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| Main Authors: | , , , , , , |
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| Format: | Book |
| Language: | English |
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New York, NY
W.W. Norton & Company
[2022]
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| Edition: | Seventh edition, international student edition |
| Subjects: | |
| Links: | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=033267276&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| Physical Description: | xxxviii, 1404, G:37, I:70 Seiten Illustrationen, Diagramme |
| ISBN: | 9780393884852 9780393884821 |
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| adam_text | xxv Contents Chapter 1 Cells, Genomes, and the Diversity of Life 1 THE UNIVERSAL FEATURES OF LIFE ON EARTH All Cells Store Their Hereditary Information in the Form of Double-Strand DNA Molecules All Cells Replicate Their Hereditary Information by Templated Polymerization All Cells Transcribe Portions of Their DNA into RNA Molecules All Cells Use Proteins as Catalysts All Cells Translate RNA into Protein in the Same Way Each Protein Is Encoded by a Specific Gene Life Requires a Continual Input of Free Energy All Cells Function as Biochemical Factories All Cells Are Enclosed in a Plasma Membrane Across Which Nutrients and Waste Materials Must Pass Cells Operate at a Microscopic Scale Dominated by Random Thermal Motion A Living Cell Can Exist with 500 Genes Summary 2 GENOME DIVERSIFICATION AND THE TREE OF LIFE The Tree of Life Has Three Major Domains: Eukaryotes, Bacteria, and Archaea Eukaryotes Make Up the Domain of Life That Is Most Familiar to Us On the Basis of Genome Analysis, Bacteria Are the Most Diverse Group of Organisms on the Planet Archaea: The Most Mysterious Domain of Life Organisms Occupy Most of Our Planet Cells Can Be Powered by a Wide Variety of Free-Energy Sources Some Cells Fix Nitrogen and Carbon Dioxide for Other Cells Genomes Diversify Over Evolutionary Time, Producing New Types of Organisms New Genes Are Generated from Preexisting Genes Gene Duplications Give Rise to Families of Related Genes Within a Single Genome The Function of a Gene Can Often Be Deduced from Its Nucleotide Sequence More Than 200 Gene Families Are Common to All Three Domains of Life
Summary 2 3 5 6 6 7 7 8 8 9 10 10 10 11 13 13 15 15 15 17 18 19 20 20 21 21 EUKARYOTES AND THE ORIGIN OF THE EUKARYOTIC CELL Eukaryotic Cells Contain a Variety of Organelles Mitochondria Evolved from a Symbiotic Bacterium Captured by an Ancient Archaeon Chloroplasts Evolved from a Symbiotic Photosynthetic Bacterium Engulfed by an Ancient Eukaryotic Cell Eukaryotes Have Hybrid Genomes Eukaryotic Genomes Are Big Eukaryotic Genomes Are Rich in Regulatory DNA Eukaryotic Genomes Define the Program of Multicellular Development Many Eukaryotes Live as Solitary Cells Summary 22 23 MODEL ORGANISMS Mutations Reveal the Functions of Genes Molecular Biology Began with a Spotlight on One Bacterium and Its Viruses The Focus on E. coli as a Model Organism Has Accelerated Many Subsequent Discoveries A Yeast Serves as a Minimal Model Eukaryote 31 32 25 26 27 28 28 29 30 31 33 35 36 The Expression Levels of All the Genes of an Organism Can Be Determined Arabidopsis Has Been Chosen as a Model Plant The World of Animal Cells Is Mainly Represented by a Worm, a Fly, a Fish, a Mouse, and a Human Studies in the Fruit Fly Drosophila Provide a Key to Vertebrate Development The Frog and (he Zebrafish Provide Highly Accessible Vertebrate Models The Mouse Is the PredominantMammalian Model Organism The COVID-19 Pandemic Has Focused Scientists on the SARS֊CoV-2 Coronavirus Humans Are Unique in Reporting on Their Own Peculiarities To Understand Cells and Organisms Will Require Mathematics. Computers, and Quantitative Information Summary Problems References 37 38 38 39 40 41 42 44 44 45 46 47 Chapter 2
Cell Chemistry and Bioenergetics 49 THE CHEMICAL COMPONENTS OF A CELL Water Is Held Together by Hydrogen Bonds Four Types of Noncovalent Attractions Help Bring Molecules Together in Cells Some Polar Molecules Form Acids and Bases in Water A Cell Is Formed from Carbon Compounds Cells Contain Four Major Families of Small Organic Molecules The Chemistry of Cells Is Dominated by Macromolecules with Remarkable Properties Noncovalent Bonds Specify Both the Precise Shape of a Macromolecule and Its Binding to Other Molecules Summary 49 50 CATALYSIS AND THE USE OF ENERGY BY CELLS Cell Metabolism Is Organized by Enzymes Biological Order Is Made Possible by the Release of Heat Energy from Cells Cells Obtain Energy by the Oxidation of Organic Molecules Oxidation and Reduction Involve ElectronTransfers Enzymes Lower the Activation-Energy Barriers That Block Chemical Reactions Enzymes Can Drive Substrate Molecules Along Specific Reaction Pathways How Enzymes Find Their Substrates: The Enormous Rapidity of Molecular Motions The Free-Energy Change for a Reaction, AG. Determines Whether It Can Occur Spontaneously The Concentration of Reactants Influences the Free-Energy Change and a Reaction s Direction The Standard Free-Energy Change. AG . Makes It Possible to Compare the Energetics of Different Reactions The Equilibrium Constant and AG“ Are Readily Derived from Each Other The Free-Energy Changes of Coupled Reactions Are Additive Activated Carrier Molecules Are Essential for Biosynthesis The Formation of an Activated Carrier Is Coupled to an Energetically Favorable Reaction ATP Is the Most
Widely Used Activated Carrier Molecule Energy Stored in ATP Is Often Harnessed to Join Two Molecules Together 51 52 53 53 54 55 56 57 57 58 61 62 63 64 65 66 67 67 68 69 69 70 71 72
xxvi CONTENTS NADH and NADPH Are Important Electron Carriers There Are Many Other Activated Carrier Molecules in Cells The Synthesis of Biological Polymers Is Driven by ATP Hydrolysis Summary HOW CELLS OBTAIN ENERGY FROM FOOD Glycolysis Is a Central ATP-producing Pathway Glycolysis Illustrates How Enzymes Couple Oxidation to Energy Storage Fermentations Produce ATP in the Absence of Oxygen Organisms Store Food Molecules in Special Reservoirs Between Meals, Most Animal Cells Derive Their Energy from Fatty Acids Obtained from Fat Sugars and Fats Are Both Degraded to Acetyl CoA in Mitochondria The Citric Acid Cycle Generates NADH by Oxidizing Acetyl Groups to CO2 Electron Transport Drives the Synthesis of the Majority of the ATP in Most Cells Many Biosynthetic Pathways Begin with Glycolysis or the Citric Acid Cycle Animals Must Obtain All the Nitrogen and Sulfur They Need from Food Metabolism Is Highly Organized and Regulated Summary Problems References Chapter 3 Proteins THE ATOMIC STRUCTURE OF PROTEINS The Structure of a Protein Is Specified by Its Amino Acid Sequence Proteins Fold into a Conformation of Lowest Energy The a Helix and the ß Sheet Are Common Folding Motifs Four Levels of Organization Are Considered to Contribute to Protein Structure Protein Domains Are the Modular Units from Which Larger Proteins Are Built Proteins Also Contain Unstructured Regions All Protein Structures Are Dynamic, Interconverting Rapidly Between an Ensemble of Closely Related Conformations Because of Thermal Energy Function Has Selected for a Tiny Fraction of the Many Possible Polypeptide
Chains Proteins Can Be Classified into Many Families Some Protein Domains Are Found in Many Different Proteins The Human Genome Encodes a Complex Set of Proteins, Revealing That Much Remains Unknown Protein Molecules Often Contain More Than One Polypeptide Chain Some Globular Proteins Form Long Helical Filaments Protein Molecules Can Have Elongated, Fibrous Shapes Covalent Cross-Linkages Stabilize Extracellular Proteins Protein Molecules Often Serve as Subunits for the Assembly of Large Structures Many Structures in Cells Are Capable of Self-Assembly Assembly Factors Often Aid the Formation of Complex Biological Structures When Assembly Processes Go Wrong: The Case of Amyloid Fibrils Amyloid Structures Can Also Perform Useful Functions in Cells Summary PROTEIN FUNCTION All Proteins Bind to Other Molecules The Surface Conformation of a Protein Determines Its Chemistry Sequence Comparisons Between Protein Family Members Highlight Crucial Ligand-binding Sites Proteins Bind to Other Proteins Through Several Types of Interfaces Antibody Binding Sites Are Especially Versatile The Equilibrium Constant Measures Binding Strength Enzymes Are Powerful and Highly Specific Catalysts Substrate Binding Is the First Step in Enzyme Catalysis 73 75 76 78 80 80 83 84 85 86 87 88 90 90 91 92 93 112 114 115 115 115 121 121 123 124 126 126 126 127 129 Enzymes Speed Reactions by Selectively Stabilizing Transition States 148 Enzymes Can Use Simultaneous Acid and Base Catalysis 148 Lysozyme Illustrates How an Enzyme Works 149 Tightly Bound Small Molecules Add Extra Functions to Proteins 152 The
Cell Regulates the Catalytic Activities of Its Enzymes 155 Allosteric Enzymes Have Two or More Binding Sites That Interact 155 Two Ligands Whose Binding Sites Are Coupled Must Reciprocally Affect Each Other’s Binding 157 Symmetrical Protein Assemblies Produce Cooperative Allosteric Transitions 158 Many Changes in Proteins Are Driven by Protein Phosphorylation 159 A Eukaryotic Cell Contains a Large Collection of Protein Kinases and Protein Phosphatases 159 The Regulation of the Src Protein Kinase Reveals How a Protein Can Function as a Microprocessor 161 Regulatory GTP-binding Proteins Are Switched On and Oft by the Gain and Loss of a Phosphate Group 162 Proteins Can Be Regulated by the Covalent Addition of Other Proteins 162 An Elaborate Ubiquitin-conjugating System Is Used to Mark Proteins 163 Protein Complexes with Interchangeable Parts Make Efficient Use of Genetic Information 164 A GTP-binding Protein Shows How Large Protein Movements Can Be Generated from Small Ones 166 Motor Proteins Produce Directional Movement in Cells 167 Proteins Often Form Large Complexes That Function as Protein Machines 167 The Disordered Regions in Proteins Are Critical for a Set of Different Functions 168 Scaffolds Bring Sets of Interacting Macromolecules Together and Concentrate Them in Selected Regions of a Cell 170 Macromolecules Can Self-assemble to Form Biomolecular Condensates 171 Classical Studies of Phase Separation Have Relevance for Biomolecular Condensates 173 A Comparison of Three Important Types of Large Biological Assemblies 174 Many Proteins Are Controlled by Covalent
Modifications That Direct Them to Specific Sites Inside the Cell 175 A Complex Network of Protein Interactions Underlies Cell Function 176 Protein Structures Can Be Predicted and New Proteins Designed 178 Summary 179 Problems 179 References 181 130 130 131 132 133 134 136 136 137 139 140 140 140 142 142 143 144 145 146 146 Chapter 4 DNA, Chromosomes, and Genomes 183 THE STRUCTURE AND FUNCTION OF DNA A DNA Molecule Consists of Two Complementary Chains of Nucleotides The Structure of DNA Provides a Mechanism for Heredity In Eukaryotes, DNA Is Enclosed in a Cell Nucleus Summary 185 CHROMOSOMAL DNA AND ITS PACKAGING IN THE CHROMATIN FIBER Eukaryotic DNA Is Packaged into a Set of Chromosomes Chromosomes Contain Long Strings of Genes The Nucleotide Sequence of the Human Genome Shows How Our Genes Are Arranged Each DNA Molecule That Forms a Linear Chromosome Must Contain a Centromere, Two Telomeres, and Replication Origins DNA Molecules Are Highly Condensed in Chromosomes Nucleosomes Are a Basic Unit of Eukaryotic Chromosome Structure The Structure of the Nucleosome Core Particle Reveals How DNA Is Packaged Nucleosomes Have a Dynamic Structure and Are Frequently Subjected to Changes Catalyzed by ATP-dependent Chromatin-remodeling Complexes 185 187 189 189 189 190 191 193 195 197 197 198 200
