltelouf dlolarus et e+olpap eup slolop tu ]qa loudppluauq o+ ] qsaa>ra1o udfelqnr,eir 61 )prsa l rrsaroOutzep es e to dnupalblepnela apn)p}ol e} ll1 Mqalo qo qps }en6 q6laue1r:s 1 noupet6tepneles ;or lueu {{aers 6ONIA )UllglU lMsqrteqa edplo}ossor. ru }qa 6adeyuau lo g1r0106^ e} } qnaessetqnsa}} sluslt}nla o1}e)quo1o6{ 1o rqrs luuo^plr^ a}ae)qtu6 on}upatbtepnel eqlo;o6i ,pup qnue duqlsro;o6{r es Mol le s6repn reala11-qto1o6 {lonrsas' qa qe sla)al^ap unJueJon seMelps Ht s;eqoteiol,qe suLep eloullrqnlrous ]o o nnJuparsleupru6 orltoxLqreu 1aregr:1ru6 lqton6q rq e9o16t eddetelns eup qes )louap pu plqelepauzap raredlo drrolaru srrudorleu l1o r1 Jquao^aULau] o )]qolaslolol tulo eup onl o] lalls' rupnpru6 ]qa HC Ira)adlor l lVtIH]M d. S)O"1I l sdrolassor o6+ena1oduau1e ;91o;o6 [gaua}r)s' eu gproau6rueeuub e 1S}eu}olp lutnatstl{, slqool ol napt)tua eu lpU^asltbelol e] ]q agonnerp pn6qas \/epr)e lluslr]nle Ha rs p ]uauqar o] ]q aNplroue ly:epauLI o ;S)lru)as eup lq avlrLartle uyrepeUL^ o1 vr.]s pup sDau)as eup e des gdresrpau lo1 lqa 5oDalI 6;oarne1odr.ueule 6lto1o6i, ge ts )uoMu ]or qls mol) ptuanaqoduaule qlro1o6{ eu p6aua1 dlse'r;rtn;er.;i, r ueJaps o ]lall-)a sllr6uelru6 eu qpouLaoqo x6auas eup ; optlstonettu6 }qa lola sp oa}nalodr.uaul etlebn;elors ru )eu)ar Cr S)o }}tap)qas )al le puepnalodLuaule lqro;o6 {1 noupat6tepnela slnpauls' panalodluaul eu pprseps reuelqeursxrs } oruapr)e sl}npau}s' ppuepnalodr-uau1e qlto1o6{ 1o 6lepnela slnpauls e S}}eu} o1r6purnarsr1{ VNIHONA SUIIS)HjU ldsrorresso lo t1,a1 1gro1o6{ el folue ll6l urnarsrlI eup vsso)relo Clallo rot, ]qa forual lluslr]nla o+ fall eu pj\fola)nle Jgro;o61 p ls;eqoje1ou f rmsa11 )uoMu t o;pleu1r!,ru6 eu p)qere:leuzru 6uan rrrou-tdoueuls o; lqa Pl}lu r{yoslalatou eu paln)tpelluo l qqaro1o6)e 1}nu)}tous o }}qosa toltdouauls r ulelp}rou }o )a ldlo;eu1{ eu rpuajuqreua llelll) lo llqls qrs MoJ)' leqotelo ra{xd;o rqlsro)qeJur)el '6eua1) 'eup la qllrolobrr eedl droe>qes tu }M rolLop sa{lsleu" r^sa'i.]aqrP laadllqalt e>le1;s eup ]qo qnppru6 {aesl 6 rgra}s)qa tlap)qos la lqlrolo6i,1 Oorepnel aslnpau}s p} foru lo6lulrnarsr1{ HIOCI dlg3gH lsdlo}assor ol €rolo6I el lqJnepsse)qnsal} sluslr}n}a o }lorquolob{ eup e uaruqor ot lqa Mqllellae pluslrtnlo ,ol. BroJuapt )gpalsaer.)lL Oua oj ]l lannopp E;aepr ur.6asapr)qars ru ruunua slslar uqaqenrol C 4r1oa6 qsinptes lq a^Puons ]Ppt)s }qPl nrtnsa sau-rdlo {1o o^epa o nrluLlunu laesdousas eup }q naaei,s on riuJun uso{rsle Lpurslru6nrsqas lueup lrorlL ]oa C 6l1oa6q ieelqas ruuunuolo6{ 1 onupetbtepnel eslnpauls e 1Hpurer plurnarsrli leup nl1 PusLIsHgn: SaraT enney ExecurrvE Eonon: Katherine Ahr DpvEr-opneNrRI- Eorrons: Matthew Tontonoz, Erica PantagesF rost, Elizabeth Rice AssocIRrp Pnoyrcr MexecBR: Hannah Thonet AssrsreNr EorroR: Nick Tymoczko AsssocrerED nacton op MeRrrrrNc: Debbie Clare SeNIoRP no;ecr Eonon: Mary Louise Byrd Tsxr DpsrcNBR: Marsha Cohen Pacp Mnreup: Aptara, Inc. CovpR Drsrcrs:B lakeL ogan IlLuslReltoN CooRorNetoR: SusanT immrns ILrustR,q.rroNs: Nerwork Graphics, Erica Beade,H . Adam Steinberg Puoro Eorron: CeciliaV aras PHoro RpseencHrn: Christina Micek PRooucnoN CooRoneton: Susan\ 7ein Mron RNo Suppr-rvENTSE DrroR: Hannah Thonet Mron DEvgLoplns: Biostudio, Inc., Sumanas,I nc. CotvtposrrloN: Aptara, Inc. MeNupRcruRrNG: RR Donnelley & SonsC ompany About the cover: Mitotic PtK2 cellsi n late anaphases tainedb lue for DNA and greenf or tubulin. Courtesyo f Torsten\ gittman. Library of CongressC ataloging-in-PublicationD ata Molecular cell biology I Harvey Lodish . . . [et al.]