FOURTH EDITIO N

MOLECULA RCEL LBIOLOGY Harvey Lodis h

Arnold Berk

S . Lawrence Zipursky

Paul Matsudaira

:iAtrov 1

4 '

David Baltimore

James Darnell

PART I Laying the Groundwork

PART III Building and Fuelin gthe Cell

1

The Dynamic Cell 1

2

Chemical Foundations 14

15 Transport across Cell Membranes 578

3

Protein Structure and Function 50

16 Cellular Energetics : Glycolysis, Aerobi c

Oxidation, and Photosynthesis 61 6

4

Nucleic Acids, the Genetic Code, and the

Synthesis of Macromolecules 100

17 Protein Sorting: Organelle Biogenesis an d

Protein Secretion 675

5

Biomembranes and the Subcellular

Organization of Eukaryotic Cells 138

18 Cell Motility and Shape I:

Microfilaments 751

6

Manipulating Cells and Viruses in

Culture 180

19 Cell Motility and Shape II : Microtubule s

and Intermediate Filaments 79 5

7

Recombinant DNA and Genomics 20 7

8

Genetic Analysis in Cell Biology 254

PART IV Cell Interactions

PART II Nuclear Control of

20 Cell-to-Cell Signaling: Hormones and

Cellular Activity

Receptors 848

21 Nerve Cells 91 1

9

Molecular Structure of Genes an d

Chromosomes 294

22 Integrating Cells into Tissues 968

10 Regulation of Transcription Initiation 341

23 Cell Interactions in Development 100 3

11 RNA Processing, Nuclear Transport, and

24 Cancer 1054

Post-Transcriptional Control 404

12 DNA Replication, Repair, and

Recombination 453

13 Regulation of the Eukaryotic Cell Cycle 495

14 Gene Control in Development 537

Chapter-Opening Illustrations xxxvii

Asymmetric Carbon Atoms Are Present in Most Biologica lMolecules 1 9

a and /3 Glycosidic Bonds Link Monosaccharides 2 1PART I : Laying the Groundwork

2 .2 Noncovalent Bonds 2 2

The Hydrogen Bond Underlies Water's Chemical and

1 The Dynamic Cell

Biological Properties 22

Ionic Interactions Are Attractions between Oppositel y1 .1 Evolution : At the Core of Molecular Change 3

Charged Ions 2 3

Van der Waals Interactions Are Caused by Transient1 .2 The Molecules of Life 3

Dipoles 2 4

1.3 The Architecture of Cells 5

Hydrophobic Bonds Cause Nonpolar Molecules to Adher e

Cells Are Surrounded by Water-Impermeable

to One Another 2 5

Membranes 5

Multiple Noncovalent Bonds Can Confer Binding

Membranes Serve Functions Other Than Segregation 6

Specificity 2 6

Prokaryotes Comprise a Single Membrane-Limited

Phospholipids Are Amphipathic Molecules 2 6

Compartment 7

The Phospholipid Bilayer Forms the Basic Structure of Al l

Eukaryotic Cells Contain Many Organelles and a

Biomembranes 2 7

Complex Cytoskeleton 7

2 .3 Chemical Equilibrium 29Cellular DNA Is Packaged within Chromosomes 8

Equilibrium Constants Reflect the Extent of a Chemica l1 .4 The Life Cycle of Cells 9

Reaction 2 9

The Cell Cycle Follows a Regular Timing Mechanism 9

The Concentration of Complexes Can Be Estimated fro m

Mitosis Apportions the Duplicated Chromosomes Equally

Equilibrium Constants for Binding Reactions 3 1

to Daughter Cells 10

Biological Fluids Have Characteristic pH Values 3 1

Cell Differentiation Creates New Types of Cells 10

Hydrogen Ions Are Released by Acids and Taken Up b y

Cells Die by Suicide 10

Bases 32

The Henderson-Hasselbalch Equation Relates pH and K e q1 .5 Cells into Tissues 11

of an Acid-Base System 3 3Multicellularity Requires Extracellular Glues 11

Buffers Maintain the pH of Intracellular and Extracellula rTissues Are Organized into Organs 11

Fluids 33

Body Plan and Rudimentary Tissues Form Early in

2 .4 Biochemical Energetics 3 5Embryonic Development 12

Living Systems Use Various Forms of Energy, Which Ar e1 .6 Molecular Cell Biology : An Integrated View of Cells

Interconvertible 3 5

at Work 13

The Change in Free Energy AG Determines the Directio n

MEDIA CONNECTIONS of a Chemical Reaction 3 6

Overview: Life Cycle of a Cell

The AG of a Reaction Depends on Changes in Enthalpy(Bond Energy) and Entropy 3 6

Several Parameters Affect the AG of a Reaction 3 7

2 Chemical Foundations

The AG° ' of a Reaction Can Be Calculated from Its K eq 3 8

Cells Must Expend Energy to Generate Concentratio n2.1 Covalent Bonds 15

Gradients 3 9Each Atom Can Make a Defined Number of Covalent

Many Cellular Processes Involve Oxidation-Reductio nBonds 16

Reactions 3 9The Making or Breaking of Covalent Bonds Involves

An Unfavorable Chemical Reaction Can Proceed If It I sLarge Energy Changes 17

Coupled with an Energetically Favorable Reaction 4 1Covalent Bonds Have Characteristic Geometries 17

Hydrolysis of Phosphoanhydride Bonds in ATP Release sElectrons Are Shared Unequally in Polar Covalent

Substantial Free Energy 4 1Bonds 18

ATP Is Used to Fuel Many Cellular Processes 43

2.5 Activation Energy and Reaction Rate 45

3 .4 Membrane Proteins 7 8Chemical Reactions Proceed through High-Energy

Proteins Interact with Membranes in Different Ways 7 8Transition States 45

Hydrophobic a Helices in Transmembrane Proteins AreEnzymes Accelerate Biochemical Reactions by Reducing

Embedded in the Bilayer 7 9Transition-State Free Energy 47

Many Integral Proteins Contain Multiple Transmembran eMEDIA CONNECTIONS

a Helices 79

Overview: Biological Energy Interconversions

Multiple ß Strands in Porins Form Membrane-Spannin g"Barrels " 8 1

Covalently Attached Hydrocarbon Chains Anchor SomeProteins to the Membrane 8 1

3 Protein Structure and Function

Some Peripheral Proteins Are Soluble Enzymes That Ac t

3 .1 Hierarchical Structure of Proteins 51

on Membrane Components 82

The Amino Acids Composing Proteins Differ Only in

3 .5 Purifying, Detecting, and Characterizing

Their Side Chains 51

Proteins 83

Peptide Bonds Connect Amino Acids into Linear

Proteins Can Be Removed from Membranes by DetergentsChains 53

or High-Salt Solutions 8 3

Four Levels of Structure Determine the Shape of

Centrifugation Can Separate Particles and Molecules That

Proteins 54

Differ in Mass or Density 8 5

Graphic Representations of Proteins Highlight Different

Electrophoresis Separates Molecules according to Thei r

Features 54

Charge :Mass Ratio 87

Secondary Structures Are Crucial Elements of Protein

Liquid Chromatography Resolves Proteins by Mass,

Architecture 56

Charge, or Binding Affinity 8 8

Motifs Are Regular Combinations of Secondary

Highly Specific Enzyme and Antibody Assays Can Detect

Structures 58

Individual Proteins 90

Structural and Functional Domains Are Modules of

Radioisotopes Are Indispensable Tools for Detectin g

Tertiary Structure 60

Biological Molecules 90

Sequence Homology Suggests Functional and Evolutionary

Protein Primary Structure Can Be Determined b y

Relationships between Proteins 60

Chemical Methods and from Gene Sequences 9 4

Time-of-Flight Mass Spectrometry Measures the Mass o f3 .2 Folding, Modification, and Degradation of

Proteins and Peptides 94Proteins 62

Peptides with a Defined Sequence Can Be Synthesize dThe Information for Protein Folding Is Encoded in the

Chemically 94Sequence 63

Protein Conformation Is Determined by Sophisticate dFolding of Proteins in Vivo Is Promoted by

Physical Methods 9 5Chaperones 63

Chemical Modifications and Processing Alter theMEDIA CONNECTIONS

Biological Activity of Proteins 64

Focus: Chaperone-Mediated Foldin g

Cells Degrade Proteins via Several Pathways 66

Overview: Life Cycle of a Protein

Technique: 5DS Gel ElectrophoresisAberrantly Folded Proteins Are Implicated in Slowly

Developing Diseases 67

Technique: Immunoblotting

Classical Experiment 3.1 : Bringing an Enzyme Back

3.3 Functional Design of Proteins 68

to Life

Proteins Are Designed to Bind a Wide Range ofMolecules 6 8

Antibodies Exhibit Precise Ligand Binding

4 Nucleic Acids, the Genetic

Specificity 70

Code, and the SynthesisEnzymes Are Highly Efficient and Specific Catalysts 71

of MacromoleculesAn Enzyme 's Active Site Binds Substrates and Carries Out

Catalysis 71

4.1 Structure of Nucleic Acids 10 1

Kinetics of an Enzymatic Reaction Are Described by V,,,ax

Polymerization of Nucleotides Forms Nucleic Acids 10 1

and Km 73

Native DNA Is a Double Helix of Complementary

Many Proteins Contain Tightly Bound Prosthetic

Antiparallel Chains 103

Groups 74

DNA Can Undergo Reversible Strand Separation 10 5

A Variety of Regulatory Mechanisms Control Protein

Many DNA Molecules Are Circular 10 7

Function 75

Local Unwinding of DNA Induces Supercoiling 108

RNA Molecules Exhibit Varied Conformations an dFunctions 108

5 Biomembranes and th eSubcellular Organization

4.2 Synthesis of Biopolymers : Rules of Macromolecula rCarpentry 110

of Eukaryotic Cells

4.3 Nucleic Acid Synthesis 111

5 .1 Microscopy and Cell Architecture 14 0

Both DNA and RNA Chains Are Produced by Copying of

Light Microscopy Can Distinguish Objects Separated b y

Template DNA Strands 111

0 .2 µm or More 140

Nucleic Acid Strands Grow in the 5'

3'

Samples for Light Microscopy Usually Are Fixed,

Direction 112

Sectioned, and Stained 14 1

RNA Polymerases Can Initiate Strand Growth but DNA

Fluorescence Microscopy Can Localize and Quantify

Polymerases Cannot 112

Specific Molecules in Cells 14 2

Replication of Duplex DNA Requires Assembly of Many

Confocal Scanning and Deconvolution Microscop y

Proteins at a Growing Fork 113

Provide Sharper Images of Three-Dimensiona l

Organization of Genes in DNA Differs in Prokaryotes and

Objects 144

Eukaryotes 114

Phase-Contrast and Nomarski Interference Microscop y

Eukaryotic Primary RNA Transcripts Are Processed to

Visualize Unstained Living Cells 14 6

Form Functional mRNAs 115

Transmission Electron Microscopy Has a Limit o fResolution of 0 .1 nm 14 7

4.4 The Three Roles of RNA in Protein

Scanning Electron Microscopy Visualizes Details on th eSynthesis 116

Surfaces of Cells and Particles 15 2Messenger RNA Carries Information from DNA in a