CONTENTS Attractions Between Nucleosomes Compact the Chromatin Fiber Summary 202 203 THE EFFECT OF CHROMATIN STRUCTURE ON DNA FUNCTION 203 Different Regions of the Human Genome Are Packaged Very Differently in Chromatin 204 Heterochromatin Is Highly Condensed and Restricts Gene Expression 204 The Heterochromatic State Can Spread Along a Chromosome and Be Inherited from One Cell Generation to the Next 205 The Core Histones Are Covalently Modified at Many Different Sites 206 Chromatin Acquires Additional Variety Through the Site-specific Insertion of a Small Set of Histone Variants 208 Covalent Modifications and Histone Variants Can Act in Concert to Control Chromosome Functions 208 A Complex of Reader and Writer Proteins Can Spread Specific Chromatin Modifications Along a Chromosome 210 Barrier DNA-Protein Complexes Block the Spread of Reader-Writer Complexes and Thereby Separate Neighboring Chromatin Domains 212 Centromeres Have a Special, Inherited Chromatin Structure 213 Some Forms of Chromatin Can Be Directly Inherited 215 The Abnormal Perturbations of Heterochromatin That Arise During Tumor Progression Contribute to Many Cancers 215 Summary 217 THE GLOBAL STRUCTURE OF CHROMOSOMES 217 Chromosomes Are Folded into Large Loops of Chromatin 217 Polytene Chromosomes Are Uniquely Useful for Visualizing Chromatin Structures 218 Chromosome Loops Decondense When the Genes Within Them Are Expressed 220 Mammalian Interphase Chromosomes Occupy Discrete Territories in the Nucleus, with Their Heterochromatin and Euchromatin Distributed Differently 220 A Biochemical Technique Called
Ні-C Reveals Details of Chromosome Organization 221 Chromosomal DNA Is Organized into Loops by Large Protein Rings 223 Euchromatin and Heterochromatin Separate Spatially in the Nucleus 225 Mitotic Chromosomes Are Highly Condensed 227 Summary 228 HOW GENOMES EVOLVE 229 Genome Comparisons Reveal Functional DNA Sequences by Their Conservation Throughout Evolution 230 Genome Alterations Are Caused by Failures of the Normal Mechanisms for Copying and Maintaining DNA, as Well as by Transposable DNA Elements 231 The Genome Sequences of Two Species Differ in Proportion to the Length of Time Since They Have Separately Evolved 232 Phylogenetic Trees Constructed from a Comparison of DNA Sequences Trace the Relationships of All Organisms 233 A Comparison of Human and Mouse Chromosomes Shows How the Structures of Genomes Diverge 234 The Size of a Vertebrate Genome Reflects the Relative Rates of DNA Addition and DNA Loss in a Lineage 236 Multispecies Sequence Comparisons Identify Many Conserved DNA Sequences of Unknown Function 237 Changes in Previously Conserved Sequences Can Help Decipher Critical Steps in Evolution 238 Mutations in the DNA Sequences That Control Gene Expression Have Driven Many of the Evolutionary Changes in Vertebrates 239 Gene Duplication Also Provides an Important Source of Genetic Novelty During Evolution 240 Duplicated Genes Diverge 240 The Evolution of the Globin Gene Family Shows How DNA Duplications Contribute to the Evolution of Organisms 241 Genes Encoding New Proteins Can Be Created by the Recombination of Exons 242 Neutral Mutations Often Spread to Become
Fixed in a Population, with a Probability That Depends on Population Size 243 We Can Trace Human History by Analyzing Genomes The Sequencing of Hundreds of Thousands of Human Genomes Reveals Much Variation Most of the Variants Observed in the Human Population Are Common Alleles, with at Most a Weak Effect on Phenotype Forensic Analyses Exploit Special DNA Sequences with Unusually High Mutation Rates An Understanding of Human Variation Is Critical for Improving Medicine Summary Problems References Chapter 5 DNA Replication, Repair, and Recombination xxvii 244 245 246 247 248 248 249 251 253 THE MAINTENANCE OF DNA SEQUENCES Mutation Rates Are Extremely Low Low Mutation Rates Are Necessary for Life as We Know It Summary 253 253 254 255 DNA REPLICATION MECHANISMS Base-pairing Underlies DNA Replication and DNA Repair The DNA Replication Fork Is Asymmetrical The High Fidelity of DNA Replication Requires Several Proofreading Mechanisms DNA Replication in the 5 -to-3 Direction Allows Efficient Error Correction A Special Nucleotide-polymerizing Enzyme Synthesizes Short RNA Primer Molecules Special Proteins Help to Open Up the DNA Double Helix in Front of the Replication Fork A Sliding Ring Holds a Moving DNA Polymerase onto the DNA The Proteins at a Replication Fork Cooperate to Form a Replication Machine DNA Replication Is Fundamentally Similar in Eukaryotes and Bacteria A Strand-directed Mismatch Repair System Removes Replication Errors That Remain in the Wake of the Replication Machine The Accidental Incorporation of Ribonucleotides During DNA Replication Is Corrected DNA
Topoisomerases Prevent DNA Tangling During Replication Summary 255 255 256 258 260 260 261 262 263 265 267 269 269 272 THE INITIATION AND COMPLETION OF DNA REPLICATION IN CHROMOSOMES 272 DNA Synthesis Begins at Replication Origins 272 Bacterial Chromosomes Typically Have a Single Origin of DNA Replication 273 Eukaryotic Chromosomes Contain Multiple Origins of Replication 273 In Eukaryotes, DNA Replication Takes Place During Only One Part of the Cell Cycle 276 Eukaryotic Origins of Replication Are “Licensed” for Replication by the Assembly of an Origin Recognition Complex 276 Features of the Human Genome That Specify Origins of Replication Remain to Be Fully Understood 277 Properties of the ORC Ensure That Each Region of the DNA Is Replicated Once and Only Once in Each S Phase 277 New Nucleosomes Are Assembled Behind the Replication Fork 279 Termination of DNA Replication Occurs Through the Ordered Disassembly of the Replication Fork 280 Telomerase Replicates the Ends of Chromosomes 281 Telomeres Are Packaged into Specialized Structures That Protect the Ends of Chromosomes 282 Telomere Length Is Regulated by Cells and Organisms 282 Summary 284 DNA REPAIR Without DNA Repair, Spontaneous DNA Damage Would Rapidly Change DNA Sequences The DNA Double Helix Is Readily Repaired DNA Damage Can Be Removed by More Than One Pathway 284 286 288 288
xxviii CONTENTS Coupling Nucleotide Excision Repair to Transcription Ensures That the Cell’s Most Important DNA Is Efficiently Repaired The Chemistry of the DNA Bases Facilitates Damage Detection Special Translesion DNA Polymerases Are Used in Emergencies Double-Strand Breaks Are Efficiently Repaired DNA Damage Delays Progression of the Cell Cycle Summary 290 290 292 292 295 295 HOMOLOGOUS RECOMBINATION 296 Homologous Recombination Has Common Features in All Cells 296 DNA Base-pairing Guides Homologous Recombination 296 Homologous Recombination Can Flawlessly Repair Double-Strand Breaks in DNA 297 Specialized Processing of Double-Strand Breaks Commits Repair to Homologous Recombination 298 Strand Exchange Is Directed by the RecA/Rad51 Protein 298 Homologous Recombination Can Rescue Broken and Stalled DNA Replication Forks 299 DNA Repair by Homologous Recombination Entails Risks to the Cell 300 Homologous Recombination Is Crucial for Meiosis 301 Melotie Recombination Begins with a Programmed Double-Strand Break 302 Holliday Junctions Are Recognized by Enzymes That Drive Branch Migration 302 Homologous Recombination Produces Crossovers Between Maternal and Paternal ChromosomesDuringMeiosis 304 Homologous Recombination Often Resultsin GeneConversion 305 Summary 306 TRANSPOSITION AND CONSERVATIVE SITE-SPECIFIC RECOMBINATION 306 Through Transposition, Mobile Genetic Elements Can Insert into Any DNA Sequence 307 DNA-only Transposons Can Move by a Cut-and-Paste Mechanism 307 Some DNA-only Transposons Move by Replicating Themselves 309 Some Viruses Use a Transposition Mechanism to
Move Themselves into Host-Cell Chromosomes 309 Some RNA Viruses Replicate and Express Their Genomes Without Using DNA as an Intermediate 311 Retroviral-like Retrotransposons Resemble Retroviruses, but Cannot Move from Cell to Cell 313 A Large Fraction of the Human Genome Is Composed of Nonretroviral Retrotransposons 313 Different Transposable Elements Predominate in Different Organisms 314 Genome Sequences Reveal the Approximate Times at Which Transposable Elements Have Moved 314 Conservative Site-specific Recombination Can Reversibly Rearrange DNA 315 Conservative Site-specific Recombination Can Be Used to Turn Genes On or Off 316 Bacterial Conservative Site-specific Recombinases Have Become Powerful Tools for Cell and Developmental Biologists 317 Summary 317 Problems 318 References 320 Chapter 6 How Cells Read the Genome: From DNA to Protein 321 FROM DNA TO RNA 323 RNA Molecules Are Single-Stranded 324 Transcription Produces RNA Complementary to One Strand of DNA 325 RNA Polymerases Carry Out DNA Transcription 325 Cells Produce Different Categories of RNA Molecules 327 Signals Encoded in DNA Tell RNA Polymerase Where to Start and Stop 328 Bacterial Transcription Start and Stop Signals Are Heterogeneous in Nucleotide Sequence 329 Transcription Initiation in Eukaryotes Requires Many Proteins 331 To Initiate Transcription, RNA Polymerase II Requires a Set of General Transcription Factors 332 In Eukaryotes, Transcription Initiation Also Requires Activator, Mediator, and Chromatin-modifying Proteins Transcription Elongation in Eukaryotes Requires Accessory Proteins
Transcription Creates Superhelical Tension Transcription Elongation in Eukaryotes Is Tightly Coupled to RNA Processing RNA Capping Is the First Modification of Eukaryotic Pre-mRNAs RNA Splicing Removes Intron Sequences from Newly Transcribed Pre-mRNAs Nucleotide Sequences Signal Where Splicing Occurs RNA Splicing Is Performed by the Spliceosome The Spliceosome Uses ATP Hydrolysis to Produce a Complex Series of RNA-RNA Rearrangements Other Properties of Pre-mRNA and Its Synthesis Help to Explain the Choice of Proper Splice Sites RNA Splicing Has Remarkable Plasticity Spliceosome-catalyzed RNA Splicing Evolved from RNA Self-splicing Mechanisms RNA-processing Enzymes Generate the 3 End of Eukaryotic mRNAs Mature Eukaryotic mRNAs Are Selectively Exported from the Nucleus Noncoding RNAs Are Also Synthesized and Processed in the Nucleus The Nucleolus Is a Ribosome-producing Factory The Nucleus Contains a Variety of Subnuclear Biomolecular Condensates Summary 334 335 335 337 338 339 341 341 343 345 346 347 348 349 351 353 355 357 FROM RNA TO PROTEIN 358 An mRNA Sequence Is Decoded in Sets of Three Nucleotides 358 tRNA Molecules Match Amino Acids to Codons in mRNA 359 tRNAs Are Covalently Modified Before They Exit from the Nucleus 361 Specific Enzymes Couple Each Amino Acid to Its Appropriate tRNA Molecule 361 Editing by tRNA Synthetases Ensures Accuracy 363 Amino Acids Are Added to the C-terminal End of a Growing Polypeptide Chain 364 The RNA Message Is Decoded in Ribosomes 365 Elongation Factors Drive Translation Forward and Improve Its Accuracy 368 Induced Fit and Kinetic
