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18The Numbersof GeneFamilies,classifiedby Function,That Are common to AllThreeDomainsof the LivingWorldp.24Covalentand NoncovalentChemicalBondsp. 53TheTypesof MoleculesThat Form a BacterialCellp.55ApproximateChemicalCompositionsof a TypicalBacteriumand a TypicalMammalianCellp.63RelationshipBetweenthe StandardFree-EnergyChange,AG, and theEquilibrium Constantp.77ChemicalBondsand GroupsCommonlyEncounteredin BiologicalMolecules pp. 106-107Waterand Its Influenceon the Behaviorof BiologicalMoleculespp. 108-109The PrincipalTypesof weak NoncovalentBondsthat Hold MacromoleculesTogetherpp.

r 1 0 - 1 1 1An Outline of Someof the Typesof SugarsCommonlyFoundin Cellspp. 1 1 2 - 1 1 3FattyAcidsand Other Lipidspp. I l4-1 I5A Surveyof the Nucleotidespp. I 16-1r7FreeEnergyand BiologicalReactionspp. I IB-t 19Detailsof the t0 Stepsof Glycolysispp. r20-I2lThe CompleteCitric Acid Cyclepp. I22-t23The 20 Amino AcidsFoundin Proteinspp.tzg-729Four DifferentWaysof Depictinga SmallProtein,the SH2Domainpp. 132-133SomeCommonTypesof Enzymesp.159Someof the MethodsUsedto StudyEnzymespp. 162-163SomeVitalStatisticsfor the Human Genomep.206ThreeMajor Classesof TransposableElementsp.318PrincipalTlpes of RNAsProducedin Cellsp.336Reviewof ClassicalGeneticspp.

554-555ApproximateLipid Compositionsof DifferentCellMembranesp.624A Comparisonof Ion ConcentrationsInsideand Outsidea TypicalMammalianCell p . 6 5 2The Derivationof the NernstEquationp.670SomeClassicalExperimentson the SquidGiantAxonp. 679RelativeVolumesOccupiedby the Major IntracellularCompartmentsin a LiverCell (Hepatocyre)p. 697RelativeAmounts of MembraneTypesin Two Kinds of Eucaryoticcellsp.697ProductYieldsfrom the Oxidationof Sugarsand Fatsp.824RedoxPotentialsp.830The RasSuperfamilyof MonomericGTpasesp.926The Polymerizationof Actin and Tubulinpp.

978-979AccessoryProteinsthat Controlthe Assemblyand positionof CvtoskeletalFilamentspp. 994-995Summaryof the Major Cell-CycleRegulatoryproteinsp. 1066The PrincinleStases of M Phasp (Mitnsis nnrl Crrfnlrinpcic\ in qn Animal/-ollnnrATo rA?aDetailedContentsChapter 1 Cells and Genomes1THEUNIVERSALFEATURESOF CELLSON EARTH1Informationin the SameLinearAllCellsStoreTheirHereditaryChemicalCode(DNA)byTemplatedHereditaryInformationAllCellsReplicateTheirPolymerizationPortionsof TheirHereditaryInformationintoAll CellsTranscribeForm(RNA)the SameIntermediaryAll CellsUseProteinsasCatalystsRNAinto Proteinin the SameWayAll CellsTranslateto OneTheFragmentof GeneticInformationCorrespondingProteinlsOneGeneLifeRequiresFreeEnergywith theFactoriesDealingAllCellsFunctionasBiochemicalBuildingBlocksSameBasicMolecularAcrossWhichin a PlasmaMembraneAllCellsAreEnclosedMustPassNutrientsandWasteMaterialsA LivingCellCanExistwith FewerThan500GenesSummary545o78891011OF GENOMESAND THETREEOF LIFETHEDIVERSITYCellsCanBePoweredby a Varietyof FreeEnergySourcesSomeCellsFixNitrogenand CarbonDioxidefor OthersCellsTheGreatestBiochemicalDiversityExistsAmongProcaryoticArchaea,Bacteria,TheTreeof LifeHasThreePrimaryBranches:and EucaryotesOthersAreHighlyConservedSomeGenesEvolveRapidly;Genesand ArchaeaHave1000-6000MostBacteriafrom PreexistingGenesNewGenesAreGeneratedof RelatedGenesWithinGiveRiseto FamiliesGeneDuplicationsa SingleCellBothin theBetweenOrganisms,GenesCanBeTransferredand in NatureLaboratoryof GeneticInformationin HorizontalExchangesSexResultsWithina SpeciesTheFunctionof a GeneCanOftenBeDeducedfrom lts SequenceAreCommonto AllThreePrimaryMoreThan200GeneFamiliesBranchesof the Treeof Lifethe Functionsof GenesMutationsRevealHaveFocuseda Spotlighton E coliMolecularBiologistsSummary11IN EUCARYOTESGENETICINFORMATIONCellsMayHaveOriginatedasPredatorsEucaryoticCellsEvolvedfrom a SymbiosisModernEucaryoticHaveHybridGenomesEucaryotesEucaryoticGenomesAreBigDNAGenomesAreRichin RegulatoryEucaryoticDevelopmentTheGenomeDefinesthe Programof MulticellularLiveasSolitaryCells:the ProtistsManyEucaryotesA YeastServesasa MinimalModelEucaryoteLevelsof AllTheGenesof An OrganismCanBeTheExpressionMonitoredSimultaneouslyandComputers,To MakeSenseof Cells,We NeedMathematics,InformationQuantitativeAsa ModelHasBeenChosenOut of 300,000SpeciesArabidopsis26Plant121314t5to17181921222223z)242626303031315Z333435JOBya Worm,a Fly,TheWorldof AnimalCellsls Representedanda Humana Mouse,DevelopmentProvidea Keyto VertebrateStudiesin DrosophilaDuplicationGenomels a Productof RepeatedTheVertebrateButlt Createsls a Problemfor Geneticists,GeneticRedundancyfor EvolvingOrganismsOpportunitiesasa Modelfor MammalsTheMouseServesReporton TheirOwnPeculiaritiesHumansWeAreAll Differentin DetailSummoryProblemsReferencesChapter2 CellChemistryand BiosynthesisOFA CELLCOMPONENTSTHECHEMICAL363738395>40414242444545of AtomsCellsAreMadeFroma FewTypesDetermineHow AtomslnteractTheOutermostElectronsCovalentBondsFormby the Sharingof ElectronsThereAreDifferentTypesof CovalentBondsasif lt Hasa FixedRadiusAn AtomOftenBehavesin CellsWaterlsthe MostAbundantSubstanceAreAcidsand BasesSomePolarMoleculesAttractionsHelpBringMoleculesof NoncovalentFourTypesTogetherin CellsA Cellls Formedfrom CarbonCompoundsMoleculesof SmallOrganicCellsContainFourMajorFamiliesSugarsProvidean EnergySourcefor CellsandArethe Subunitsof PolysaccharidesasWellasaof CellMembranes,FattyAcidsAreComponentsSourceof EnergYAminoAcidsArethe Subunitsof Proteinsof DNAandRNAArethe SubunitsNucleotideswithof Cellsls Dominatedby MacromoleculesTheChemistryPropertiesRemarkableShapeof aBondsSpecifyBoththe PreciseNoncovalentanditsBindingto OtherMoleculesMacromoleculeSummary45464850515152AND THE USEOF ENERGYBY CELLSCATALYSISby EnzymesCellMetabolismls Organizedof HeatEnergyby the ReleaseOrderls MadePossibleBiologicalfrom CellsOrganicUseSunlightto SynthesizeOrganismsPhotosyntheticMoleculesCellsObtainEnergyby the Oxidationof OrganicMoleculesTransfersOxidationand ReductionInvolveElectronThatBlockChemicalReactionsLowerthe BarriersEnzymesRapidityofTheEnormousFindTheirSubstrates:HowEnzymesMolecularMotionsWhetherltChangefor a ReactionDeterminesTheFree-EnergyCanOccurthe Free-EnergyInfluencesof ReactantsTheConcentrationDirectionChangeand a Reaction'sAG"ValuesAreAdditiveReactions,ForSequentialfor BiosynthesisAreEssentialActivatedCarrierMoleculesof an ActivatedCarrierlsCoupledto anTheFormationReactionFavorableEneroeticallv6553545555585961oz63656666687071727475767778ATPlsthe MostWidelyUsedActivatedCarrierMoleculeEnergyStoredin ATPlsOftenHarnessedto JoinTwoMoleculesTogetherNADHand NADPHAre lmportantElectronCarriersThereAreManyOtherActivatedCarrierMoleculesin CellsTheSynthesisof BiologicalPolymersls Drivenby ATpHydrolysisSummary808182838487HOW CELLSOBTAINENERGYFROMFOOD88pathwayGlycolysisls a CentralATP-producing88FermentationsProduceATPin the Absenceof OxygenRqGlycolysislllustratesHow EnzymesCoupleOxidationto EnergyStorage91OrganismsStoreFoodMoleculesin SpecialReservoirs91MostAnimalCellsDeriveTheirEnergyfrom FattyAcidsBetweenMeals95Sugarsand FatsAreBothDegradedto AcetylCoAin Mitochondria voTheCitricAcidCycleGeneratesNADHby OxidizingAcetylGroupsto CO2o7ElectronTransportDrivesthe Synthesisof the Majorityof the ATpin MostCells100AminoAcidsand NucleotidesAre partof the NitrogenCycle100Metabolismls Organizedand Regulated101Summary103Problems103References124Chapter3 ProteinsTHESHAPEANDSTRUCTUREOFPROTEINSTheShapeof a Proteinls Specifiedby lts AminoAcidSequenceProteinsFoldinto a Conformationof LowestEnergyThecrHelixand the B SheetAreCommonFoldingpatternsProteinDomainsAreModularUnitsfrom whichLargerproteinsAreBuiltFewof the ManyPossiblePolypeptideChainsWillBeUsefurto CellsProteinsCanBeClassifiedintoManyFamiliesSequenceSearchesCanldentifyCloseRelativesSomeProteinDomainsFormpartsof ManyDifferentproteinsCertainPairsof DomainsAreFoundTogetherin ManyproteinsTheHumanGenomeEncodesa ComplexSetof proteins,RevealingMuchThatRemainsUnknownLargerProteinMoleculesOftenContainMoreThanOnePolypeptideChainSomeProteinsFormLongHelicalFilamentsManyProteinMoleculesHaveElongated,FibrousShapesManyProteinsContaina SurprisinglyLargeAmountofUnstructuredPolypeptideChainproteinsCovalentCross-LinkagesOftenStabilizeExtracellularProteinMoleculesOftenServeasSubunitsfor the Assembryof LargeStructuresManyStructuresin CellsAreCapableof Self-AssemblyAssemblyFactorsOftenAidthe Formationof ComolexBiologicalStructuresSummary125125tzJ130131tJ)I Jt)137139140141142"t42143t4)"146147148149151't52PROTEINFUNCTION152All ProteinsBindto OtherMolecules153TheSurfaceConformationof a ProteinDetermineslts Chemistrv 154SequenceComparisonsBetweenproteinFamilyMembersHighlightCrucialLigand-BindingSites155ProteinsBindto OtherProteinsThroughSeveralTypesofInterfacestf,oAntibodyBindingSitesAreEspeciallyVersatile156TheEquilibriumConstantMeasuresBindingStrength157EnzymesArePowerfuland HighlySpecificCatalysts158SubstrateBindingls the FirstStepin EnzymeCatalysisi59EnzymesSpeedReactionsby SelectivelyStabilizingTransitronStates160EnzymesCanUseSimultaneousAcidandBaseCatalysis160LysozymelllustratesHowan EnzymeWorks16"1TightlyBoundSmallMoleculesAdd ExtraFunctionsto prorerns166MolecularTunnelsChannelSubstratesin Enzymeswith'167MultipleCatalyticSitesMultienzymeComplexesHelpto Increasethe Rateof CellMetabolism168TheCellRegulatesthe CatalyticActivitiesof its Enzymes169AllostericEnzymesHaveTwoor MoreBindingSitesThatInteract 1 7 1TwoLigandsWhoseBindingSitesAreCoupledMustReciprocallyAffectEachOther'sBinding171SymmetricProteinAssembliesProduceCooperativeAllosteflcTransitions172TheAllostericTransitionin AspartateTranscarbamoylaselsUnderstoodin AtomicDetail173ManyChangesin ProteinsAre Drivenby ProteinPhosphorylation175A EucaryoticCellContainsa LargeCollectionof ProteinKinasesand ProteinPhosphatases176TheRegulationof Cdkand SrcProteinKinasesShowsHowaProteinCanFunctionasa Microchip177ProteinsThatBindand HydrolyzeGTPAreUbiquitousCellularRegulators178proteinsRegulatoryProteinsControlthe Activityof GTP-Bindingby DeterminingWhetherGTPor GDPls Bound179LargeProteinMovementsCanBeGeneratedFromSmallOnes179MotorProteinsProduceLargeMovementsin Cells181Membrane-BoundTransportersHarnessEnergyto PumpMoleculesThroughMembranes182ProteinsOftenFormLargeComplexesThatFunctionasProteinMachines184ProteinMachineswith InterchangeablePartsMakeEfficientUseof Geneticlnformation184TheActivationof ProteinMachinesOftenInvolvesPositioningThemat SpecificSites185ManyProteinsAreControlledby MultisiteCovalentModification t 6 0A ComplexNetworkof ProteinInteractionsUnderliesCellFunction 187Summary190Problems191References193Chapter4 DNA,Chromosomes,and Genomes195THESTRUCTUREANDFUNCTIONOFDNA197A DNAMoleculeConsistsof TwoComplementaryChainsof NucleotidesTheStructureof DNAProvidesa Mechanismfor HeredityIn Eucaryotes,DNAls Enclosedin a CellNucleusSummory197199200201CHROMOSOMALDNA AND ITSPACKAGINGIN THECHROMATINFIBER202EucaryoticDNAls Packagedinto a Setof Chromosomes202ChromosomesContainLongStringsof Genes204TheNucleotideSequenceofthe HumanGenomeShowsHowOurGenesAreArranged205GenomeComparisonsRevealEvolutionarilyConservedDNA)equences207ChromosomesExistin