ESSENTIAL

CELL BIOLOGY

FIFTH EDITION
 FI F T H
ED I T I O N

ESSENTIAL

CELL BIOLOGY
Bruce Alberts
UNIVERSIT Y OF CALIFORNIA, SAN FRANCISCO

Karen Hopkin
SCIENCE WRITER

Alexander Johnson
UNIVERSIT Y OF CALIFORNIA, SAN FRANCISCO

David Morgan
UNIVERSIT Y OF CALIFORNIA, SAN FRANCISCO

Martin Raff
UNIVERSIT Y COLLEGE LONDON (EMERITUS)

Keith Roberts
UNIVERSIT Y OF EAST ANGLIA (EMERITUS)

Peter Walter
UNIVERSIT Y OF CALIFORNIA, SAN FRANCISCO

n 
W . W . N O R T O N & C O M PA N Y
NE W YORK • LONDON
W. W. Norton & Company has been independent since its founding in 1923, when William
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Copyright © 2019 by Bruce Alberts, Dennis Bray, Karen Hopkin, Alexander Johnson, the Estate of Julian
Lewis, David Morgan, Martin Raff, Nicole Marie Odile Roberts, and Peter Walter

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Library of Congress Cataloging-in-Publication Data

Names: Alberts, Bruce, author.

Title: Essential cell biology / Bruce Alberts, Karen Hopkin, Alexander
Johnson, David Morgan, Martin Raff, Keith Roberts, Peter Walter.
Description: Fifth edition. | New York : W.W. Norton & Company, [2019] |
Includes index.
Identifiers: LCCN 2018036121 | ISBN 9780393679533 (hardcover)
Subjects: LCSH: Cytology. | Molecular biology. | Biochemistry.
Classification: LCC QH581.2 .E78 2019 | DDC 571.6—dc23 LC record available at
https://lccn.loc.gov/2018036121

W. W. Norton & Company, Inc., 500 Fifth Avenue, New York, NY 10110
wwnorton.com
W. W. Norton & Company Ltd., 15 Carlisle Street, London W1D 3BS

1 2 3 4 5 6 7 8 9 0
PREFACE

Nobel Prize–winning physicist Richard Feynman once noted that nature

has a far, far better imagination than our own. Few things in the universe
illustrate this observation better than the cell. A tiny sac of molecules
capable of self-replication, this marvelous structure constitutes the fun-
damental building block of life. We are made of cells. Cells provide all
the nutrients we consume. And the continuous activity of cells makes
our planet habitable. To understand ourselves—and the world of which
we are a part—we need to know something of the life of cells. Armed
with such knowledge, we—as citizens and stewards of the global
community—will be better equipped to make well-informed decisions
about increasingly sophisticated issues, from climate change and food
security to biomedical technologies and emerging epidemics.
In Essential Cell Biology we introduce readers to the fundamentals of
cell biology. The Fifth Edition introduces powerful new techniques that
allow us to examine cells and their components with unprecedented
precision—such as super-resolution fluorescence microsocopy and
cryoelectron microscopy—as well as the latest methods for DNA
sequencing and gene editing. We discuss new thinking about how cells
organize and encourage the chemical reactions that make life possible,
and we review recent insights into human origins and genetics.
With each edition of Essential Cell Biology, its authors re-experience the
joy of learning something new and surprising about cells. We are also
reminded of how much we still don’t know. Many of the most fascinat-
ing questions in cell biology remain unanswered. How did cells arise on
the early Earth, multiplying and diversifying through billions of years of
evolution to fill every possible niche—from steaming vents on the ocean
floor to frozen mountaintops—and, in doing so, transform our planet’s
entire environment? How is it possible for billions of cells to seamlessly
cooperate and form large, multicellular organisms like ourselves? These
are among the many challenges that remain for the next generation of
cell biologists, some of whom will begin a wonderful, lifelong journey
with this textbook.
Readers interested in learning how scientific inquisitiveness can fuel break-
throughs in our understanding of cell biology will enjoy the stories of dis-
covery presented in each chapter’s “How We Know” feature. Packed with
experimental data and design, these narratives illustrate how biologists
tackle important questions and how experimental results shape future
ideas. In this edition, a new “How We Know” recounts the discoveries that
first revealed how cells transform the energy locked in food molecules into
the forms used to power the metabolic reactions on which life depends.
As in previous editions, the questions in the margins and at the end of
each chapter not only test comprehension but also encourage careful
thought and the application of newly acquired information to a broader
biological context. Some of these questions have more than one valid
v
vi Preface

answer and others invite speculation. Answers to all of the questions

are included at the back of the book, and many provide additional
information or an alternative perspective on material presented in the
main text.
More than 160 video clips, animations, atomic structures, and high-
resolution micrographs complement the book and are available online.
The movies are correlated with each chapter and callouts are highlighted
in color. This supplemental material, created to clarify complex and critical
concepts, highlights the intrinsic beauty of living cells.

For those who wish to probe even more deeply, Molecular Biology of
the Cell, now in its sixth edition, offers a detailed account of the life of
the cell. In addition, Molecular Biology of the Cell, Sixth Edition: A Prob-
lems Approach, by John Wilson and Tim Hunt, provides a gold mine of
thought-provoking questions at all levels of difficulty. We have drawn
upon this tour-de-force of experimental reasoning for some of the ques-
tions in Essential Cell Biology, and we are very grateful to its authors.