Three-Letter Genetic Code 117

5.2 Purification of Cells and Their Parts 15 2Experiments with Synthetic mRNAs and Trinucleotides

Flow Cytometry Separates Different Cell Types 15 3Broke the Genetic Code 119

Disruption of Cells Releases Their Organelles and Othe rThe Folded Structure of tRNA Promotes Its Decoding

Contents 153Functions 120

Different Organelles Can Be Separated b yNonstandard Base Pairing Often Occurs between Codons

Centrifugation 154and Anticodons 122

Organelle-Specific Antibodies Are Useful in Preparin gAminoacyl-tRNA Synthetases Activate Amino Acids by

Highly Purified Organelles 15 7Linking Them to tRNAs 12 3

Each tRNA Molecule Is Recognized by a Specific

5.3 Biomembranes : Structural Organization and Basi cAminoacyl-tRNA Synthetase 124

Functions 15 7Ribosomes Are Protein-Synthesizing Machines 125

Phospholipids Are the Main Lipid Constituents of Mos tBiomembranes 15 7

4.5 Stepwise Formation of Proteins on Every Cellular Membrane Forms a Closed Compartmen tRibosomes 128

and Has a Cytosolic and an Exoplasmic Face 16 0The AUG Start Codon Is Recognized by Methionyl-

Several Types of Evidence Point to the Universality of th etRNAm, et 128

Phospholipid Bilayer 16 0Bacterial Initiation of Protein Synthesis Begins Near a

All Integral Proteins and Glycolipids Bind Asymmetricall yShine-Dalgarno Sequence in mRNA 129

to the Lipid Bilayer 16 2Eukaryotic Initiation of Protein Synthesis Occurs at the 5'

The Phospholipid Composition Differs in Two Membran eEnd and Internal Sites in mRNA 130

Leaflets 162During Chain Elongation Each Incoming Aminoacyl-

Most Lipids and Integral Proteins Are Laterally Mobile i ntRNA Moves through Three Ribosomal Sites 131

Biomembranes 162Protein Synthesis Is Terminated by Release Factors When

Fluidity of Membranes Depends on Temperature an da Stop Codon Is Reached 132

Composition 164Simultaneous Translation by Multiple Ribosomes and

Membrane Leaflets Can Be Separated and Each Fac eTheir Rapid Recycling Increase the Efficiency of

Viewed Individually 16 5Protein Synthesis 133

The Plasma Membrane Has Many Common Functions i nMEDIA CONNECTIONS

All Cells 16 6Focus: Basic Transcriptional Mechanism

Overview: Life Cycle of an mRNA

5 .4 Organelles of the Eukaryotic Cell 16 8Focus: Protein Synthesis

Lysosomes Are Acidic Organelles That Contain a Batter yClassic Experiment 4.1 : Cracking the Genetic Code

of Degradative Enzymes 169

Plant Vacuoles Store Small Molecules and Enable the Cell

Animal Viruses Are Classified by Genome Type an dto Elongate Rapidly 170

mRNA Synthesis Pathway 19 9Peroxisomes Degrade Fatty Acids and Toxic

Viral Vectors Can Be Used to Introduce Specific Gene sCompounds 171

into Cells 20 3

Mitochondria Are the Principal Sites of ATP Production

MEDIA CONNECTION Sin Aerobic Cells 171

Technique: Preparing Monoclonal Antibodie sChloroplasts, the Sites of Photosynthesis, Contain Three

Overview: Life Cycle of a Retroviru sMembrane Limited Compartments 172

Classic Experiment 6.1 : The Discovery of ReverseThe Endoplasmic Reticulum Is a Network of

TranscriptaseInterconnected Internal Membranes 17 2

Golgi Vesicles Process and Sort Secretory and Membran eProteins 173

7 Recombinant DNA and GenomicsThe Double-Membraned Nucleus Contains the Nucleolu s

and a Fibrous Matrix 174

7.1 DNA Cloning with Plasmid Vectors 20 8The Cytosol Contains Many Particles and Cytoskeletal

Plasmids Are Extrachromosomal Self-Replicating DN AFibers 175

Molecules 209

MEDIA CONNECTIONS

E . Coll Plasmids Can Be Engineered for Use as Clonin g

Overview: Protein Secretion

Vectors 20 9

Technique: Reporter Constructs

Plasmid Cloning Permits Isolation of DNA Fragment s

Classic Experiment 5 .1: Separating Organellesfrom Complex Mixtures 210

Restriction Enzymes Cut DNA Molecules at Specifi cSequences 21 1

6 Manipulating Cells and

Restriction Fragments with Complementary "Sticky Ends "Are Ligated Easily 21 2

Viruses in Culture

Polylinkers Facilitate Insertion of Restriction Fragment s

6 .1 Growth of Microorganisms in Culture 181

into Plasmid Vectors 214

Many Microorganisms Can Be Grown in Minimal

Small DNA Molecules Can Be Chemically

Medium 181

Synthesized 215

Mutant Strains of Bacteria and Yeast Can Be Isolated by

7 .2 Constructing DNA Libraries with A Phage and

Replica Plating 182

Other Cloning Vectors 21 6

Bacteriophage A Can Be Modified for Use as a Cloning6.2 Growth of Animal Cells in Culture 183

Vector and Assembled in Vitro 21 6Rich Media Are Required for Culture of Animal Cells 183

Nearly Complete Genomic Libraries of Higher Organism s

Most Cultured Animal Cells Grow Only on Special Solid

Can Be Prepared by A Cloning 21 8Surfaces 183

cDNA Libraries Are Prepared from Isolate dPrimary Cell Cultures Are Useful, but Have a Finite Life

mRNAs 21 9Span 185

Larger DNA Fragments Can Be Cloned in Cosmids an d

Transformed Cells Can Grow Indefinitely in

Other Vectors 22 1Culture 18 6

Fusion of Cultured Animal Cells Can Yield Interspecific

7 .3 Identifying, Analyzing, and Sequencin g

Hybrids Useful in Somatic-Cell Genetics 187

Cloned DNA 223

Hybrid Cells Often Are Selected in HAT Medium 189

Libraries Can Be Screened with Membrane Hybridizatio n

Hybridomas Are Used to Produce Monoclonal

Assay 224

Antibodies 189

Oligonucleotide Probes Are Designed Based on Partia l

Protein Sequences 225

6.3 Viruses : Structure, Function, and Uses 191

Specific Clones Can Be Identified Based on Properties of

Viral Capsids Are Regular Arrays of One or a Few Types

the Encoded Proteins 22 7

of Protein 192

Gel Electrophoresis Resolves DNA Fragments of Differen t

Most Viral Host Ranges Are Narrow 194

Size 22 8

Viruses Can Be Cloned and Counted in Plaque

Multiple Restriction Sites Can Be Mapped on a Clone d

Assays 194

DNA Fragment 23 0

Viral Growth Cycles Are Classified as Lytic or

Pulsed-Field Gel Electrophoresis Separates Large DN A

Lysogenic 194

Molecules 23 1

Four Types of Bacterial Viruses Are Widely Used in

Purified DNA Molecules Can Be Sequenced Rapidly b y

Biochemical and Genetic Research 196

Two Methods 231

7.4 Bioinformatics 235

Mutations Occur Spontaneously and Can B e

Stored Sequences Suggest Functions of Newly Identified

Induced 25 7

Genes and Proteins 235

Some Human Diseases Are Caused by Spontaneou s

Comparative Analysis of Genomes Reveals Much about

Mutations 25 8

an Organism's Biology 236

8 .2 Isolation and Analysis of Mutants 26 1Homologous Proteins Involved in Genetic Information

Temperature-Sensitive Screens Can Isolate Letha lProcessing Are Widely Distributed 238

Mutations in Haploids 26 1Many Yeast Genes Function in Intracellular Protein

Recessive Lethal Mutations in Diploids Can Be ScreenedTargeting and Secretion 239

by Use of Visible Markers 26 3The C. elegans Genome Encodes Numerous Proteins

Complementation Analysis Determines If Differen tSpecific to Multicellular Organisms 239

Mutations Are in the Same Gene 26 4

7.5 Analyzing Specific Nucleic Acids in Complex

Metabolic and Other Pathways Can Be Generically

Mixtures 240

Dissected 265

Southern Blotting Detects Specific DNA Fragments 240

Suppressor Mutations Can Identify Genes Encodin gInteracting Proteins 265

Northern Blotting Detects Specific RNAs 24 1

Specific RNAs Can Be Quantitated and Mapped on DNA

8 .3 Genetic Mapping of Mutations 26 6

by Nuclease Protection 241

Segregation Patterns Indicate Whether Mutations Are o n

Transcription Start Sites Can Be Mapped by Si Protection

the Same or Different Chromosomes 26 7

and Primer Extension 243

Chromosomal Mapping Locates Mutations on Particula rChromosomes 26 8

7 .6 Producing High Levels of Proteins from Cloned

Recombinational Analysis Can Map Genes Relative t ocDNAs 244

Each Other on a Chromosome 26 9F. coli Expression Systems Can Produce Full-Length

DNA Polymorphisms Are Used to Map Huma nProteins 244

Mutations 27 1Eukaryotic Expression Systems Can Produce Proteins with

Some Chromosomal Abnormalities Can Be Mapped byPost-Translational Modifications 245

Banding Analysis 272Cloned cDNAs Can Be Translated in Vitro to Yield

8 .4 Molecular Cloning of Genes Defined byLabeled Proteins 245

Mutations 2747.7 Polymerase Chain Reaction : An Alternative

Cloned DNA Segments Near a Gene of Interest Ar eto Cloning 246

Identified by Various Methods 27 4

PCR Amplification of Mutant Alleles Permits Their

Chromosome Walking Is Used to Isolate a Limited Regio nDetection in Small Samples 246

of Contiguous DNA 27 5

DNA Sequences Can Be Amplified for Use in Cloning and

Physical Maps of Entire Chromosomes Can Beas Probes 247

Constructed by Screening YAC Clones for Sequence -Tagged Sites 276

7 .8 DNA Microarrays : Analyzing Genome-Wide

Physical and Genetic Maps Can Be Correlated with th eExpression 248

Aid of Known Markers 277MEDIA CONNECTIONS

Further Analysis Is Needed to Locate a Mutation-Define dTechnique: Plasmid Cloning