DifferentStatesThroughoutthe Lifeofa Cell2OBEachDNAMoleculeThatFormsa LinearChromosomeMustContaina Centromere,TwoTelomeres,and ReplicationOrigins 2OgDNAMoleculesAre HighlyCondensedin Chromosomes210NucleosomesArea BasicUnitof EucaryoticChromosomeStructure211TheStructureofthe NucleosomeCoreParticleRevealsHowDNAls PackagedZ'tZNucleosomesHavea DynamicStructure,and AreFrequentrySubjectedto ChangesCatalyzedby ATp-DependentChromatinRemodelingComplexes215NucleosomesAreUsuallyPackedTogetherinto a CompactChromatinFiberltoSummary218THEREGULATIONOFCHROMATINSTRUCTURESomeEarlyMysteriesConcerningChromatinStructure219220ResistantHeterochromatinls HighlyOrganizedandUnusually220to GeneExoressionModifiedat ManyDifferentSitesTheCoreHistonesAreCovalentlyChromatinAcquiresAdditionalVarietythroughthe Site-SpecificVariantslnsertionof a SmallSetof Histoneandthe HistoneVariantsAct inTheCovalentModificationsConcertto Producea "HistoneCode"ThatHelpstoFunctionDetermineBiologicalandCode-WriterProteinsCanSpreadA Comolexof Code-ReaderAlongafor LongDistancesSpecificChromatinModificationsChromosomeComplexesBlockthe Spreadof Reader-WriterBarrierDNASequencesDomainsSeparateNeighboringChromatinandTherebyHow HistoneVariantsRevealsTheChromatinin Centromereszt6CanCreateSpecialStructures230CanBeDirectlyInheritedChromatinStructuresto EucaryoticAdd UniqueFeaturesChromatinStructures231FunctionChromosome233SummaryTHEGLOBALSTRUCTUREOF CHROMOSOMES233AreFoldedinto LargeLoopsof ChromatinChromosomesChromosomesAreUniquelyUsefulfor VisualizingPolyteneChromatinStructuresThereAreMultipleFormsof HeterochromatinWhenthe GenesWithinThemAreChromatinLoopsDecondenseExoressedChromatinCanMoveto SpecificSitesWithinthe NucleustoAlterTheirGeneExoressionForma Setof DistinctBiochemicalNetworksof Macromoleculesinsidethe NucleusEnvironmentsAreFormedfrom Chromatinin lts MostMitoticChromosomesStateCondensedSummary234EVOLVEHOW GENOMES245of the NormaAreCausedby FailuresGenomeAlterationsDNAfor CopyingandMaintainingMechanismsDifferin Proportiontoof TwoSpeciesTheGenomeSequencesEvolvedthe LengthofTimeThatTheyHaveSeparatelyof DNAfrom a ComparisonTreesConstructedPhylogeneticof All OrganismsTracethe RelationshipsSequencesShowsof HumanandMouseChromosomesA ComoarisonHowthe Structuresof GenomesDivergeRatesofGenomeReflectsthe RelativeTheSizeof a VertebrateDNAAdditionand DNALossin a Lineagethe Sequenceof SomeAncientGenomesWeCanReconstructldentifylmportantDNAComparisonsMultispeciesSequenceSequencesof UnknownFunctionSequencesCanConservedChangesin PreviouslyAcceleratedHelpDecipherCriticalStepsin HumanEvolutionan lmportantSourceof GeneticGeneDuplicationProvidesNoveltyDuringEvolutionGenesDivergeDuplicatedTheEvolutionof the GlobinGeneFamilyShowsHow DNAof OrganismsContributeto the EvolutionDuplicationsCanBeCreatedby theGenesEncodingNewProteinsRecombinationof ExonsNeutralMutationsOftenSpreadto BecomeFixedin a Population,that Dependson PopulationSizewith a ProbabilityoftheVariationA GreatDealCanBeLearnedfrom AnalysesAmongHumansSummaryProblemsReferencesChapter5 DNA Replication,Repair,andRecombinationOFDNASEQUENCESTHEMAINTENANCELowMutationRatesAre Extremelyfor LifeasWe KnowltLowMutationRatesAreNecessarySummory2362562392392412432452462472482492512512s2253z>5254257257258260lou262263263205265265266MECHANISMSDNA REPLICATIONtooandDNARepairDNAReplicationUnderliesBase-Pairing266Forkls AsymmetricalTheDNAReplicationProofreadingSeveralRequiresTheHighFidelityof DNAReplicationMechanismsAllowsEfficientErrorin the 5'-to-3'DirectionOnlyDNAReplication27"1CorrectionShortRNAEnzymeSynthesizesA 5pecialNucleotide-Polymerizing272on the LaggingStrandPrimerMoleculesHelpto OpenUpthe DNADoubleHelixin FrontProteinsSpecial273Forkofthe Replication273ontothe DNAA SlidingRingHoldsa MovingDNAPolymeraseto Forma ReplicationForkCooperateat a ReplicationTheProteins275MachineReplicationMismatchRepairSystemRemovesA Strand-Directed276Machinefrom the ReplicationErrorsThatEscapePreventDNATanglingDuringReplication z I dDNATopoisomerasesandin EucaryotesSimilarls FundamentallyDNAReplication280Bacteria281SummaryOF DNA REPLICATIONAND COMPLETIONTHEINITIATION281IN CHROMOSOMES281OriginsReplicationatBeginsDNASynthesisTypicallyHavea SingleOriginof DNAChromosomesBacterial26lReolicationContainMultipleOriginsof Replication 282ChromosomesEucaryoticTakesPlaceDuringOnlyOnePartDNAReplicationIn Eucaryotes284of the cell cycleat DistinctReplicateon the SameChromosomeDifferentRegions285Timesin S PhaseLate,WhileGenesinChromatinReplicatesHighlyCondensed285EarlyTendto ReplicateChromatinLessCondensedOriginsin aServeasReplicationDNASequencesWell-Defined260the BuddingYeastSimpleEucaryote,OriginsofA LargeMultisubunitComplexBindsto Eucaryotic287ReolicationThatSpecifythe InitiationofTheMammalianDNASequences288HaveBeenDifficultto ldentifyReplication289ForkBehindthe ReplicationAreAssembledNewNucleosomesDuplicationEnsureChromosomeof EucaryoticTheMechanisms290CanBeInheriteoof HistoneModificationThatPatterns292the Endsof ChromosomesReplicatesTelomerasezY5by CellsandOrganismsLengthls RegulatedTelomere294SummaryDNA REPAIRDNADamageWouldRapidlySpontaneousWithoutDNARepair,ChangeDNASequencesTheDNADoubleHelixls ReadilyRepairedDNADamageCanBeRemovedby MoreThanOne PathwayThatthe Cell'sMostEnsuresCouplingDNARepairto TranscriptionRepairedlmportantDNAls EfficientlyDamageDetectionof the DNABasesFacilitatesTheChemistryto RepairDNAAreUsedin EmergenciesSpecialDNAPolymerasesRepairedAre EfficientlyBreaksDouble-Strandof the CellCycleDNADamageDelaysProgressionSummary295RECOMBINATIONHOMOLOGOUSHasManyUsesin the CellRecombinationHomologousin All CellsHasCommonFeaturesRecombinationHomologousRecombinationGuidesHomologousDNABase-PairingTheRecAProteinand its HomologsEnablea DNA5ingleStrandRegionof DNADoubleHelixto Pairwith a HomologousorRegionsBranchMigrationCanEitherEnlargeHetroduplexDNAasa SingleStrandNewlySynthesizedReleaseDoubleRepairCanFlawlesslyRecombinationHomologousin DNABreaksStrandedRecombinationthe Useof HomologousCellsCarefullyRegulatein DNARepairHollidayJunctionsAreOftenFormedDuringHomologousEventsRecombination304296296297299300302302303304304305305307308308310311MeioticRecombinationBeginswith a programmedDoubleStrandBreakHomologousRecombinationOftenResultsin GeneConversronpromiscuousMismatchProofreadingPreventsRecombinatronBetweenTwoPoorlyMatchedDNASequencesSummaryTRANSPOSITIONAND CONSERVATIVESITE-SPECIFICRECOMBINATION3123143155to316ThroughTransposition,MobileGeneticElementsCanInsertlntoAnyDNASequencey7DNA-OnlyTransposonsMoveby BothCut-and-pasteand ReplicativeMechanisms317SomeVirusesUsea TranspositionMechanismto MoveThemselvesintoHostCellChromosomes319Retroviral-likeRetrotransposonsResembleRetroviruses,but LackaProteinCoat320A LargeFractionof the HumanGenomels ComoosedofNonretroviralRetrotransposons32,lpredominateDifferentTransposableElementsin DifferentOrganisms322GenomeSequencesRevealthe ApproximateTimesthatTransposableElementsHaveMoved323ConservativeSite-SpecificRecombinationCanReversiblyRearrangeDNA323ConservativeSite-SpecificRecombinationWasDiscoveredinBacteriophage),n+ConservativeSite-SpecificRecombinationCanBeUsedto TurnGenesOn or Off324Summary326Problems327References328Chapter6 How CellsReadthe Genome:FromDNAto Protein329FROMDNATORNA331Portionsof DNASequenceAreTranscribedinto RNA552TranscriptionProducesRNAComplementaryto OneStrandof DNA 5 5 5CellsProduceSeveralTypesof RNA335SignalsEncodedin DNATellRNApolymeraseWhereto StartandStop336TranscriptionStartand StopSignalsAreHeterogeneousinNucleotideSequence338TranscriptionInitiationin EucaryotesRequiresManyproteins339RNAPolymerasell RequiresGeneralTranscriptionFactors340Polymerasell AlsoRequiresActivator,Mediator,andChromatinModifyingProteins342TranscriptionElongationProducesSuperhelicalTensionin DNA343TranscriptionElongationin EucaryoteslsTightlyCoupledto RNAProcessing345pre-mRNAs 346RNACappinglsthe FirstModificationof EucaryoticRNASplicingRemovesIntronSequencesfrom NewlyTranscribedPre-mRNAs347NucleotideSequencesSignalWhereSplicingOccurs349RNASplicingls Performedby the Spliceosome349TheSpliceosomeUsesATPHydrolysisto producea ComplexSeriesof RNA-RNARearrangements351OtherPropertiesof Pre-mRNAand lts SynthesisHelpto Explainthe Choiceof ProperSpliceSites352A Second5et of snRNPsSplicea SmallFractionof IntronSequencesin AnimalsandPlants353plasticityRNASplicingShowsRemarkableJ55Spliceosome-CatalyzedRNASplicingprobablyEvolvedfromSelf-SplicingMechanisms355RNA-ProcessingEnzymesGeneratethe 3, Endof EucaryoticmRNAs5 t /MatureEucaryoticmRNAsAreSelectivelyExportedfrom tneNucleus358ManyNoncodingRNAsAreAlsoSynthesizedand processedin theNucleus360TheNucleolusls a Ribosome-producingFactory502TheNucleusContainsa Varietyof SubnuclearStructures50JSummarv366FROMRNATO PROTEIN366An mRNASequencels Decodedin SetsofThreeNucleotideIRNAMoleculesMatchAminoAcidsto Codonsin mRNAtRNAsAreCovalentlyModifiedBeforeTheyExitfrom the NucleusSpecificEnzymesCoupleEachAminoAcidto ltsAppropriateIRNAMoleculeEditingby RNASynthetasesEnsuresAccuracyAminoAcidsAreAddedto the C-terminalEndof a GrowingPolypeptideChainTheRNAMessagels Decodedin RibosomesElongationFactorsDriveTranslationForwardand lmproveltsAccuracyTheRibosomels a RibozymeNucleotideSequencesin mRNASignalWhereto StartProteinSynthesisStopCodonsMarktheEndofTranslationProteinsAreMadeon PolyribosomesThereAreMinorVariationsin the StandardGeneticCodeInhibitorsof ProcaryoticProteinSynthesisAreUsefulasAntibioticsAccuracyin TranslationRequiresthe Expenditureof FreeEnergyActto PreventQualityControlMechanismsTranslationof DamaqedmRNAsSomeProteinsBeginto FoldWhileStillBeingSynthesizedMolecularChaperonesHelpGuidethe Foldingof MostproteinsExposedHydrophobicRegionsProvideCritical5ignalsfor proteinQualityControlTheProteasomelsa CompartmentalizedProteasewithSequesteredActiveSitesAn ElaborateUbiquitin-ConjugatingSystemMarksProteinsforDestructionManyProteinsAreControlledby RegulatedDestructionAbnormallyFoldedProteinsCanAggregateto CauseDestructiveHumanDiseasesThereAreManyStepsFromDNAto ProteinSummory367368369THERNAWORLDAND THEORIGINSOF LIFELifeRequiresStoredInformationPolynucleotidesCanBothStoreInformationand CatalyzeChemicalReactionsA Pre-RNAWorldMayPredatethe RNAWorldSingle-StrandedRNAMoleculesCanFoldintoHighlyElaborateStructuresSelf-ReplicatingMoleculesUndergoNaturalSelectionHow Did ProteinSynthesisEvolve?All Present-DayCellsUseDNAasTheirHereditaryMaterialSummaryProblemsReferencesChapter7 Controlof GeneExpressionAN OVERVIEWOF GENECONTROLTheDifferentCellTypesof a MulticellularOrganismContaintheSameDNADifferentCellTypesSynthesizeDifferentSetsof proteinsExternalSignalsCanCausea Cellto Changethe ExpressionofItsGenesGeneExpressionCanBeRegulatedat Manyofthe Stepsin thePathwayfrom DNAto RNAto ProteinSummary3703715t537337737937938139139238338538538738839039139339s3963gg3gg4OO4014014024034044074084084094104114'11411412413415415DNA-BINDINGMOTIFSINGENEREGULATORYPROTEINS 416GeneRegulatoryProteinsWereDiscoveredUsingBacterialGeneticsTheOutsideof