Every chapter of Essential Cell Biology is the product of a communal effort:

both text and figures were revised and refined as drafts circulated from
one author to another—many times over and back again! The numer-
ous other individuals who have helped bring this project to fruition are
credited in the Acknowledgments that follow. Despite our best efforts, it
is inevitable that errors will have crept into the book, and we encourage
eagle-eyed readers who find mistakes to let us know, so that we can
correct them in the next printing.

Acknowledgments
The authors acknowledge the many contributions of professors and
students from around the world in the creation of this Fifth Edition. In
particular, we received detailed reviews from the following instructors
who had used the fourth edition, and we would like to thank them for
their important contributions to our revision:
Delbert Abi Abdallah, Thiel College, Pennsylvania
Ann Aguanno, Marymount Manhattan College
David W. Barnes, Georgia Gwinnett College
Manfred Beilharz, The University of Western Australia
Christopher Brandl, Western University, Ontario
Marion Brodhagen, Western Washington University
David Casso, San Francisco State University
Shazia S. Chaudhry, The University of Manchester, United Kingdom
Ron Dubreuil, The University of Illinois at Chicago
Heidi Engelhardt, University of Waterloo, Canada
Sarah Ennis, University of Southampton, United Kingdom
David Featherstone, The University of Illinois at Chicago
Yen Kang France, Georgia College
Barbara Frank, Idaho State University
Daniel E. Frigo, University of Houston
Marcos Garcia-Ojeda, University of California, Merced
David L. Gard, The University of Utah
Adam Gromley, Lincoln Memorial University, Tennessee
Elly Holthuizen, University Medical Center Utrecht, The Netherlands
Harold Hoops, The State University of New York, Geneseo
Bruce Jensen, University of Jamestown, North Dakota
Andor Kiss, Miami University, Ohio
Annette Koenders, Edith Cowan University, Australia
Arthur W. Lambert, Whitehead Institute for Biomedical Research
Denis Larochelle, Clark University, Massachusetts
David Leaf, Western Washington University
Esther Leise, The University of North Carolina at Greensboro
Bernhard Lieb, University of Mainz, Germany
 Preface vii

Julie Lively, Louisiana State University

Caroline Mackintosh, University of Saint Mary, Kansas
John Mason, The University of Edinburgh, Scotland
Craig Milgrim, Grossmont College, California
Arkadeep Mitra, City College, Kolkata, India
Niels Erik Møllegaard, University of Copenhagen
Javier Naval, University of Zaragoza, Spain
Marianna Patrauchan, Oklahoma State University
Amanda Polson-Zeigler, University of South Carolina
George Risinger, Oklahoma City Community College
Laura Romberg, Oberlin College, Ohio
Sandra Schulze, Western Washington University
Isaac Skromne, University of Richmond, Virginia
Anna Slusarz, Stephens College, Missouri
Richard Smith, University of Tennessee Health Science Center
Alison Snape, King’s College London
Shannon Stevenson, University of Minnesota Duluth
Marla Tipping, Providence College, Rhode Island
Jim Tokuhisa, Virginia Polytechnic Institute and State University
Guillaume van Eys, Maastricht University, The Netherlands
Barbara Vertel, Rosalind Franklin University of Medicine and Science, Illinois
Jennifer Waby, University of Bradford, United Kingdom
Dianne Watters, Griffith University, Australia
Allison Wiedemeier, University of Louisiana at Monroe
Elizabeth Wurdak, St. John’s University, Minnesota
Kwok-Ming Yao, The University of Hong Kong
Foong May Yeong, National University of Singapore
We are also grateful to those readers who alerted us to errors that they
found in the previous edition.
Working on this book has been a pleasure, in part due to the many people
who contributed to its creation. Nigel Orme again worked closely with
author Keith Roberts to generate the entire illustration program with his
usual skill and care. He also produced all of the artwork for both cover
and chapter openers as a respectful digital tribute to the “squeeze-bottle”
paintings of the American artist Alden Mason (1919–2013). As in previ-
ous editions, Emma Jeffcock did a brilliant job in laying out the whole
book and meticulously incorporated our endless corrections. We owe a
special debt to Michael Morales, our editor at Garland Science, who co-
ordinated the whole enterprise. He oversaw the initial reviewing, worked
closely with the authors on their chapters, took great care of us at numer-
ous writing meetings, and kept us organized and on schedule. He also
orchestrated the wealth of online materials, including all video clips
and animations. Our copyeditor, Jo Clayton, ensured that the text was
stylistically consistent and error-free. At Garland, we also thank Jasmine
Ribeaux, Georgina Lucas, and Adam Sendroff.
For welcoming our book to W. W. Norton and bringing this edition to
print, we thank our editor Betsy Twitchell, as well as Roby Harrington,
Drake McFeely, Julia Reidhead, and Ann Shin for their support. Taylere
Peterson and Danny Vargo deserve thanks for their assistance as
the book moved from Garland to Norton and through production.
We are grateful to media editor Kate Brayton and content develop-
ment specialist Todd Pearson, associate editors Gina Forsythe and
Katie Callahan, and media editorial assistant Katie Daloia whose
coordination of electronic media development has resulted in an un-
matched suite of resources for cell biology students and instructors
alike. We are grateful for marketing manager Stacy Loyal’s tireless
enthusiasm and advocacy for our book. Megan Schindel, Ted Szczepanski,
and Stacey Stambaugh are all owed thanks for navigating the permis-
sions for this edition. And Jane Searle’s able management of produc-
tion, Carla Talmadge’s incredible attention to detail, and their shared
knack for troubleshooting made the book you hold in your hands
a reality.
viii Preface

Denise Schanck deserves extra special thanks for providing continuity

as she helped shepherd this edition from Garland to Norton. As always,
she attended all of our writing retreats and displayed great wisdom in
orchestrating everything she touched.
Last but not least, we are grateful, yet again, to our colleagues and our
families for their unflagging tolerance and support. We give our thanks
to everyone in this long list.