Proofreading Help Biological Processes Overcome the Inherent Limitations of Complementary Base-Pairing 369 Accuracy in Translation Requires a Large Expenditure of Free Energy 370 The Ribosome Is a Ribozyme 371 Nucleotide Sequences in mRNA Signal Where to Start Protein Synthesis 373 Stop Codons Mark the End of Translation 374 Proteins Are Made on Polyribosomes 375 There Are Minor Variations in the Standard Genetic Code 375 Inhibitors of Prokaryotic Protein Synthesis Are Useful as Antibiotics 376 Quality-Control Mechanisms Act to Prevent Translation of Damaged mRNAs 378 Stalled Ribosomes Can Be Rescued 379 The Ribosome Coordinates the Folding, Enzymatic Modification, and Assembly of Newly Synthesized Proteins 380 Molecular Chaperones Help Guide the Folding of Most Proteins 380 Proper Folding of Newly Synthesized Proteins Is Also Aided by Translation Speed and Subunit Assembly 383 Proteins That Ultimately Fail to Fold Correctly Are Marked for Destruction by Polyubiquitin 384 The Proteasome Is a Compartmentalized Protease with Sequestered Active Sites 384 Many Proteins Are Controlled by Regulated Destruction 386 There Are Many Steps from DNA to Protein 387 Summary 388 THE RNA WORLD AND THE ORIGINS OF LIFE Single-Strand RNA Molecules Can Fold into Highly Elaborate Structures Ribozymes Can Be Produced in the Laboratory 389 390 390
CONTENTS RNA Can Both Store Information and Catalyze Chemical Reactions How Did Protein Synthesis Evolve? All Present-Day Cells Use DNA as Their Hereditary Material Summary Problems References Chapter 7 Control of Gene Expression AN OVERVIEW OF GENE CONTROL The Different Cell Types of a Multicellular Organism Contain the Same DNA Different Cell Types Synthesize Different Sets of RNAs and Proteins The Spectrum of mRNAs Present in a Cell Can Be Used to Accurately Identify the Cell Type External Signals Can Cause a Cell to Change the Expression of Its Genes Gene Expression Can Be Regulated at Many of the Steps in the Pathway from DNA to RNA to Protein Summary CONTROL OF TRANSCRIPTION BY SEQUENCE-SPECIFIC DNA-BINDING PROTEINS The Sequence of Nucleotides in the DNA Double Helix Can Be Read by Proteins Transcription Regulators Contain Structural Motifs That Can Read DNA Sequences Dimerization of Transcription Regulators Increases Their Affinity and Specificity for DNA Many Transcription Regulators Bind Cooperatively to DNA Nucleosome Structure Promotes Cooperative Binding of Transcription Regulators DNA-Binding by Transcription Regulators Is Dynamic Summary TRANSCRIPTION REGULATORS SWITCH GENES ON AND OFF The Tryptophan Repressor Switches Genes Off Repressors Turn Genes Off and Activators Turn Them On Both an Activator and a Repressor Control the Lac Operon DNA Looping Can Occur During Bacterial Gene Regulation Complex Switches Control Gene Transcription in Eukaryotes A Eukaryotic Gene Control Region Includes Many c/s-Regulatory Sequences Eukaryotic Transcription Regulators Work
in Groups Activator Proteins Promote the Assembly of RNA Polymerase at the Start Point of Transcription Eukaryotic Transcription Activators Direct the Modification of Local Chromatin Structure Some Transcription Activators Work by Releasing Paused RNA Polymerase Transcription Activators Work Synergistically Condensate Formation Likely Increases the Efficiency of Transcription Initiation Eukaryotic Transcription Repressors Can Inhibit Transcription in Several Ways Insulator DNA Sequences Prevent Eukaryotic Transcription Regulators from Influencing Distant Genes Summary MOLECULAR GENETIC MECHANISMS THAT CREATE AND MAINTAIN SPECIALIZED CELL TYPES Complex Genetic Switches That Regulate Drosophila Development Are Built Up from Smaller Modules The Drosophila Eve Gene Is Regulated by Combinatorial Controls Transcription Regulators Are Brought into Play by Extracellular Signals Combinatorial Gene Control Creates Many Different Cell Types Specialized Cell Types Can Be Experimentally Reprogrammed to Become Pluripotent Stem Cells Combinations of Master Transcription Regulators Specify Cell Types by Controlling the Expression of Many Genes Specialized Cells Must Rapidly Turn Some Genes On and Off Differentiated Cells Maintain Their Identity 391 392 393 393 394 395 397 397 397 398 400 400 401 402 402 402 403 406 407 408 409 410 410 410 411 412 412 414 414 415 416 417 418 419 420 420 422 422 xxix Transcription Circuits Allow the Cell to Carry Out Logic Operations 433 Summary 434 MECHANISMS THAT REINFORCE CELL MEMORY IN PLANTS AND ANIMALS 435 Patterns of DNA Methylation Can Be Inherited
When Vertebrate Cells Divide 435 CG-Rich Islands Are Associated with Many Genes in Mammals 436 Genomic Imprinting Is Based on DNA Methylation 438 A Chromosome-wide Alteration in Chromatin Structure Can Be Inherited 440 The Mammalian X-lnactivation in Females Is Triggered by the Synthesis of a Long Noncoding RNA 442 Stable Patterns of Gene Expression Can Be Transmitted to Daughter Cells 443 Summary 445 POST-TRANSCRIPTIONAL CONTROLS 445 Transcription Attenuation Causes the Premature Termination of Some RNA Molecules 445 Riboswitches Probably Represent Ancient Forms of Gene Control 446 Alternative RNA Splicing Can Produce Different Forms of a Protein from the Same Gene 446 The Definition of a Gene Has Been Modified Since the Discovery of Alternative RNA Splicing 448 Back Splicing Can Produce Circular RNA Molecules 449 A Change in the Site of RNA Transcript Cleavage and Poly-A Addition Can Change the C-terminus of a Protein 449 Nucleotides in mRNA Can Be Covalently Modified 450 RNA Editing Can Change the Meaning of the RNA Message 451 The Human AIDS Virus Illustrates How RNA Transport from the Nucleus Can Be Regulated 452 mRNAs Can Be Localized to Specific Regions of the Cytosol 453 Untranslated Regions of mRNAs Control Their Translation 456 The Phosphorylation of an Initiation Factor Regulates Protein Synthesis Globally 457 Initiation at AUG Codons Upstream of the Translation Start Can Regulate Eukaryotic Translation Initiation 458 Internal Ribosome Entry Sites Also Provide Opportunities for Translational Control 458 Changes in mRNA Stability Can Control Gene Expression 459
Regulation of mRNA Stability Involves P-bodies and Stress Granules 461 Summary 462 REGULATION OF GENE EXPRESSION BY NONCODING RNAs Small Noncoding RNA Transcripts Regulate Many Animal and Plant Genes Through RNA Interference mIRNAs Regulate mRNA Translation and Stability RNA Interference Also Serves as a Cell Defense Mechanism RNA Interference Can Direct Heterochromatin Formation piRNAs Protect the Germ Line from Transposable Elements RNA Interference Has Become a Powerful Experimental Tool Cells Have Additional Mechanisms to Hold Transposons and Integrated Viral Genomes in Check 467 Bacteria Use Small Noncoding RNAs to Protect Themselves from Viruses 468 Long Noncoding RNAs Have Diverse Functions in the Cell Summary Problems References 462 462 463 464 465 466 467 469 471 472 474 423 Chapter 8 Analyzing Cells, Molecules, and Systems 475 423 424 428 ISOLATING CELLS AND GROWING THEM INCULTURE Cells Can Be Isolated from Tissues and Grown in Culture Eukaryotic Cell Lines Are a Widely Used Source of Homogeneous Cells Hybridoma Cell Lines Are Factories That Produce Monoclonal Antibodies Summary 429 430 431 PURIFYING PROTEINS Cells Can Be Separated into Their Component Fractions Cell Extracts Provide Accessible Systems to Study Cell Functions Proteins Can Be Separated by Chromatography 426 427 476 476 478 478 480 480 480 482 483
xxx CONTENTS Immunoprecipitation Is a Rapid Affinity Purification Method 486 Genetically Engineered Tags Provide an Easy Way to Purify Proteins 486 Purified Cell-free Systems Are Required for the Precise Dissection of Molecular Functions 486 Summary 487 ANALYZING PROTEINS Proteins Can Be Separated by SDS Polyacrylamide-Gel Electrophoresis Two-dimensional Gel Electrophoresis Provides Greater Protein Separation Specific Proteins Can Be Detected by Blotting with Antibodies Hydrodynamic Measurements Reveal the Size and Shape of a Protein Complex Mass Spectrometry Provides a Highly Sensitive Method for Identifying Unknown Proteins Sets of Interacting Proteins Can Be Identified by Biochemical Methods Optical Methods Can Monitor Protein Interactions Protein Structure Can Be Determined Using X-ray Diffraction NMR Can Be Used to Determine Protein Structure in Solution Protein Sequence and Structure Provide Clues About Protein Function Summary 487 487 489 490 490 491 493 493 494 496 497 498 ANALYZING AND MANIPULATING DNA 498 Restriction Nucleases Cut Large DNA Molecules into Specific Fragments 498 Gel Electrophoresis Separates DNA Moleculesof Different Sizes 499 Purified DNA Molecules Can Be Specifically Labeled with Radioisotopes or Chemical Markers in Vitro 501 Genes Can Be Cloned Using Bacteria 501 An Entire Genome Can Be Represented in a DNA Library 503 Hybridization Provides a Powerful but Simple Way to Detect Specific Nucleotide Sequences 505 Genes Can Be Cloned in Vitro Using PCR 506 PCR Is Also Used for Diagnostic and Forensic Applications 507 PCR and Synthetic DNA Are Ideal
Sources of Specific Gene Sequences for Cloning 510 DNA Cloning Allows Any Protein to Be Produced in Large Amounts 511 DNA Can Be Sequenced Rapidly by Dideoxy Sequencing 512 Next-Generation Sequencing Methods Have Revolutionized DNA and RNA Analysis 514 To Be Useful, Genome Sequences Must Be Annotated 516 Summary 518 STUDYING GENE FUNCTION AND EXPRESSION 518 Classical Genetic Screens Identify Random Mutants with Specific Abnormalities 519 Mutations Can Cause Loss or Gainof Protein Function 522 Complementation Tests Reveal Whether Two Mutations Are in the Same Gene or Different Genes 523 Gene Products Can Be Ordered in Pathways by Epistasis Analysis 523 Mutations Responsible for a Phenotype Can Be Identified Through DNA Analysis 524 Rapid and Cheap DNA Sequencing Has Revolutionized Human Genetic Studies 524 Linked Blocks of Polymorphisms Have Been Passed Down from Our Ancestors 525 Sequence Variants Can Aid the Search for Mutations Associated with Disease 526 Genomics Is Accelerating the Discovery of Rare Mutations That Predispose Us to Serious Disease 527 The Cellular Functions of a Known Gene Can Be Studied with Genome Engineering 527 Animals and Plants Can Be Genetically Altered 528 The Bacterial CRISPR System Has Been Adapted to Edit Genomes in a Wide Variety of Species 530 Large Collections of Engineered Mutations Provide a Tool for Examining the Function of Every Gene in an Organism 531 RNA Interference Is a Simple and Rapid Way to Test Gene Function 533 Reporter Genes Reveal When and Where a Gene Is Expressed 534 In Situ Hybridization Can Reveal the Location of mRNAs