the DNAHelixCanBeReadby proteinsShortDNASequencesAre FundamentalComponentsof GeneticSwitchesGeneRegulatoryProteinsContainStructuralMotifsThatCanReadDNASeouencesTheHelix-Turn-HelixMotif lsOneof the Simplestand MostCommonDNA-B|ndingMotifs416416418418419ProteinsConstitutea SpecialClassof Helix-TurnHomeodomain420HelixProteins421of DNA-B|ndingZincFingerMotifsThereAreSeveralTypesp sheetsCanAlsoRecognize422DNASomeProteinsUseLoopsThatEnterthe Majorand MinorGroove423to RecognizeDNATheLeucineZipperMotifMediatesBothDNABindingand Protein423DimerizationThatExpandsthe Repertoireof DNASequencesHeterodimerization424ProteinsCanRecognizeGeneRegulatoryand DNAMotifAlsoMediatesDimerizationTheHelix-Looo-Helix425BindingRecognizedto Predictthe DNASequencesIt ls NotYetPossible426Proteinsby All GeneRegulatoryShiftAssayReadilyDetectsSequence-SpecificA Gel-Mobility427ProteinsDNA-BindingofFacilitatesthe PurificationDNAAffinityChromatography428ProteinsDNA-BindingSequence-SpecificProteinRecognizedby a GeneRegulatoryTheDNASequence429CanBeDeterminedExperimentallySequencesFootprintingldentifiesDNARegulatoryPhylogenetic431GenomicsThroughComparativeldentifiesManyof the SitesChromatinlmmunoprecipitation431ProteinsOccupyin LivingCellsThatGeneRegulatory432Summary432WORKHOW GENETICSWITCHESGenesThatTurnsRepressorlsaSimpleSwitchTheTryptophan433On and Off in Bacteria435ActivatorsTurnGenesOnTranscriptionalRepressorActivatorand a TranscriptionalA Transcriptional435Controlthe LocOperon437GeneRegulationDNALoopingOccursDuringBacterialto HelpRNAPolymeraseSubunitsBacteriaUseInterchangeable438GeneTranscriptionRegulateComplexSwitchesHaveEvolvedto ControlGeneTranscription439in Eucaryotesof a PromoterPlusGeneControlRegionConsistsA Eucaryotic440DNASequencesRegulatoryof RNAGeneActivatorProteinsPromotethe AssemblyEucaryoticat theFactorsPolymeraseand the GeneralTranscription441Startpointof TranscriptionAlsoModifyLocalChromatinGeneActivatorProteinsEucaryotic442Structure444WorkSynergisticallyGeneActivatorProteinsProteinsCanInhibitTranscriptionGeneRepressorEucaryotic445in VariousWaysProteinsOftenBindDNAGeneRegulatoryEucaryotic445CooperativelyDevelopmentThatRegulateDrosophilaComplexGeneticSwitches447ModulesAreBuiltUp fromSmallerControls 448by CombinatorialEveGenels Regulatedfhe DrosophilaAreAlsoConstructedGeneControlRegionsComplexMammalian450Modulesfrom SimpleRegulatoryGeneThatPreventEucaryoticAre DNASequencesInsulators+)zfrom InfluencingDistantGenesProteinsRegulatory453RapidlyEvolveGeneSwitches453SummaryTHATCREATEMECHANISMSGENETICTHEMOLECULAR454CELLTYPESSPECIALIZED454inBacteriaPhaseVariationMediateDNARearrangementsCellTypein aProteinsDeterminesA Setof GeneRegulatory455BuddingYeasttheDetermineEachOther! SynthesisRepressTwo ProteinsThatLambdaHeritableStateof BacteriophageCircuitsCanBeUsedto MakeMemorySimpleGeneRegulatory458DevicesAllowthe Cellto CanyOut LogicOperations 459CircuitsTranscriptionalParts 460Biologicalfrom ExistingNewDevicesBiologyCreatesSyntheticLoopsin GeneRegulation 460ClocksAre Basedon FeedbackCircadianthe ExpressionProteinCanCoordinateA SingleGeneRegulatoryof a Setof GenesProteinCanTriggerof a CriticalGeneRegulatoryExpressionGenesof a WholeBatteryof Downstreamthe ExpressionManyDifferentCellTypesGeneControlCreatesCombinatorialin EucaryotesProteinCanTriggerthe FormationA SingleGeneRegulatoryof an EntireOrganThePatternof DNAMethylationCanBeInheritedWhenCellsDivideVertebrateon DNAMethylationlmprintingls BasedGenomicwith ManyGenesin MammalslslandsAreAssociatedCG-RichofThatStablePatternsEnsureMechanismsEpigeneticto DaughterCellsCanBeTransmittedGeneExpressionin ChromatinStructureAlterationsChromosome-WideCanBeInheritedNoisyis IntrinsicallyTheControlof GeneExpressionSummaryPTIONALCONTROLSPOST-TRANSCRITerminationthe PrematureAttenuationCausesTranscriptionof SomeRNAMoleculesAncientFormsof GeneControlMightRepresentRiboswitchesAlternativeRNASplicingCanProduceDifferentFormsof aProteinfrom the SameGeneTheDefinitionof a GeneHasHadto BeModifiedSincetheRNASplicingof AlternativeDiscoveryDependson a RegulatedDrosophiloSexDeterminationinSeriesof RNASplicingEventsand Poly-ACleavageA Changein the Siteof RNATranscriptof a ProteinAdditionCanChangethe C-terminusthe Meaningof the RNAMessageRNAEditingCanChangefrom the NucleusCanBeRegulatedRNATransportof the Cytoplasmto SpecificRegionsSomemRNAsAre LocalizedControlof mRNAsRegionsThe5'and3'UntranslatedTheirTranslationProteinof an lnitiationFactorRegulatesThePhosphorylationGloballySynthesisStartlnitiationat AUGCodonsUpstreamof the TranslationInitiationTranslationCanRegulateEucaryoticforEntrySitesProvideOpportunitiesInternalRibosomeControlTranslationGeneExpressionChangesin mRNAStabilityCanRegulatePoly-AAdditionCanRegulateTranslationCytoplasmicManyAnimalandRegulateRNATranscriptsSmallNoncodingPlantGenesls a CellDefenseMechanismRNAInterferenceFormationCanDirectHeterochromatinRNAInterferenceToolHasBecomea PowerfulExperimentalRNAlnterferenceSummoryProblemsReferences464465467468470471473476477477477478479480481482483485486488488489491492493493495496497497497499Chapter8 ManipulatingProteins,DNA,and RNA 50r501THEMINCULTUREANDGROWINGCELLSISOLATINGCellsCanBelsolatedfrom IntactTissuesCellsCanBeGrownin CultureCellLinesArea WidelyUsedSourceofEucaryoticCellsHomogeneousMedicineStemCellsCouldRevolutionizeEmbryonicMayProvidea WaytoSomaticCellNuclearTransplantationStemCellsPersonalizedGenerateThatProduceMonoclonalHybridomaCellLinesAreFactoriesAntibodiesSummary502s02PROTEINSPURIFYINGintoTheirComponentFractionsCellsCanBeSeparatedto StudyCellFunctionsSystemsProvideAccessibleCellExtractsby ChromatographyCanBeSeparatedProteinsExploitsSpecificBindingSitesonAffinityChromatographyProteinsTagsProvidean EasyWayto PurifyGenetically-EngineeredProteins51050s505s07508s10510511512513514PurifiedCell-FreeSystemsAreRequiredfor the preciseDissectionofMolecularFunctionsSummoryANALYZINGPROTEINSProteinsCanBeSeparatedby SDSpolyacrylamide-GelElectrophoresisSpecificProteinsCanBeDetectedby Blottingwith AntibodiesMassSpectrometryProvidesa HighlySensitiveMethodfor ldentifyingUnknownproteinsTwo-DimensionalpowerfulSeparationMethodsareEspeciallyHydrodynamicMeasurementsRevealthe SizeandShapeofa ProteincomolexSetsof InteractingProteinsCanBeldentifiedby BiochemicalMethodsProtein-ProteinInteractionsCanAlsoBeldentifiedby aTwo-HybridTechniquein yeastproducesCombiningDataDerivedfrom DifferentTechniquesReliableProtein-lnteractionMaDsOpticalMethodsCanMonitorProteinInteractionsin RealTimeSomeTechniquesCanMonitorSingleMoleculesProteinFunctionCanBeSelectivelyDisruptedwith SmallMoleculesProteinStructureCanBeDeterminedUsingX-RayDiffractionNMRCanBeUsedto DetermineproteinStructurein SolutronProteinSequenceand StructureprovideCluesAboutproteinFunctionSummoryANALYZINGAND MANIPULATINGDNARestrictionNucleasesCut LargeDNAMoleculesinto FragmentsGelElectrophoresisSeparatesDNAMoleculesof DifferentSizesPurifiedDNAMoleculesCanBeSpecificallyLabeledwithRadioisotopesor ChemicalMarkersin yitroprovidea SensitiveNucleicAcidHybridizationReactionsWayofDetectingSpecificNucleotideSequencesNorthernand SouthernBlottingFacilitateHybridizationwithElectrophoreticallySeparatedNucleicAcidMoleculesGenesCanBeClonedUsingDNALibrariesTwoTypesof DNALibrariesServeDifferentpuroosescDNAClonesContainUninterruptedCodingSequencesGenesCanBeSelectivelyAmplifiedby pCRCellsCanBeUsedAs Factoriesto produceSoecificproteinsProteinsand NucleicAcidsCanBeSynthesizedDirectlybyChemicalReactionsDNACanBeRapidlySequencedNucleotideSequencesAreUsedto predictthe AminoAcioSequencesof ProteinsTheGenomesof ManyOrganismsHaveBeenFullySequenceoSummarySTUDYINGGENEEXPRESSIONAND FUNCTIONClassicalGeneticsBeginsby Disruptinga Cellprocessby RanoomMutagenesisGeneticScreensldentifyMutantswith SpecificAbnormalirresMutationsCanCauseLossor Gainof proteinFunctionComplementationTestsRevealWhetherTwoMutationsArein the SameGeneor DifferentGenesGenesCanBeOrderedin Pathwaysby EpistasisAnalysisGenesldentifiedby MutationsCanBeClonedHumanGeneticsPresents5pecialproblemsandSpecialOpportunitiesHumanGenesAreInheritedin HaplotypeBlocks,WhichCanAid in the Searchfor MutationsThatCauseDiseaseComplexTraitsAre Influencedby MultipleGenesReverseGeneticsBeginswith a KnownGeneand DeterminesWhichCellProcessesRequirelts FunctionGenesCanBeRe-Engineeredin SeveralWaysEngineeredGenesCanBeInsertedintothe GermLineofManyOrganismsAnimalsCanBeGeneticallyAlteredTransgenicPlantsAre lmportantfor BothCellBiologyandAgriculture) to) to517517518519521522523523524524526J2/ill529530)Jl532s32534s35)J)s38540541544544546548548550551))z553553556558558s59s60561s63LargeCollectionsofTaggedKnockoutsProvidea ToolforExaminingthe Functionof EveryGenein an OrganismRNAInterferencels a Simpleand RapidWayto TestGeneFunctionReporterGenesand /n SituHybridizationRevealWhenanoWherea Genels ExpressedExpressionof IndividualGenesCanBeMeasuredUsinoRT-PCRQuantitativeMicroarraysMonitorthe Expressionof Thousandsof GenesatOnce5ingle-CellGeneExpressionAnalysisRevealsBiological"Noise"SummaryProblemsReferencesChapter 9 Visualizing Cells569571572573574575576576579579LOOKINGAT CELLSIN THELIGHTMICROSCOPE579TheLightMicroscopeCanResolveDetails0.2pm Aparts80LivingCellsAreSeenClearlyin a Phase-Contrastor a DifferentialInterference-ContrastMicroscooe583lmagesCanBeEnhancedandAnalyzedby DigitalTechniques583IntactTissuesAreUsuallyFixedand SectionedbeforeMicroscopy 585SpecificMoleculesCanBeLocatedin Cellsby FluorescenceMicroscopy586AntibodiesCanBeUsedto DetectSpecificMolecules588lmagingof ComplexThree-DimensionalObjectslsPossiblewith the OpticalMicroscope589TheConfocalMicroscopeProducesOpticalSectionsby ExcludingOut-of-FocusLight590FluorescentProteinsCanBeUsedtoTagIndividualproteinsinLivingCellsandOrganisms592ProteinDynamicsCanBeFollowedin LivingCells593Light-EmittingIndicatorsCanMeasureRapidlyChangingIntracellularlonConcentrations596SeveralStrategiesAreAvailableby WhichMembrane-lmpermeantSubstancesCanBeIntroducedinto Cells597LightCanBeUsedto ManipulateMicroscopicObjectsAsWellAsto lmageThem598SingleMoleculesCanBeVisualizedby UsingTotalInternalReflectionFluorescenceMicroscopy5ggIndividualMoleculesCanBeTouchedandMovedUsingAtomicForceMicroscopy600MoleculesCanBeLabeledwith Radioisotopes600RadioisotopesAreUsedtoTraceMoleculesin CellsandOrganisms602Summary603LOOKINGAT CELLSAND MOLECULESIN THEELECTRONMtcRoScoPE604TheElectronMicroscopeResolvesthe FineStructureofthe Cell604BiologicalSpecimensRequireSpecialPreparationfor the ElectronMicroscope605SpecificMacromoleculesCanBeLocalizedby lmmunogoldElectronMicroscopy606lmagesof SurfacesCanBeObtainedby ScanningElectronMicroscopy607MetalShadowingAllowsSurfaceFeaturesto BeExaminedatHighResolutionbyTransmissionElectronMicroscopy60gNegativeStainingand CryoelectronMicroscopyBothAllowMacromoleculesto BeViewedat HighResolution6l OMultiplelmagesCanBeCombinedto IncreaseResolution610DifferentViewsof a SingleObjectCanBeCombinedto GiveaThree-DimensionalReconstruction612Summaryot2Problems614Referencesot)s63564Chapter10 