Resources for Instructors

and Students
INSTRUCTOR RESOURCES
wwnorton.com/instructors

Smartwork5
Smartwork5 is an easy-to-use online assessment tool that helps stu-
dents become better problem solvers through a variety of interactive
question types and extensive answer-specific feedback. All Smartwork5
questions are written specifically for the book, are tagged to Bloom’s
levels and learning objectives, and many include art and animations.
Get started quickly with our premade assignments or take advantage
of Smartwork5’s flexibility by customizing questions and adding your
own content. Integration with your campus LMS saves you time by al-
lowing Smartwork5 grades to report right to your LMS gradebook, while
individual and class-wide performance reports help you see students’
progress.

Interactive Instructor’s Guide

An all-in-one resource for instructors who want to integrate active
learning into their course. Searchable by chapter, phrase, topic, or
learning objective, the Interactive Instructor’s Guide compiles the many
valuable teaching resources available with Essential Cell Biology. This
website includes activities, discussion questions, animations and videos,
lecture outlines, learning objectives, primary literature suggestions,
medical topics guide, and more.

Coursepacks
Easily add high-quality Norton digital media to your online, hybrid, or
lecture course. Norton Coursepacks work within your existing learning
management system. Content is customizable and includes chapter-
based, multiple-choice reading quizzes, text-based learning objectives,
access to the full suite of animations, flashcards, and a glossary.

Test Bank
Written by Linda Huang, University of Massachusetts Boston, and Cheryl
D. Vaughan, Harvard University Division of Continuing Education,
the revised and expanded Test Bank for Essential Cell Biology includes
65–80 questions per chapter. Questions are available in multiple-choice,
matching, fill-in-the-blank, and short-answer formats, with many using
art from the textbook. All questions are tagged to Bloom’s taxonomy
level, learning objective, book section, and difficulty level, allowing in-
structors to easily create meaningful exams. The Test Bank is available in
ExamView and as downloadable PDFs from wwnorton.com/instructors.
 Preface ix

Animations and Videos

Streaming links give access to more than 130 videos and animations,
bringing the concepts of cell biology to life. The movies are correlated
with each chapter and callouts are highlighted in color.

Figure-integrated Lecture Outlines

All of the figures are integrated in PowerPoint, along with the section
and concept headings from the text, to give instructors a head start
creating lectures for their course.

Image Files
Every figure and photograph in the book is available for download in
PowerPoint and JPG formats from wwnorton.com/instructors.

STUDENT RESOURCES
digital.wwnorton.com/ecb5

Animations and Videos

Streaming links give access to more than 130 videos and animations,
bringing the concepts of cell biology to life. Animations can also be
accessed via the ebook and in select Smartwork5 questions. The movies
are correlated with each chapter and callouts are highlighted in color.

Student Site
Resources for self-study are available on the student site, including
multiple-choice quizzes, cell explorer slides, challenge and concept
questions, flashcards, and a glossary.
 ABOUT THE AUTHORS

BRUCE ALBERTS received his PhD from Harvard University and is a

professor in the Department of Biochemistry and Biophysics at the
University of California, San Francisco. He was the editor in chief of
Science from 2008 to 2013 and served as president of the U.S. National
Academy of Sciences from 1993 to 2005.
KAREN HOPKIN received her PhD from the Albert Einstein College of
Medicine and is a science writer. Her work has appeared in various
scientific publications, including Science, Proceedings of the National
Academy of Sciences, and The Scientist, and she is a regular contributor to
Scientific American’s daily podcast, “60-Second Science.”
ALEXANDER JOHNSON received his PhD from Harvard University and
is a professor in the Department of Microbiology and Immunology at the
University of California, San Francisco.
DAVID MORGAN received his PhD from the University of California, San
Francisco, where he is a professor in the Department of Physiology and
vice dean for research in the School of Medicine.
MARTIN RAFF received his MD from McGill University and is emeritus
professor of biology at the Medical Research Council Laboratory for
Molecular Cell Biology at University College London.
KEITH ROBERTS received his PhD from the University of Cambridge and
was deputy director of the John Innes Centre. He is emeritus professor at
the University of East Anglia.
PETER WALTER received his PhD from The Rockefeller University in New
York and is a professor in the Department of Biochemistry and Biophysics
at the University of California, San Francisco, and an investigator of the
Howard Hughes Medical Institute.

x
 Preface xi

LIST OF CHAPTERS and

SPECIAL FEATURES

CHAPTE R 1 Cells: The Fundamental Units of Life  1

PANEL 1–1 Microscopy 12
TABLE 1–1 Historical Landmarks in Determining Cell Structure  24
PANEL 1–2 Cell Architecture  25
How We Know: Life’s Common Mechanisms  30
TABLE 1–2 Some Model Organisms and Their Genomes  35

CHAPTE R 2 Chemical Components of Cells  39

TABLE 2–1 Length and Strength of Some Chemical Bonds  48
TABLE 2–2 The Chemical Composition of a Bacterial Cell  52
How We Know: The Discovery of Macromolecules  60
PANEL 2–1 Chemical Bonds and Groups  66
PANEL 2–2 The Chemical Properties of Water  68
PANEL 2–3 The Principal Types of Weak Noncovalent Bonds  70
PANEL 2– 4 An Outline of Some of the Types of Sugars  72
PANEL 2–5 Fatty Acids and Other Lipids  74
PANEL 2– 6 The 20 Amino Acids Found in Proteins  76
PANEL 2–7 A Survey of the Nucleotides  78