and Noncoding RNAs 535 Expression of Individual Genes Can Be Measured Using Quantitative RT-PCR 536 Global Analysis of mRNAs by RNA-seq Provides a Snapshot of Gene Expression 536 Genome-wide Chromatin Immunoprecipitation Identifies Sites on the Genome Occupied by Transcription Regulators 538 Ribosome Profiling Reveals Which mRNAs Are Being Translated in the Cell 538 Recombinant DNA Methods Have Revolutionized Human Health 539 Transgenic Plants Are Important for Agriculture 540 Summary 542 MATHEMATICAL ANALYSIS OF CELL FUNCTION 542 Regulatory Networks Depend on Molecular Interactions 543 Differential Equations Help Us Predict Transient Behavior 545 Promoter Activity and Protein Degradation Affect the Rate of Change of Protein Concentration 546 The Time Required to Reach Steady State Depends on Protein Lifetime 547 Quantitative Methods Are Similar for Transcription Repressors and Activators 548 Negative Feedback Is a Powerful Strategy in Cell Regulation 549 Delayed Negative Feedback Can Induce Oscillations 549 DNA Binding by a Repressor or an Activator Can Be Cooperative 551 Positive Feedback Is Important for Switchlike Responses and Bistability 551 Robustness Is an Important Characteristic of Biological Networks 553 Two Transcription Regulators That Bind to the Same Gene Promoter Can Exert Combinatorial Control 554 An Incoherent Feed-forward Interaction Generates Pulses 555 A Coherent Feed-forward Interaction Detects Persistent Inputs 556 The Same Network Can Behave Differently in Different Cells Because of Stochastic Effects 557 Several Computational Approaches Can Be Used
to Model the Reactions inCells 557 Statistical Methods Are Critical for the Analysis of Biological Data 558 Summary 558 Problems 559 References 561 Chapter 9Visualizing Cells and Their Molecules 563 LOOKING AT CELLS AND MOLECULES IN THE LIGHT MICROSCOPE 563 The Conventional Light Microscope Can Resolve Details 0.2 μm Apart 564 Photon Noise Creates Additional Limits to Resolution When Light Levels Are Low 567 Living Cells Are Seen Clearly in a Phase-Contrast or a Differential-Interference-Contrast Microscope 567 Images Can Be Enhanced and Analyzed by Digital Techniques 568 Intact Tissues Are Usually Fixed and Sectioned Before Microscopy 569 Specific Molecules Can Be Located in Cells by Fluorescence Microscopy 570 Antibodies Can Be Used to Detect Specific Proteins 572 Individual Proteins Can Be Fluorescently Tagged in Living Cells and Organisms 573 Protein Dynamics Can Be Followed in Living Cells 575 Fluorescent Biosensors Can Monitor Cell Signaling 576 Imaging of Complex Three-dimensional Objects Is Possible with the Optical Microscope 577 The Confocal Microscope Produces Optical Sections by Excluding Out-of-Focus Light 578 Superresolution Fluorescence Techniques Can Overcome Diffraction-limited Resolution 580 Single-Molecule Localization Microscopy Also Delivers Superresolution 583 Expanding the Specimen Can Offer Higher Resolution, but with a Conventional Microscope 585 Large Multicellular Structures Can Be Imaged Over Time 586 Single Molecules Can Be Visualized by Total Internal Reflection Fluorescence Microscopy 587 Summary 588
CONTENTS LOOKING AT CELLS AND MOLECULES IN THE ELECTRON MICROSCOPE 588 The Electron Microscope Resolves the Fine Structure of the Cell 588 Biological Specimens Require Special Preparation for Electron Microscopy 589 Heavy Metals Can Provide Additional Contrast 590 Images of Surfaces Can Be Obtained by Scanning Electron Microscopy 591 Electron Microscope Tomography Allows the Molecular Architecture of Cells to Be Seen in ThreeDimensions 593 Cryo-electron Microscopy Can Determine Molecular Structures at Atomic Resolution 595 Light Microscopy and Electron Microscopy Are Mutually Beneficial 597 Using Microscopy to Study Cells Always Involves Trade-Offs 598 Summary 599 Problems 600 References 601 Chapter 10 Membrane Structure 603 THE LIPID BILAYER 604 Glycerophospholipids, Sphingolipids, and Sterols Are the Major Lipids in Cell Membranes 605 Phospholipids Spontaneously Form Bilayers 606 The Lipid Bilayer Is a Two-dimensional Fluid 608 The Fluidity of a Lipid Bilayer Depends on Its Composition 609 Despite Their Fluidity, Lipid Bilayers Can Form Domains of Different Compositions 610 Lipid Droplets Are Surrounded by aPhospholipid Monolayer 611 The Asymmetry of the Lipid Bilayer Is Functionally Important 612 Glycolipids Are Found on the Surface of All Eukaryotic Plasma Membranes 613 Summary 614 MEMBRANE PROTEINS 615 Membrane Proteins Can Be Associated with the Lipid Bilayer in Various Ways 615 Lipid Anchors Control the Membrane Localization of Some Signaling Proteins 616 In Most Transmembrane Proteins, the Polypeptide Chain Crosses the Lipid Bilayer in an a-Helical Conformation 617
Transmembrane « Helices Often Interact with One Another 619 Some ß Barrels Form Large Channels 619 Many Membrane Proteins Are Glycosylated 621 Membrane Proteins Can Be Solubilized and Purified in Detergents 622 Bacteriorhodopsin Is a Light-driven Proton (H+) Pump That Traverses the Lipid Bilayer as Seven a Helices 625 Membrane Proteins Often Function as Large Complexes 627 Many Membrane Proteins Diffuse in the Plane of the Membrane 627 Cells Can Confine Proteins and Lipids to Specific Domains Within a Membrane 629 The Cortical Cytoskeleton Gives Membranes Mechanical Strength and Restricts Membrane ProteinDiffusion 630 Membrane-bending Proteins Deform Bilayers 632 Summary 633 Problems 634 References 635 Chapter 11 Small-Molecule Transport and Electrical Properties of Membranes 637 PRINCIPLES OF MEMBRANE TRANSPORT Protein-free Lipid Bilayers Are Impermeable to Ions There Are Two Main Classes of Membrane Transport Proteins: Transporters and Channels Active Transport Is Mediated by Transporters Coupled to an Energy Source Summary 637 638 TRANSPORTERS AND ACTIVE MEMBRANE TRANSPORT Active Transport Can Be Driven by Ion-Concentration Gradients Transporters in the Plasma MembraneRegulate Cytosolic pH An Asymmetric Distribution of Transporters in Epithelial Cells Underlies the Transcellular Transport of Solutes There Are Three Classes of ATP-driven Pumps 640 642 644 638 639 640 645 646 xxxi A P-type ATPase Pumps Ca2’ into the Sarcoplasmic Reticulum in Muscle Cells 647 The Plasma Membrane Na՝ -K’ Pump Establishes Na՛ and K՛ Gradients Across the Plasma Membrane 648 ABC Transporters
Constitute the Largest Family of Membrane Transport Proteins 649 Summary 651 CHANNELS AND THE ELECTRICAL PROPERTIES OF MEMBRANES 651 Aquaporins Are Permeable to Water but Impermeable to Ions 652 Ion Channels Are Ion-selective and Fluctuate Between Open and Closed States 653 The Membrane Potential in Animal Cells Depends Mainly on K’ Leak Channels and the K’ Gradient Across the Plasma Membrane 655 The Resting Potential Decays Only Slowly When the Na+-K+ Pump Is Stopped 655 The Three-dimensional Structure of a Bacterial K+ Channel Shows How an Ion Channel Can Work 657 Mechanosensitive Channels Allow Cells to Sense Their Physical Environment 659 The Function of a Neuron Depends on Its Elongated Structure 661 Voltage-gated Cation Channels Generate Action Potentials in Electrically Excitable Cells 662 Myelination Increases the Speed and Efficiency of Action Potential Propagation in Nerve Cells 666 Patch-Clamp Recording Indicates That Individual Ion Channels Open in an AII-or-Nothing Fashion 666 Voltage-gated Cation Channels Are Evolutionary and Structurally Related 668 Different Neuron Types Display Characteristic Stable Firing Properties 668 Transmitter-gated Ion Channels Convert Chemical Signals into Electrical Ones at Chemical Synapses 669 Chemical Synapses Can Be Excitatory or Inhibitory 670 The Acetylcholine Receptors at the Neuromuscular Junction Are Excitatory Transmitter-gated Cation Channels 671 Neurons Contain Many Types of Transmitter-gated Channels 672 Many Psychoactive Drugs Act at Synapses 673 Neuromuscular Transmission Involves the Sequential Activation of Five
Different Sets of Ion Channels 673 Single Neurons Are Complex Computation Devices 674 Neuronal Computation Requires a Combination of at Least Three Kinds of K+ Channels 675 Long-term Potentiation in the Mammalian Hippocampus Dependson Ca2+EntryThrough NMDA-Receptor Channels 677 The Use of Channelrhodopsins Has Revolutionized the Study of Neural Circuits 678 Summary 679 Problems 680 References 681 Chapter 12 Intracellular Organization and Protein Sorting 683 THE COMPARTMENTALIZATION OF CELLS 683 All Eukaryotic Cells Have the Same Basic Set of Membrane-enclosed Organelles 683 Evolutionary Origins Explain the Topological Relationships of Organelles 686 Macromolecules Can Be Segregated Without a Surrounding Membrane 688 Multivalent Interactions Mediate Formation of Biomolecular Condensates 690 Biomolecular Condensates Create Biochemical Factories 690 Biomolecular Condensates Form and Disassemble in Response to Need 693 Proteins Can Move Between Compartments inDifferent Ways 694 Sorting Signals and Sorting Receptors Direct Proteins to the Correct Cell Address 695 Construction of Most Organelles Requires Information in the Organelle Itself 697 Summary 697
xxxii CONTENTS THE ENDOPLASMIC RETICULUM 698 The ER Is Structurally and Functionally Diverse 698 Signal Sequences Were First Discovered in Proteins Imported into the Rough ER 701 A Signal-Recognition Particle (SRP) Directs the ER Signal Sequence to a Specific Receptor at the ER 702 The Polypeptide Chain Passes Through a Signal Sequence-gated Aqueous Channel in the Translocator 705 Translocation Across the ER Membrane Does Not Always Require Ongoing Polypeptide Chain Elongation 707 Transmembrane Proteins Contain Hydrophobic Segments That Are Recognized Like Signal Sequences 709 Hydrophobic Segments of Multipass Transmembrane Proteins Are Interpreted Contextually to Determine Their Orientation 710 Some Proteins Are Integrated into the ER Membrane by a Post-translational Mechanism 711 Some Membrane Proteins Acquire a Covalently Attached Glycosylphosphatidylinositol (ΘΡΙ) Anchor 712 Translocated Polypeptide Chains Fold and Assemble in the Lumen of the Rough ER 712 Most Proteins Synthesized in the Rough ER Are Glycosylated by the Addition of a Common W-Linked Oligosaccharide 714 Oligosaccharides Are Used as Tags to Mark the State of Protein Folding 715 Improperly Folded Proteins Are Exported from the ER and Degraded in the Cytosol 716 Misfolded Proteins in the ER Activate an Unfolded Protein Response 717 The ER Assembles Most Lipid Bilayers 720 Membrane Contact Sites Between the ER and Other Organelles Facilitate Selective Lipid Transfer 722 Summary 723 The Assembly of a Clathrin Coat Drives Vesicle Formation 752 Adaptor Proteins Select Cargo into Clathrin-coated Vesicles 753
Phosphoinositides Mark Organelles and Membrane Domains 754 Membrane-bending Proteins Help Deform the Membrane During Vesicle Formation 755 Cytoplasmic Proteins Regulate the Pinching off and Uncoating of Coated Vesicles 756 Monomeric GTPases Control Coat Assembly 756 Coat-recruitment GTPases Participate in Coat Disassembly 758 The Shape and Size of Transport Vesicles Are Diverse 759 Rab Proteins Guide Transport Vesicles to Their Target Membrane 760 Rab Proteins Create and Change the Identity of an Organelle 761 SNAREs Mediate Membrane Fusion 762 Interacting SNAREs Need to Be Pried Apart Before They Can Function Again 763 Viruses Encode Specialized Membrane Fusion Proteins Needed for Cell Entry 764 Summary 764 723 771 772 773 PEROXISOMES Peroxisomes Use Molecular Oxygen and Hydrogen Peroxide to Perform Oxidation Reactions Short Signal Sequences Direct the Import of Proteins into Peroxisomes Summary 724 724 726 THE TRANSPORT OF PROTEINS INTO MITOCHONDRIA AND CHLOROPLASTS 726 Translocation into Mitochondria Depends on Signal Sequences and Protein Translocators 727 Mitochondrial Proteins Are Imported Post-translationally as Unfolded Polypeptide Chains 728 Protein Import Is Powered by ATP Hydrolysis, a Membrane Potential, and Redox Potential 730 Transport into the Inner Mitochondrial Membrane Occurs Via Several Routes 731 Bacteria and Mitochondria Use Similar Mechanisms to Insert ß Barrels into Their Outer Membrane 733 Two Signal Sequences Direct Proteins to the Thylakoid Membrane in Chloroplasts 733 Summary 735 THE TRANSPORT OF MOLECULES BETWEEN THE NUCLEUS AND THE CYTOSOL 735