Gene in Cloned DNA 27 8Technique: Dideoxy Sequencing of DNA

Protein Structure Is Deduced from cDNA Sequence 27 9Technique: Polymerase Chain Reaction

8 .5 Gene Replacement and Transgenic Animals 28 1Classic Experiment 7 .1 : Unleashing the Power of

Specific Sites in Cloned Genes Can Be Altered i nExponential Growth: The Polymerase Chain

Vitro 28 1Reactio n

Classic Experiment 7 .2: Demonstrating Sequence-

DNA Is Transferred into Eukaryotic Cells in Variou s

Specific Cleavage by a Restriction Enzyme

Ways 28 2

Normal Genes Can Be Replaced with L1utant Alleles i nYeast and Mice 28 2

8 Genetic Analysis in Cell Biology

Foreign Genes Can Be Introduced into Plants an dAnimals 287

8 .1 Mutations : Types and Causes 255

MEDIA CONNECTION SMutations Are Recessive or Dominant 255

Technique: In Vitro Mutagenesis of Cloned Gene sInheritance Patterns of Recessive and Dominant

Technique : Creating a Transgenic Mous eMutations Differ 256

Classic Experiment 8 .1 : Expressing Foreign GenesMutations Involve Large or Small DNA Alterations 257

in Mice

PART II : Nuclear Control of

9.5 Organizing Cellular DNA into Chromosomes 32 0Cellular Activity

Most Bacterial Chromosomes Are Circular with On eReplication Origin 32 0

Eukaryotic Nuclear DNA Associates with Histon eProteins to Form Chromatin 32 1

9 Molecular Structure of Genes and

Chromatin Exists in Extended and Condense dForms 321Chromosomes

Acetylation of Histone N-Termini Reduces Chromati nCondensation 3239.1 Molecular Definition of a Gene 295

Eukaryotic Chromosomes Contain One Linear DN ABacterial Operons Produce Polycistronic mRNAs 295

Molecule 32 4Most Eukaryotic mRNAs Are Monocistronic and Contai n

Introns 295

Simple and Complex Transcription Units Are Found in

9 .6 Morphology and Functional Elements of Eukaryoti cEukaryotic Genomes 296

Chromosomes 32 4

Chromosome Number, Size, and Shape at Metaphase Are9.2 Chromosomal Organization of Genes and

Species Specific 32 5Noncoding DNA 297

Nonhistone Proteins Provide a Structural Scaffold fo rGenomes of Higher Eukaryotes Contain Much

Long Chromatin Loops 32 5Nonfunctional DNA 297

Chromatin Contains Small Amounts of Other Proteins i nCellular DNA Content Does Not Correlate with

Addition to Histones and Scaffold Proteins 32 7Phylogeny 298

Stained Chromosomes Have Characteristic BandingProtein-Coding Genes May Be Solitary or Belong to a

Patterns 327Gene Family 299

Chromosome Painting Distinguishes Each Homologou sTandemly Repeated Genes Encode rRNAs, tRNAs, and

Pair by Color 328Histones 300

Heterochromatin Consists of Chromosome Regions Tha tReassociation Experiments Reveal Three Major Fractions

Do Not Uncoil 32 9of Eukaryotic DNA 301

Three Functional Elements Are Required for Replicatio nSimple-Sequence DNAs Are Concentrated in Specific

and Stable Inheritance of Chromosomes 329Chromosomal Locations 301

Yeast Artificial Chromosomes Can Be Used to Clon eDNA Fingerprinting Depends on Differences in Length of

Megabase DNA Fragments 33 1Simple-Sequence DNAs 30 2

9.3 Mobile DNA 303

9.7 Organelle DNAs 33 2

Movement of Mobile Elements Involves a DNA or RNA

Mitochondria Contain Multiple mtDNA Molecules 33 2

Intermediate 304

Genes in mtDNA Exhibit Cytoplasmic Inheritance an d

Mobile Elements That Move as DNA Are Present in

Encode rRNAs, tRNAs, and Some Mitochondria l

Prokaryotes and Eukaryotes 304

Proteins 33 3

Viral Retrotransposons Contain LTRs and Behave Like

The Size and Coding Capacity of mtDNA Var y

Retroviruses in the Genome 307

Considerably in Different Organisms 33 4

Nonviral Retrotransposons Lack LTRs and Move by an

Products of Mitochondrial Genes Are No t

Unusual Mechanism 308

Exported 335

Retrotransposed Copies of Cellular RNAs Occur in

Mitochondrial Genetic Codes Differ from the Standard

Eukaryotic Chromosomes 312

Nuclear Code 335

Mobile DNA Elements Probably Had a Significant

Mutations in Mitochondrial DNA Cause Several Genetic

Influence on Evolution 312

Diseases in Man 33 6

Chloroplasts Contain Large Circular DNAs Encodin g

9.4 Functional Rearrangements in Chromosomal

More Than a Hundred Proteins 33 6

DNA 314

MEDIA CONNECTION SInversion of a Transcription-Control Region Switches

Focus: Retroviral Reverse Transcription

Salmonella Flagellar Antigens 314

Focus: Three-Dimensional Packing of Nuclear

Antibody Genes Are Assembled by Rearrangements of

Chromosomes

Germ-Line DNA 315

Classic Experiment 9.1 : Two Genes Become One:

Generalized DNA Amplification Produces Polytene

Somatic Rearrangement of Immunoglobin

Chromosomes 318

Genes

10 Regulation of Transcription

RNA Polymerase II Initiates Transcription at DN ASequences Corresponding to the 5' Cap o f

Initiation

mRNAs 36 2

10.1 Bacterial Gene Control : The Jacob-Monod

10 .4 Regulatory Sequences in Eukaryotic Protein-Codin gModel 342

Genes 365Enzymes Encoded at the lac Operon Can Be Induced

TATA Box, Initiators, and CpG Islands Function a sand Repressed 342

Promoters in Eukaryotic DNA 36 5

Mutations in lac? Cause Constitutive Expression of lac

Promoter-Proximal Elements Help Regulate Eukaryoti cOperon 343

Genes 366

Isolation of Operator Constitutive and Promoter

Transcription by RNA Polymerase II Often Is Stimulate dMutants Support Jacob-Monod Model 343

by Distant Enhancer Sites 36 8

Regulation of lac Operon Depends on Cis-Acting DNA

Most Eukaryotic Genes Are Regulated by Multipl eSequences and Trans-Acting Proteins 344

Transcription-Control Elements 36 9Biochemical Experiments Confirm That Induction of th e

lac Operon Leads to Increased Synthesis of lac

10 .5 Eukaryotic Transcription Activators an dmRNA 344

Repressors 370Biochemical and Genetic Techniques Have Been Used t o

10.2 Bacterial Transcription Initiation 346

Identify Transcription Factors 370Footprinting and Gel-Shift Assays Identify Protein-DNA

Transcription Activators Are Modular Proteins Compose dInteractions 346

of Distinct Functional Domains 372The lac Control Region Contains Three Critical Cis-

DNA-Binding Domains Can Be Classified int oActing Sites 347

Numerous Structural Types 37 3RNA Polymerase Binds to Specific Promoter Sequences

Heterodimeric Transcription Factors Increase Gene -to Initiate Transcription 347

Control Options 376Differences in E. coli Promoter Sequences Affect

Activation Domains Exhibit Considerable Structura lFrequency of Transcription Initiation 349

Diversity 377Binding of lac Repressor to the lac Operator Blocks

Multiprotein Complexes Form on Enhancers 37 8Transcription Initiation 349 Many Repressors Are the Functional Converse o f

Most Bacterial Repressors Are Dimers Containing a

Activators 37 9Helices That Insert into Adjacent Major Grooves o f

Operator DNA 349

10 .6 RNA Polymerase II Transcription-Initiation

Ligand-Induced Conformational Changes Alter Affinity

Complex 38 0of Many Repressors for DNA 352

Initiation by Pol II Requires General Transcription

Positive Control of the lac Operon Is Exerted by cAMP-

Factors 38 1

CAP 352

Proteins Comprising the Pol II Transcription-Initiatio n

Cooperative Binding of cAMP-CAP and RNA

Complex Assemble in a Specific Order in Vitro 38 1

Polymerase to lac Control Region Activates

A Pol II Holoenzyme Multiprotein Complex Functions i n

Transcription 353

Vivo 383

Transcription Control at All Bacterial Promoters Involve sSimilar but Distinct Mechanisms 354

10 .7 Molecular Mechanisms of Eukaryoti c

Transcription from Some Promoters Is Initiated by

Transcriptional Control 38 4

Alternative Sigma (v) Factors 355

N-Termini of Histones in Chromatin Can B eModified 38 4

Many Bacterial Responses Are Controlled by Two -Component Regulatory Systems 356

Formation of Heterochromatin Silences Gene Expressio nat Telomeres and Other Regions 38 4

10 .3 Eukaryotic Gene Control : Purposes and General

Repressors Can Direct Histone Deacetylation at Specific

Principles 358

Genes 38 7

Most Genes in Higher Eukaryotes Are Regulated by

Activators Can Direct Histone Acetylation at Specifi cControlling Their Transcription 358

Genes 38 9

Regulatory Elements in Eukaryotic DNA Often Are

Chromatin-Remodeling Factors Participate in Activatio nMany Kilobases from Start Sites 360

at Some Promoters 390

Three Eukaryotic Polymerases Catalyze Formation of

Activators Stimulate the Highly Cooperative Assembly o f

Different RNAs 361

Initiation Complexes 39 0

The Largest Subunit in RNA Polymerase II Has an

Repressors Interfere Directly with Transcriptio nEssential Carboxyl-Terminal Repeat 362

Initiation in Several Wavs 391

Regulation of Transcription-Factor Expression

Portions of Two Different RNAs Are Trans-Spliced i nContributes to Gene Control 392

Some Organisms 41 8Lipid-Soluble Hormones Control the Activities of

Self-Splicing Group II Introns Provide Clues to theNuclear Receptors 392

Evolution of snRNAs 41 9Polypeptide Hormones Signal Phosphorylation of Some

Most Transcription and RNA Processing Occur in aTranscription Factors 394

Limited Number of Domains in Mammalian Cel lNuclei 42010.8 Other Transcription Systems 39 7

Transcription Initiation by Pol I and Pol III Is Analogous

11 .3 Regulation of mRNA Processing 422to That by Pol II 397

U1A Protein Inhibits Polyadenylation of Its Pre -T7 and Related Bacteriophages Express Monomeric,

mRNA 422Largely Unregulated RNA Polymerases 398

Tissue-Specific RNA Splicing Controls Expression o fMitochondrial DNA Is Transcribed by RNA Polymerases

Alternative Fibronectins 42 3with Similarities to Bacteriophage and Bacterial

A Cascade of Regulated RNA Splicing Control sEnzymes 398

Drosophila Sexual Differentiation 42 3Transcription of Chloroplast DNA Resembles Bacterial