MembraneStructure565THELIPIDBILAYERPhosphoglycerides,Sphingolipids,andSterolsAretheMajor617L i p i d si n C e l lM e m b r a n e sP h o s p h o l i o i d sS o o n t a n e o u s l vF o r m B i l a v e r s618foo)oaJ6",7A)6TheLipidBilayerlsa Two-DimensionalFluidTheFluidityof a LipidBilayerDependson lts CompositionCanFormDomainsofDespiteTheirFluidity,LipidBilayersDifferentCompositionsMonolayerLipidDropletsAreSurroundedby a PhospholipidlmportantTheAsymmetryof the LipidBilayerls FunctionallyAre Foundon the Surfaceof All PlasmaMembranesGlycolipidsSummaryollMEMBRANEPROTEINS629with the LipidBilayerinMembraneProteinsCanBeAssociatedVariousWaysof SomeLipidAnchorsControlthe MembraneLocalizationProteinsSignalingProteinsthe PolypeptideChainCrossesIn MostTransmembranethe LipidBilayerin an o-HelicalConformationTransmembranecrHelicesOftenlnteractwith OneAnotherFormLargeTransmembraneChannelsSomep BarrelsAreGlycosylatedManyMembraneProteinsand Purifiedin DetergentsMembraneProteinsCanBeSolubilizedlsa Light-DrivenProtonPumpThatTraversesBacteriorhodopsinthe LipidBilayerasSevens HelicesOftenFunctionasLargeComplexesMembraneProteinsManyMembraneProteinsDiffusein the Planeof the Membraneand Lipidsto SpecificDomainsWithinCellsCanConfineProteinsa MembraneMechanicalStrengthGivesMembranesTheCorticalCytoskeletonand RestrictMembraneProteinDiffusionSummaryProblemsReferences622624ot>626628629629630631632634o5f636640642642645646648648650Chapter11 MembraneTransportof SmallMolecules651and the ElectricalPropertiesof MembranesPRINCIPLESOF MEMBRANETRANSPORT651to lonsLipidBilayersAreHighlylmpermeableProtein-FreeTransportProteins:of MembraneThereAreTwo MainClassesand ChannelsTransportersCoupledto anActiveTransportls MediatedbyTransportersEnergySourceSummary652AND ACTIVEMEMBRANETRANSPORTTRANSPORTERSCanBeDrivenby lon GradientsActiveTransportpHCytosolicin the PlasmaMembraneRegulateTransportersCellsin EpithelialDistributionof TransportersAn AsymmetricTransportof SolutesUnderliesthe TranscellularPumpsof ATP-DrivenThereAreThreeClassesP-typeATPaseTheCa2+Pumplsthe Best-UnderstoodthePumpEstablishesThePlasmaMembraneP-typeNa+-K+Na+GradientAcrossthe PlasmaMembraneConstitutethe LargestFamilyof MembraneABCTransportersTransoortProteinsSummary6546566526s3654o)t658oou661663667OFPROPERTIESANDTHEELECTRICALION CHANNELS667MEMBRANESand FluctuateBetweenOpenandArelon-Selectivelon Channels667closedStatesTheMembranePotentialin AnimalCellsDependsMainlyon K+Leak669and the K+GradientAcrossthe PlasmaMembraneChannelsPumpthe Na+-K+TheRestingPotentialDecaysOnlySlowlyWhen669ls StoppedK+ChannelShowsStructureof a BacterialTheThree-Dimensional671CanWorkHowan lonChannel673to lonsto WaterButlmpermeableArePermeableAquaporins675StructureTheFunctionofa NeuronDependson lts ElongatedinActionPotentialsGenerateCationChannelsVoltage-Gated676ExcitableCellsElectricallyof ActionPotentialthe Speedand EfficiencyMyelinationIncreaseso/6in NerveCellsPropagationIndividualGatedChannelsIndicatesThatRecordingPatch-Clamp680FashionOpenin an All-or-Nothingand StructurallyAre EvolutionarilyCationChannelsVoltage-Gated682RelatedConvertChemicalSignalsintolon ChannelsTransmittercated682Onesat ChemicalSynapsesElectrical684or InhibitoryCanBeExcitatoryChemicalSynapsesJunctionAreat the NeuromuscularReceptorsTheAcetylcholine684CationChannelsTransmitter-Gatedfor PsychoactiveAreMajorTargetslon ChannelsTransmitterGated686DrugsActivationthe SequentialInvolvesTransmissionNeuromuscular687of FiveDifferentSetsof lon Channels688SingleNeuronsAreComplexComputationDevicesof at Leasta CombinationNeuronalComputationRequires689ThreeKindsof K+Channels(LTP)in the MammalianHippocampusPotentiationLong-Term691ChannelsNMDA-ReceptorDependson Ca2+EntryThrough692Summary693Problems694ReferencesandCompartmentsChapter12IntracellularProteinSortingOFCELLSTHECOMPARTMENTALIZATIONSetof MembraneBasicCellsHavetheSameAllEucaryoticOrganellesEnclosedofRelationshipsOriginsExplainthe TopologicalEvolutionaryOrganellesin DifferentWaysCanMoveBetweenCompartmentsProteinsto the CorrectCellAddressDirectProteinsSignalSequencesDeNovo:TheyRequireCannotBeConstructedMostOrganellesInformationin the OrganelleltselfSummary695695695697699701702704THE NUCLEUSBETWEENOF MOLECULESTHETRANSPORT704ANDTHE CYTOSOL705EnvelopeNuclearthePerforateComplexesPoreNuclearto the Nucleus 705SignalsDirectNuclearProteinsNuclearLocalizationBindto BothNuclearLocalizationNuclearlmportReceptors707andNPCProteinsSignals708NuclearExportWorksLikeNuclearlmport,Butin ReverseThroughon TransportlmposesDirectionalityTheRanGTPase708NPCsby ControllingNPCsCanBeRegulatedTransportThrough709MachinerYto the TransPortAccess7't0DisassemblesDuringMitosisthe NuclearEnvelope712SummaryINTOMITOCHONDRIAOF PROTEINSTHETRANsPORTAND CHLOROPLASTSDependson SignalSequencesinto MitochondriaTranslocationand ProteinTranslocatorsArelmportedasUnfoldedProteinsPrecursorMitochondrialChainsPolypeptideand a MembranePotentialDriveProteinlmportATPHydrolysisIntothe MatrixSpaceto lnsertMechanismsUseSimilarandMitochondriaBacteria2PorinsintotheirOuterMembranMembraneandIntothe InnerMitochondrialTransDortSpaceOccursViaSeveralRoutesIntermembraneto the ThylakoidDirectProteinsTwoSignalSequencesin ChloroplastsMembraneSummaryPEROXISOMEStoUseMolecularOxygenand HydrogenPeroxidePeroxisomesPerformOxidativeReactionsDirectsthe lmportof ProteinsintoA ShortSignalSequencePeroxisomesSummary7137'13715716717717719720721721722t25THEENDOPLASMICRETICULUM723TheERlsStructurallyand FunctionallyDiverse724SignalSequencesWereFirstDiscoveredin proteinslmoorteointo the RoughER726A Signal-RecognitionParticle(SRp)DirectsERSignalSequencesto a SpecificReceptorin the RoughERMembrane727porein theThePolypeptideChainPassesThroughan AqueousTranslocator730TranslocationAcrossthe ERMembraneDoesNot AlwaysRequireOngoingPolypeptideChainElongation731In Single-PassTransmembraneProteins,a SingleInternalERSignalSequenceRemainsin the LipidBilayerasa Membrane-spanningo Helix732Combinationsof Start-Transferand Stop-TransferSignalsDetermineproteinsthe Topologyof MultipassTransmembrane734TranslocatedPolypeptideChainsFoldandAssemblein the Lumenof the RoughERn6MostProteinsSynthesizedin the RoughERAreGlycosylatedbythe Additionof a CommonN-LinkedOligosaccharide736OligosaccharidesAre UsedasTagsto Markthe Stateof proteinFolding738lmproperlyFoldedProteinsAre Exportedfrom the ERandDegradedin the Cytosol739MisfoldedProteinsin the ERActivatean UnfoldedproteinResoonse740SomeMembraneProteinsAcquirea CovalentlyAttachedGlycosylphosphatidylinositol(Gpl)Anchor742TheERAssemblesMostLipidBilayers743Summory745Problems746References748Chapter 13 Intracellular VesicularTrafficTHEMOLECULARMECHANISMSOFMEMBRANETRANSPORTANDTHEMAINTENANCEOFCOMPARTMENTALDIVERSITYThereAreVariousTypesof CoatedVesiclesTheAssemblyof a ClathrinCoatDrivesVesicleFormationNotAllCoatsFormBasket-likeStructuresPhosphoinositidesMarkOrganellesandMembraneDomarnsCytoplasmicProteinsRegulatethepinching-OffandUncoarrngof CoatedVesiclesMonomericGTPasesControlCoatAssemblyNotAllTransportVesiclesAreSphericalRabProteinsGuideVesicleTargetingSNAREsMediateMembraneFusionInteractingSNAREsNeedto BepriedApartBeforeTheyCanFunctionAgainViralFusionProteinsandSNAREsMayUseSimilarFusionMechanismsSummaryTRANSPORTFROMTHEERTHROUGHTHEGOLGIAPPARATUSProteinsLeavethe ERin COPII-CoatedTransportVesiclesOnlyProteinsThatAre properlyFoldedand AssembledCanLeavethe ERVesicularTubularClustersMediateTransportfrom the ERto theGolgiApparatusTheRetrievalPathwayto the ERUsesSortingSignalsManyProteinsAreSelectivelyRetainedin the CompartmentsinWhichTheyFunctionTheGolgiApparatusConsistsof an OrderedSeriesofCompartmentsOligosaccharideChainsAreProcessedin the GolgiApparatusProteoglycansAreAssembledin the GolgiApparatusWhatlsthe Purposeof GlycosyfationtTransportThroughthe GolgiApparatusMayOccurbyVesicularTransportor CisternalMaturationGolgiMatrixProteinsHelpOrganizethe StackSummory749750751754757t)I758760760toz76476476676676776776876977177177377577677777g77gTRANSPORTFROMTHE IRANSGOLGINETWORKTO LYSOSOMES779LysosomesArethe PrincipalSitesof IntracellularDigestionLysosomesAreHeterogeneousPlantand FungalVacuolesAre RemarkablyVersatileLysosomesMultiplePathwaysDeliverMaterialsto LysosomesA Mannose6-PhosphateReceptorRecognizesLysosomalProteinsin the lronsGolgiNetworkTheM6PReceptorShuttlesBetweenSpecificMembranesA SignalPatchin the HydrolasePolypeptideChainProvidesthe Cuefor M6PAdditionDefectsin the GlcNAcPhosphotransferaseCausea LysosomalStorageDiseasein HumansSomeLysosomesUndergoExocytosisSummary779780781792783784785785786786TRANSPORTINTOTHECELLFROMTHEPLASMAMEMBRANE:ENDOCYTOSIS787SpecializedPhagocyticCellsCanIngestLargeParticles787PinocyticVesiclesFormfrom CoatedPitsin the PlasmaMemorane 789Not All PinocyticVesiclesAreClathrin-Coated790CellsUseReceptor-MediatedEndocytosisto lmportSelectedExtracellularMacromolecules791EndocytosedMaterialsThatAreNot Retrievedfrom EndosomesEndUp in Lysosomes792SpecificProteinsAreRetrievedfrom EarlyEndosomesandReturnedto the PlasmaMembrane793MultivesicularBodiesFormon the Pathwayto LateEndosomes 795TranscytosisTransfersMacromoleculesAcrossEpithelialCellSheets797EpithelialCellsHaveTwoDistinctEarlyEndosomalCompartmentsbut a CommonLateEndosomalComoartment798Summory799TRANSPORTFROMTHE IRANSGOLGINETWORKTO THECELLEXTERIOR:EXOCYTOSIS799ManyProteinsand LipidsSeemto BeCarriedAutomaticallvfrom the GolgiApparatusto the CellSurface800SecretoryVesiclesBudfrom thefuonsGolgiNetwork801ProteinsAreOftenProteolyticallyProcessedDuringtheFormationof SecretoryVesicles803SecretoryVesiclesWaitNearthe PlasmaMembraneUntilSignaledto ReleaseTheirContents803RegulatedExocytosisCanBea LocalizedResponseofthePlasmaMembraneandltsUnderlyingCytoplasm804SecretoryVesicleMembraneComponentsAreeuicklyRemovedfrom the PlasmaMembrane805SomeRegulatedExocytosisEventsServeto Enlargethe plasmaMembrane80sPolarizedCellsDirectProteinsfrom the lransGolgiNetworktothe AppropriateDomainof the PlasmaMembrane805DifferentStrategiesGuideMembraneProteinsand LipidsSelectivelyto the CorrectPlasmaMembraneDomains806SynapticVesiclesCanFormDirectlyfrom EndocyticVesicles807>ummary809Problems810References812Chapter14 EnergyConversion:Mitochondriaand ChloroplastsT H EM I T O C H O N D R I O NTheMitochondrionContainsan OuterMembrane,an InnerMembrane,andTwoInternalCompartmentsTheCitricAcidCycleGeneratesHigh-EnergyElectronsA ChemiosmoticProcessConvertsOxidationEnergyinto ATpNADHTransfersits Electronsto OxygenThroughThreeLargeRespiratoryEnzymeComplexesAs ElectronsMoveAlongthe RespiratoryChain,Energyls Storedasan ElectrochemicalProtonGradientAcrossthe lnnerMembraneTheProtonGradientDrivesATPSynthesis813815916817917gl9820a2'lTheProtonGradientDrivesCoupledTransportAcrossthe InnerMembraneProduceMostof the Cell'sATPProtonGradientsMitochondriaMaintaina HighATP:ADPRatioin CellsMakesATPA LargeNegativeValueof AGfor ATPHydrolysisUsefulto the Cellto HydrolyzeATPandATPSynthaseCanFunctionin ReversePumoHrSummaryELECTRON-TRANSPORTCHAINSAND THEIRPROTOI'PUMPS822822823824826827827827ProtonsAre