Nuclear Pore Complexes Perforate the Nuclear Envelope 736 Nuclear Localization Signals Direct Proteins to theNucleus 738 Nuclear Import Receptors Bind to Both Nuclear Localization Signals and NPC Proteins 739 The Ran GTPase Imposes Directionality on Nuclear Import Through NPCs 740 Nuclear Export Works Like Nuclear Import, but in Reverse 741 Transport Through NPCs Can Be Regulated by Controlling Access to the Transport Machinery 742 The Nuclear Envelope Disassembles and Reassembles During Mitosis 743 Summary 745 Problems 746 References 748 Chapter 13 Intracellular Membrane Traffic MECHANISMS OF MEMBRANE TRANSPORT AND COMPARTMENT IDENTITY There Are Various Types of Coated Vesicles 749 751 751 TRANSPORT FROM THE ENDOPLASMIC RETICULUM THROUGH THEGOLGIAPPARATUS Proteins Leave the ER inCOPII-coatedTransport Vesicles Only Proteins That Are Properly Folded and Assembled Can Leave the ER Vesicular Tubular Clusters Mediate Transport from the ER to the Golgi Apparatus The Retrieval Pathway to the ER Uses Sorting Signals Many Proteins Are Selectively Retained in the Compartments in Which They Function The Golgi Apparatus Consists of an Ordered Series of Compartments Oligosaccharide Chains Are Processed in the Golgi Apparatus Proteoglycans Are Assembled in the Golgi Apparatus What Is the Purpose of Glycosylation? Transport Through the Golgi Apparatus Occurs by Multiple Mechanisms Golgi Matrix Proteins Help Organizethe Stack Summary 765 765 766 766 768 768 769 774 775 776 TRANSPORT FROM THE TRANS GOLGI NETWORK TO THE CELL EXTERIOR ANDENDOSOMES 776 Many Proteins and Lipids Are Carried
Automatically from the Trans Golgi Network to the Cell Surface 777 A Mannose 6-Phosphate Receptor Sorts Lysosomal Hydrolases in the Trans Golgi Network 777 Defects in the GIcNAc Phosphotransferase Cause a Lysosomal Storage Disease in Humans 779 Secretory Vesicles Bud from the Trans Golgi Network 780 Precursors of Secretory Proteins Are Proteolytically Processed During the Formation of Secretory Vesicles 781 Secretory Vesicles Wait Near the Plasma Membrane Until Signaled to Release Their Contents 782 For Rapid Exocytosis, Synaptic Vesicles Are Primed at the Presynaptic Plasma Membrane 782 Synaptic Vesicles Can Be Recycled Locally After Exocytosis 783 Secretory Vesicle Membrane Components Are Quickly Removed from the Plasma Membrane 784 Some Regulated Exocytosis Events Serve to Enlarge the Plasma Membrane 785 Polarized Cells Direct Proteins from the Trans Golgi Network to the Appropriate Domain of the Plasma Membrane 786 Summary 787 TRANSPORT INTO THE CELL FROM THE PLASMA MEMBRANE: ENDOCYTOSIS 788 Pinocytic Vesicles Form from Coated Pits in the Plasma Membrane 789 Not All Membrane Invaginations and Pinocytic Vesicles Are Clathrin Coated 789 Cells Use Receptor-mediated Endocytosis to Import Selected Extracellular Macromolecules 791 Specific Proteins Are Retrieved from Early Endosomes and Returned to the Plasma Membrane 792 Recycling Endosomes Regulate Plasma Membrane Composition 793 Plasma Membrane Signaling Receptors Are Down-regulated by Degradation in Lysosomes 794
CONTENTS Early Endosomes Mature into Late Endosomes ESCRT Protein Complexes Mediate the Formation of Intralumenal Vesicles in Multivesicular Bodies Summary 795 796 798 THE DEGRADATION AND RECYCLING OF MACROMOLECULES IN LYSOSOMES 798 Lysosomes Are the Principal Sites of Intracellular Digestion 798 Lysosomes Are Heterogeneous 799 Plant and Fungal Vacuoles Are Remarkably Versatile Lysosomes 800 Multiple Pathways Deliver Materials to Lysosomes 801 Cells Can Acquire Nutrients from the Extracellular Fluid by Macropinocytosis 802 Specialized Phagocytic Cells Can Ingest Large Particles 802 Cargo Recognition by Cell-surface Receptors Initiates Phagocytosis 803 Autophagy Degrades Unwanted Proteins and Organelles 804 The Rate of Nonselective Autophagy Is Regulated by Nutrient Availability 805 A Family of Cargo-specific Receptors Mediates Selective Autophagy 806 Some Lysosomes and Multivesicular Bodies Undergo Exocytosis 807 Summary 807 Problems 808 References 810 Chapter 14 Energy Conversion and Metabolic Compartmentation: Mitochondria and Chloroplasts THE MITOCHONDRION The Mitochondrion Has an Outer Membrane and an Inner Membrane Fission, Fusion, Distribution, and Degradation of Mitochondria The Inner Membrane Cristae Contain the Machinery for Electron Transport and ATP Synthesis The Citric Acid Cycle in the Matrix Produces NADH Mitochondria Have Many Essential Roles in Cellular Metabolism A Chemiosmotic Process Couples Oxidation Energy to ATP Production The Energy Derived from Oxidation Is Stored as an Electrochemical Gradient Summan/ 811 813 814 815 817 817 818 821 822 823 THE
PROTON PUMPS OF THE ELECTRON-TRANSPORT CHAIN 823 The Redox Potential Is a Measure of Electron Affinities 823 Electron Transfers Release Large Amounts of Energy 824 Transition Metal Ions and Quinones Accept and Release Electrons Readily 824 NADH Transfers Its Electrons to Oxygen Through Three Large Enzyme Complexes Embedded in the Inner Membrane 827 The NADH Dehydrogenase Complex Contains Separate Modules for Electron Transport and Proton Pumping 828 Cytochrome c Reductase Takes Up and Releases Protons on Opposite Sides of the Crista Membrane, Thereby Pumping Protons 829 The Cytochrome c Oxidase Complex Pumps Protons and Reduces Օշ Using a Catalytic Iron-Copper Center 831 Succinate Dehydrogenase Acts in Both the Electron-Transport Chain and the Citric Acid Cycle 832 The Respiratory Chain Forms a Supercomplex in the Crista Membrane 833 Protons Can Move Rapidly Through Proteins Along Predefined Pathways 834 Summary 835 ATP PRODUCTION IN MITOCHONDRIA 835 The Large Negative Value of AG for ATP Hydrolysis Makes ATP Useful to the Cell 835 The ATP Synthase Is a Nanomachine That Produces ATP by Rotary Catalysis 837 Proton-driven Turbines Are Ancient and Critical for Energy Conversion 839 Mitochondrial Cristae Help toMakeATP Synthesis Efficient 840 Special Transport Proteins Move Solutes Through the Inner Membrane 841 Chemiosmotic Mechanisms FirstArose in Bacteria 842 Summary 842 xxxiii CHLOROPLASTS AND PHOTOSYNTHESIS 843 Chloroplasts Resemble Mitochondria but Have a Separate Thylakoid Compartment 843 Chloroplasts Capture Energy from Sunlight and Use It to Fix Carbon 844 Carbon
Fixation Uses ATP and NADPH to Convert CO2 into Sugars 845 Carbon Fixation in Some Plants Is Compartmentalized to Facilitate Growth at Low CO2 Concentrations 846 The Sugars Generated by Carbon Fixation Can Be Stored as Starch or Consumed to Produce ATP 849 The Thylakoid Membranes of Chloroplasts Contain the Protein Complexes Required for Photosynthesis and ATP Generation 849 Chlorophyll-Protein Complexes Can Transfer Either Excitation Energy or Electrons 850 A Photosystem Contains Chlorophylls in Antennae and a Reaction Center 851 The Thylakoid Membrane Contains Two Different Photosystems Working in Series 852 Photosystem II Uses a Manganese Cluster to Withdraw Electrons from Water 853 The Cytochrome bg-f Complex Connects Photosystem II to Photosystem I 854 Photosystem I Carries Out the Second Charge-Separation Step in the Z Scheme 855 The Chloroplast ATP Synthase Uses the Proton Gradient Generated by the Photosynthetic Light Reactions to Produce ATP 855 The Proton-Motive Force for ATP Production in Mitochondria and Chloroplasts Is Essentially the Same 856 Chemiosmotic Mechanisms Evolved in Stages 856 By Providing an Inexhaustible Source of Reducing Power, Photosynthetic Bacteria Overcame a Major Evolutionary Obstacle 857 The Photosynthetic Electron-Transport Chains of Cyanobacteria Produced Atmospheric Oxygen and Permitted New Life-Forms 857 Summary 860 THE GENETIC SYSTEMS OF MITOCHONDRIA AND CHLOROPLASTS 861 The Genetic Systems of Mitochondria and Chloroplasts Resemble Those of Prokaryotes 861 Over Time, Mitochondria and Chloroplasts Have Exported Most of Their Genes to
the Nucleus by Gene Transfer 862 Mitochondria Have a Relaxed Codon Usage and Can Have a Variant Genetic Code 864 Chloroplasts and Bacteria Share Many Striking Similarities 865 Organellar Genes Are Maternally Inherited in Animals and Plants 866 Mutations in Mitochondrial DNA Can Cause Severe Inherited Diseases 866 Why Do Mitochondria and Chloroplasts Maintain a Costly Separate System for DNA Transcription and Translation? 867 Summary 868 Problems 869 References 871 Chapter 15 Cell Signaling PRINCIPLES OF CELL SIGNALING Extracellular Signals Can Act Over Short or Long Distances Extracellular Signal Molecules Bind to Specific Receptors Each Cell Is Programmed to Respond to Specific Combinations of Extracellular Signals There Are Three Major Classes of Cell-Surface Receptor Proteins Cell-Surface Receptors Relay Signals Via Intracellular Signaling Molecules 879 Intracellular Signals Must Be Specific and Robust in a Noisy Cytoplasm 881 Intracellular Signaling Complexes Form at Activated Cell-Surface Receptors 882 Modular Interaction Domains Mediate Interactions Between Intracellular Signaling Proteins 883 The Relationship Between Signal and Response Varies in Different Signaling Pathways 885 The Speed of a Response Depends on the Turnover of Signaling Molecules 886 873 873 874 875 876 878
xxxiv CONTENTS Cells Can Respond Abruptly to a Gradually Increasing Signal Positive Feedback Can Generate an AII֊or֊None Response Negative Feedback Is a Common Feature of Intracellular Signaling Systems Cells Can Adjust Their Sensitivity to a Signal Summary SIGNALING THROUGH G-PROTEIN-COUPLED RECEPTORS Heterotrimeric G Proteins Relay Signals from GPCRs Some G Proteins Regulate the Production of Cyclic AMP Cyclic-AMP-dependent Protein Kinase (PKA) Mediates Most of the Effects of Cyclic AMP Some G Proteins Signal Via Phospholipids Ca2+ Functions as a Ubiquitous Intracellular Mediator Feedback Generates Ca2+ Waves and Oscillations Ca2+/Calmodulin֊dependent Protein Kinases Mediate Many Responses to Ca2+ Signals Some G Proteins Directly Regulate Ion Channels Smell and Vision Depend on GPCRs That Regulate Ion Channels Nitric Oxide Gas Can Mediate Signaling Between Cells Second Messengers and Enzymatic Cascades Amplify Signals GPCR Desensitization Depends on Receptor Phosphorylation Summary 887 888 890 890 892 892 йот ОУО 895 896 898 899 900 902 904 905 908 909 909 910 SIGNALING THROUGH ENZYME-COUPLED RECEPTORS Activated Receptor Tyrosine Kinases (RTKs) Phosphorylate Themselves Phosphorylated Tyrosines on RTKs Serve as Docking Sites for Intracellular Signaling Proteins Proteins with SH2 Domains Bind to Phosphorylated Tyrosines The Monomeric GTPase Ras Mediates Signaling by Most RTKs Ras Activates a MAP Kinase Signaling Module Scaffold Proteins Reduce Cross-Talk Between Different MAP Kinase Modules Rho Family GTPases Functionally Couple Cell-Surface Receptors to the Cytoskeleton PI