CHAPTE R 3 Energy, Catalysis, and Biosynthesis  81

PANEL 3–1 Free Energy and Biological Reactions  94
TABLE 3–1 Relationship Between the Standard Free-Energy Change, G°, and the Equilibrium Constant  96
How We Know: “High-Energy” Phosphate Bonds Power Cell Processes  102
TABLE 3–2 Some Activated Carriers Widely Used in Metabolism  109

CHAPTE R 4 Protein Structure and Function  117

PANEL 4 –1 A Few Examples of Some General Protein Functions  118
PANEL 4 –2 Making and Using Antibodies  140
TABLE 4 –1 Some Common Functional Classes of Enzymes  142
How We Know: Measuring Enzyme Performance  144
TABLE 4 –2 Historical Landmarks in Our Understanding of Proteins  160
PANEL 4 –3 Cell Breakage and Initial Fractionation of Cell Extracts  164
PANEL 4 – 4 Protein Separation by Chromatography  166
PANEL 4 –5 Protein Separation by Electrophoresis  167
PANEL 4 – 6 Protein Structure Determination  168

CHAPTE R 5 DNA and Chromosomes  173

How We Know: Genes Are Made of DNA  193

xi
xii List of Chapters and Special Features

CHAPTE R 6 DNA Replication and Repair  199

How We Know: The Nature of Replication  202
TABLE 6 –1 Proteins Involved in DNA Replication  213
TABLE 6 –2 Error Rates  218

CHAPTE R 7 From DNA to Protein: How Cells Read the Genome  227
TABLE 7–1 Types of RNA Produced in Cells  232
TABLE 7–2 The Three RNA Polymerases in Eukaryotic Cells  235
How We Know: Cracking the Genetic Code  246
TABLE 7–3 Antibiotics That Inhibit Bacterial Protein or RNA Synthesis  256
TABLE 7– 4 Biochemical Reactions That Can Be Catalyzed by Ribozymes  261

CHAPTE R 8 Control of Gene Expression  267

How We Know: Gene Regulation—The Story of Eve 280

CHAPTE R 9 How Genes and Genomes Evolve  297

TABLE 9–1 Viruses That Cause Human Disease  318
TABLE 9–2 Some Vital Statistics for the Human Genome  322
How We Know: Counting Genes  324

CHAPTE R 10 Analyzing the Structure and Function of Genes  333

How We Know: Sequencing the Human Genome  348

CHAPTE R 11 Membrane Structure  365

TABLE 11–1 Some Examples of Plasma Membrane Proteins and Their Functions  375
How We Know: Measuring Membrane Flow  384

CHAPTE R 12 Transport Across Cell Membranes   389

TABLE 12–1 A Comparison of Ion Concentrations Inside and Outside a Typical Mammalian Cell  391
TABLE 12–2 Some Examples of Transmembrane Pumps  403
How We Know: Squid Reveal Secrets of Membrane Excitability  412
TABLE 12–3 Some Examples of Ion Channels  419

CHAPTE R 13 How Cells Obtain Energy from Food  427

TABLE 13–1 Some Types of Enzymes Involved in Glycolysis  431
PANEL 13–1 Details of the 10 Steps of Glycolysis  436
PANEL 13–2 The Complete Citric Acid Cycle  442
How We Know: Unraveling the Citric Acid Cycle  444

CHAPTE R 14 Energy Generation in Mitochondria and Chloroplasts  455

TABLE 14 –1 Product Yields from Glucose Oxidation  469
PANEL 14 –1 Redox Potentials  472
How We Know: How Chemiosmotic Coupling Drives ATP Synthesis  476

CHAPTE R 15 Intracellular Compartments and Protein Transport  495

TABLE 15 –1 The Main Functions of Membrane-enclosed Organelles of a Eukaryotic Cell  497
TABLE 15 –2 The Relative Volumes and Numbers of the Major Membrane-enclosed Organelles
in a Liver Cell (Hepatocyte)  498
 List of Chapters and Special Features xiii

TABLE 15 –3 Some Typical Signal Sequences  502

TABLE 15 – 4 Some Types of Coated Vesicles  513
How We Know: Tracking Protein and Vesicle Transport  520

CHAPTE R 16 Cell Signaling  533

TABLE 16 –1 Some Examples of Signal Molecules  536
TABLE 16 –2 Some Foreign Substances That Act on Cell-Surface Receptors  544
TABLE 16 –3 Some Cell Responses Mediated by Cyclic AMP  550
TABLE 16 – 4 Some Cell Responses Mediated by Phospholipase C Activation  552
How We Know: Untangling Cell Signaling Pathways  563

CHAPTE R 17 Cytoskeleton  573

TABLE 17–1 Drugs That Affect Microtubules  584
How We Know: Pursuing Microtubule-associated Motor Proteins  588
TABLE 17–2 Drugs That Affect Filaments  594

CHAPTE R 18 The Cell-Division Cycle  609

TABLE 18–1 Some Eukaryotic Cell-Cycle Durations  611
How We Know: Discovery of Cyclins and Cdks  615
TABLE 18–2 The Major Cyclins and Cdks of Vertebrates  617
PANEL 18–1 The Principal Stages of M Phase in an Animal Cell  628

CHAPTE R 19 Sexual Reproduction and Genetics  651

PANEL 19–1 Some Essentials of Classical Genetics  675
How We Know: Using SNPs to Get a Handle on Human Disease  684