Multiple Protein Isoforms Are Common in theTranscription 399

Vertebrate Nervous System 42 5Transcription by Archaeans Is Closer to Eukaryotic Than

to Bacterial Transcription 399

11 .4 Signal-Mediated Transport through Nuclear Por eMEDIA CONNECTIONS

Complexes 426Focus: Combinatorial Control of Transcription

Nuclear Pore Complexes Actively Transpor tMacromolecules between the Nucleus andCytoplasm 427

11 RNA Processing,

Receptors for Nuclear-Export Signals Transport Proteinsand mRNPs out of the Nucleus 42 8

Nuclear Transport, and Post-

Pre-mRNAs in Spliceosomes Are Not Exported from theTranscriptional Control

Nucleus 43 1

Receptors for Nuclear-Localization Signals Transpor t11 .1 Transcription Termination 405

Proteins into the Nucleus 432Rho-Independent Termination Occurs at Characteristic

Various Nuclear-Transport Systems Utilize Simila rSequences in E . cull DNA 405

Proteins 434Premature Termination by Attenuation Helps Regulate

HIV Rev Protein Regulates the Transport of Unsplice dExpression of Some Bacterial Operons 405

Viral mRNAs 435Rho-Dependent Termination Sites Are Present in Som e

A-Phage and E. coli Genes 407

11 .5 Other Mechanisms of Post-Transcriptiona lSequence-Specific RNA-Binding Proteins Can Regulate

Control 436Termination by E. coli RNA Polymerase 407

RNA Editing Alters the Sequences of Pre-mRNAs 43 7Three Eukaryotic RNA Polymerases Employ Different

Some mRNAs Are Associated with Cytoplasmi cTermination Mechanisms 408

Structures or Localized to Specific Regions 43 8Transcription of HIV Genome Is Regulated by an

Stability of Cytoplasmic mRNAs Varies Widely 440Antitermination Mechanism 409

II

Degradation Rate of Some Eukaryotic mRNAs IsPromoter Proximal Pausing of RNA Polymerase Regulated 440

Occurs in Some Rapidly Induced Genes 409Translation of Some mRNAs Is Regulated by Specifi c

11 .2 Processing of Eukaryotic mRNA 410

RNA-Binding Proteins 44 2

The 5 ' -Cap Is Added to Nascent RNAs Shortly after

Antisense RNA Regulates Translation of Transposase

Initiation by RNA Polymerase II 410

mRNA in Bacteria 44 2

Pre-mRNAs Are Associated with hnRNP Protein sContaining Conserved RNA-Binding Domains 410

11.6 Processing of rRNA and tRNA 44 3

hnRNP Proteins May Assist in Processing and Transport

Pre-rRNA Genes Are Similar in All Eukaryotes an d

of mRNAs 413

Function as Nucleolar Organizers 44 3

Pre-mRNAs Are Cleaved at Specific 3' Sites and Rapidly

Small Nucleolar RNAs (snoRNAs) Assist in Processin g

Polyadenylated 413

rRNAs and Assembling Ribosome Subunits 44 4

Splicing Occurs at Short, Conserved Sequences in Pre-

Self-Splicing Group I Introns Were the First Examples o f

mRNAs via Two Transesterification Reactions 415

Catalytic RNA 445

Spliceosomes, Assembled from snRNPs and a Pre-

All Pre-tRNAs Undergo Cleavage and Base

mRNA, Carry Out Splicing 416

Modification 446

Splicing of Pre-tRNAs Differs from Other Splicing

DNA Damage Can Be Repaired by Severa lMechanisms 448

Mechanisms 47 5

MEDIA CONNECTIONS

Eukaryotes Have DNA-Repair Systems Analogous t o

Overview: Life Cycle of an mRNA

Those of E. colt 479

Focus: mRNA Splicing

Inducible DNA-Repair Systems Are Error-Prone 48 1

Classic Experiment 11 .1 : Catalysis without

12.5 Recombination between Homologous DNAProteins: The Discovery of Self-Splicing RNA

Sites 482The Crossed-Strand Holliday Structure Is a n

Intermediate in Recombination 48 2

12 DNA Replication, Repair,

Double-Strand Breaks in DNA Initiat eRecombination 484and Recombination

The Activities of E. coil Recombination Proteins Have12 .1 General Features of Chromosomal

Been Determined 486Replication 454

Cre Protein and Other Recombinases Catalyze Site-DNA Replication Is Semiconservative 454

Specific Recombination 48 8

Most DNA Replication Is Bidirectional 455

MEDIA CONNECTION SDNA Replication Begins at Specific Chromosomal

Focus: Bidirectional Replication of DN ASites 456

Focus: Nucleotide Polymerization by DN APolymerase

12.2 The DNA Replication Machinery 458

Focus: Coordination of Leading and Laggin gDnaA Protein Initiates Replication in E. coli 459

Strand Synthesis

DnaB Is an E . colt Helicase That Melts Duplex

Focus: Telomere Replicatio nDNA 460

Classic Experiment 12 .1: Proving That DNAE. coli Primase Catalyzes Formation of RNA Primers for

Replication Is SemiconservativeDNA Synthesis 46 0

At a Growing Fork One Strand Is Synthesize dDiscontinuously from Multiple Primers 46 1

E. colt DNA Polymerase III Catalyzes Nucleotide

13 Regulation of the EukaryoticAddition at the Growing Fork 462

Cell CycleThe Leading and Lagging Strands Are Synthesized

Concurrently 463

13 .1 Overview of the Cell Cycle and Its Control 496

Eukaryotic Replication Machinery Is Generally Similar

The Cell Cycle Is an Ordered Series of Events Leading t o

to That of E. colt 464

Replication of Cells 496

Telomerase Prevents Progressive Shortening of Lagging

Regulated Protein Phosphorylation and Degradatio n

Strands during Eukaryotic DNA Replication 467

Control Passage through the Cell Cycle Diverse 49 6

Diverse Experimental Systems Have Been Used t o

12 .3 The Role of Topoisomerases in DNA

Identify and Isolate Cell-Cycle Control Proteins 49 8

Replication 468

13 .2 Biochemical Studies with Oocytes, Eggs, and Earl yType I Topoisomerases Relax DNA by Nicking and Then

Embryos 500Closing One Strand of Duplex DNA 468

MPF Promotes Maturation of Oocytes and Mitosis i nType II Topoisomerases Change DNA Topology by

Somatic Cells 500Breaking and Rejoining Double Stranded DNA 469

Mitotic Cyclin Was First Identified in Early Sea Urchi nReplicated Circular DNA Molecules Are Separated by

Embryos 50 1Type II Topoisomerases 470

Cyclin B Levels and MPF Activity Change in CyclingLinear Daughter Chromatids Also Are Separated by

Xenopus Egg Extracts 50 2Type II Topoisomerases 471

Ubiquitin-Mediated Degradation of Mitotic Cyclin sPromotes Exit from Mitosis 50 3

12 .4 DNA Damage and Repair and Their Role in

Regulation of APC Activity Controls Degradation o fCarcinogenesis 472

Cyclin B 504Proofreading by DNA Polymerase Corrects Copying

Errors 472

13 .3 Genetic Studies with S . pombe 506

Chemical Carcinogens React with DNA Directly or after

Two Classes of Mutations in S. pombe Produce Eithe rActivation 474

Elongated or Very Small Cells 50 6

The Carcinogenic Effect of Chemicals Correlates with

S. pombe Cdc2-Cdc13 Heterodimer Is Equivalent t oTheir Mutagenicity 475

Xenopus MPF 506

Phosphorylation of the Catalytic Subunit Regulates MPF

Classic Experiment 13 .1: Cell Biology EmergingKinase Activity 507

from the sea: The Discovery of Cyclin s

Conformational Changes Induced by Cyclin Binding andPhosphorylation Increase MPF Activity 50 8

Other Mechanisms Also Control Entry into Mitosis b yRegulating MPF Activity 509

14 Gene Control in Development

13.4 Molecular Mechanisms for Regulating Mitotic

14 .1 Cell-Type Specification and Mating-Type

Events 510

Conversion in Yeast 53 8

Phosphorylation of Nuclear Lamins by MPF Leads to

Combinations of DNA-Binding Proteins Regulate Cell -

Nuclear-Envelope Breakdown 510

Type Specification in Yeast 53 8

Mating of a and a Cells Is Induced by Pheromone -Other Early Mitotic Events May Be Controlled Directly

Stimulated Gene Expression 54 0or Indirectly by MPF 512Multiple Regulation of HO Transcription ControlsAPC-Dependent Unlinking of Sister Chromatids Initiates

Mating Type Conversion 54 1Anaphase 513Silencer Elements Repress Expression at HML and

Phosphatase Activity Is Required for Reassembly of the

HMR 542Nuclear Envelope and Cytokinesis 51 4

13.5 Genetic Studies with S. cerevisiae 517

14 .2 Cell-Type Specification in Animals 54 3S . cerevisiae Cdc28 Is Functionally Equivalent to

Embryonic Somites Give Rise to Myoblasts, th eS. pombe Cdc2 518

Precursors of Skeletal Muscle Cells 54 3

Three G I Cyclins Associate with Cdc238 to Form

Myogenic Genes Were First Identified in Studies with

S Phase-Promoting Factors 519

Cultured Fibroblasts 544

Kinase Activity of Cdc28-G, Cyclin Complexes Prepares

Myogenic Proteins Are Transcription Factors Containing

Cells for the S Phase 519

a Common bHLH Domain 546

Degradation of the S-Phase Inhibitor Sicl Triggers DNA

MEFs Function in Concert with MRFs to Confe r

Replication 520

Myogenic Specificity 546

Multiple Cyclins Direct Kinase Activity of Cdc28 during

Myogenic Stages at Which MRFs and MEFs Function i n

Different Cell-Cycle Phases 522

Vivo Have Been Identified 547

Replication at Each Origin Is Initiated Only Once during

Multiple MRFs Exhibit Functional Diversity and Permi t

the Cell Cycle 522

Flexibility in Regulating Development 54 8

Terminal Differentiation of Myoblasts Is under Positiv e

13.6 Cell-Cycle Control in Mammalian Cells 524

and Negative Control 549

Mammalian Restriction Point Is Analogous to START in

A Network of Cross-Regulatory Interactions Maintain sYeast Cells 524

the Myogenic Program 549

Multiple Cdks and Cyclins Regulate Passage of

Neurogenesis Requires Regulatory Proteins Analogous t oMammalian Cells through the Cell Cycle 524