З-Kinase Produces Lipid Docking Sites in the Plasma Membrane The РІ-3-Kinase-Akt Signaling Pathway Stimulates Animal Cells to Survive and Grow RTKs and GPCRs Activate Overlapping Signaling Pathways Some Enzyme-coupled Receptors Associate with Cytoplasmic Tyrosine Kinases Cytokine Receptors Activate the JAK-STAT Signaling Pathway Extracellular Signal Proteins of the TGFß Superfamily Act Through Receptor Serine/Threonine Kinases and Smads Summary 911 ALTERNATIVE SIGNALING ROUTES IN GENE REGULATION The Receptor Notch Is a Latent Transcription Regulator Wnt Proteins Activate Frizzled and Thereby Inhibit ß-Catenin Degradation Hedgehog Proteins Initiate a Complex Signaling Pathway in the Primary Cilium Many Inflammatory and Stress Signals Act Through an NFi B-dependent Signaling Pathway Nuclear Receptors Are Ligand-modulated Transcription Regulators Circadian Clocks Use Negative Feedback Loops to Control Gene Expression Three Purified Proteins Can Reconstitute a Cyanobacterial Circadian Clock in a Test Tube Summary 928 928 SIGNALING IN PLANTS Multicellularity and Cell Communication Evolved Independently in Plants and Animals Receptor Serine/Threonine Kinases Are the Largest Class of Cell-Surface Receptors in Plants Ethylene Blocks the Degradation of Specific Transcription Regulatory Proteins in the Nucleus Regulated Positioning of Auxin Transporters Patterns Plant Growth Phytochromes Detect Red Light, and Cryptochromes Detect Blue Light Summary Problems References 940 911 01 У 1Զ О 913 915 916 918 QI У 1Q У 920 921 923 923 924 926 927 930 932 934 935 937 938 939 940 941 941 943
944 945 946 948 Chapter 16 The Cytoskeleton 949 FUNCTION AND DYNAMICS OF THE CYTOSKELETON Cytoskeletal Filaments Are Dynamic, but Can Nevertheless Form Stable Structures The Cytoskeleton Determines Cellular Organization and Polarity Filaments Assemble from Protein Subunits That Impart Specific Physical and Dynamic Properties Accessory Proteins and Motors Act on Cytoskeletal Filaments Molecular Motors Operate in a Cellular Environment Dominated by Brownian Motion Summary 949 ACTIN Actin Subunits Assemble Head-to-Tail to Create Flexible, Polar Filaments Nucleation Is the Rate-limiting Step in the Formation of Actin Filaments Actin Filaments Have Two Distinct Ends That Grow at Different Rates ATP Hydrolysis Within Actin Filaments Leads to Treadmilling at Steady State The Functions of Actin Filaments Are Inhibited by Both Polymer-stabilizing and Polymer-destabilizing Chemicals Actin-binding Proteins Influence Filament Dynamics and Organization Actin Nucleation Is Tightly Regulated and Generates Branched or Straight Filaments Actin Filament Elongation Is Regulated by Monomer-binding Proteins Actin Filament-binding Proteins Alter Filament Dynamics and Organization Severing Proteins Regulate Actin Filament Depolymerization Bacteria Can Hijack the Host Actin Cytoskeleton Actin at the Cell Cortex Determines Cell Shape Distinct Modes of Cell Migration Rely on the Actin Cytoskeleton Cells Migrating in Three Dimensions Can Navigate Around Barriers Summary 957 951 952 953 955 956 957 958 958 962 962 963 964 964 967 968 970 971 971 972 974 975 MYOSIN AND ACTIN 976 Actin-based Motor
Proteins Are Members of the Myosin Superfamily 976 Myosin Generates Force by Coupling ATP Hydrolysis 977 to Conformational Changes Sliding of Myosin II Along Actin Filaments Causes Muscles 977 to Contract A Sudden Rise in Cytosolic Ca2+ Concentration Initiates Muscle Contraction 981 984 Heart Muscle Is a Precisely Engineered Machine Actin and Myosin Perform a Variety of Functions in Non-Muscle Cells 984 986 Summary MICROTUBULES Microtubules Are Hollow Tubes Made of Protofilaments Microtubules Undergo a Process Called Dynamic Instability Microtubule Functions Are Inhibited by Both Polymer-stabilizing and Polymer-destabilizing Drugs A Protein Complex Containing y-Tubulin Nucleates Microtubules The Centrosome Is a Prominent Microtubule Nucleation Site Microtubule Organization Varies Widely Among Cell Types Microtubule-binding Proteins Modulate Filament Dynamics and Organization Microtubule Plus End-binding Proteins Modulate Microtubule Dynamics and Attachments Tubulin-sequestering and Microtubule-severing Proteins Modulate Microtubule Dynamics Two Types of Motor Proteins Move Along Microtubules Microtubules and Motors Move Organelles and Vesicles Motile Cilia and Flagella Are Built from Microtubules and Dyneins Primary Cilia Perform Important Signaling Functions in Animal Cells Summary INTERMEDIATE FILAMENTS AND OTHER CYTOSKELETAL POLYMERS Intermediate Filament Structure Depends on the Lateral Bundling and Twisting of Colled-Coils Intermediate Filaments Impart Mechanical Stability to Animal Cells Linker Proteins Connect Cytoskeletal Filaments and Bridge the Nuclear Envelope
987 988 988 991 991 991 993 995 996 998 999 1002 1004 1005 1006 1007 1007 1009 1011
CONTENTS Septiris Form Filaments That Contribute to Subcellular Organization 1012 Bacterial Cell Shape and Division Depend on Homologs of Eukaryotic CytoskeletalProteins 1013 Summary 1016 CELL POLARITY AND COORDINATION OF THE CYTOSKELETON Cell Polarity Is Governed by SmallGTPases in Budding Yeast PAR Proteins Generate Anterior-Posterior Polarity in Embryos Conserved Complexes Polarize Epithelial Cells and Control Their Growth Cell Migration Requires Dynamic Cell Polarity External Signals Can Dictate the Direction of Cell Migration Communication Among Cytoskeletal Elements Supports Whole-Cell Polarity and Locomotion Summary Problems References Chapter 17 The Cell Cycle OVERVIEW OF THE CELL CYCLE The Eukaryotic Cell Cycle Usually Consists of Four Phases Cell-Cycle Control Is Similar in All Eukaryotes Cell-Cycle Progression Can Be Studied in Various Ways Summary 1016 1016 1018 1019 1020 1022 1023 1023 1024 1025 1027 1027 1028 1030 1030 1031 THE CELL-CYCLE CONTROL SYSTEM 1031 The Cell-Cycle Control System Triggers the Major Events of the Cell Cycle 1032 The Cell-Cycle Control System Depends on Cyclically Activated Cyclin-dependent Protein Kinases 1033 Protein Phosphatases Reverse the Effects of Cdks 1035 Hundreds of Cdk Substrates Are Phosphorylated in a Defined Order 1035 Positive Feedback Generates the Switchlike Behavior of Cell-Cycle Transitions 1036 The Anaphase-promoting Complex/Cyclosome (APC/C) Triggers the Metaphase֊to-Anaphase Transition 1038 The G i Phase Is a Stable State of Cdk Inactivity 1040 The Cell-Cycle Control System Functions as a Linked Series of
Biochemical Switches 1041 Summary 1042 SPHASE S-Cdk Initiates DNA Replication Once Per Cell Cycle Chromosome Duplication Requires Duplication of Chromatin Structure Cohesins Hold Sister Chromatids Together Summary 1042 1043 1045 1045 1046 MITOSIS 1046 М-Cdk and Other Protein Kinases Drive Entry into Mitosis 1047 Condensin Helps Configure Duplicated Chromosomes for Separation 1047 The Mitotic Spindle Is a Dynamic Microtubule-based Machine 1050 Microtubules Are Nucleated in Multiple Regions of the Spindle 1051 Microtubule Instability Increases Greatly in Mitosis 1052 Microtubule-based Motor Proteins Govern Spindle Assembly and Function 1052 Bipolar Spindle Assembly in Most Animal Cells Begins with Centrosome Duplication 1053 Spindle Assembly in Animal Cells Requires Nuclear-Envelope Breakdown 1054 Mitotic Chromosomes Promote Bipolar Spindle Assembly 1055 Kinetochores Attach Sister Chromatids to the Spindle 1056 Bi-orientation Is Achieved by Trial and Error 1057 Multiple Forces Act on Chromosomes in the Spindle 1059 The APC/C Triggers Sister-Chromatid Separation and the Completion of Mitosis 1060 Unattached Chromosomes Block Sister-Chromatid Separation: The Spindle Assembly Checkpoint 1062 Chromosomes Segregate in Anaphase A and В 1062 Segregated Chromosomes Are Packaged in Daughter Nuclei at Telophase 1063 Summary 1064 CYTOKINESIS 1064 xxxv Actin and Myosin II in the Contractile Ring Guide the Process of 1065 Cytokinesis Local Activation of RhoA Triggers Assembly and Contraction of the Contractile Ring 1065 The Microtubules of the Mitotic Spindle Determine the Plane of Animal
Cell Division 1066 The Phragmoplast Guides Cytokinesis in Higher Plants 1068 Membrane-enclosed Organelles Must Be Distributed to Daughter Cells During Cytokinesis 1069 Some Cells Reposition Their Spindle to Divide Asymmetrically 1069 Mitosis Can Occur Without Cytokinesis 1070 Summary 1070 MEIOSIS 1071 Meiosis Includes Two Rounds of Chromosome Segregation 1071 Duplicated Homologs Pair During Meiotic Prophase 1073 Homolog Pairing Culminates in the Formation of a Synaptonemal Complex 1073 Homolog Segregation Depends on Several Unique Features of Meiosis I 1075 Crossing-Over Is Highly Regulated 1076 Meiosis Frequently Goes Wrong 1077 Summary 1077 CONTROL OF CELL DIVISION AND CELL GROWTH 1077 Mitogens Stimulate Cell Division 1078 Cells Can Enter a Specialized Nondividing State 1078 Mitogens Stimulate G,-Cdk and G,/S-Cdk Activities 1079 DNA Damage Blocks Cell Division 1080 Many Human Cells Have a Built-In Limitation on the Number of Times They Can Divide 1082 Cell Proliferation Is Accompanied by Cell Growth 1083 Proliferating Cells Usually Coordinate Their Growth and Division 1084 Summary 1084 Problems 1085 References 1087 Chapter 18 Cell Death 1089 Apoptosis Eliminates Unwanted Cells 1090 Apoptosis Depends on an Intracellular Proteolytic Cascade Mediated by Caspases 1091 Activation of Cell-Surface Death Receptors Initiates the Extrinsic Pathway of Apoptosis 1093 The Intrinsic Pathway of Apoptosis Depends on Proteins Released from Mitochondria 1094 Bcl2 Proteins Are the Critical Controllers of the Intrinsic Pathway of Apoptosis 1095 An Inhibitor of Apoptosis (an IAP) and Two
Anti-IAP Proteins Help Control Caspase Activation in the Cytosol of Some Mammalian Cells 1098 Extracellular Survival Factors Inhibit Apoptosis in Various Ways 1098 Healthy Neighbors Phagocytose and Digest Apoptotic Cells 1100 Either Excessive or Insufficient Apoptosis Can Contribute to Disease 1100 Summary 1102 Problems 1103 References 1104 Chapter 19 Cell Junctions and the Extracellular Matrix 1105 CELL-CELL JUNCTIONS 1108 Cadherins Form a Diverse Family of Adhesion Molecules 1108 Cadherins Mediate Homophilic Adhesion 1108 Cadherin-dependent Cell-Cell Adhesion Guides the Organization of Developing Tissues 1110 Assembly of Strong Cell-Cell Adhesions Requires Changes in the Actin Cytoskeleton 1112 Catenins Link Classical Cadherins to the Actin Cytoskeleton 1113 Adherens Junctions Respond to Tension from Inside and Outside the Tissue 1113 Tissue Remodeling Depends on the Coordination of Actin-mediated Contraction with Cell-Cell Adhesion 1114 Desmosomes Give Epithelia Mechanical Strength 1116 Tight Junctions Form a Seal Between Cells and a Fence Between Plasma Membrane Domains 1116