CHAPTE R 20 Cell Communities: Tissues, Stem Cells, and Cancer  691

TABLE 20 –1 A Variety of Factors Can Contribute to Genetic Instability  721
TABLE 20 –2 Examples of Cancer-critical Genes  728
How We Know: Making Sense of the Genes That Are Critical for Cancer  730
 Preface xv

CONTENTS

Preface v
About the Authors  x

CHAPTER 1

Cells: The Fundamental Units of Life  1

UNITY AND DIVERSITY OF CELLS  2
Cells Vary Enormously in Appearance and Function  2
Living Cells All Have a Similar Basic Chemistry  3
Living Cells Are Self-Replicating Collections of Catalysts  4
All Living Cells Have Apparently Evolved from the Same Ancestral Cell  5
Genes Provide Instructions for the Form, Function, and Behavior of Cells and Organisms  6
CELLS UNDER THE MICROSCOPE  6
The Invention of the Light Microscope Led to the Discovery of Cells  7
Light Microscopes Reveal Some of a Cell’s Components  8
The Fine Structure of a Cell Is Revealed by Electron Microscopy  9
THE PROKARYOTIC CELL  11
Prokaryotes Are the Most Diverse and Numerous Cells on Earth  14
The World of Prokaryotes Is Divided into Two Domains: Bacteria and Archaea  15
THE EUKARYOTIC CELL  16
The Nucleus Is the Information Store of the Cell  16
Mitochondria Generate Usable Energy from Food Molecules  17
Chloroplasts Capture Energy from Sunlight  18
Internal Membranes Create Intracellular Compartments with Different Functions  19
The Cytosol Is a Concentrated Aqueous Gel of Large and Small Molecules  21
The Cytoskeleton Is Responsible for Directed Cell Movements  22
The Cytosol Is Far from Static  23
Eukaryotic Cells May Have Originated as Predators  24
MODEL ORGANISMS  27
Molecular Biologists Have Focused on E. coli 27
Brewer’s Yeast Is a Simple Eukaryote  28
Arabidopsis Has Been Chosen as a Model Plant  28
Model Animals Include Flies, Worms, Fish, and Mice  29
Biologists Also Directly Study Humans and Their Cells  32
Comparing Genome Sequences Reveals Life’s Common Heritage  33
Genomes Contain More Than Just Genes  35
ESSENTIAL CONCEPTS  36
QUESTIONS  37
xv
xvi Contents

CHAPTER 2

Chemical Components of Cells  39

CHEMICAL BONDS  40
Cells Are Made of Relatively Few Types of Atoms  40
The Outermost Electrons Determine How Atoms Interact  41
Covalent Bonds Form by the Sharing of Electrons  43
Some Covalent Bonds Involve More Than One Electron Pair  44
Electrons in Covalent Bonds Are Often Shared Unequally  45
Covalent Bonds Are Strong Enough to Survive the Conditions Inside Cells  45
Ionic Bonds Form by the Gain and Loss of Electrons  46
Hydrogen Bonds Are Important Noncovalent Bonds for Many Biological Molecules  47
Four Types of Weak Interactions Help Bring Molecules Together in Cells  47
Some Polar Molecules Form Acids and Bases in Water  49
SMALL MOLECULES IN CELLS  50
A Cell Is Formed from Carbon Compounds  50
Cells Contain Four Major Families of Small Organic Molecules  51
Sugars Are both Energy Sources and Subunits of Polysaccharides  52
Fatty Acid Chains Are Components of Cell Membranes  54
Amino Acids Are the Subunits of Proteins  56
Nucleotides Are the Subunits of DNA and RNA  56
MACROMOLECULES IN CELLS  58
Each Macromolecule Contains a Specific Sequence of Subunits  59
Noncovalent Bonds Specify the Precise Shape of a Macromolecule  62
Noncovalent Bonds Allow a Macromolecule to Bind Other Selected Molecules  62
ESSENTIAL CONCEPTS  64
QUESTIONS  65

CHAPTER 3

Energy, Catalysis, and Biosynthesis  81

THE USE OF ENERGY BY CELLS  82
Biological Order Is Made Possible by the Release of Heat Energy from Cells  83
Cells Can Convert Energy from One Form to Another  84
Photosynthetic Organisms Use Sunlight to Synthesize Organic Molecules  85
Cells Obtain Energy by the Oxidation of Organic Molecules  86
Oxidation and Reduction Involve Electron Transfers  87
FREE ENERGY AND CATALYSIS  88
Chemical Reactions Proceed in the Direction That Causes a Loss of Free Energy  89
Enzymes Reduce the Energy Needed to Initiate Spontaneous Reactions  89
The Free-Energy Change for a Reaction Determines Whether It Can Occur  90
G Changes as a Reaction Proceeds Toward Equilibrium  92
The Standard Free-Energy Change, G°, Makes It Possible to Compare the Energetics of
Different Reactions  92
The Equilibrium Constant Is Directly Proportional to G° 96
In Complex Reactions, the Equilibrium Constant Includes the Concentrations of
All Reactants and Products  96
 Contents xvii