bHLH Myogenic Proteins 55 0

Regulated Expression of Two Classes of Genes Returns

Progressive Restriction of Neural Potential Require s

Go Mammalian Cells to the Cell Cycle 526

Inhibitory HLH Proteins and Local Cell-Cel l

Passage through the Restriction Point Depends on

Interactions 55 1

Activation of E2F Transcription Factors 526

bHLH Regulatory Circuitry May Operate to Specify

Cyclin A Is Required for DNA Synthesis and Cdk1 for

Other Cell Types 55 2

Entry into Mitosis 52 8

Mammalian Cyclin-Kinase Inhibitors Contribute to Cell-

14.3 Anteroposterior Specification duringCycle Control 528

Embryogenesis 553Drosophila Has Two Life Forms 554

13.7 Checkpoints in Cell-Cycle Regulation 529

Patterning Information Is Generated during Oogenesi sThe Presence of Unreplicated DNA Prevents Entry into

and Early Embryogenesis 55 5Mitosis 530

Four Maternal Gene Systems Control Early Patterning i n

Improper Assembly of the Mitotic Spindle Leads to

Fly Embryos 55 6Arrest in Anaphase 530

Morphogens Regulate Development as a Function of

G I and G2 Arrest in Cells with Damaged DNA Depends

Their Concentration 55 6on a Tumor Suppressor and Cyclin-Kinase

Maternal bicoid Gene Specifies Anterior Region inInhibitor 531

Drosophila 55 7

MEDIA CONNECTIONS

Maternally Derived Inhibitors of Translation Contribut e

Overview: Cell Cycle Control

to Early Drosophila Patterning 558

Graded Expression of Several Gap Genes Further

Muscle Ca t+ ATPase Pumps Ca t+ Ions from the Cytoso lSubdivides Fly Embryo into Unique Spatial

into the Sarcoplasmic Reticulum 59 1Domains 560

Na + /K + ATPase Maintains the Intracellular Na ' and K +Expression of Three Groups of Zygotic Genes

Concentrations in Animal Cells 59 3Completes Early Patterning in Drosophila 560

V-Class H + ATPases Pump Protons across Lysosoma lSelector (Hox) Genes Occur in Clusters in the

and Vacuolar Membranes 594Genome 563

The ABC Superfamily Transports a Wide Variety o fCombinations of Different Hox Proteins Contribute to

Substrates 59 5Specifying Parasegment Identity in Drosophila 565

15 .6 Cotransport by Symporters and Antiporters 59 7Specificity of Drosophila Hox-Protein Function IsMediated by Exd Protein 566

Na + -Linked Symporters Import Amino Acids an dGlucose into Many Animal Cells 59 8

Hox-Gene Expression Is Maintained by Autoregulation

+

2 +and Changes in Chromatin Structure 567

Na Linked Antiporter Exports Ca from Cardia c

Mammalian Homologs of Drosophila ANT-C and BX-C

Muscle Cells 598

Genes Occur in Four Hox Complexes 568

AEI Protein, a Cl -1HC0 3 - Antiporter, Is Crucial toCO 2 Transport by Erythrocytes 59 9

Mutations in Hox Genes Result in Homeoti cTransformations in the Developing Mouse 569

Several Cotransporters Regulate Cytosolic pH 600

Numerous Transport Proteins Enable Plant Vacuoles t o14.4 Specification of Floral-Organ Identity in

Accumulate Metabolites and Ions 60 1Arabidopsis 571

15 .7 Transport across Epithelia 602Flowers Contain Four Different Organs 571

The Intestinal Epithelium Is Highly Polarized 60 2Three Classes of Genes Control Floral-Orga nIdentity 572

Transepithelial Movement of Glucose and Amino Acid sRequires Multiple Transport Proteins 602Many Floral Organ-Identity Genes Encode MADS

Parietal Cells Acidify the Stomach Contents Whil eFamily Transcription Factors 573Maintaining a Neutral Cytosolic pH 60 4

MEDIA CONNECTIONS

Tight Junctions Seal Off Body Cavities and Restric tOverview: Gene Control In Embryonic

Diffusion of Membrane Components 60 4Development

Classic Experiment 14 .1 : Using Lethal Injection to

Other Junctions Interconnect Epithelial Cells an d

Study Development

Control Passage of Molecules between Them 60 7

15 .8 Osmosis, Water Channels, and the Regulation o f

PART III : Building and Fueling the Cell

Cell Volume 60 8Osmotic Pressure Causes Water to Move across

Membranes 60 8

15 Transport across Cell Membranes

Different Cells Have Various Mechanisms fo rControlling Cell Volume 60 9

15 .1 Diffusion of Small Molecules across Phospholipid

Water Channels Are Necessary for Bulk Flow of Wate rBilayers 579

across Cell Membranes 61 0

15 .2 Overview of Membrane Transport Proteins 580

Simple Rehydration Therapy Depends on Osmoti cGradient Created by Absorption of Glucose and

15.3 Uniporter-Catalyzed Transport 582

Na' 610Three Main Features Distinguish Uniport Transport from

Changes in Intracellular Osmotic Pressure Cause Lea fPassive Diffusion 582

Stomata to Open 61 1GLUT1 Transports Glucose into Most Mammalia n

Cells 583

MEDIA CONNECTION S

Overview: Biological Energy Intercom ersion s15 .4 Intracellular Ion Environment and Membrane

Classic Experiment 15 .1: Stumbling upon ActiveElectric Potential 585

Transpor t

Ionic Gradients and an Electric Potential Are Maintaine dacross the Plasma Membrane 585

16 Cellular Energetics: Glycolysis,The Membrane Potential in Animal Cells Depends

Aerobic Oxidation, andLargely on Resting K + Channels 58 6

Na' Entry into Mammalian Cells Has a Negative AG

Photosynthesis587

16.1 Oxidation of Glucose and Fatty Acids to CO 2 61 815 .5 Active Transport by ATP-Powered Pumps 588

Cytosolic Enzymes Convert Glucose to Pyruvate 61 9

Plasma-Membrane Ca t+ ATPase Exports Ca t+ Ions

Substrate-Level Phosphorylation Generates ATP durin gfrom Cells 591

Glycolysis 619

Anaerobic Metabolism of Each Glucose Molecule Yields

Chlorophyll a Is Present in Both Components of aOnly Two ATP Molecules 619

Photosystem 65 1Mitochondria Possess Two Structurally and Functionally

Light Absorption by Reaction-Center Chlorophyll sDistinct Membranes 622

Causes a Charge Separation across the Thylakoi dMitochondrial Oxidation of Pyruvate Begins with the

Membrane 652Formation of Acetyl CoA 623

Light-Harvesting Complexes Increase the Efficiency o fOxidation of the Acetyl Group of Acetyl CoA in the

Photosynthesis 653Citric Acid Cycle Yields CO 2 and Reduced

16.4 Molecular Analysis of Photosystems 65 5Coenzymes 62 5

Inner-Membrane Proteins Allow the Uptake of Electrons

Photoelectron Transport in Purple Bacteria Produces a

from Cytosolic NADH 626

Charge Separation 65 5

Mitochondrial Oxidation of Fatty Acids Is Coupled to

Both Cyclic and Noncyclic Electron Transport Occur in

ATP Formation 627

Bacterial Photosynthesis 65 6

Oxidation of Fatty Acids in Peroxisomes Generates No

Chloroplasts Contain Two Functionally and Spatiall y

ATP 629

Distinct Photosystems 65 8

The Rate of Glucose Oxidation Is Adjusted to Meet the

An Oxygen-Evolving Complex in PSII Regenerate s

Cell's Need for ATP 630

P 680 65 9

Cyclic Electron Flow in PSI Generates ATP but N o

16.2 Electron Transport and Oxidative

NADPH 66 1

Phosphorylation 632

PSI and PSII Are Functionally Coupled 66 1

The Proton Motive Force in Mitochondria Is Due

Both Plant Photosystems Are Essential for Formation o f

Largely to a Voltage Gradient across the Inner

NADPH and 02 66 2

Membrane 633

16.5 CO 2 Metabolism during Photosynthesis 66 4Electron Transport in Mitochondria Is Coupled to

CO 2 Fixation Occurs in the Chloroplast Stroma 664Proton Translocation 634

Synthesis of Sucrose Incorporating Fixed CO2 I sElectrons Flow from FADH2 and NADH to 02 via a

Completed in the Cytosol 66 5Series of Multiprotein Complexes 634

Light Stimulates CO 2 Fixation by Severa lCoQ and Cytochrome c Shuttle Electrons from One

Mechanisms 66 7Electron Transport Complex to Another 639

Photorespiration, Which Consumes CO2 and Liberate sReduction Potentials of Electron Carriers Favor Electron

CO 2 , Competes with Photosynthesis 667Flow from NADH to 02 639

The C4 Pathway for CO2 Fixation Is Used by Man yCoQ and Three Electron Transport Complexes Pump

Tropical Plants 66 7Protons out of the Mitochondrial Matrix 639

Sucrose Is Transported from Leaves through the PhloemExperiments with Membrane Vesicles Support the

to All Plant Tissues 67 0Chemiosmotic Mechanism of ATP Formation 64 1

Bacterial Plasma-Membrane Proteins Catalyze Electron

MEDIA CONNECTIONS

Transport and Coupled ATP Synthesis 643

Focus: Electron Transport

ATP Synthase Comprises a Proton Channel (Fo) and

Focus: Photosynthesi s

ATPase (F l ) 643

Focus: ATP Synthesis

The FoF l Complex Harnesses the Proton-Motive Forc eto Power ATP Synthesis 64 5

Transporters in the Inner Mitochondrial Membrane Are

17 Protein Sorting: OrganellePowered by the Proton-Motive Force 64 6

Rate of Mitochondrial Oxidation Normally Depends on

Biogenesis and Protein Secretion

ADP Levels 647

17.1 Synthesis and Targeting of Mitochondrial andBrown-Fat Mitochondria Contain an Uncoupler of

Chloroplast Proteins 677Oxidative Phosphorylation 647

Most Mitochondrial Proteins Are Synthesized a sCytosolic Precursors Containing Uptake-Targeting

16.3 Photosynthetic Stages and Light-Absorbing

Sequences 677Pigments 648

Cytosolic Chaperones Deliver Proteins to Channel-Photosynthesis Occurs on Thylakoid Membranes 649

Linked Receptors in the Mitochondria l

Three of the Four Stages in Photosynthesis Occur Only

Membrane 679

during Illumination 649

Matrix Chaperones and Chaperonins Are Essential fo r

Each Photon of Light Has a Defined Amount of

the Import and Folding of Mitochondria l

Energy 651

Proteins 680

Studies with Chimeric Proteins Confirm Major Features

Correct Folding of Newly Made Proteins Is Facilitate dof Mitochondrial Import 682

by Several ER Proteins 70 8The Uptake of Mitochondrial Proteins Requires

Assembly of Subunits into Multimeric Proteins Occurs i nEnergy 682

the ER 709Proteins Are Targeted to Submitochondrial

Only Properly Folded Proteins Are Transported from th eCompartments by Multiple Signals and Several