xxxvi CONTENTS Tight Junctions Contain Strands of Transmembrane Adhesion Proteins 1119 Scaffold Proteins Organize Junctional Protein Complexes 1120 Gap Junctions Couple Cells Both Electrically and Metabolically 1121 A Gap-Junction Connexon Is Made of Six Transmembrane Connexin Subunits 1122 In Plants, Plasmodesmata Perform Many of the Same Functions as Gap Junctions 1123 Selectins Mediate Transient Cell-Cell Adhesions in the Bloodstream 1125 Members of the Immunoglobulin Superfamily Mediate Ca2+independent Cell-Cell Adhesion 1126 Summary 1127 THE EXTRACELLULAR MATRIX OF ANIMALS 1127 The Extracellular Matrix Is Made and Oriented by the Cells Within It 1128 Glycosaminoglycan (GAG) Chains Occupy Large Amounts of Space and Form Hydrated Gels 1129 Hyaluronan Acts as a Space Filler During Tissue Morphogenesis and Repair 1129 Proteoglycans Are Composed of GAG Chains Covalently Linked to a Core Protein 1130 Collagens Are the Major Proteins of the Extracellular Matrix 1132 Collagen Chains Undergo a Series of Post-translational Modifications 1133 Secreted Fibril-associated Collagens Help Organize the Fibrils 1135 Elastin Gives Tissues Their Elasticity 1136 Cells Govern and Respond to the Mechanical Properties of the Matrix 1137 Fibronectin and Other Multidomain Glycoproteins Help Organize the Matrix 1138 Fibronectin Binds to Integrins 1139 Tension Exerted by Cells Regulates the Assembly of Fibronectin Fibrils 1140 The Basal Lamina Is a Specialized Form of Extracellular Matrix 1141 Laminin and Type IV Collagen Are Major Components of the Basal Lamina 1141 Basal Laminae Have Diverse
Functions 1143 Cells Have to Be Able to Degrade Matrix, as Well as Make It 1144 Matrix Proteoglycans and Glycoproteins Regulate the Activities of Secreted Proteins 1145 Summary 1146 CELL-MATRIX JUNCTIONS 1147 Integrins Are Transmembrane Heterodimers That Link the Extracellular Matrix to the Cytoskeleton 1147 Integrin Defects Are Responsible for Many Genetic Diseases 1148 Integrins Can Switch Between an Active and an Inactive Conformation 1149 Integrins Cluster to Form Strong Adhesions 1151 Extracellular Matrix Attachments Act Through Integrins to Control Cell Proliferation and Survival 1151 Integrins Recruit Intracellular Signaling Proteins at Sites of Cell-Matrix Adhesion 1152 Cell-Matrix Adhesions Respond to Mechanical Forces 1153 Summary 1154 THE PLANT CELL WALL 1154 The Composition of the Cell Wall Depends on the Cell Type 1155 The Tensile Strength of the Cell Wall Allows Plant Cells to Develop Turgor Pressure 1155 The Primary Cell Wall Is Built from Cellulose Microfibrils Interwoven with a Network of Pectic Polysaccharides 1156 Oriented Cell Wall Deposition Controls Plant Cell Growth 1157 Microtubules Orient Cell Wall Deposition 1158 Summary 1159 Problems 1160 References 1162 Chapter 20 Cancer CANCER AS A MICROEVOLUTIONARY PROCESS Cancer Cells Bypass Normal Proliferation Controls and Colonize Other Tissues Most Cancers Derive from a Single Abnormal Cell 1163 1163 1164 1165 Cancer Cells Contain Somatic Mutations 1166 A Single Mutation Is Not Enough to Change a Normal Cell into a Cancer Cell 1166 Many Cancers Develop Gradually Through Successive Rounds of Random
Inherited Change Followed by Natural Selection 1167 Cancers Can Evolve Abruptly Due to Genetic Instability 1168 Some Cancers May Harbor a Small Population of Stem Cells 1170 A Common Set of Hallmarks Typically Characterizes Cancerous Growth 1171 Cancer Cells Display an Altered Control of Growth and Homeostasis 1172 Human Cancer Cells Escape a Built-in Limit to Cell Proliferation 1173 Cancer Cells Have an Abnormal Ability to Bypass Death Signals 1174 Cancer Cells Have Altered Sugar Metabolism 1175 The Tumor Microenvironment Influences Cancer Development 1175 Cancer Cells Must Survive and Proliferate in a Foreign Environment 1176 Summary 1178 CANCER-CRITICAL GENES: HOW THEY ARE FOUND AND WHAT THEY DO 1178 The Identification of Gain-of-Function and Loss-of-Function Cancer Mutations Has Traditionally Required Different Methods 1179 Retroviruses Led to the Identification of Oncogenes 1180 Genes Mutated in Cancer Can Be Made Overactive in Many Ways 1181 Studies of Rare Hereditary Cancer Syndromes First Identified Tumor Suppressor Genes 1182 Both Genetic and Epigenetic Mechanisms Can Inactivate Tumor Suppressor Genes 1183 Systematic Sequencing of Cancer Cell Genomes Has Transformed Our Understanding of the Disease 1184 Many Cancers Have an Extraordinarily Disrupted Genome 1185 Epigenetic and Chromatin Changes Contribute to Most Cancers 1185 Hundreds of Human Genes Contribute to Cancer 1186 Disruptions in a Handful of Key Pathways Are Common to Many Cancers 1187 Mutations in the PI 3-kinase/Akt/mTOR Pathway Drive Cancer Cells to Grow 1188 Mutations in the p53 Pathway Enable Cancer
Cells to Survive and Proliferate Despite Stress and DNA Damage 1189 Studies Using Mice Help to Define the Functions of Cancer-critical Genes 1190 Cancers Become More and More Heterogeneous as They Progress 1192 Colorectal Cancers Evolve Slowly Via a Succession of Visible Changes 1192 A Few Key Genetic Lesions Are Common to a Large Fraction of Colorectal Cancers 1194 Some Colorectal Cancers Have Defects in DNA Mismatch Repair 1195 The Steps of Tumor Progression Can Often Be Correlated with Specific Mutations 1196 The Changes in Tumor Cells That Lead to Metastasis Are Still Largely a Mystery 1197 Summary 1197 CANCER PREVENTION AND TREATMENT: PRESENT AND FUTURE 1198 Epidemiology Reveals That Many Cases of Cancer Are Preventable 1198 Sensitive Assays Can Detect Those Cancer-causing Agents That Damage DNA 1199 Fifty Percent of Cancers Could Be Prevented by Changes in Lifestyle 1200 Viruses and Other Infections Contribute to a Significant Proportion of Human Cancers 1201 Cancers of the Uterine Cervix Can Be Prevented by Vaccination Against Human Papillomavirus 1202 Infectious Agents Can Cause Cancer in a Variety of Ways 1203 The Search for Cancer Cures Is Difficult but Not Hopeless 1204 Traditional Therapies Exploit the Genetic Instability and Loss of Cell-Cycle Checkpoint Responses in Cancer Cells 1204 New Drugs Can Kill Cancer Cells Selectively by Targeting Specific Mutations 1204 PARP Inhibitors Kill Cancer Cells That Have Defects in Brcal or Brca2 Genes 1205
CONTENTS Small Molecules Can Be Designed to Inhibit Specific Oncogenic Proteins Many Cancers May Be Treatable by Enhancing Immune Responses Immunosuppression Is a Major Hurdle for Cancer Immunotherapy Cancers Evolve Resistance to Therapies We Now Have the Tools to Devise Combination Therapies Tailored to the Individual Summary Problems References Chapter 21 Development of Multicellular Organisms 1207 1209 1210 1212 1212 1213 1214 1216 1217 OVERVIEW OF DEVELOPMENT 1218 Conserved Mechanisms Establish the Core Tissues of Animals 1218 The Developmental Potential of Cells Becomes Progressively Restricted 1219 Cell Memory Underlies Cell Decision-Making 1220 Several Model Organisms Have Been Crucial for Understanding Development 1220 Regulatory DNA Seems Largely Responsible for the Differences Between Animal Species 1220 Small Numbers of Conserved Cell-Cell Signaling Pathways Coordinate Spatial Patterning 1221 Through Combinatorial Control and Cell Memory, Simple Signals Can Generate Complex Patterns 1221 Morphogens Are Diffusible Inductive Signals That Exert Graded Effects 1222 Lateral Inhibition Can Generate Patterns of Different Cell Types 1223 Asymmetric Cell Division Can Also Generate Diversity 1224 Initial Patterns Are Established in Small Fields of Cells and Refined by Sequential Induction as the Embryo Grows 1225 Developmental Biology Provides Insights into Disease and Tissue Maintenance 1225 Summaiy 1226 MECHANISMS OF PATTERN FORMATION 1226 Different Animals Use Different Mechanisms to Establish Their Primary Axes of Polarization 1226 Studies in Drosophila Have Revealed
Many Genetic Control Mechanisms Underlying Development 1228 Gene Products Deposited in the Egg Organize the Axes of the Early Drosophila Embryo 1228 Three Groups of Genes Control Drosophila Segmentation Along the A- P Axis 1230 A Hierarchy of Gene Regulatory Interactions Subdivides the Drosophila Embryo 1231 Egg-Polarity, Gap, and Pair-Rule Genes Create a Transient Pattern That Is Remembered by Segment-Polarity and Hox Genes 1233 Hox Genes Permanently Pattern the А-P Axis 1233 Hox Proteins Give Each Segment Its Individuality 1234 Hox Genes Are Expressed According to Their Order in the Hox Complex 1234 Trithorax and Polycomb Group Proteins Regulate Hox Expression to Maintain a Permanent Record of Positional Information 1235 The D-V Signaling Genes Create a Gradient of the Transcription Regulator Dorsal 1236 A Hierarchy of Inductive Interactions Subdivides the Vertebrate Embryo 1238 A Competition Between Secreted Signaling Proteins Patterns the Vertebrate Embryonic Axes 1239 Hox Genes Control the Vertebrate А-P Axis 1240 Some Transcription Regulators Can Activate a Program That Defines a Cell Type or Creates an Entire Organ 1241 Notch-mediated Lateral Inhibition Refines Cellular Spacing Patterns 1242 Cell-fate Determinants Can Be Asymmetrically Inherited 1244 Evolution of Regulatory DNA Explains Many Morphological Differences 1245 Summary 1247 DEVELOPMENTAL TIMING Molecular Lifetimes Play a Critical Part in Developmental Timing 1248 1248 xxxvii A Gene Expression Oscillator Acts as a Clock to Control Vertebrate Segmentation 1249 Cell-intrinsic Timing Mechanisms Can Lead to
Different Cell Fates 1251 Cells Rarely Count Cell Divisions to Time Their Development 1252 MicroRNAs Can Regulate Developmental Transitions 1252 Cell and Nuclear Size Relationships Schedule the Onset of Zygotic Gene Expression 1254 Hormonal Signals Coordinate the Timing of Developmental Transitions 1255 Environmental Cues Determine the Time of Flowering 1256 Summary 1257 MORPHOGENESIS 1257 Imbalance in Physical Forces Acting on Cells Drives Morphogenesis 1258 Tension and Adhesion Determine Cell Packing Within Epithelial Sheets 1258 Changing Patterns of Cell Adhesion Molecules Force Cells into New Arrangements 1259 Repulsive Interactions Help Maintain Tissue Boundaries 1259 Groups of Similar Cells Can Perform Dramatic Collective Rearrangements 1261 Planar Cell Polarity Orients Cell Behaviors Within an Embryo 1261 An Epithelium Can Bend During Development to Form a Tube 1263 Interactions Between an Epithelium and Mesenchyme Generate Branching Tubular Structures 1264 The Extracellular Matrix Also Influences Tissue Shape 1265 Cell Migration Is Guided by Environmental Signals 1266 The Distribution of Migrant Cells Depends on Survival Factors 1267 Cells Migrate in Groups to Achieve Large-Scale Morphogenetic Movements 1268 Summary 1269 GROWTH 1269 The Proliferation, Death, and Size of Cells Determine Organ and Organism Size 1270 Changes in Cell Size Usually Result from Modified Cell Cycles 1271 Animals and Organs Can Assess and Regulate Total Cell Mass 1272 Various Extracellular Signals Stimulate or Inhibit Growth 1273 The Hippo Pathway Relays Mechanical Signals Regulating Growth