The Equilibrium Constant Also Indicates the Strength of Noncovalent Binding Interactions  97
For Sequential Reactions, the Changes in Free Energy Are Additive  98
Enzyme-catalyzed Reactions Depend on Rapid Molecular Collisions  99
Noncovalent Interactions Allow Enzymes to Bind Specific Molecules  100
ACTIVATED CARRIERS AND BIOSYNTHESIS  101
The Formation of an Activated Carrier Is Coupled to an Energetically Favorable Reaction  101
ATP Is the Most Widely Used Activated Carrier  104
Energy Stored in ATP Is Often Harnessed to Join Two Molecules Together  106
NADH and NADPH Are Both Activated Carriers of Electrons  106
NADPH and NADH Have Different Roles in Cells  108
Cells Make Use of Many Other Activated Carriers  108
The Synthesis of Biological Polymers Requires an Energy Input  110
ESSENTIAL CONCEPTS  113
QUESTIONS  114

CHAPTER 4

Protein Structure and Function  117

THE SHAPE AND STRUCTURE OF PROTEINS  119
The Shape of a Protein Is Specified by Its Amino Acid Sequence  119
Proteins Fold into a Conformation of Lowest Energy  122
Proteins Come in a Wide Variety of Complicated Shapes  124
The a Helix and the b Sheet Are Common Folding Patterns  126
Helices Form Readily in Biological Structures  127
b Sheets Form Rigid Structures at the Core of Many Proteins  129
Misfolded Proteins Can Form Amyloid Structures That Cause Disease  129
Proteins Have Several Levels of Organization  129
Proteins Also Contain Unstructured Regions  130
Few of the Many Possible Polypeptide Chains Will Be Useful  131
Proteins Can Be Classified into Families  132
Large Protein Molecules Often Contain More than One Polypeptide Chain  132
Proteins Can Assemble into Filaments, Sheets, or Spheres  134
Some Types of Proteins Have Elongated Fibrous Shapes  134
Extracellular Proteins Are Often Stabilized by Covalent Cross-Linkages  135
HOW PROTEINS WORK  137
All Proteins Bind to Other Molecules  137
Humans Produce Billions of Different Antibodies, Each with a Different Binding Site  138
Enzymes Are Powerful and Highly Specific Catalysts  139
Enzymes Greatly Accelerate the Speed of Chemical Reactions   142
Lysozyme Illustrates How an Enzyme Works  143
Many Drugs Inhibit Enzymes  147
Tightly Bound Small Molecules Add Extra Functions to Proteins  148
HOW PROTEINS ARE CONTROLLED  149
The Catalytic Activities of Enzymes Are Often Regulated by Other Molecules  150
Allosteric Enzymes Have Two or More Binding Sites That Influence One Another  151
Phosphorylation Can Control Protein Activity by Causing a Conformational Change  152
Covalent Modifications Also Control the Location and Interaction of Proteins  153
Regulatory GTP-Binding Proteins Are Switched On and Off by the Gain and Loss of a Phosphate Group  154
xviii Contents

ATP Hydrolysis Allows Motor Proteins to Produce Directed Movements in Cells  154
Proteins Often Form Large Complexes That Function as Machines  155
Many Interacting Proteins Are Brought Together by Scaffolds  156
Weak Interactions Between Macromolecules Can Produce Large Biochemical
Subcompartments in Cells  157
HOW PROTEINS ARE STUDIED  158
Proteins Can Be Purified from Cells or Tissues  158
Determining a Protein’s Structure Begins with Determining Its Amino Acid Sequence  159
Genetic Engineering Techniques Permit the Large-Scale Production, Design, and Analysis of
Almost Any Protein  161
The Relatedness of Proteins Aids the Prediction of Protein Structure and Function  162
ESSENTIAL CONCEPTS  162
QUESTIONS  170

CHAPTER 5

DNA and Chromosomes  173

THE STRUCTURE OF DNA  174
A DNA Molecule Consists of Two Complementary Chains of Nucleotides  175
The Structure of DNA Provides a Mechanism for Heredity  176
THE STRUCTURE OF EUKARYOTIC CHROMOSOMES  178
Eukaryotic DNA Is Packaged into Multiple Chromosomes  179
Chromosomes Organize and Carry Genetic Information  180
Specialized DNA Sequences Are Required for DNA Replication
and Chromosome Segregation  181
Interphase Chromosomes Are Not Randomly Distributed Within the Nucleus  182
The DNA in Chromosomes Is Always Highly Condensed  183
Nucleosomes Are the Basic Units of Eukaryotic Chromosome Structure  184
Chromosome Packing Occurs on Multiple Levels  186
THE REGULATION OF CHROMOSOME STRUCTURE  188
Changes in Nucleosome Structure Allow Access to DNA  188
Interphase Chromosomes Contain both Highly Condensed
and More Extended Forms of Chromatin  189
ESSENTIAL CONCEPTS  192
QUESTIONS  196
 Contents xix

CHAPTER 6

DNA Replication and Repair  199

DNA REPLICATION  200
Base-Pairing Enables DNA Replication  200
DNA Synthesis Begins at Replication Origins  201
Two Replication Forks Form at Each Replication Origin  201
DNA Polymerase Synthesizes DNA Using a Parental Strand as a Template  205
The Replication Fork Is Asymmetrical  206
DNA Polymerase Is Self-correcting  207
Short Lengths of RNA Act as Primers for DNA Synthesis  208
Proteins at a Replication Fork Cooperate to Form a Replication Machine  210
Telomerase Replicates the Ends of Eukaryotic Chromosomes  213
Telomere Length Varies by Cell Type and with Age  214
DNA REPAIR  215
DNA Damage Occurs Continually in Cells  215
Cells Possess a Variety of Mechanisms for Repairing DNA  217
A DNA Mismatch Repair System Removes Replication Errors That Escape Proofreading  218
Double-Strand DNA Breaks Require a Different Strategy for Repair  219
Homologous Recombination Can Flawlessly Repair DNA Double-Strand Breaks  220
Failure to Repair DNA Damage Can Have Severe Consequences for a Cell or Organism  222
A Record of the Fidelity of DNA Replication and Repair Is Preserved in Genome Sequences  223
ESSENTIAL CONCEPTS  224
QUESTIONS  225