UnusuallyEasyto Move828TheRedoxPotentialls a Measureof ElectronAffinities829EfectronTransfersReleaseLargeAmountsofEnergyin theMethodsldentifiedManyElectronCarriersSpectroscopic829RespiratoryChainTheRespiratoryChainIncludesThreeLargeEnzymeComplexes831in the InnerMembraneEmbeddedEfficientAn lron-CopperCenterin CytochromeOxidaseCatalyzes83202 ReductionTransfersin the InnerMitochondrialMembraneAreMediatedElectron834TunnelingduringRandomCollisionsby ElectronA LargeDropin RedoxPotentialAcrossEachoftheThreeRespiratory835EnzymeComplexesProvidesthe Energyfor H+Pumpingin theThreeMajorby DistinctMechanismsTheH+PumpingOccurs835EnzymeComplexesTransportfrom ATPSynthesis 836H+lonophoresUncoupleElectronElectronFlowThroughRespiratoryControlNormallyRestrains837the Chainin BrownFatintoNaturalUncouolersConvertthe Mitochondria838Heat-GeneratingMachinesPlaysManyCriticalRolesin CellMetabolism 838TheMitochondrionMechanismsto HarnessBacteriaAlsoExploitChemiosmotic839Energy840Summary840AND PHOTOSYNTHESISCHLOROPLASTSls OneMemberof the PlastidFamilyofTheChloroplast841OrganellesResembleMitochondriaButHavean ExtraChloroplasts842CompartmentfromSunlightandUselt to FixCaptureEnergyChloroplasts843Carbonby RibuloseBisphosphateCarbonFixationlsCatalyzed844CarboxylaseThreeMoleculesEachCO2MoleculeThatls FixedConsumes845ofNADPHofATPandTwoMoleculesto FacilitateCarbonFixationin SomePlantslsCompartmentalized846Growthat LowCO2Concentrationsof ChlorophyllDependson the PhotochemistryPhotosynthesis847MoleculesReactionCenterPlusan AntennaComplexA Photochemical848Forma PhotosystemIn a ReactionCenter,LightEnergyCapturedby Chlorophyll849Createsa StrongElectronDonorfrom a WeakOneBothNADPHand ATP 850ProducesNoncyclicPhotophosphorylationCanMakeATPby CyclicPhotophosphorylationChloroplasts853WithoutMakingNADPHand AlsoResembleI and ll HaveRelatedStructures,Photosystems8s3PhotosystemsBacterialandForcelsthe Samein MitochondriaTheProton-Motive6fJChloroplastsControlin the ChloroplastInnerMembraneProteinsCarrier854with the CytosolMetaboliteExchange855AlsoPerformOtherCrucialBiosynthesesChloroplasts855SummaryANDOF MITOCHONDRIATHEGENETICSYSTEMS85sPLASTIDSContainCompleteGeneticSystems856Mitochondriaand Chloroplaststhe NumberofDetermineGrowthandDivisionOrganelle857in a CellMitochondriaandPlastids859HaveDiverseGenomesand ChloroplastsMitochondriaProbablyBothEvolvedfromand ChloroplastsMitochondria859BacteriaEndosymbioticCodonUsageand CanHaveaHavea RelaxedMitochondria861VariantGeneticCodeKnown 862Containthe SimplestGeneticSystemsAnimalMitochondria863GenesContainIntronsSomeOrganelleAboutGenomeof HigherPlantsContainsTheChloroplast863120Genesby a Non-MendelianGenesAreInheritedMitochondrial864Mechanism866in ManyOrganismsInheritedGenesAreMaternallyOrganellethe OverwhelmingDemonstratePetiteMutantsin YeastsBiogenesis 866for Mitochondrialof the CellNucleuslmportancethatProteinsContainTissue-Specificand PlastidsMitochondria867in the CellNucleusAreEncodedMakeChloroplastslmportMostof TheirLipids;Mitochondria867Mostof TheirsMayContributeto the Agingof CellsandOrganisms 606MitochondriaHaveTheirOwn Geneticand ChloroplastsWhyDo Mitochondria868Systems?870Summary870CHAINSOF ELECTRON-TRANSPORTTHE EVOLUTION870ATPtoProduceFermentationCellsProbablyUsedTheEarliestto UseChainsEnabledAnaerobicBacteriaElectron-Transoort871asTheirMajorSourceof EnergyMoleculesNonfermentableSourceof ReducingPower,ByProvidingan Inexhaustiblea MajorEvolutionaryOvercameBacteriaPhotosynthetic872ObstacleChainsof CyanobacteriaElectron-TransportThePhotosyntheticOxygenand PermittedNewLife-Forms 873AtmosphericProduced875Summary877Problems878ReferencesChapter 15 Mechanisms of Cell Communication879879OF CELLCOMMUNICATIONPRINCIPLESGENERAL880ReceptorsBindto SpecificSignalMoleculesExtracellularCanAct OverEitherShortor LongSignalMoleculesExtracellular881DistancesCellsto ShareSignalingAllowNeighboringGapJunctions884lnformationofCombinationsto Specificto RespondEachCellls Programmed884SignalMolecule5Extracellularto the SameDifferentTypesof CellsUsuallyRespondDifferently885SignalMoleculeExtracellularCellsDependson TheirPositioninTheFateof SomeDeveloping886MorphogenGradientsMoleculeof an lntracellularA CellCanAlterthe Concentration886QuicklyOnlylf the Lifetimeof the Moleculels Shortthe ActivityofNitricOxideGasSignalsby DirectlyRegulating887SpecificProteinsInsidetheTargetCellGeneRegulatoryAreLigand-ModulatedNuclearReceptors889ProteinsProteinsArelonReceptorof Cell-SurfaceTheThreeLargestClassesand Enzyme-CoupledG-Protein-Coupled,Channel-Coupled,891ReceptorsViaSmallRelaySignalsReceptorsMostActivatedCell-Surface893SignalingProteinsand a Networkof IntracellularMoleculesSwitchesasMolecularFunctionProteinsSignalingManyIntracellular895or GTPBindingThatAreActivatedby Phosphorylationthe Speed,Efficiency,EnhanceComplexesSignalingIntracellular897ofthe Responseand SpecificityBetweenModularInteractionDomainsMediatelnteractions897SignalingProteinsIntracellularAbruptlytoto RespondCellsCanUseMultipleMechanismsSignal 899ofan ExtracellularConcentrationIncreasinga GraduallyMakeUseofUsuallyNetworksSignalingIntracellular901LoopsFeedback902to a SignalSensitivityCellsCanAdjustTheir903SummarySIGNALINGTHROUGHG-PROTEIN-COUPLEDCELL(GPCRs)sURFACERECEPTORSANDSMALLINTRACELLULARMEDIATORSTrimericGProteinsRelaySignalsfromGpCRs904SomeG ProteinsRegulatethe Productionof CyclicAMpCyclic-AMP-DependentProteinKinase(pKA)MediatesMosrof the Effectsof CyclicAMPSomeG ProteinsActivateAn InositolPhospholipidSignalingPathwayby ActivatingPhospholipaseC-pCa2+Functionsasa UbiquitousIntracellularMediatorTheFrequencyof Ca2+Oscillationslnfluencesa Cell! ResponseproteinKinasesCa2+/Calmodulin-Dependent(CaM-Kinases)MediateManyof the Responsesto Ca2+Signalsin AnimalCellsSomeG ProteinsDirectlyRegulatelon ChannelsSmellandVisionDependon GPCRsThatRegulateCyclicNucleotide-GatedlonChannelsIntracellularMediatorsand EnzymaticCascadesAmplifyExtracellularSignalsphosphorylationGPCRDesensitizationDependson ReceptorSummory90s90s908909912912914916917919920921SIGNALINGTHROUGHENZYME-COUPLEDCELL-SURFACERECEPTORS921phosphorylateActivatedReceptorTyrosine(RTKs)KinasesThemselves922PhosphorylatedTyrosineson RTKsServeas DockingSitesforIntracellularSignalingProteins923Proteinswith SH2DomainsBindto phosphorylatedTyrosines924RasBelongsto a LargeSuperfamilyof MonomericGTpases926RTKsActivateRasViaAdaptorsand GEFs:Evidencefrom theDevelopingDrosophilaEye927RasActivatesa MAPKinaseSignalingModule928ScaffoldProteinsHelpPreventCross-TalkBetweenparallelMApKinaseModules930RhoFamilyGTPasesFunctionallyCoupleCell-SurfaceReceptorsto the Cytoskeleton931Pl3-KinaseProducesLipidDockingSitesin the plasmaMemorane 932ThePl-3-Kinase-AktSignalingPathwayStimulatesAnimalCellstoSurviveand Grow934TheDownstreamSignalingPathwaysActivatedBy RTKsand GpCRsOverlaov5)Tyrosine-Kinase-AssociatedReceptorsDependon CytoplasmicTyrosineKinases935CytokineReceptorsActivatethe JAK-STATSignalingpathway,Providinga FastTrackto the Nucleus937phosphorylations 9 3 8ProteinTyrosinePhosphatasesReverseTyrosineSignalProteinsof the TGFBSuperfamilyActThroughReceptorSerine/ThreonineKinasesandSmads939proteinKinasesSerine/ThreonineandTyrosineAreStructurallyRelated941BacterialChemotaxisDependson a Two-ComponentSignalingPathwayActivatedby Histidine-Kinase-AssociatedReceptors 941ReceptorMethylationls Responsiblefor Adaptationin BacterialChemotaxis943Summory944SIGNALINGPATHWAYSDEPENDENTON REGULATEDPROTEOLYSISOF LATENTGENEREGULATORYPROTEINSproteinTheReceptorProteinNotchls a LatentGeneRegulatoryWnt ProteinsBindto FrizzledReceptorsand InhibittheDegradationof p-CateninHedgehogProteinsBindto patchedRelievinglts Inhibitionof SmoothenedManyStressfuland InflammatoryStimuliActThroughanNFrB-DependentSignalingPathwaySummory946946948950952954SIGNALINGIN PLANTS955MulticellularityandCellCommunicationEvolvedIndependentlyin PlantsandAnimals955ReceptorSerine/ThreonineKinasesArethe LargestClassofCell-SurfaceReceptorsin Plantsvf,oEthyleneBlocksthe Degradationof SpecificGeneRegulatoryProteinsin the NucleusRegulatedPositioningof AuxinTransportersPatternsPlantGrowthPhytochromesDetectRedLight,andCryptochromesDetectBlueLightSummoryProblemsReferencesChapter 16 The Cytoskeleton957959960961964965THESELF-AssEMBLYAND DYNAMICSTRUCTUREOFCYTOSKELETALFILAMENTS965CytoskeletalFilamentsAre Dynamicand Adaptable966TheCytoskeletonCanAlsoFormStableStructures969EachTypeof CytoskeletalFilamentls Constructedfrom SmallerProteinSubunits970FilamentsFormedfrom MultipleProtofilamentsHaveAdvantageousProperties971Nucleationlsthe Rate-LimitingStepin the Formationofa CytoskeletalPolymer973TheTubulinandActinSubunitsAssembleHead-to-TailtoCreatePolarFilaments973MicrotubulesandActinFilamentsHaveTwoDistinctEndsThatGrowat DifferentRates975FilamentTreadmillingandDynamicInstabilityAreConsequencesof NucleotideHydrolysisbyTubulinand Actin976Treadmillingand DynamicInstabilityAid RapidCytoskeletalRearrangement980TubulinandActinHaveBeenHighlyConservedDuringEucaryoticEvolution982IntermediateFilamentStructureDependson TheLateralBundlingandTwistingof CoiledCoils983IntermediateFilamentslmpartMechanicalStabilitytoAnimalCells985DrugsCanAlterFilamentPolymerization987BacterialCellOrganizationandCellDivisionDependonHomologsofthe EucaryoticCytoskeleton999Summary991HOWCELLSREGULATETHEIRCYTOSKELETALFILAMENTS 992A ProteinComplexContainingyTubulinNucleatesMicrotubules 992MicrotubulesEmanatefromthe Centrosomein AnimalCells992ActinFilamentsAreOftenNucleatedat the PlasmaMembrane996TheMechanismof NucleationInfluencesLarge-ScaleFilamentOrganization999ProteinsThatBindto the FreeSubunitsModifyFilamentElongation999SeveringProteinsRegulatethe Lengthand KineticBehaviorofActinFilamentsandMicrotubules1000ProteinsThatBindAlongthe Sidesof FilamentsCanEitherStabilizeor DestabilizeThem1OO1ProteinsThatInteractwith FilamentEndsCanDramaticallyChangeFilamentDynamics1OO2DifferentKindsof ProteinsAlterthe Propertiesof RapidlyGrowingMicrotubuleEnds1003FilamentsAreOrganizedinto Higher-OrderStructuresin Cells1005IntermediateFilamentsAreCross-Linkedand BundledlntoStrongArrays1005Cross-LinkingProteinswith DistinctPropertiesOrganizeDifferentAssembliesof ActinFilaments1006Filaminand SpectrinFormActinFilamentWebsl OOgCytoskeletalElementsMakeManyAttachmentsto Membrane1009Summaryl0l0MOLECULARMOTORSActin-BasedMotorProteinsAreMembersof the MvosinSuperfamilyThereAreTwoTypesof MicrotubuleMotorProteins:KinesinsandDyneinsTheStructuralSimilarityof MyosinandKinesinIndicatesaCommonEvolutionaryOriginMotorProteinsGenerateForceby CouplingATPHydrolysistoConformationalChanqes10101 0 11rc1410151016AreAdaptedto CellFunctionsMotorProteinKineticsTransportof MembraneMediatethe IntracellularMotorProteinsOrganellesEnclosedLocalizesSpecificRNAMoleculesTheCytoskeletonCellsRegulateMotorProteinFunctionSummary102010211022102310251025AND CELLBEHAVIORTHE CYTOSKELETONMusclestoCausesSlidingof Myosinll andActinFilaments1026ContractInitiatesMuscleCa2+ConcentrationA SuddenRisein Cytosolic1028Contraction10 3 1EngineeredMachineHeartMusclelsa