1273 Hormones Coordinate Growth Throughout the Body 1274 The Duration of Growth Influences Organism Size 1275 Summary 1275 Problems 1276 References 1278 Chapter 22 Stem Cells in Tissue Homeostasis and Regeneration 1279 STEM CELLS AND TISSUE HOMEOSTASIS 1279 Stem Cells Are Defined by Their Ability to Self-renew and Produce Differentiated Cells 1280 The Epithelial Lining of the Small Intestine Is Continually Renewed Through Cell Proliferation in Crypts 1281 Epidermal Stem Cells Maintain a Self-renewing, Waterproof, Epithelial Barrier on the Body Surface 1282 Cell Lineage Tracing Reveals the Location of Stem Cells and Their Progeny 1284 Quiescent Stem Cells Are Difficult to Identify by Lineage Tracing 1285 Hematopoietic Stem Cells Can Be Identified by Transplantation 1286 Some Tissues Do Not Require Stem Cells for Their Maintenance 1289 In Response to Injury, Some Differentiated Cells Can Revert to Progenitor Cells and Some Progenitor Cells Can Revert to Stem Cells 1289 Some Tissues Lack Stem Cells and Are Not Renewable 1290 Summary 1290 CONTROL OF STEM-CELL FATE AND SELF-RENEWAL 1291 The Stem-Cell Niche Maintains Stem-Cell Self-Renewal 1291 The Size of the Niche Can Determine the Number of Stem Cells 1292 Asymmetric Stem-Cell Division Can Maintain Stem-Cell Number 1293 In Many Symmetric Stem-Cell Divisions, Daughter Cells Choose Their Fates Independently and Stochastically 1294 A Decline in Stem-Cell Function Contributes to Tissue Aging 1294
xxxviii CONTENTS Summary 1296 REGENERATION AND REPAIR 1296 Planarian Flatworms Contain Stem Cells That Can Regenerate a Whole New Body 1297 Some Vertebrates Can Regenerate Entire Limbs and Organs 1298 Stem Cells Can Be Used Clinically to Replace Lost Hematopoietic or Skin Cells 1299 Neural Stem Cells Can Be Manipulated in Culture and Used to Repopulate a Diseased Central Nervous System 1299 Summary 1300 CELL REPROGRAMMING AND PLURIPOTENTSTEM CELLS 1300 Nuclei Can Be Reprogrammed by Transplantation into Foreign Cytoplasm 1301 Reprogramming of a Transplanted Nucleus Involves Drastic Changes in Chromatin 1301 Embryonic Stem (ES) Cells Can Generate Any Part of the Body 1302 A Core Set of Transcription Regulators Defines and Maintains the ES֊Cell State 1303 Fibroblasts Can Be Reprogrammed to Create Induced Pluripotent Stem (¡PS) Cells 1303 Reprogramming Involves a Massive Upheaval of the Gene Control System 1304 An Experimental Manipulation of Factors That Modify Chromatin Can Increase Reprogramming Efficiencies 1305 ES and ÌPS Cells Can Be Guided to Generate Specific Adult Cell Types and Even Organoids 1306 Cells of One Specialized Type Can Be Forced to Transdifferentiate Directly into Another 1306 ES and ÌPS Cells Are Also Useful for Drug Discovery and Analysis of Disease 1308 Summary 1309 Problems 1310 References 1312 Chapter 23 Pathogens and Infection 1313 INTRODUCTION TO PATHOGENS 1313 Pathogens Can Be Viruses, Bacteria, or Eukaryotes 1314 Pathogens Interact with Their Hosts in Different Ways 1314 Bacteria Are Diverse and Occupy a Remarkable Variety of Ecological Niches
1315 Bacterial Pathogens Carry Specialized Virulence Genes 1317 Bacterial Virulence Genes Encode Toxins and Secretion Systems That Deliver Effector Proteins to Host Cells 1319 Fungal and Protozoan Parasites Have Complex Life Cycles Involving Multiple Forms 1321 All Aspects of Viral Propagation Depend on Host-Cell Machinery 1322 Summary 1325 CELL BIOLOGY OF PATHOGEN INFECTION 1325 Pathogens Breach Epithelial Barriers to Infectthe Host 1326 Pathogens That Colonize an Epithelium Must Overcome Its Protective Mechanisms 1326 Extracellular Pathogens Use Toxins and Contact-dependent Secretion Systems to Disturb Host Cells Without Entering Them 1328 Intracellular Pathogens Have Mechanisms for Both Entering and Leaving Host Cells 1329 Viruses Bind to Virus Receptors at the Host-Cell Surface 1329 Viruses Enter Host Cells by Membrane Fusion, Pore Formation, or Membrane Disruption 1330 Bacteria Enter Host Cells by Phagocytosis 1331 Intracellular Eukaryotic Parasites Actively Invade Host Cells 1333 Some Intracellular Pathogens Escape from the Phagosome into the Cytosol 1334 Many Pathogens Alter Membrane Traffic in the Host Cell to Survive and Replicate 1335 Bacteria and Viruses Use the Host-Cell Cytoskeleton for Intracellular Movement 1338 Many Microbes Manipulate Autophagy 1340 Viruses Can Take Over the Metabolism of the Host Cell 1340 Pathogens Can Evolve Rapidly by Antigenic Variation 1341 Error-prone Replication Dominates Viral Evolution 1343 Drug-resistant Pathogens Are a Growing Problem 1344 Summary 1346 THE HUMAN MICROBIOTA The Human Microbiota Is a Complex Ecological System The
Microbiota Influences Our Developmentand Health Summary Problems References Chapter 24 The Innate and Adaptive Immune Systems 1347 1347 1348 1349 1350 1351 1353 THE INNATE IMMUNE SYSTEM 1354 Epithelial Surfaces Serve as Barriers to Infection 1354 Pattern Recognition Receptors (PRRs) Recognize Conserved Features of Pathogens 1354 There Are Multiple Families of PRRs 1355 Activated PRRs Trigger an Inflammatory Response at Sites of Infection 1356 Phagocytic Cells Seek, Engulf, and Destroy Pathogens 1358 Complement Activation Targets Pathogens for Phagocytosis or Lysis 1358 Virus-infected Cells Take Drastic Measures to Prevent Viral Replication 1360 Natural Killer Cells Induce Virus-infected Cells to Kill Themselves 1361 Dendritic Ceils Provide the Link Between the Innate and Adaptive Immune Systems 1362 Summary 1362 OVERVIEW OF THE ADAPTIVE IMMUNE SYSTEM 1364 В Cells Develop in the Bone Marrow, T Cells in the Thymus 1365 Immunological Memory Depends on Both Clonal Expansion and Lymphocyte Differentiation 1366 Most В and T Cells Continually Recirculate Through Peripheral Lymphoid Organs 1368 Immunological Self-tolerance Ensures That В and T Cells Do Not Attack Normal Host Cells and Molecules 1370 Summary 1372 В CELLS AND IMMUNOGLOBULINS 1372 В Cells Make Immunoglobulins (Igs) as Both Cell-Surface Antigen Receptors and Secreted Antibodies 1373 Mammals Make Five Classes of Igs 1373 Ig Light and Heavy Chains of Antibodies Consist of Constant and Variable Regions 1375 Ig Genes Are Assembled from Separate Gene Segments During В Cell Development 1377 Antigen-driven Somatic
Hypermutation Fine-Tunes Antibody Responses 1379 В Cells Can Switch the Class of Ig They Make 1379 Summary 1381 T CELLS AND MHC PROTEINS 1382 T Cell Receptors (TCRs) Are lg-like Heterodimers 1382 Activated Dendritic Cells Activate Naive T Cells 1383 T Cells Recognize Foreign Peptides Bound to MHC Proteins 1384 MHC Proteins Are the Most Polymorphic Human Proteins Known 1388 CD4 and CD8 Co-receptors on T Cells Bind to Invariant Parts of MHC Proteins 1389 Developing Thymocytes Undergo Positive and Negative Selection 1389 Cytotoxic T Cells Induce Infected Target Cells to Undergo Apoptosis 1391 Effector Helper T Cells Help Activate Other Cells of the Innate and Adaptive Immune Systems 1392 Naive Helper T Cells Can Differentiate into Different Types of Effector T Cells 1393 Both T and В Cells Require Multiple Extracellular Signals for Activation 1394 Many Cell-Surface Proteins Belong tothe Ig Superfamily 1396 Vaccination Against Pathogens Has Been Immunology’s Greatest Contributionto HumanHealth 1396 Summary 1400 Problems 1402 References 1404 Glossary Index G:1 Г.1
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| any_adam_object | 1 |
| author | Alberts, Bruce 1938- Heald, Rebecca 1963- Johnson, Alexander 1968- Morgan, David 1958- Raff, Martin 1938- Roberts, Keith 1945- Walter, Peter 1954- |
| author_GND | (DE-588)111053013 (DE-588)1081954698 (DE-588)1089764340 (DE-588)173873553 (DE-588)1130334937 (DE-588)1130343138 (DE-588)1130343545 (DE-588)124923429 |
| author_facet | Alberts, Bruce 1938- Heald, Rebecca 1963- Johnson, Alexander 1968- Morgan, David 1958- Raff, Martin 1938- Roberts, Keith 1945- Walter, Peter 1954- |
| author_role | aut aut aut aut aut aut aut |
| author_sort | Alberts, Bruce 1938- |
| author_variant | b a ba r h rh a j aj d m dm m r mr k r kr p w pw |
| building | Verbundindex |
| bvnumber | BV047885036 |
| classification_rvk | WE 2400 WD 4150 WE 1000 WE 2401 |
| classification_tum | BIO 200 |
| ctrlnum | (ELiSA)ELiSA-9780393884852 (OCoLC)1310640551 (DE-599)HBZHT021228713 |
| discipline | Biologie |
| edition | Seventh edition, international student edition |
| format | Book |
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| genre | (DE-588)4123623-3 Lehrbuch gnd-content |
| genre_facet | Lehrbuch |
| geographic | Zelle (DE-588)1072011069 gnd |
| geographic_facet | Zelle |
| id | DE-604.BV047885036 |
| illustrated | Illustrated |
| indexdate | 2024-12-20T19:31:18Z |
| institution | BVB |
| isbn | 9780393884852 9780393884821 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-033267276 |
| oclc_num | 1310640551 |
| open_access_boolean | |
| owner | DE-20 DE-703 DE-19 DE-BY-UBM DE-91G DE-BY-TUM DE-M49 DE-BY-TUM DE-384 DE-83 DE-11 DE-355 DE-BY-UBR DE-29T DE-578 DE-634 DE-29 DE-188 |
| owner_facet | DE-20 DE-703 DE-19 DE-BY-UBM DE-91G DE-BY-TUM DE-M49 DE-BY-TUM DE-384 DE-83 DE-11 DE-355 DE-BY-UBR DE-29T DE-578 DE-634 DE-29 DE-188 |
| physical | xxxviii, 1404, G:37, I:70 Seiten Illustrationen, Diagramme |
| publishDate | 2022 |
| publishDateSearch | 2022 |
| publishDateSort | 2022 |
| publisher | W.W. Norton & Company |
| record_format | marc |
| spellingShingle | Alberts, Bruce 1938- Heald, Rebecca 1963- Johnson, Alexander 1968- Morgan, David 1958- Raff, Martin 1938- Roberts, Keith 1945- Walter, Peter 1954- Molecular biology of the cell Molekularbiologie (DE-588)4039983-7 gnd Cytologie (DE-588)4070177-3 gnd |
| subject_GND | (DE-588)4039983-7 (DE-588)4070177-3 (DE-588)1072011069 (DE-588)4123623-3 |
| title | Molecular biology of the cell |
| title_alt | The cell |
| title_auth | Molecular biology of the cell |
| title_exact_search | Molecular biology of the cell |
| title_full | Molecular biology of the cell Bruce Alberts, Rebecca Heald, Alexander Johnson, David Morgan, Martin Raff, Keith Roberts, Peter Walter ; with problems by John Wilson, Tim Hunt |
| title_fullStr | Molecular biology of the cell Bruce Alberts, Rebecca Heald, Alexander Johnson, David Morgan, Martin Raff, Keith Roberts, Peter Walter ; with problems by John Wilson, Tim Hunt |
| title_full_unstemmed | Molecular biology of the cell Bruce Alberts, Rebecca Heald, Alexander Johnson, David Morgan, Martin Raff, Keith Roberts, Peter Walter ; with problems by John Wilson, Tim Hunt |
| title_short | Molecular biology of the cell |
| title_sort | molecular biology of the cell |
| topic | Molekularbiologie (DE-588)4039983-7 gnd Cytologie (DE-588)4070177-3 gnd |
| topic_facet | Molekularbiologie Cytologie Zelle Lehrbuch |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=033267276&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT albertsbruce molecularbiologyofthecell AT healdrebecca molecularbiologyofthecell AT johnsonalexander molecularbiologyofthecell AT morgandavid molecularbiologyofthecell AT raffmartin molecularbiologyofthecell AT robertskeith molecularbiologyofthecell AT walterpeter molecularbiologyofthecell AT wilsonjohn molecularbiologyofthecell AT hunttim molecularbiologyofthecell AT albertsbruce thecell AT healdrebecca thecell AT johnsonalexander thecell AT morgandavid thecell AT raffmartin thecell AT robertskeith thecell AT walterpeter thecell AT wilsonjohn thecell AT hunttim thecell |
Branch Library Chemistry, Textbook Collection
Branch Library Chemistry
| Call Number: | 0304 BIO 200 1989 B 782(7) |
|---|---|
| Copy 1 | Not available for loan On Shelf |
Branch Library Weihenstephan, Textbook Collection
Branch Library Weihenstephan
| Call Number: | 1004 BIO 200 2008 B 921(7) |
|---|---|
| Copy 1 | Not available for loan On Shelf |