CHAPTER 7

From DNA to Protein: How Cells Read

the Genome  227
FROM DNA TO RNA  228
Portions of DNA Sequence Are Transcribed into RNA  229
Transcription Produces RNA That Is Complementary to One Strand of DNA  230
Cells Produce Various Types of RNA  232
Signals in the DNA Tell RNA Polymerase Where to Start and Stop Transcription  233
Initiation of Eukaryotic Gene Transcription Is a Complex Process  235
Eukaryotic RNA Polymerase Requires General Transcription Factors  235
Eukaryotic mRNAs Are Processed in the Nucleus  237
In Eukaryotes, Protein-Coding Genes Are Interrupted
by Noncoding Sequences Called Introns  239
Introns Are Removed from Pre-mRNAs by RNA Splicing  239
RNA Synthesis and Processing Takes Place in “Factories” Within the Nucleus  242
Mature Eukaryotic mRNAs Are Exported from the Nucleus  242
mRNA Molecules Are Eventually Degraded in the Cytosol  242
FROM RNA TO PROTEIN  243
An mRNA Sequence Is Decoded in Sets of Three Nucleotides  244
tRNA Molecules Match Amino Acids to Codons in mRNA  245
xx Contents

Specific Enzymes Couple tRNAs to the Correct Amino Acid  249

The mRNA Message Is Decoded on Ribosomes  249
The Ribosome Is a Ribozyme   252
Specific Codons in an mRNA Signal the Ribosome Where to Start and to Stop Protein
Synthesis 253
Proteins Are Produced on Polyribosomes  255
Inhibitors of Prokaryotic Protein Synthesis Are Used as Antibiotics  255
Controlled Protein Breakdown Helps Regulate the Amount of Each Protein in a Cell  256
There Are Many Steps Between DNA and Protein  257
RNA AND THE ORIGINS OF LIFE  259
Life Requires Autocatalysis  259
RNA Can Store Information and Catalyze Chemical Reactions  260
RNA Is Thought to Predate DNA in Evolution  261
ESSENTIAL CONCEPTS  262
QUESTIONS  264

CHAPTER 8

Control of Gene Expression  267

AN OVERVIEW OF GENE EXPRESSION  268
The Different Cell Types of a Multicellular Organism Contain the Same DNA  268
Different Cell Types Produce Different Sets of Proteins  269
A Cell Can Change the Expression of Its Genes in Response to External Signals  270
Gene Expression Can Be Regulated at Various Steps from DNA to RNA to Protein  270
HOW TRANSCRIPTION IS REGULATED  271
Transcription Regulators Bind to Regulatory DNA Sequences  271
Transcription Switches Allow Cells to Respond to Changes in Their Environment  273
Repressors Turn Genes Off and Activators Turn Them On  274
The Lac Operon Is Controlled by an Activator and a Repressor  275
Eukaryotic Transcription Regulators Control Gene Expression from a Distance  276
Eukaryotic Transcription Regulators Help Initiate Transcription
by Recruiting Chromatin-Modifying Proteins  276
The Arrangement of Chromosomes into Looped Domains Keeps Enhancers in Check  278
GENERATING SPECIALIZED CELL TYPES  278
Eukaryotic Genes Are Controlled by Combinations of Transcription Regulators  279
The Expression of Different Genes Can Be Coordinated by a Single Protein  279
Combinatorial Control Can Also Generate Different Cell Types  282
The Formation of an Entire Organ Can Be Triggered by a Single Transcription Regulator  284
Transcription Regulators Can Be Used to Experimentally Direct the Formation of Specific Cell
Types in Culture  285
Differentiated Cells Maintain Their Identity  286
 Contents xxi

POST-TRANSCRIPTIONAL CONTROLS  287

mRNAs Contain Sequences That Control Their Translation  288
Regulatory RNAs Control the Expression of Thousands of Genes  288
MicroRNAs Direct the Destruction of Target mRNAs  289
Small Interfering RNAs Protect Cells From Infections  290
Thousands of Long Noncoding RNAs May Also Regulate Mammalian Gene Activity  291
ESSENTIAL CONCEPTS  292
QUESTIONS  293

CHAPTER 9

How Genes and Genomes Evolve  297

GENERATING GENETIC VARIATION  298
In Sexually Reproducing Organisms, Only Changes to the Germ Line
Are Passed On to Progeny  299
Point Mutations Are Caused by Failures of the Normal Mechanisms
for Copying and Repairing DNA  300
Mutations Can Also Change the Regulation of a Gene  302
DNA Duplications Give Rise to Families of Related Genes  302
Duplication and Divergence Produced the Globin Gene Family  304
Whole-Genome Duplications Have Shaped the Evolutionary History of Many Species  306
Novel Genes Can Be Created by Exon Shuffling  306
The Evolution of Genomes Has Been Profoundly Influenced by Mobile Genetic Elements  307
Genes Can Be Exchanged Between Organisms by Horizontal Gene Transfer  308
RECONSTRUCTING LIFE’S FAMILY TREE  309
Genetic Changes That Provide a Selective Advantage Are Likely to Be Preserved  309
Closely Related Organisms Have Genomes That Are Similar
in Organization as Well as Sequence  310
Functionally Important Genome Regions Show Up as Islands of Conserved DNA Sequence  310
Genome Comparisons Show That Vertebrate Genomes Gain and Lose DNA Rapidly  313
Sequence Conservation Allows Us to Trace Even the Most Distant Evolutionary Relationships  313
MOBILE GENETIC ELEMENTS AND VIRUSES  315
Mobile Genetic Elements Encode the Components They Need for Movement  315
The Human Genome Contains Two Major Families of Transposable Sequences  316
Viruses Can Move Between Cells and Organisms  317
Retroviruses Reverse the Normal Flow of Genetic Information  318
EXAMINING THE HUMAN GENOME  320
The Nucleotide Sequences of Human Genomes Show How Our Genes Are Arranged  321
Differences in Gene Regulation May Help Explain How Animals with Similar Genomes Can Be So Different  323
The Genome of Extinct Neanderthals Reveals Much about What Makes Us Human  326
Genome Variation Contributes to Our Individuality—But How?  327
ESSENTIAL CONCEPTS  328
QUESTIONS  329
xxii Contents