Rough ER to the Golgi Complex 71 0Pathways 684

Many Unassembled or Misfolded Proteins in the ER Ar eThe Synthesis of Mitochondrial Proteins Is

Transported to the Cytosol and Degraded 71 1Coordinated 685

ER-Resident Proteins Often Are Retrieved from the Cis -Several Uptake-Targeting Sequences Direct Proteins

Golgi 71 1Synthesized in the Cytosol to the Appropriat eChloroplast Compartment 685

17.7 Protein Glycosylation in the ER and Golg i

17 .2 Synthesis and Targeting of Peroxisomal

Complex 71 2

Proteins 689

Different Structures Characterize N- and 0-Linke d

C- and N-Terminal Targeting Sequences Direct Entry of

Oligosaccharides 71 2

Folded Proteins into the Peroxisomal Matrix 689

0-Linked Oligosaccharides Are Formed by th e

Peroxisomal Protein Import Is Defective in Some Genetic

Sequential Transfer of Sugars from Nucleotide

Diseases 690

Precursors 71 2

ABO Blood Type Is Determined by Two17.3 Overview of the Secretory Pathway 691

Glycosyltransferases 71 5Secretory Proteins Move from the Rough ER Lumen

A Common Preformed N-Linked Oligosaccharide I sthrough the Golgi Complex and Then to the Cell

Added to Many Proteins in the Rough ER 71 6Surface 692

Modifications to N-Linked Oligosaccharides Ar eAnalysis of Yeast Mutants Defined Major Steps in the

Completed in the Golgi Complex 71 8Secretory Pathway 694

Oligosaccharides May Promote Folding and Stability o fAnterograde Transport through the Golgi Occurs by

Glycoproteins 71 9Cisternal Progression 695

Mannose 6-Phosphate Residues Target Proteins toPlasma-Membrane Glycoproteins Mature via the Same

Lysosomes 71 9Pathway as Continuously Secreted Proteins 695

Lysosomal Storage Diseases Provided Clues to Sorting o f

17.4 Translocation of Secretory Proteins across the ER

Lysosomal Enzymes 72 0

Membrane 69 6A Signal Sequence on Nascent Secretory Proteins Targets

17.8 Golgi and Post Golgi Protein Sorting an d

Them to the ER and Is Then Cleaved Off 696

Proteolytic Processing 72 2

Two Proteins Initiate the Interaction of Signal Sequences

Sequences in the Membrane-Spanning Domain Cause th e

with the ER Membrane 697

Retention of Proteins in the Golgi 72 2

Polypeptides Move through the Translocon into the ER

Different Vesicles Are Used for Continuous an d

Lumen 699

Regulated Protein Secretion 72 3

GTP Hydrolysis Powers Protein Transport into the ER in

Proproteins Undergo Proteolytic Processing Late i n

Mammalian Cells 700

Maturation 72 3

.5 Insertion of Membrane Proteins into the ER

Some Proteins Are Sorted from the Golgi Complex t o17 .5

Apical or Basolateral Plasma Membrane 72 4Membrane 70 2Most Nominal Cytosolic Transmembrane Proteins Have

17 .9 Receptor-Mediated Endocytosis and the Sorting o fan N-Terminal Signal Sequence and Internal

Internalized Proteins 72 7Topogenic Sequence 702

The LDL Receptor Binds and Internalizes Cholesterol -A Single Internal Topogenic Sequence Directs Insertion

Containing Particles 72 8of Some Single Pass Transmembrane Proteins 704

Cytosolic Sequences in Some Cell-Surface ReceptorsMultipass Transmembrane Proteins Have Multiple

Target Them for Endocytosis 72 8Topogenic Sequences 70 5

After Insertion in the ER Membrane, Some Proteins Are

The Acidic pH of Late Endosomes Causes Mos tReceptors and Ligands to Dissociate 72 9

Transferred to a GPI Anchor 705

The Endocytic Pathway Delivers Transferrin-Bound Iro n

17.6 Post-Translational Modifications and Quality

to Cells 73 1

Control in the Rough ER 707

Some Endocytosed Proteins Remain within the

Disulfide Bonds Are Formed and Rearranged in the ER

Cell 73 1

Lumen 707

Transcytosis Moves Some Ligands across Cells 732

17.10 Molecular Mechanisms of Vesicular

18 .3 Myosin: The Actin Motor Protein 76 9

Traffic 733

All Myosins Have Head, Neck, and Tail Domains with

At Least Three Types of Coated Vesicles Transport

Distinct Functions 76 9

Proteins from Organelle to Organelle 733

Myosin Heads Walk along Actin Filaments 77 0

Clathrin Vesicles Mediate Several Types of Intracellular

Myosin Heads Move in Discrete Steps, Each Coupled toTransport 733

Hydrolysis of One ATP 77 1

COP I Vesicles Mediate Retrograde Transport within the

Myosin and Kinesin Share the Ras Fold with Certai nGolgi and from the Golgi Back to the ER 738

Signaling Proteins 77 1COP II Vesicles Mediate Transport from the ER to the

Conformational Changes in the Myosin Head CoupleGolgi 741

ATP Hydrolysis to Movement 773

Specific Fusion of Intracellular Vesicles Involves aConserved Set of Fusion Proteins 741

18.4 Muscle : A Specialized Contractile Machine 77 4Conformational Changes in Influenza HA Protein

Some Muscles Contract, Others Generate Tension 775Trigger Membrane Fusion 743

Skeletal Muscles Contain a Regular Array of Actin andMEDIA CONNECTIONS

Myosin 775Overview: Protein Sorting

Smooth Muscles Contain Loosely Organized Thick an dOverview: Protein Secretion

Thin Filaments 777Focus: Synthesis of Secreted and Membrane-

Thick and Thin Filaments Slide Past One Another durin gBound Proteins

Contraction 777Classic Experiment 17 .1: Following a Protein out

Titin and Nebulin Filaments Organize th eof the Cell

Sarcomere 77 8

A Rise in Cytosolic Ca" Triggers Muscle

18 Cell Motility and Shape I:

Contraction 779

Actin-Binding Proteins Regulate Contraction in Bot hMicrofilaments

Skeletal and Smooth Muscle 780

Myosin-Dependent Mechanisms Also Contro l18.1 The Actin Cytoskeleton 752

Contraction in Some Muscles 78 1Eukaryotic Cells Contain Abundant Amounts of Highly

Conserved Actin 753

18.5 Actin and Myosin in Nonmuscle Cells 783ATP Holds Together the Two Lobes of the Actin

Actin and Myosin II Are Arranged in Contractil eMonomer 753

Bundles That Function in Cell Adhesion 78 3G -Actin Assembles into Long, Helical F-Actin

Myosin II Stiffens Cortical Membranes 78 4Polymers 754

Actin and Myosin II Have Essential Roles inF-Actin Has Structural and Functional Polarity 754

Cytokinesis 78 4The Actin Cytoskeleton Is Organized into Bundles and

Membrane-Bound Myosins Power Movement of SomeNetworks of Filaments 755

Vesicles 785Cortical Actin Networks Are Connected to th e

Membrane 756

Actin Bundles Support Projecting Fingers of

18 .6 Cell Locomotion 78 7

Membrane 760

Controlled Polymerization and Rearrangements of Acti nFilaments Occur during Keratinocyte Movement 78 7

18.2 The Dynamics of Actin Assembly 761

Ameboid Movement Involves Reversible Gel-SolActin Polymerization In Vitro Proceeds in Three

Transitions of Actin Networks 78 9Steps 761

Myosin I and Myosin II Have Important Roles in Cel l

Actin Filaments Grow Faster at One End Than at the

Migration 78 9Other 761

Migration of Cells Is Coordinated by Various Secon dToxins Disrupt the Monomer-Polymer Equilibrium 763

Messengers and Signal-Transductio n

Actin Polymerization Is Regulated by Proteins That Bind

Pathways 790

G-Actin 763

MEDIA CONNECTION SSome Proteins Control the Lengths of Actin Filaments by

Focus: Actin PolymerizationSevering Them 765

Technique: In Vitro Motility AssayActin Filaments Are Stabilized by Actin-Capping

Focus: Myosin Crossbridge CycleProteins 765

Overview: Cell Motilit yMany Movements Are Driven by Actin

Classic Experiment 18 .1: Looking at MusclePolymerization 766

Contraction

Axonemal Dyneins Are Multiheaded Motor19 Cell Motility and Shape II :

Proteins 820

Microtubules and Intermediate

Conversion of Microtubule Sliding into Axonema l

Filaments

Bending Depends on Inner-Arm Dyneins 82 1

Proteins Associated with Radial Spokes May Contro l19.1 Microtubule Structures 796

Flagellar Beat 82 1

Heterodimeric Tubulin Subunits Compose the Wall of a

Axonemal Microtubules Are Dynamic and Stable 82 2Microtubule 79 6

Microtubules Form a Diverse Array of Both Permanent

19.5 Microtubule Dynamics and Motor Proteins durin gand Transient Structures 797

Mitosis 823Microtubules Assemble from Organizing

The Mitotic Apparatus Is a Microtubule Machine fo rCenters 799

Separating Chromosomes 823Most Microtubules Have a Constant Orientation

The Kinetochore Is a Specialized Attachment Site at theRelative to MTOCs 800

Chromosome Centromere 82 5The y-Tubulin Ring Complex Nucleates Polymerization

Centrosome Duplication Precedes and Is Required forof Tubulin Subunits 800

Mitosis 827

Dynamic Instability of Microtubules Increases during19.2 Microtubule Dynamics and Associated

Mitosis 82 8Proteins 802

Organization of the Spindle Poles Orients the Assembl yMicrotubule Assembly and Disassembly Occur

of the Mitotic Apparatus 82 9Preferentially at the (+) End 802

Formation of Poles and Capture of Chromosomes Ar eDynamic Instability Is an Intrinsic Property of

Key Events in Spindle Assembly 82 9Microtubules 805

Kinetochores Generate the Force for PolewardColchicine and Other Drugs Disrupt Microtubule

Chromosome Movement 83 1Dynamics 806

During Anaphase Chromosomes Separate and th eAssembly MAPs Cross-Link Microtubules to One

Spindle Elongates 83 2Another and Other Structures 807

Astral Microtubules Determine Where Cytokinesis Take sBound MAPs Alter Microtubule Dynamics 809

Place 83 3

Plant Cells Reorganize Their Microtubules and Build a19.3 Kinesin, Dynein, and Intracellular Transport 809

New Cell Wall during Mitosis 834Fast Axonal Transport Occurs along Microtubules 80 9