. -6th ed. p. cm. Includesb ibliographicalr eferencesa nd index. 1. Cytology. 2. Molecular biology. I. Lodish, Harvey F. QH581.2.M6552 007 57L5-dc22 2007006188 ISBN-13 : 978 -0-71 67- 76 01-7 ISBN-10:0 -71 67- 7 601-4 @ 1986,1.990,1 995,2000,2004,2008 by tJf.H . Freemana nd Company All rights reserved. Printed in the United Stateso f America Secondp rinting W. H. Freemana nd Company 41 Madison Avenue,N ew York, NY 10010 Houndmills, Basingstoke RG21 6XS, England www.whfreeman.com To our studentsa nd to our teachers, from whom we continuet o learn, and to our familiesf,o r their support, encouragemenat,n d love PREFACE n writing the sixth edition of Molecular Cell Biology what we know. A number of experimental organisms,f rom I we have incorporated many of the spectaculara dvances yeastst o worms to mice, are used throughout so the student I I made over the past four years in biomedical science,d riven can seeh ow discoveriesm ade with a "lower organism" can in part by new experimental technologiest hat have revolu- Iead directly to insights even about human biology and dis- tionized many fields. High-velocity techniquesf or sequenc- ease.T his experimental approach, evident in the text itself, ing DNA, for example,h aveg eneratedt he completes equence has also been thoroughly integrated into the pedagogical of dozens of eukaryotic genomes;t hese in turn have led to framework. For example: important discoveriesa bout the organization of the human genome and regulation of gene expression,a s well as novel r Experimental Figures lead students through important insights into the evolution of life-forms and the functions of experimental results. individual members of multiprotein families. New imaging techniquesh ave generatedp rofound revelations about cell r Classic Experiments essaysf ocus on historically impor- organization and movement, and new molecular structures tant and Nobel Prize-winninge xperiments. have greatly increasedo ur understanding of life processes r New and revised Analyzet he Data problems at the end such as cell-cell signaling, photosynthesis,g ene transcrip- of each chapter require the student to synthesizer eal ex- tion, and chromatin structure. perimental data to answer a serieso f questions. New Author Team r Updated Perspectives for the Future essays explore potential applications of future discoveriesa nd unanswered Two new authors have been instrumental in refocusing this questionst hat lie ahead in research. book toward these exciting new developments. Anthony Bretscher of Cornell University is known for identifying and characterizing new components