PreciselyAreMotileStructuresBuiltfrom MicrotubulesCiliaand Flagella1031andDyneinsMicrotubuleof the MitoticSpindleRequiresConstruction1034of ManyMotorProteinsDynamicsand the Interactions1036ManyCellsCanCrawlAcrossA SolidSubstratum1037DrivesPlasmaMembraneProtrusionActinPolymerizationCellAdhesionandTractionAllowCellsto PullThemselves1040ForwardMembersof the RhoProteinFamilyCauseMajorRearrangements1041of the ActinCytoskeletonExtracellularSignalsCanActivatethe ThreeRhoProtein1043FamilyMembers1045ExternalSignalsCanDictatethe Directionof CellMigrationBetweenthe Microtubuleand ActinCytoskeletonsCommunication1046and LocomotionWhole-CellPolarizationCoordinatesof NeuronsDependsSpecializationTheComplexMorphological1047on the Cytoskeleton1050Summary1050Problems1052ReferencesChapter17 The CellCycleOFTHECELLCYCLEOVERVIEWCellCyclels Dividedinto FourPhasesTheEucaryoticCell-CycleControlls Similarin All Eucaryotesby AnalysisofGeneticallyCell-CycleControlCanBeDissectedYeastMutantsin AnimalControlCanBeAnalyzedBiochemicallyCell-CycleEmbryosCellsCell-CycleControlCanBeStudiedin CulturedMammalianProgressionCanBeStudiedin VariousWaysCell-CycleSummaryTHE CELL-CYCLECONTROLSYSTEMTriggersthe MajorEventsof theTheCell-CycleControlSystemCellCycleActivatedControlSystemDependson CyclicallyTheCell-Cycle(Cdks)ProteinKinasesCyclin-Dependentand CdkInhibitoryProteins(CKls)InhibitoryPhosphorylationCdkActivityCanSuppressProteolysisControlSystemDependson CyclicalTheCell-CycleRegulationControlAlsoDependson TranscriptionalCell-Cycleasa NetworkofControlSystemFunctionsTheCell-CycleSwitchesBiochemicalSummaty5 PHASEOncePerCycleS-CdkInitiatesDNAReplicationDuplicationof ChromatinDuplicationRequiresChromosomeStructureTogetherHelpHoldSisterChromatidsCohesinsSummory10531054105410561056105710591059106010601060106210631064I uof,1065't067't0671067106910701071MITOSIS1071M-CdkDrivesEntryInto MitosisM-Cdkat the Onsetof MitosisActivatesDephosphorylationforChromosomesHelpsConfigureDuplicatedCondensinSeparationMachineTheMitoticSpindlels a Microtubule-Based1071107410751075GovernSpindleMotorProteinsMicrotubule-Dependentand FunctionAssemblyof a BipolarMitoticin the AssemblyCollaborateTwoMechanismsSoindleOccursEarlyin the CellCycleDuplicationCentrosomein ProphaseM-CdkInitiatesSpindleAssemblyin AnimalCellsRequiresTheCompletionof SpindleAssemblyBreakdownNuclearEnvelopeGreatlyin MitosisMicrotubuleInstabilityIncreasesPromoteBipolarSpindleAssemblyMitoticChromosomesto the SpindleAttachSisterChromatidsKinetochoresls AchievedbyTrialand ErrorBi-Orientationon the SpindleMultipleForcesMoveChromosomesandtheSeparationTriggersSister-ChromatidTheAPC/CCompletionof MitosisSeparation:BlockSister-ChromatidChromosomesUnattachedCheckPointTheSpindleAssemblYA and Bin AnaphaseSegregateChromosomesin DaughterNucleiatArePackagedChromosomesSegregatedTeloohaseMeiosisls a SoecialFormof NuclearDivisionInvolvedin SexualReproductionSummory10771077l 07810781079108010811082108310851087108810891o9o109010921092CYTOKINESISfortheForceRingGenerateActinand Myosinll in the Contractile1093Cytokinesisof theandContractionLocalActivationof RhoATriggersAssembly1094RingContractilethe Planeofof the MitoticSpindleDetermineTheMicrotubules1095AnimalCellDivision1097in HigherPlantsGuidesCytokinesisThePhragmoplastto DaughterMustBeDistributedOrganellesMembrane-Enclosed1098CellsDuringCytokinesisTheirSpindleto DivideAsymmetrically 1099SomeCellsReposition1099MitosisCanOccurWithoutCytokinesis1100TheG1Phasels a StableStateof Cdklnactivity11 0 1SummaryCONTROLOF CELLDIVISIONAND CELLGROWTHMitogensStimulateCellDivisionNondividingCellsCanDelayDivisionby Enteringa SpecializedStateActivitiesMitogensStimulateGr-Cdkand GrlS-CdkTheDNADamageResponseDNADamageBlocksCellDivision:on the NumberManyHumanCellsHavea Built-lnLimitationof TimesTheyCanDivideArrestorSignalsCauseCell-CycleAbnormalProliferationExceptin CancerCellsApoptosis,OrganismandOrganGrowthDependon CellGrowthTheirGrowthand DivisionCellsUsuallyCoordinateProliferatingSignalProteinsCellsCompetefor ExtracellularNeighboringCellMassby UnknownMechanismsAnimalsControlTotalSummaryProblemsReferencesChapter18 APoPtosis11 0 111 0 21103110311051oo71107r 10811 0 81110111111121112111311 1 51115UnwantedCellsCellDeathEliminatesProgrammed1117RecognizableApoptoticCellsAreBiochemicallyCascadeProteolyticApoptosisDependson an Intracellular1118Thatls MediatedbYCasPasesPathwayActivatethe ExtrinsicDeathReceptorsCell-Surface1120ofApoptosis1121TheIntrinsicPathwayof ApoptosisDependson Mitochondria1121the IntrinsicPathwayof ApoptosisBcf2ProteinsRegulate1124lAPsInhibitCaspases'1126WaysVariousinApoptosisInhibitFactorsSurvivalExtracellularto Disease1127CanContributeApoptosisor InsufficientEitherExcessive1128Summary1128problems1129ReferencesChapter19 CellJunctions,CellAdhesion,andthe ExtracellularMatrixCADHERINSANDCELL-CELLADHESIONI 13111 3 3CadherinsMediateCa2+-DependentCell-CellAdhesioninAllAnimalsTheCadherinSuperfamilyin VertebratesIncludesHundredsofDifferentProteins,IncludingManywith SignalingFunctionsCadherinsMediateHomophilicAdhesion5electiveCell-CellAdhesionEnablesDissociatedVertebrareCellsto Reassembleinto OrganizedTissuesCadherinsControlthe SelectiveAssortmentof CellsTwistRegulatesEpithelial-MesenchymaI TransitionsCateninsLinkClassicalCadherinsto the ActinCytoskeletonAdherensJunctionsCoordinatethe Actin-BasedMotilityofAdjacentCellsDesmosomeJunctionsGiveEpitheliaMechanicalStrenqthCell-CellJunctionsSendSignalsintothe CellInteriorSelectinsMediateTransientCell-CellAdhesionsin theBloodstreamMembersof the lmmunoglobulin5uperfamilyof proteinsMediateCa2+-lndependentCell-CellAdhesionManyTypesof CellAdhesionMoleculesAct in parallelto Createa SynapseScaffoldProteinsOrganizeJunctionalComplexesSummary114711 4 81149TIGHTJUNCTIONSAND THEORGANIZATIONOFEPITHELIA11 5 011 3 5tt501137139140141142114211431"t4511451146TightJunctionsForma SealBetweenCellsand a FenceBetweenMembraneDomainsplaya KeypartInScaffoldProteinsin JunctionalComplexesthe Controlof CellProliferationCell-CellJunctionsandthe BasalLaminaGovernAoico-BasalPolarityin EpitheliaplanarCellpolarityA SeparateSignalingSystemControlsSummary11 5 5115711 5 8PASSAGEWAYSFROMCELLTO CELL:GAp JUNCT|ONSAND PLASMODESMATA11 5 811 5 011 5 3GapJunctionsCoupleCellsBothElectricallyandMetabolicallyA Gap-JunctionConnexonlsMadeUp of SixTransmembraneConnexinSubunitsGapJunctionsHaveDiverseFunctionsCellsCanRegulatethe Permeabilityof TheirGapJunctionsperformManyof the SameFunctionsIn Plants,PlasmodesmataasGapJunctionsSummary116211 6 3THEBASALLAMINA^t't64BasalLaminaeUnderlieAll EpitheliaandSurroundSomeNonepithelialCellTypesLamininlsa PrimaryComponentof the BasalLaminaTypelV CollagenGivesthe BasalLaminaTensileStrenothBasalLaminaeHaveDiverseFunctionsSummaryINTEGRINSAND CELL-MATRIXADHESIONIntegrinsAreTransmembraneHeterodimersThatLinkto tneCytoskeletonIntegrinsCanSwitchBetweenan Activeand an InactiveConformationIntegrinDefectsAre Responsiblefor ManyDifferentGeneticDiseasesIntegrinsClusterto FormStrongAdhesionsExtracellularMatrixAttachmentsActThroughIntegrinstoControlCellProliferationand SurvivalproteinsIntegrinsRecruitIntracellularSignalingat Sitesof CellSubstratumAdhesionIntegrinsCanProduceLocalizedIntracellularEffectsSummoryTHEEXTRACELLULARMATRIXOFANIMALCONNECTIVETlsSuES1178TheExtracellularMatrixls Madeand Orientedby the Cellsj179Withinlt(GAG)ChainsOccupyLargeAmountsofGlycosaminoglycanSpaceandFormHydratedGels1179HyaluronanActsasa SpaceFilleranda Facilitatorof CellMigrationDuringTissueMorphogenesisandRepair1180ProteoglycansAreComposedof GAGChainsCovalentlyLinkedto a CoreProtein11 8 1ProteoglycansCanRegulatethe Activitiesof SecretedProterns 1182Cell-SurfaceProteoglycansAct asCo-Receptors11 8 3CollagensArethe MajorProteinsof the ExtracellularMatrix1184CollagenChainsUndergoa Seriesof Post-TranslationalModifications11 8 6PropeptidesAreClippedOff ProcollagenAfterlts Secretionto AllowAssemblyof Fibrils1187't187SecretedFibril-AssociatedCollagensHelpOrganizethe FibrilsCellsHelpOrganizethe CollagenFibrilsTheySecretebyExertingTensionon the Matrix11 8 9ElastinGivesTissuesTheirElasticitv11 8 9Fibronectinls an ExtracellularProteinThatHelpsCellsAttachto the Matrix1191TensionExertedby CellsRegulatesAssemblyof Fibronectin't't91FibrilsFibronectinBindsto IntegrinsThroughan RGDMotif11 9 3CellsHaveto BeAbleto DegradeMatrix,asWellasMakeit11 9 3MatrixDegradationls Localizedto the Vicinityof Cells1194Summary1195THEPLANTCELLWALLTheCompositionof the CellWallDependson the CellTypeTheTensileStrengthof the CellWallAllowsPlantCellstoDevelopTurgorPressureThePrimaryCellWallls BuiltfromCelluloseMicrofibrilsInterwovenwith a Networkof PecticPolysaccharidesOrientedCell-WallDepositionControlsplantCellGrowthMicrotubulesOrientCell-WallDepositionSummaryProblemsReferences11 9 511 9 5't't9711971199120012021202120411 5 811 5 911 6 111 6 1116411 6 5't16611671169116911701"170"117211741175117611 7 71178Chapter20 CancerCANCERA5A MICROEVOLUTIONARYPROCESSCancerCellsReproduceWithoutRestraintand ColonizeOtherTissuesMostCancersDerivefrom a SingleAbnormalCellCancerCellsContainSomaticMutationsA SingleMutationls Not Enoughto CauseCancerCancersDevelopGraduallyfromIncreasinglyAberrantCellsCervicalCancersAre Preventedby EarlyDetectionTumorProgressionInvolvesSuccessiveRoundsof RandomInheritedChangeFollowedby NaturalSelectionTheEpigeneticChangesThatAccumulatein CancerCellsInvolveInheritedChromatinStructuresandDNAMethylationHumanCancerCellsAreGeneticallyUnstableCancerousGrowthOftenDependson DefectiveControlofCellDeath,CellDifferentiation,or BothCancerCellsAre UsuallyAlteredin TheirResponsesto DNADamageand OtherFormsof StressHumanCancerCellsEscapea Built-lnLimitto CellproliferationA SmallPopulationof CancerStemCellsMaintainsManyTumorsHow Do CancerStemCellsArise?To Metastasize,MalignantCancerCellsMustSurviveandProliferatein a ForeignEnvlronmentTumorsInduceAngiogenesisTheTumorMicroenvironmentInfluencesCancerDevelopmentManyPropertiesTypicallyContributeto CancerousGrowthSummary1205120512061207I 2081209121012111212121312141215121612'.t71217121812201220122212231223CAU5E5OF CANCERTHEPREVENTABLE1224AgentsDamageDNAMany,ButNotAll,Cancer-CausingDo NotDamageDNA;TumorPromotersTumorInitiatorsContributeto a SignificantVirusesandOtherInfectionsof HumanCancersProportionRevealsWaysto Avoidldentificationof CarcinogensCancerSummary122512261227122912301230GENESFINDINGTHECANCER-CRITICALand Loss-of-Functionof Gain-of-FunctionTheldentification1231MutationsRequiresDifferentMethodsThatAlterCanAct asVectorsfor OncogenesRetroviruses1232CellBehavioron thefor OncogenesHaveConvergedDifferentSearches1233SameGene-RasFirstldentifiedCancerSyndromesof RareHereditaryStudies1234GenesTumorSuppressorfromStudiesGenesCanAlsoBeldentifiedTumorSuopressorIl5>of TumorsTumorMechanismsCanInactivateandEpigeneticBothGenetic1235GenesSuppressorin ManyCanBeMadeOveractiveGenesMutatedin Cancer1237Ways1239GenesContinuesTheHuntfor CancerCritical1240Summary1240BEHAVIORBASISOF CANCER-CELLTHEMOLECULAREmbryosandGeneticallyof