Microtubules Provide Tracks for the Movement of

19.6 Intermediate Filaments 836Pigment Granules 811

Functions and Structure of Intermediate FilamentsIntracellular Membrane Vesicles Travel along

Distinguish Them from Other Cytoskeleta lMicrotubules 812

Fibers 836Kinesin Is a (+) End-Directed Microtubule Motor

IF Proteins Are Classified into Six Types 83 7Protein 812

Intermediate Filaments Can Identify the Cellular OriginEach Member of the Kinesin Family Transports a

of Certain Tumors 83 8Specific Cargo 815

All IF Proteins Have a Conserved Core Domain and AreDynein Is a (-) End-Directed Microtubule Motor

Organized Similarly into Filaments 83 8Protein 815

Intermediate Filaments Are Dynamic Polymers in th eDynein-Associated MBPs Tether Cargo to

Cell 840Microtubules 816

Various Proteins Cross-Link Intermediate Filaments an dMultiple Motor Proteins Are Associated with Membrane

Connect Them to Other Cell Structures 84 0Vesicles 816

IF Networks Support Cellular Membranes 84 0

19.4 Cilia and Flagella : Structure and

Intermediate Filaments Are Anchored in Cel lJunctions 842

Movement 817

Desmin and Associated Proteins Stabilize Sarcomeres inAll Eukaryotic Cilia and Flagella Contain Bundles of

Muscle 842Doublet Microtubules 817

Disruption of Keratin Networks Causes Blistering 84 3Ciliary and Flagellar Beating Are Produced by

Controlled Sliding of Outer Doublet

MEDIA CONNECTIONS

Microtubules 820

Focus: Mitosis

Dynein Arms Generate the Sliding Forces in

Focus: Microtubule Dynamics

Axonemes 820

Classic Experiment 19 .1: Racing Down the Axon

PART IV: Cell Interactions

Gio, and Gs , Interact with Different Regions of Adenyly lCyclase 87 1

Degradation of cAMP Also Is Regulated 87 1

20 Cell-to-Cell Signaling :

20.4 Receptor Tyrosine Kinases and Ras 87 1

Hormones and Receptors

Ligand Binding Leads to Autophosphorylation o fRTKs 872

20.1 Overview of Extracellular Signaling 849

Ras and G s , Subunits Belong to the GTPase Superfamil ySignaling Molecules Operate over Various Distances in

of Intracellular Switch Proteins 872Animals 849

An Adapter Protein and GEF Link Most Activated RTK sReceptor Proteins Exhibit Ligand-Binding and Effector

to Ras 87 3Specificity 850

SH2 Domain in GRB2 Adapter Protein Binds to aHormones Can Be Classified Based on Their Solubility

Specific Phosphotyrosine in an Activatedand Receptor Location 850

RTK 876

Cell-Surface Receptors Can Belong to Four Major

Sos, a Guanine-Nucleotide-Exchange Factor, Binds toClasses 852

the SH3 Domains in GRB2 87 7

Effects of Many Hormones Are Mediated by Secon dMessengers 854

20.5 MAP Kinase Pathways 878

Other Conserved Proteins Function in Signal

Signals Pass from Activated Ras to a Cascade of Protei nTransduction 854

Kinases 87 8

Common Signaling Pathways Are Initiated by Different

Ksr May Function as a Scaffold for the MAP KinaseReceptors in a Class 856

Cascade Linked to Ras 87 9

The Synthesis, Release, and Degradation of Hormones

Phosphorylation of a Tyrosine and a Threonine Activate sAre Regulated 856

MAP Kinase 88 0

Various Types of Receptors Transmit Signals to MA P20.2 Identification and Purification of Cell-Surface

Kinase 88 1

Receptors 858

Multiple MAP Kinase Pathways Are Found i n

Hormone Receptors Are Detected by Binding

Eukaryotic Cells 882Assays 859

Specificity of MAP Kinase Pathways Depends on Severa l

KD Values for Cell-Surface Hormone Receptors

Mechanisms 88 3Approximate the Concentrations of CirculatingHormones 860

20.6 Second Messengers 88 4Affinity Techniques Permit Purification of Receptor

cAMP and Other Second Messengers Activate SpecificProteins 860

Protein Kinases 884

Many Receptors Can Be Cloned without Prior

cAPKs Activated by Epinephrine Stimulation Regulat ePurification 860

Glycogen Metabolism 88 5

Kinase Cascades Permit Multienzyme Regulation and20.3 G Protein-Coupled Receptors and Their

Amplify Hormone Signals 88 6Effectors 862

Cellular Responses to cAMP Vary among Different Cel l

Binding of Epinephrine to Adrenergic Receptors Induces

Types 88 7Tissue-Specific Responses 862

Anchoring Proteins Localize Effects of cAMP to Specific

Stimulation of ß-Adrenergic Receptors Leads to a Rise in

Subcellular Regions 887cAMP 863

Modification of a Common Phospholipid Precursor

Critical Features of Catecholamines and Their Receptors

Generates Several Second Messengers 88 8

Have Been Identified 863

Hormone-Induced Release of Ca Z+ from the ER I s

Trimeric Gs Protein Links ß-Adrenergic Receptors and

Mediated by IP3 889Adenylyl Cyclase 865

Opening of Ryanodine Receptors Releases Ca Z+ Stores

Some Bacterial Toxins Irreversibly Modify

in Muscle and Nerve Cells 89 1G Proteins 868

Ca2tCalmodulin Complex Mediates Many Cellula r

Adenylyl Cyclase Is Stimulated and Inhibited by

Responses 89 1

Different Receptor-Ligand Complexes 868

DAG Activates Protein Kinase C, Which Regulates Man y

GTP-Induced Changes in G 5,, Favor Its Dissociation

Other Proteins 893

from Gß, and Association with Adenylyl

Synthesis of cGMP Is Induced by Both Peptid eCyclase 869

Hormones and Nitric Oxide 893

20.7 Interaction and Regulation of Signaling

Action Potentials Are Propagated Unidirectionall yPathways 894

without Diminution 92 3

The Same RTK Can Be Linked to Different Signaling

Movements of Only a Few Na ' and K ` Ions GeneratePathways 895

the Action Potential 92 3

Multiple G Proteins Transduce Signals to Different

Myelination Increases the Rate of Impuls eEffector Proteins 895

Conduction 92 3

Gp,, Acts Directly on Some Effectors in Mammalia nCells 895

21.3 Molecular Properties of Voltage-Gated Ion

Glycogenolysis Is Promoted by Multiple Second

Channels 92 7Messengers 897

Patch Clamps Permit Measurement of Ion Movement s

Insulin Stimulation Activates MAP Kinase and Protein

through Single Channels 92 7Kinase B 897

Voltage-Gated K + Channels Have Fou r

Insulin and Glucagon Work Together to Maintain a

Subunits Each Containing Six Transmembrane a

Stable Blood Glucose Level 898

Helices 92 9

Receptors for Many Peptide Hormones Are Down-

P Segments Form the Ion-Selectivity Filter 93 0Regulated by Endocytosis 898

The S4 Transmembrane a Helix Acts as a Voltag ePhosphorylation of Cell-Surface Receptors Modulates

Sensor 93 2

Their Activity 900

Movement of One N-Terminal Segment Inactivate s

Arrestins Have Two Roles in Regulating G Protein-

Shaker K + Channel 93 2

Coupled Receptors 901

All Pore-Forming Ion Channels Are Similar in Structur eto the Shaker K + Channel 93 2

20.8 From Plasma Membrane to Nucleus 902

Voltage-Gated Channel Proteins Probably Evolved fro mCREB Links cAMP Signals to Transcription 902

a Common Ancestral Gene 93 3MAP Kinase Regulates the Activity of Man y

Transcription Factors 904

21 .4 Neurotransmitters, Synapses, and ImpulsePhosphorylation-Dependent Protein Degradation

Transmission 935Regulates NF KB 904

Many Small Molecules Transmit Impulses at Chemica lMEDIA CONNECTIONS

Synapses 935

Focus : Second Messengers in Signaling Pathways

Influx of Ca t+ Triggers Release o fOverview: Extracellular Signaling

Neurotransmitters 93 6

Focus: Expression Cloning of Receptors

Synaptic Vesicles Can Be Filled, Exocytosed, an dClassic Experiment 20 .1: The Infancy of Signal

Recycled within a Minute 93 6Transduction : DTP Stimulation of CAMP

Multiple Proteins Participate in Docking and Fusion ofSynthesis

Synaptic Vesicles 93 6Chemical Synapses Can Be Excitatory o r

Inhibitory 93 8

21 Nerve Cells

Two Classes of Neurotransmitter Receptors Operate a t

21.1 Overview of Neuron Structure and Function 912

Vastly Different Speeds 93 9

Specialized Regions of Neurons Carry Out Different

Acetylcholine and Other Transmitters Can Activat e

Functions 912

Multiple Receptors 94 0

Synapses Are Specialized Sites Where Neurons

Transmitter-Mediated Signaling Is Terminated by Severa l

Communicate with Other Cells 914

Mechanisms 94 1

Neurons Are Organized into Circuits 915

Impulses Transmitted across Chemical Synapses Can B eAmplified and Computed 942

21 .2 The Action Potential and Conduction of Electric

Impulse Transmission across Electric Synapses Is Nearl yImpulses 917

Instantaneous 94 3

The Resting Potential, Generated Mainly by Ope n"Resting" K + Channels, Is Near EK 918

21 .5 Neutotransmitter Receptors 94 4Opening and Closing of Ion Channels Cause Predictable

Opening of Acetylcholine-Gated Cation Channels Lead sChanges in the Membrane Potential 919

to Muscle Contraction 944

Membrane Depolarizations Spread Passively Only Short

All Five Subunits in the Nicotinic Acetylcholine Recepto rDistances 920

Contribute to the Ion Channel 94 5

Voltage-Gated Cation Channels Generate Action

Two Types of Glutamate-Gated Cation Channels MayPotentials 921

Function in a Type of "Cellular Memory " 946

GABA- and Glycine-Gated Cl- Channels Are Found at

22.2 Cell-Matrix Adhesion 97 6Many Inhibitory Synapses 947

Integrins Mediate Weak Cell-Matrix and Cell-Cel lCardiac Muscarinic Acetylcholine Receptors Activate a

Interactions 977G Protein That Opens K + Channels 948

Cell-Matrix Adhesion Is Modulated by Changes in theCatecholamine Receptors Induce Changes in Second-

Activity and Number of Integrins 97 7Messenger Levels That Affect Ion-Channel

De-adhesion Factors Promote Cell Migration and Ca nActivity 949

Remodel the Cell Surface 97 8A Serotonin Receptor Indirectly Modulates K + Channel

Integrin-Containing Junctions Connect Cells to th eFunction by Activating Adenylyl Cyclase 949