of the actin cytoskeleton and elucidating their biological functions in relation to cell polarity and membrane traffic. Hidde Ploegh, of the Massachusetts Institute of Technologg has made major contributions to our understanding of immune system behavior, particularly in regard to the various tactics that viruses employ to evade our immune responsesa nd the ways our immune systemr esponds. Both authors are widely recognized for their researcha s well as their classroomt eachinga bilities. 'We are grateful to Paul Matsudaira, Jim Darnell, Larry ZipurskS and David Baltimore for their exceptional contri- butions to the previous editions of Molecular Cell Biology. Much of their vision and insight is apparent at many places in this book. ExperimentaEl mphasis Fluorescenmceic roscopsyh owst he locationo f DNAa nd multiple The hallmark of Molecular Cell Biology has always beent he proteinws ithint he samec ell.l FromB N G Giepmaents a l, 2006S, cience use of experimentst o teach students how we have learned 3'12:21|7 vtl New DiscoveriesN,e w Methodologies Coiled-coisl talk Methodological advances continue to expand and enrich our knowledge of molecular cell biology and lead to new understanding. Following are just a selection of the new Motor head experimental methodologiesa nd cutting-edges ciencei ntro- Neckl inkers Microtubule (+) duced in this edition: r Expanded coverage of proteomics, including organelle proteome profiling and advances in mass spectroscopy (Chapter3 ) I Forwardm otorb indsB -tubulin, ^ releasinAgD P r Expandedc overageo f RNAi, including the useo f shRNAs to inhibit any gene of interest in a cultured cell or organism (Chapters5 , 8) r Updated discussionso f chromatin, including structure and condensation( Chapter6 ), control of genee xpressionb y chro- matin remodeling (Chapter 71, and chromatin-remodeling p Forwardh eadb indsA TP proteins and tumor development( Chapter 25) ? r Evolution of chromosomes and the mitochondrion (Chapter 6) r New molecular models, including pre-initiation complex and mediator complex (Chapter 7); annular phospholipids (Chapter 1,0);C az* ATPase( Chapter 11); rhodopsin, trans- p Conformationacl hangei n neckl inkerc ausesr ear ducin, and protein kinase A (Chapter 15); and myosin head to swing forward ATPase (Chapter 17) r Latest advancesi n light and electron microscopy,i nclud- ing cryoelectron tomography (Chapter 9) r Reactive oxygen species( ROS) (Chapter 12) [ rue* forwardh eadr eleaseAs DB ^ trailingh eadh ydrolyzesATP r Role of supercomplexesi n electron transport (Chapter 12) V andr eleasePs . r Human epidermal growth factor receptors (HERs) and treatment of cancer (Chapter 16) r Myosin ATPasec ycle (Chapter 17) r Kinesin-1M Pase cycle (Chapter 18) r Use of retrovirus infection for tracing cell lineage (Chapter2 1) r Axon guidance molecules (Chapter 23) r Somaticg ener earrangementi n immune cells (Chapter 24) r Cancers tem cells (Chapter2 5) r Use of DNA microarray analysis in tumor typing (Chapter2 5) Figure1 8-22K inesin-u1s esA TPt o "walk"d owna microtubule vill