BothDevelopingStudiesofthe FunctionMiceHaveHelpedto UncoverEngineered1241GenesCancer-Critical1242CellProliferationGenesRegulateManyCancer-Criticalof Cell-CycleMayMediatethe DisregulationDistinctPathwaysof CellGrowthinandthe DisregulationProgression1244CellsCancerCellsAllowCancerThatRegulateApoptosisin GenesMutations1245WhenTheyShouldNotto SurviveCellsto Survivein thep53GeneAllowManyCancerMutations1246DespiteDNADamageand ProliferateBlockthe Actionof KeyTumorSuppressorDNATumorViruses1247ProteinsAreStillThatLeadto Metastasisin TumorCellsTheChanges1249Largelya Mysteryof Visiblea SuccessionEvolveSlowlyViaColorectalCancers1250ChangesAreCommonto a LargeFractionofA FewKeyGeneticLesions1251ColorectalCancersRepair 1254in DNAMismatchCancersHaveDefectsSomeColorectalwithCanOftenBeCorrelatedTheStepsof TumorProgression1254MutationsSDecificby lts Own Arrayof GeneticEachCaseof CancerlsCharacterizedI z)oLesionsIz>oSummaryAND FUTUREPRESENTTREATMENT:CANCERbut Not HopelessCureslsDifficultforCancerTheSearchandLossofInstabilityExploitthe GeneticTraditionalTherapiesin CancerCellsResponsesCheckpointCell-CycleGeneticof a Tumor'sCausethe SpecificNewDrugsCanExploitInstabilityMoreBecomeProgressivelyGeneticInstabilityHelpsCancersResistantto Therapiesof CancerAreEmergingfrom Our KnowledgeNewTherapiesBiologyOncogenicto InhibitSpecificCanBeDesignedSmallMoleculesProteinsAreLogicalTargetsfor CancerTherapyTumorBloodVesselsthe lmmuneby EnhancingMayBeTreatableManyCancersTumorAgainsta SpecificResponseHaswith SeveralDrugsSimultaneouslyPatientsTreatingfor CancerTherapyPotentialAdvantagesintoCancersProfilingCanHelpClassifyGeneExpressionSubgroupsMeaningfulClinically1256125712571257125912601260I loz| 202| 20512641264126512651267Therels StillMuchMoreto DoSummoryproblemsReferencesChapters21-25 availableon Media DVD-ROMMeiosis,Chapter2t SexualReproduction:FertilizationGermCells,and1269OF SEXUALREPRODUCTIOIIOVERVIEWls BriefTheHaploidPhasein HigherEucaryotesDiversityGeneticCreatesMeiosisAdvantagea CompetitiveGivesOrganismsSexualReproductionSummary126912691271127112721272ME|OS|S1272byTwoMeioticCellDivisionsAreProducedGametesPairDuringEarly(andSexChromosomes)HomologsDuplicated1274proohase1aSynaptonemalofFormationintheCulminatesPairingHomolog1275ComplexKinetochoreDependson Meiosis-Specific,HomologSegregation1276ProteinsAssociated1278GoesWrongFrequentlyMeiosis1279GeneticReassortmentEnhancesCrossing-Over1280ls HighlyRegulatedCrossing-Over1280Mammalsin MaleandFemaleDifferentlylsRegulatedMeiosis1281SummaryINGERMCELLSAND sEXDETERMINATIONPRIMORDIALMAMMALSSignalsfrom NeighborsSpecifyPGCsin MammalianEmbryosGonadsMigrateintothe DevelopingPGCSGonadtoTheSryGeneDirectsthe DevelopingMammalianBecomea TestisVaryGreatlybetweenManyAspectsof SexualReproductionAnimalsPeciesSummary128212821283128312851286EGGS1287for IndependentDevelopmentAn Eggls HighlySpecializedEggsDevelopin Stagesto Growto TheirLargeSizeOocytesUseSpecialMechanismsMostHumanOocytesDieWithoutMaturingSummary12871288129012911292't292SPERMTheirDNAto an EggSpermAre HighlyAdaptedfor DeliveringTestisin the MammalianContinuouslySpermAreProducedSpermDevelopasa SYncYtiumSummary12921293129412961297FERTILIZATIONin the FemaleGenitalTract 1297SpermBecomeCapacitatedEjaculatedand UndergoanPellucidaZonatotheBindSpermCapacitated1298AcrosomeReaction1298of Sperm-EggFusionls StillUnknownTheMechanismCa2+in the Cytosol 1299the Eggby IncreasingSpermFusionActivatesOnlyOneSpermFertilizesTi'reCorticalReactionHelpsEnsureThat1300the EggasWellaslts Genometo the Zygote1301CentriolesTheSoermProvidestheTreatmentof HumanIVFand lCSlHaveRevolutionized1301Infertility1303Summary1304Referencesof MulticellularChapter22 DevelopmentOrganisms1305OFANIMALDEVELOPMENT 1305MECHANISMSUNIVERSAL1307FeaturesAnatomicalBasicSomeShareAnimalsMulticellularAnimalsAreEnrichedin proteinsMediatinoCellInteractionsandGeneRegulation1308RegulatoryDNADefinesthe programof Development1309Manipulationof the EmbryoRevealsthe InteractionsBetweenItsCells13 1 0Studiesof MutantAnimalsldentifythe GenesThatControlDevelopmentalProcesses131A CellMakesDevelopmentalDecisionsLongBeforelt Showsa VisibleChange131CellsHaveRememberedPositionalValuesThatReflectTheirLocationin the Body1312InductiveSignalsCanCreateOrderlyDifferencesBetweenInitiallyldenticalCells13 1 3SisterCellsCanBeBornDifferentby an AsymmetricCellDivision1313PositiveFeedbackCanCreateAsymmetryWhereThereWasNoneBefore1314patterns,PositiveFeedbackGeneratesCreatesAll-or-NoneOutcomes,and ProvidesMemoryt5t)A SmallSetof SignalingPathways,UsedRepeatedly,ControlsDevelopmentalPatterning13 1 6MorphogensAreLong-RangeInducersThatExertGradedEffects 13 1 6ExtracellularInhibitorsof SignalMoleculesShapethe Responseto the Inducer1317DevelopmentalSignalsCanSpreadThroughTissuein SeverarDifferentWays13 1 8ProgramsThatAreIntrinsicto a CellOftenDefinethe Time-Courseof its Develooment1319InitialPatternsAreEstablishedin SmallFieldsof CellsanoRefinedby SequentialInductionasthe EmbrvoGrows13 1 9Summory1320CAENORHABDITISELEGANS:DEVELOPMENTFRoM THEPERSPECTIVEOFTHEINDIVIDUALCELLCaenorhabditiselegansls AnatomicallySimpleCellFatesin the DevelopingNematodeAreAlmostperfectlyPredictableProductsof Maternal-EffectGenesOrganizethe AsymmetricDivisionof the EggProgressivelyMoreComplexpatternsAreCreatedby Cell-CellInteractionsMicrosurgeryandGeneticsRevealthe Logicof DevelopmentalControl;GeneCloningandSequencingRevealltsMolecularMechanismsCellsChangeOverTimein TheirResponsivenesstoDevelopmentalSignalsHeterochronicGenesControlthe Timingof DevelopmentCellsDo NotCountCellDivisionsin TimingTheirInternalProgramsSelectedCellsDie by Apoptosisaspartof the proqramofDevelopmentSummary13 2 1't321132213231324| 5l)13251326132713271328DROSOPHILAAND THEMOLECULARGENETICSOFPATTERNFORMATION:GENESISOFTHEBODYPLAN1328TheInsectBodylsConstructedasa Seriesof SegmentalUnits1329DrosophiloBeginslts Developmentasa Syncytium1330GeneticScreensDefineGroupsofGenesRequiredfor SpecificAspectsof EarlyPatterning1332Interactionsof the OocyteWith lts SurroundingsDefinetheAxesof the Embryo:the Roleof the Egg-polarityGenes13 3 3TheDorsoventralSignalingGenesCreatea Gradientof aproternNuclearGeneRegulatory1334DppandSogSetUp a SecondaryMorphogenGradienttoRefinethe Patternof the Dorsalpartof the Embrvo1336TheInsectDorsoventralAxisCorrespondsto the VeriebrateVentrodorsalAxis1336ThreeClassesof SegmentationGenesRefinethe Anterior_posteriorMaternalPatternand Subdividethe Embrvo1336TheLocalizedExpressionof SegmentationGenesls Regulatedby a Hierarchyof PositionalSignals1337TheModularNatureof RegulatoryDNAAllowsGenesto HaveMultipleIndependentlyControlledFunctionsI 339Egg-Polarity,Gap,andPair-RuleGenesCreateaTransientPatternThatlsRememberedbvOtherGenesSummaryHOMEOTICSELECTORGENESANDTHEPATTERNINGOFTHEANTEROPOSTERIORAXISThe Hox Code SpecifiesAnterior-PosteriorDifferencesproteinsHomeoticSelectorGenesCodefor DNA-BindingThatlnteractwith OtherGeneRegulatoryProteinsTheHomeoticSelectorGenesAreExpressedSequentiallyAccordingto TheirOrderin the HoxComplexTheHoxComplexCarriesa PermanentRecordof PositionalInformationTheAnteroposteriorAxisls Controlledby HoxSelectorGenesInvertebratesAlsoSummary134013411341134213421343134413441347ORGANOGENESISAND THEPATTERNINGOFAPPENDAGES1347ConditionalandInducedSomaticMutationsMakeit possibletoAnalyzeGeneFunctionsLatein Development1348BodyPartsof the Adult FlyDevelopFromlmaginalDiscs1349HomeoticSelectorGenesAre Essentialfor the MemoryofPositionalInformationin lmaginalDiscCellstSflSpecificRegulatoryGenesDefinethe CellsThatWillFormanAppendage13 5 1TheInsectWingDisclsDividedintoCompartments1352FourFamiliarSignalingPathwaysCombineto PatterntheWingDisc:Wingless,Hedgehog,Dpp,and NotchI 353TheSizeof EachCompartmentls Regulatedby InteractionsAmongltsCells13 s 3SimilarMechanismsPatternthe Limbsof Vertebrates1355LocalizedExpressionof SpecificClassesof GeneRegulatoryProteinsForeshadowsCellDifferentiation1356LateralInhibitionSinglesOut SensoryMotherCellsWithinProneuralClusters1357LateralInhibitionDrivesthe Progenyof the SensoryMotherCellTowardDifferentFinalFates857PlanarPolarityof AsymmetricDivisionsisControlledby Signalingviathe ReceptorFrizzled1359AsymmetricStem-CellDivisionsGenerateAdditionalNeuronsin the CentralNervousSystem1359AsymmetricNeuroblastDivisionsSegregatean Inhibitorof CellDivisionintoJustOneof the DaughterCells1361patternofNotchSignalingRegulatesthe Fine-GrainedDifferentiatedCellTypesin ManyDifferentTissues1362SomeKeyRegulatoryGenesDefinea CellType;OthersCanActivatethe Programfor Creationof an EntireOrgan1362Summary1363CELLMOVEMENTSAND THESHAPINGOFTHEVERTEBRATEBODY1363ThePolarityof the AmphibianEmbryoDependson the polarityof the Egg1364CleavageProducesManyCellsfrom Onel 365GastrulationTransformsa HollowBallof Cellsinto a Three-LaveredStructurewith a PrimitiveGutI JO)predictableTheMovementsof GastrulationArePrecisely| 500ChemicalSignalsTriggerthe MechanicalProcesses1367ActiveChangesof CellPackingProvidea DrivingForceforGastrulation1368ChangingPatternsof CellAdhesionMoleculesForceCellsIntoNewArrangements1369TheNotochordElongates,Whilethe NeuralplateRollsUp roFormthe NeuralTube1370A Gene-ExpressionOscillatorControlsSegmentationof the't371Mesodermlnto SomitesDelayedNegativeFeedbackMayGeneratethe Oscillationsof the SegmentationClock1373EmbryonicTissuesAreInvadedin a StrictlyControlledFashionby MigratoryCells1373TheDistributionof MigrantCellsDependson SurvivalFactorsasWellasGuidanceCues1375Left-RightAsymmetryof theVertebrateBodyDerivesFromin the EarlyEmbryoMolecularAsymmetrySummary1376T H EM O U S E1378PreambleBeginsWitha SpecializedMammalianDevelopmentEmbryols HighlyRegulativeTheEarlyMammalianTotipotentEmbryonicStemCellsCanBeObtainedFromaEmbryoMammalianGenerateBetweenEpitheliumandMesenchymeInteractionsTubularStructuresBranchingSummary13781380NEURALDEVELOPMENT13 8 3ltt I138013 8 11382Accordingto theNeuronsAreAssignedDifferentCharacters1383Timeand PlaceWhereTheyAreBorntheAssignedto a Neuronat lts BirthGovernsTheCharacter1385lt WillFormConnectionsEachAxonor DendriteExtendsby Meansof a GrowthConeat1386ItsTipTheGrowthConePilotsthe DevelopingNeuriteAlonga Precisely1387DefinedPath/n Vlvo1389asTheyTravelSensibilitiesGrowthConesCanChangeTheirNeurotrophicFactorsThatControlNerveTargetTissuesRelease1389CellGrowthand SurvivalGuidesthe Formationof OrderlyNeuralNeuronalSpecificity1391MapsAxonsFromDifferentRegionsof the RetinaRespondDifferently| sYZin theTectumof ReoulsiveMoleculesto a GradientAreSharpenedbyof SynapticConnectionsDiffusePatterns1393RemodelingActivity-Dependentin theMoldsthe Patternof SynapticConnectionsExperience1395BrainMaySynapseRemodelingAdultMemoryandDevelopmental1396MechanismsDependon Similar1397SummaryPLANTDEVELOPMENT1398ArabidopsisServesasa ModelOrganismfor PlantMolecular1398GeneticsControGenomels Richin Developmentalfhe Arabidopsis1399Genesa Root-ShootDevelopmentStartsby EstablishingEmbryonic1400AxisandThenHaltsInsidethe Seed1403by MeristemsSequentiallyThePartsof a PlantAreGenerated'1403Signalson Environmentalof the