Substratum 97 8Some Neuropeptides Function as Both Neurotransmitters

and Hormones 950

22.3 Collagen: The Fibrous Proteins of theMatrix 979

21 .6 Sensory Transduction 951

The Basic Structural Unit of Collagen Is a TripleMechanoreceptors and Some Other Receptors Are Gated

Helix 979Cation Channels 951

Collagen Fibrils Form by Lateral Interactions of Tripl eVisual Signals Are Processed at Multiple Levels 952

Helices 980The Light-Triggered Closing of Na' Channels

Assembly of Collagen Fibers Begins in the ER and I sHyperpolarizes Rod Cells 952

Completed Outside the Cell 98 1Absorption of a Photon Triggers Isomerization of Retinal

Mutations in Collagen Reveal Aspects of Its Structur eand Activation of Opsin 953

and Biosynthesis 98 2Cyclic GMP Is a Key Transducing Molecule in Rod

Collagens Form Diverse Structures 984Cells 954

Rod Cells Adapt to Varying Levels of Ambient

22.4 Noncollagen Components of the Extracellula rLight 956

Matrix 98 5Color Vision Utilizes Three Opsin Pigments 957

Laminin and Type IV Collagen Form the Two -A Thousand Different G Protein-Coupled Receptors

Dimensional Reticulum of the Basal Lamina 986Detect Odors 958

Fibronectins Bind Many Cells to Fibrous Collagens an d

21.7 Learning and Memory 960

Other Matrix Components 98 7

Proteoglycans Consist of Multiple Glycosaminoglycan sRepeated Conditioned Stimuli Cause Decrease in Aplysia

Linked to a Core Protein 989Withdrawal Response 96 0

Facilitator Neurons Mediate Sensitization of Aplysia

Many Growth Factors Are Sequestered and Presented t o

Withdrawal Reflex 961

Cells by Proteoglycans 992

Coincidence Detectors Participate in Classical

Hyaluronan Resists Compression and Facilitates Cell

Conditioning and Sensitization 961

Migration 99 2

Long-Term Memory Requires Protein Synthesis 962

22.5 The Dynamic Plant Cell Wall 993

MEDIA CONNECTIONS

The Cell Wall Is a Laminate of Cellulos e

Overview: Biological Energy Interconversions

Fibrils in a Pectin and Hemicellulos e

Classic Experiment 21.2: Sending a Signal through

Matrix 99 3

a Gas

Cell Walls Contain Lignin and an ExtendedHydroxyproline-Rich Glycoprotein 99 5

A Plant Hormone, Auxin, Signals Cell Expansion 99 622 Integrating Cells into Tissues

Cellulose Fibrils Are Synthesized and Oriented at th e

22.1 Cell-Cell Adhesion and Communication 969

Plant Cortex 996

Plasmodesmata Directly Connect the Cytosol of AdjacentCadherins Mediate Cat+-Dependent Homophilic Cell-

Cells in Higher Plants 99 8Cell Adhesion 97 1

N-CAMs Mediate Cat+-Independent Homophilic Cell - MEDIA CONNECTION S

Cell Adhesion 971

Focus: Cell-Cell Adhesion In LeukocyteExtravasation

Selectins and Other CAMs Participate in Leukocyt eExtravasation 972

Cadherin-Containing Junctions Connect Cells to One

23 Cell Interactions in Developmen tAnother 973

Gap Junctions Allow Small Molecules to Pass between

23.1 Dorsoventral Patterning by TGFß3-SuperfamilyAdjacent Cells 974

Proteins 1004Connexin, a Transmembrane Protein, Forms Cylindrical

TGF/3 Proteins Bind to Receptors That Hav eChannels in Gap Junctions 975

Serine/Threonine Kinase Activity 1005

Activated TGFß Receptors Phosphorylate Smad

Growth Cones Navigate along Specific Axon Tracts 103 2Transcription Factors 1006

Soluble Graded Signals Can Attract and Repel Growt hDpp Protein, a TGFß Homolog, Controls Dorsoventral

Cones 1034Patterning in Drosophila Embryos 1007

23 .6 Directional Control of Neurona lSequential Inductive Events Regulate Early Xenopus

Outgrowth 1034Development 1007

Three Genes Control Dorsoventral Outgrowth o fInductive Effect of TGFß Homologs Is Regulated Post-

Neurons in C. elegans 103 4Translationally 1009

Vertebrate Homologs of C. elegans UNC-6 Both AttractA Highly Conserved Pathway Determines Dorsoventral

and Repel Growth Cones 103 4Patterning in Invertebrates and Vertebrates 1012

UNC-40 Mediates Chemoattraction in Response t o

23 .2 Tissue Patterning by Hedgehog and

Netrin in Vertebrates 103 6

Wingless 1013

UNC-5 and UNC-40 Together Mediate Chemorepulsio n

Modification of Secreted Hedgehog Precursor Yields a

in Response to Netrin 103 6

Cell-Tethered Inductive Signal 1013

Prior Experience Modulates Growth-Cone Response t o

Binding of Hedgehog to the Patch Receptor Relieves

Netrin 1037

Inhibition of Smo 1014

Other Signaling Systems Can Both Attract and Repe l

Hedgehog Organizes Pattern in the Chick Limb and

Growth Cones 103 8

Drosophila Wing 1014

23 .7 Formation of Topographic Maps andHedgehog Induces Wingless, Which Triggers a Highly

Synapses 1039Conserved Signaling Pathway 1017

Visual Stimuli Are Mapped onto the Tectum 103 9

23.3 Molecular Mechanisms of Responses to

Temporal Retinal Axons Are Repelled by Posterio rTectal Membranes 1039

Morphogens 1018

Ephrin A Ligands Are Expressed as a Gradient along th eHedgehog Gradient Elicits Different Cell Fates in the

Anteroposterior Tectal Axis 103 9Vertebrate Neural Tube 1019

The EphA3 Receptor is Expressed in a Nasal-Tempora lCells Can Detect the Number of Ligand-Occupied

Gradient in the Retina 104 1Receptors 1019

Motor Neurons Induce Assembly of the Neuromuscula rTarget Genes That Respond Differentially to

Junction 1041Morphogens Have Different Control Regions 1019

23.8 Cell Death and Its Regulation 104 423.4 Reciprocal and Lateral Inductive

Programmed Cell Death Occurs throug hInteractions 1021

Apoptosis 104 5

Reciprocal Epithelial-Mesenchymal Interactions Regulate

Neutrophins Promote Survival of Neurons 104 5Kidney Development 1022

Three Classes of Proteins Function in the Apoptoti cActivation of the Ret Receptor Promotes Growth and

Pathway 104 6Branching of the Ureteric Bud 1023

Pro-Apoptotic Regulators Promote CaspaseThe Basal Lamina Is Essential for Differentiation of

Activation 104 8Many Epithelial Cells 1024

Some Trophic Factors Prevent Apoptosis by InducingCell-Surface Ephrin Ligands and Receptors Mediate

Inactivation of a Pro-Apoptotic Regulator 104 8Reciprocal Induction during Angiogenesis 1024

MEDIA CONNECTION SThe Conserved Notch Pathway Mediates Lateral Focus: TGFß Signaling Pathway

Interactions 1025 Focus: Apoptosi sInteractions between Two Equivalent Cells Give Rise to

Classic Experiment 23.1 : Hunting Down GenesAC and VU Cells in C. elegans 1025

Involved in Cell DeathNeuronal Developemnt in Drosophila and Vertebrates

Depends on Lateral Interactions 1027

24 Cancer

23.5 Overview of Neuronal Outgrowth 1028

24.1 Tumor Cells and the Onset of Cancer 1055

Individual Neurons Can Be Identified Reproducibly and

Metastatic Tumor Cells Are Invasive and Can

Studied 1029

Spread 1055

Growth Cones Guide the Migration and Elongation of

Alterations in Cell-to-Cell Interactions Are AssociatedDeveloping Axons 1030

with Malignancy 1056

Different Neurons Navigate along Different Outgrowth

Tumor Growth Requires Formation of New Bloo dPathways 1030

Vessels 105 6

Various Extracellular-Matrix Components Support

DNA from Tumor Cells Can Transform Norma lNeuronal Outgrowth 1031

Cultured Cells 1059

Development of a Cancer Requires Several

Inappropriate Expression of Nuclear Transcriptio nMutations 1059

Factors Can Induce Transformation 107 3

Cancers Originate in Proliferating Cells 106124.4 Mutations Causing Loss of Cell-Cycle

24.2 Proto-Oncogenes and Tumor-Suppressor

Control 1074Genes 1063

Passage from G I to S Phase Is Controlled by Proto -Gain-of-Function Mutations Convert Proto-Oncogenes

Oncogenes and Tumor-Suppressor Genes 1074into Oncogenes 1064

Loss of TGF(3 Signaling Contributes to Abnormal Cel lOncogenes Were First Identified in Cancer-Causing

Proliferation and Malignancy 107 5Retroviruses 106 5

Slow-Acting Carcinogenic Retroviruses Can Activate

24.5 Mutations Affecting Genome Stability 1076Cellular Proto-Oncogenes 1065

Mutations in p53 Abolish G I Checkpoin tMany DNA Viruses Also Contain Oncogenes 1066

Control 1076Loss-of-Function Mutations in Tumor-Suppressor Genes

Proteins Encoded by DNA Tumor Viruses Can Inhibi tAre Oncogenic 1066

p53 Activity 107 8The First Tumor-Suppressor Gene Was Identified in

Some Human Carcinogens Cause Inactivating Mutation sPatients with Inherited Retinoblastoma 1067

in the p53 Gene 1078Loss of Heterozygosity of Tumor-Suppressor Genes

Defects in DNA-Repair Systems Perpetuate Mutation sOccurs by Mitotic Recombination or Chromosome

and Are Associated with Certain Cancers 107 8Mis-Segregation 1068

Chromosomal Abnormalities Are Common in Human

24 .3 Oncogenic Mutations Affecting Cell

Tumors 107 9

Proliferation 1069

Telomerase Expression May Contribute to

Misexpressed Growth-Factor Genes Can Autostimulate

Immortalization of Cancer Cells 108 1

Cell Proliferation 1069

MEDIA CONNECTIONS

Virus-Encoded Activators of Growth Factor Receptors

Overview: Cell Cycle Contro lAct as Oncoproteins 1069

Focus: TOFF Signaling Pathway

Activating Mutations or Overexpression of Growth-

Classic Experiment 24 .1 : Studying the

Factor Receptors Can Transform Cells 1070

Transformation of Cells by DNA Tumor Viruses

Constitutively Active Signal-Transduction Proteins Ar eEncoded by Many Oncogenes 1070

Glossary G-1

Deletion of the PTEN Phosphatase Is a Frequen tOccurrence in Human Tumors 1073

Index 1-0