PREFACE lu)taeso 1p1er.r1 [eu Vp))assrqr;r1f 1 umr.r1ru3 lqe srxlq oprlrou rlo {rE^a lelau e sled qEJI eup es)ep ^q e.rr,\re, Es exderraura plaeJ{.rers ot qol qnupar.Srep- nelo eup 8repnela slnpeuls'reu po lo urp{o urelarreI tqel ,fEu ge penulluS ;or slnpouls uroJa N/o lrp^o eddroecqeqla' nlep lo qeleura onJ Jolare8a o;lqe lelesl spaunJrl pa^al- odruauls \^rlq slnpeuls. uaop Jor Jleer exdleuelrous oJ lqe ;nuperuaulels' eu p\yr.e lrel arulousrJrop onJ rourutllureul lo urelnuS qorq rqe couradls eu paxdarru.rauls utora eJlassrqlo' 1u derlrcnler, tlo qEAa rrudrorrap lqa cqudla roaeJrlreras' rur4ruS snJa lqet lqed 8rr,e slnpauts rqe qr8 drrlnra eup dro- ^rpe e sollp JonupElrou toJ {^qpl rs 10 N/3 qE^e elso ,fourO' srudq;rap rqa lex] eu pqavpru8s'reruor;ruS ler8ou \lgerelaJ dossrqla 'JIOEJ JouJedl-ouautap qeepruEs uom drorrrpe eu aesd-lo-roep roepured oJ eelq rqedler lenn gl6eurzellou laytltzap qnueu a6 6ra1 1sqonnlu r6.ue1a eu p]aJuele drounrlat' lfonJ]asI o L]-qa lauup UNtlsou vMprp goe]p I Iu ,fousnllelrou .^rt{r utore r{eu 196 droyassors ot leII qroyoSd ;rour €Jonup lga \^o qp^a la^rsap lqa oonulrd' lBqle oJ Jouleuls 10 nurla rolplop uelarrE IEUP urrror lqe Nan/ )qedlars or8eurzBlrou oJ urosl r{lq elso slrapulluep ?uP ,fonJses' lo,fnsap colere8a o; rueuI lodrcs g rt.,aor.SeurzruS selereI lqa srxrq epruou oJ wpacrln )a lgi toToSK rurlnpes tqree cqedters. eueglruS ns lo rrrel>e roou Jor tqa ppprrrou ot uarvr rqedlars: ua\^ urplarrpl' gel{r rqedter {rps Eu nd-to-pelo lrsr o JJeJar- eu,fes oJ leupruer{ slnpres €uJporudr.aqeusrL,e Jelre\^ ?ur- r "J{ra Wolernler JaII groloSd o ;qat,aloduraul., )J{rBdre; rles lqel prraD slnpauls eup ruslJnflors to urnfl. rPPprlrouEI 77 (dr.osaurs l{ro Jnuppuroulels oJ per,alodureul {oru Jorlrl- rzelrou lqron8q deuar.u \,^rl{ rru,freesap JoJns ou ruJoJur€lrou' ;or.utplrou( urEurul?IrEu per,elodruaut' r ,,Nar^e ]ells.. )3qedlar 79 (drorrrpes nurJre pcoriareSa o1 rqa ]e[ qroloSd o; lqesa sdonprza pca11s r'ucynpruS rga let- os plp^Eu,fes ru exoupI d?l{r ;rupruS eup sausord ra,fadlrou' ,r,1rurunuoyo3d,. )alredln 7y( eddlra sdr.rucrdlos o; rrtoler- nleJ raII qroloSd ro fqa ^arlagrplo rururnue sdslouI' wapt)el ualeneu)a 141eud upleuces ru q?srJ leIIFEr Eup u'lolatnler qroloS ql erza lep luoo.^\/, lJeeluauls 'oJ JpufaJ €up orqoJ srSurlrceul qnueu prsassos. lqase ureprlel exeudles er.e \lo^ou lqron8qonl tqe rqedlers mqa;a eddroduele lo 8rrre slnpeuts pu eddr.acrelrou Jor lqo pruloel eddlrcenous o; lqe qesr,f srreure lqod ere oJ 1oeruru8 .gryeud lqaso eddqcenous qru8e ou e porerlop nuparsleupruS oJ ruprrdr.ololu corudlaxas roua1ys-corudlaxas lqel cetpdze ca1 roSnlela CNV ruolelueuls' lreuscrtdlrou' JoorpruEla uolEqolrsu. ?up ,fouuerl lalls lo olqer rolls Bup Sxdeuueule l116nle 6-€ 0Cl]]aloulreltou ru lnllnra o ]drrueuf lo drolerus pup ,fffqoqdprEles ru l{rarr exlrErtollnlEr ou^rrou- l.uonsa selallt] a)uL^oqlesl( )alls tulo t'uns)la lolls lSonyas Io1 3 uaul. v Jourdlela IIsr oJ llra uaprJE IexEu.rdles ru lqo srxq ]ruarsou eup [ )qau 'gos]ou gtouap) uealsoet-)q lusltln]eI oprnou JEU q0 JonuP o^erlaPJ' dut lv)l IX