SeedlingDependsDevelopmentEventsCoordinateDevelopmentalHormonalSignalsLong-Range1403in SeparatePartsofthe PlantTheShapingof EachNewStructureDependson Oriented1406andExoansionCellDivisionSetof PrimordiaEachPlantModuleGrowsFroma Microscopic1407in a MeristemAuxinTransportControlsthe Patternof PrimordiaPolarized1408in the Meristem1409the MeristemMaintainsCellSignalingPlantTopologybyMutationsCanTransformRegulatory1410in the MeristemAlteringCellBehaviorTheSwitchto FloweringDependson Pastand Present1412EnvironmentalCues1413HomeoticSelectorGenesSpecifythe Partsof a Flower1415Summary1415ReferencesTissues,StemCells,Chapter23 Specializedand TissueRenewalBYSTEMCELLSANDIT5RENEWALEPIDERMIS'a41714171419BarrierWaterproofEpidermalCellsForma Multilayeredof DifferentCellsExpressa SequenceEpidermalDifferentiating1420GenesasTheyMatureStemCellsin the BasalLayerProvidefor Renewalof the Epidermis1420of a StemCellDo Not AlwaysHavetoTheTwo Daughters1421BecomeDifferentTheBasalLayerContainsBothStemCellsandTransitAmplifyingCellsArePartof the Strategyof GrowthTransitamplifyingDivisionsControlDNAOriginalRetainSelectivelyStemCellsof SomeTissuesStrandsDramaticallyDivisionCanIncreaseTheRateof Stem-CellWhenNewCellsAre NeededUrgentlYRenewalGovernEpidermalSignalsManyInteractingandCyclesof DevelopmentTheMammaryGlandUndergoesRegressionSummaryEPITHELIASENSORYReplacedOlfactorySensoryNeuronsAreContinuallyAuditoryHairCellsHaveto Lasta LifetimeCellsRenewTheirParts:the PhotoreceptorMostPermanentCellsof the RetinaSummary1422142314241425142614261428142914291430't43214331434ANDTHEGUTTHEAIRWAYS1434Lungsofthein the AlveoliAdjacentCellTypesCollaboratetoCollaborateandMacrophagesCells,CiliatedGobletCells,1434Keepthe AirwaysCleanltselfFasterThanRenewsTheLiningof the SmallIntestine1436AnyOtherTissue1438Compartmentthe GutStem-CellMaintainsWntSignaling1439GutCellDiversificationControlsNotchSignalingof GutEpithelialthe MigrationsControlsSignalingEphrin-Eph1440CellsCombinePathwaysandBMPSignalingPDGF,Wnt,Hedgehog,1441Nicheto Delimitthe Stem-CellTractasan InterfaceBetweenthe DigestiveTheLiverFunctions1442andthe Blood"t443LiverCellProliferationLiverCellLossStimulatesInsulinDoesNot Haveto Dependon StemCells:RenewalTissue1444Cellsin the PancreasSecreting1445SummaryAND ENDOTHELIALLYMPHATICS,BLOODVEsSEL5,1445CELLS1445andLymphaticsCellsLineAll BloodVesselsEndothelial1446AngiogenesisTipCellsPioneerEndothelialofVessel 1447CellsFormDifferentTypesof EndothelialDifferentTypesNotchSignalingVEGF;a BloodSupplyReleaseRequiringTissues1448the ResponseCellsRegulatesEndothelialBetweenof PericytesCellsControlRecruitmentfrom EndothelialSignals1450Walland SmoothMuscleCellsto Formthe Vessel1450SummaryBLOODCELLSTEMCELLS:BYMULTIPOTENTRENEWAL1450FORMATIONGranulocytes,AreCellsof WhiteBloodTheThreeMainCategories1451and LYmPhocytesMonocytes,of EachTypeof BloodCellin the BoneMarrowlsTheProduction1453ControlledIndividually1454StemCellsHemopoieticBoneMarrowContains1456of BloodCellsA MultipotentStemCellGivesRiseto All Classes|+)oProcessCommitmentls a StePwiseofNumbertheAmplifyCellsProgenitorofCommittedDivisions1457BloodCellsSpecialized1458StemCellsDependon ContactSignalsFromStromalCellsCanBeAnalyzedin Culture 1459HemopoiesisThatRegulateFactors1459Dependson the HormoneErythropoietinErythropoiesisProduction 1460andMacrophageNeutrophillnfluenceMultipleCSFs1461CellDependsPartlyon Chanceof a HemopoieticTheBehaviorof CelllsaslmportantasRegulationof CellSurvivalRegulation1462Proliferation1462SummaryOFAND REGENERATIONMODULATION,GENESIS,MUSCLESKELETALFuseto FormNewSkeletalMuscleFibersMyoblasts14631464MuscleCellsCanVaryTheirPropertiesby Changingthe proteinfsoformsTheyContain1465SkeletalMuscleFibersSecreteMyostatinto LimitTheirOwnGrowth 1465SomeMyoblastsPersistaseuiescentStemCellsin the Adult:|466Summary1467FIBROBLASTSANDTHEIRTRANSFORMATTONS:THECONNECTIVE-TISSUECELLFAMILY1467F i b r o b l a s tCs h a n g eT h e i rC h a r a c t e ri n R e s p o n s et o C h e m i c a lSignalsT h e E x t r a c e l l u l aMr a t r i x M a y I n f l u e n c eC o n n e c t i v e - T i s s uCee l lDifferentiation by Affecting Cell Shape and AttachmentOsteoblastsMake Bone MatrixM o s t B o n e sA r e B u i l t A r o u n d C a r t i l a g eM o d e l sB o n e l s C o n t i n u a l l yR e m o d e l e db y t h e C e l l sW i t h i n l tOsteoclastsAre Controlled by SignalsFrom OsteoblastsFat CellsCan Develop From FibroblastsLeptin Secretedby Fat CellsProvidesFeedbackto Requlate14671468i46g1470lr47214731474EatingSummary14751476S T E M - C E LELN G I N E E R I N G1476HemopoieticStemCellsCanBeUsedto ReplaceDiseasedBloodCellswith HealthyOnes1477EpidermalStemCellPopulationsCanBeExpandedin CultureforTissueRepair1477NeuralStemCellsCanBeManipulatedin Cultureir478NeuralStemCellsCanRepopulatethe CentralNervousSystem147gStemCellsin the Adult BodyAreTissue-Specific1479ESCellsCanMakeAnyPartofthe Body1480Patient-SpecificESCellsCouldSolvethe problemof lmmuneRejection1481ESCellsAreUsefulfor DrugDiscoveryand Analysisof Disease14g2Summarylr4g2Referencesl4g3Chapter24 Pathogens,Infection,andInnatelmmunityINTRODUCTIONTOPATHOGENSPathogensHave EvolvedSpecificMechanismsfor Interactingwith Their HostsT h e S i g n sa n d S y m p t o m so f I n f e c t i o nM a y B e C a u s e db y t h ePathogen or by the Host! ResponsesPathogensAre PhylogeneticallyDiverseBacterialPathogensCarry SpecializedVirulenceGenesFungal and ProtozoanParasitesHave Complex Life CycleswithMultipleFormsAlf AspectsofViral PropagationDepend on Host Cell MachineryPrionsAre Infectious ProteinsInfectious DiseaseAgents Are Linked To Cancer,Heart Disease,andOtherChroniclllnessesSummary1485148614861487148814891494149614gA1499'1501CELLBIOLOGYOF INFECTION15 0 1PathogensCrossProtectiveBarriersto Colonizethe Hostr5 0 1PathogensThatColonizeEpitheliaMustAvoidClearancebvthe Host1502IntracellularPathogensHaveMechanismsfor BothEnterinqand LeavingHostCellsI 504VirusParticlesBindto MoleculesDisplayedon the HostCellSurface1505poreFormation,VirionsEnterHostCellsby MembraneFusion,orMembraneDisruotion1506BacteriaEnterHostCellsby phagocytosis1507IntracellularEucaryoticParasitesActivelyInvadeHostCells1508ManyPathogensAlterMembraneTrafficin the HostCell151Virusesand BacteriaUsethe HostCellCytoskeletonfor IntracellularMovement1514ViralInfectionsTakeOverthe Metabolismof the HostCell1517PathogensCan Alter the Behaviorof the Host Organism to Facilitatethe Spreadofthe PathogenPathogensEvolveRapidlyAntigenicVariationin PathogensOccursby MultipleMechanismsError-ProneReplicationDominatesViralEvolutionDrug-ResistantPathogensArea GrowingProblemSummary15 1 815',191520t)zl1524B A R R I E R S TI NOF E C T I OANN D T H EI N N A T EIMMUNE5YsTEM1524EpithelialSurfacesand DefensinsHelpPreventInfectionHumanCellsRecognizeConservedFeaturesof PathogensComplementActivationTargetsPathogensfor Phagocytosisor LysisToll-likeProteinsand NODProteinsArean AncientFamilyofPatternRecognitionReceptorsPhagocyticCellsSeek,Engulf,and DestroyPathogensActivatedMacrophagesContributeto the InflammatoryResponseat Sitesof InfectionVirus-lnfectedCellsTakeDrasticMeasuresto PreventViralReplicationNaturalKillerCellsInduceVirus-lnfectedCellsto KillThemselvesDendriticCellsProvidethe LinkBetweenthe InnateandAdaptivelmmuneSystemsSummaryReferences15251526Chapter25 The Adaptivelmmune System152g153015 3 1| )551534153515361537|53t1539LYMPHOCYTESAND THECELLULARBA5I5OF ADAPTIVEIMMUNITY1540LymphocytesAreRequiredfor Adaptivelmmunity1540TheInnateand AdaptivelmmuneSystemsWorkTogether154jB LymphocytesDevelopin the BoneMarrow;TLymphocytesDevelopin theThymus1543TheAdaptivelmmuneSystemWorksby ClonalSelection1544MostAntigensActivateManyDifferentLymphocyteClones1545lmmunologicalMemoryInvolvesBothClonalExpansionandjS45LymphocyteDifferentiationlmmunologicalToleranceEnsuresThatSelfAntigensAreNotNormallyAttacked1547LymphocytesContinuouslyCirculateThroughPeripheralLymphoidOrgans1549Summary15 5 1B CELLSAND ANTIBODIES15 5 1B CellsMakeAntibodiesas BothCell-SurfaceAntigenReceptorsand SecretedProteins1552A TypicalAntibodyHasTwoldenticalAntigen-BindingSites1552An AntibodyMoleculelsComposedof HeavyandLightChains 1552ThereAre FiveClassesof AntibodyHeavyChains,EachwitnDifferentBiologicalProperties15 5 3TheStrengthofan Antibody-AntigenInteractionDependsonBoththe Numberand the Affinityof the Antigen-BindingSites15s7AntibodyLightandHeavyChainsConsistof ConstantandVariableRegions15 5 8The Light and Heavy ChainsAre Composed of RepeatinglgDomains1559An Antigen-Binding Site ls Constructedfrom HypervariableLoops 1s60't561SummaryTHEGENERATIONOFANTIBODYDIVERSITYAntibodyGenesAreAssembledFromSeparateGeneSegmentsDuringB CellDevelopmentlmpreciseJoiningof GeneSegmentsGreatlyIncreasestheDiversityof V RegionsTheControlof V(D)JRecombinationEnsuresThatB CellsAreMonospecificAntigen-DrivenSomaticHypermutationFine-TunesAntibooyResponsesB CellsCanSwitchthe Classof AntibodyTheyMakeSummary156215621564I 565156615671569T CELLSAND MHC PROTEINS1569(TCRs)AreAntibodylikeHeterodimersT CellReceptorsby DendriticCellsCanEitherActivateAntigenPresentationT CellsorTolerizeT CellsInduceInfectedTargetCellstoEffectorCytotoxicKillThemselvesEffectorHelperT CellsHelpActivateOtherCellsof the Innateand AdaptivelmmuneSystemsthe Activityof OtherT CellsRegulatoryT CellsSuppressForeignPeptidesBoundto MHCProteinsT CellsRecognizeReactionsWereldentifiedin TransplantationMHCProteinsWereKnownBeforeTheirFunctionsSimilarAreStructurallyll MHCProteinsClassI andClassHeterodimerswith aAn MHCProteinBindsa Peptideand InteractsT CellReceptorTargetsMHCProteinsHelpDirectT Cellsto TheirAppropriateBindto InvariantPartsof MHCCD4and CD8Co-ReceptorsProteinsFragmentsof ForeignCytosolicT CellsRecognizeCytotoxicwith ClassI MHCProteinsProteinsin AssociationForeignof EndocytosedHelperTCellsRespondto Fragmentswith Classll MHCProteinsProteinAssociatedin the ThymusSelectedPotentiallyUsefulT CellsArePositively15701571tJ/t1573157415751575157615771579158015 8 115831585Cytotoxicand HelperT CellsThatCouldMostDevelopingAreEliminatedComplexesBeActivatedby Self-Peptide-MHC1586in theThymusin theExpressedAreEctopicallyProteinsSomeOrgan-specific1587ThymusMedullaTheirPolymorphism1588HelpsExplainof MHCProteinsTheFunction1588SummaryACTIVATIONANDLYMPHOCYTET CELLSHELPERtoCellsUseMultipleMechanismsDendriticActivatedActivateT CellsTheActivationof T CellslsControlledby NegativeFeedbackthe Natureof EffectorHelperT CellDeterminesTheSubclasslmmuneResPonseof the Adaptiveand StimulateAnTu1CellsActivateInfectedMacrophagesResPonselnflammatory(BCRs)ls OnlyOneStepinAntigenBindingto B CellReceptorsB CellActivationfor ActivatingMostHelperTCellsAreEssentialAntigen-specificB CellsAntigensT-Cell-lndependentof B CellsRecognizeClassA SpecialBelongto theAncientlgMoleculeslmmuneRecognitionSuperfamilySummaryReferences1589159015 9 1| )YZ1594159515971598159916001600AcknowledgmentsIn writing this book we have benefited greatly from the advice of many biologists and biochemists.

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