CHAPTER 10

Analyzing the Structure and Function of

Genes 333
ISOLATING AND CLONING DNA MOLECULES  334
Restriction Enzymes Cut DNA Molecules at Specific Sites  335
Gel Electrophoresis Separates DNA Fragments of Different Sizes  335
DNA Cloning Begins with the Production of Recombinant DNA  337
Recombinant DNA Can Be Copied Inside Bacterial Cells  337
An Entire Genome Can Be Represented in a DNA Library  339
Hybridization Provides a Sensitive Way to Detect Specific Nucleotide Sequences  340
DNA CLONING BY PCR  341
PCR Uses DNA Polymerase and Specific DNA Primers to Amplify
DNA Sequences in a Test Tube  342
PCR Can Be Used for Diagnostic and Forensic Applications  343
SEQUENCING DNA  346
Dideoxy Sequencing Depends on the Analysis of DNA Chains
Terminated at Every Position  346
Next-Generation Sequencing Techniques Make Genome Sequencing Faster and
Cheaper 347
Comparative Genome Analyses Can Identify Genes and Predict Their Function  350
EXPLORING GENE FUNCTION  350
Analysis of mRNAs Provides a Snapshot of Gene Expression   351
In Situ Hybridization Can Reveal When and Where a Gene Is Expressed  352
Reporter Genes Allow Specific Proteins to Be Tracked in Living Cells  352
The Study of Mutants Can Help Reveal the Function of a Gene  354
RNA Interference (RNAi) Inhibits the Activity of Specific Genes  354
A Known Gene Can Be Deleted or Replaced with an Altered Version  355
Genes Can Be Edited with Great Precision Using the Bacterial CRISPR System  358
Mutant Organisms Provide Useful Models of Human Disease  359
Transgenic Plants Are Important for both Cell Biology and Agriculture  359
Even Rare Proteins Can Be Made in Large Amounts Using Cloned DNA  361
ESSENTIAL CONCEPTS  362
QUESTIONS  363
 Contents xxiii

CHAPTER 11

Membrane Structure  365

THE LIPID BILAYER  367
Membrane Lipids Form Bilayers in Water  367
The Lipid Bilayer Is a Flexible Two-dimensional Fluid  370
The Fluidity of a Lipid Bilayer Depends on Its Composition  371
Membrane Assembly Begins in the ER  373
Certain Phospholipids Are Confined to One Side of the Membrane  373
MEMBRANE PROTEINS  375
Membrane Proteins Associate with the Lipid Bilayer in Different Ways  376
A Polypeptide Chain Usually Crosses the Lipid Bilayer as an a Helix  377
Membrane Proteins Can Be Solubilized in Detergents  378
We Know the Complete Structure of Relatively Few Membrane Proteins  379
The Plasma Membrane Is Reinforced by the Underlying Cell Cortex  380
A Cell Can Restrict the Movement of Its Membrane Proteins   381
The Cell Surface Is Coated with Carbohydrate  382
ESSENTIAL CONCEPTS  386
QUESTIONS  387

CHAPTER 12

Transport Across Cell Membranes  389

PRINCIPLES OF TRANSMEMBRANE TRANSPORT  390
Lipid Bilayers Are Impermeable to Ions and Most Uncharged Polar Molecules  390
The Ion Concentrations Inside a Cell Are Very Different from Those Outside  391
Differences in the Concentration of Inorganic Ions Across a Cell Membrane
Create a Membrane Potential  391
Cells Contain Two Classes of Membrane Transport Proteins: Transporters
and Channels  392
Solutes Cross Membranes by Either Passive or Active Transport  392
Both the Concentration Gradient and Membrane Potential Influence the
Passive Transport of Charged Solutes  393
Water Moves Across Cell Membranes Down Its Concentration Gradient—a
Process Called Osmosis  394
TRANSPORTERS AND THEIR FUNCTIONS  395
Passive Transporters Move a Solute Along Its Electrochemical Gradient  396
Pumps Actively Transport a Solute Against Its Electrochemical Gradient  396
The Na+ Pump in Animal Cells Uses Energy Supplied by ATP to Expel Na+ and Bring in K+ 397
The Na+ Pump Generates a Steep Concentration Gradient of Na+ Across the Plasma Membrane  398
Ca2+ Pumps Keep the Cytosolic Ca2+ Concentration Low  399
Gradient-driven Pumps Exploit Solute Gradients to Mediate Active Transport  399
The Electrochemical Na+ Gradient Drives the Transport of Glucose Across the Plasma Membrane of Animal Cells  400
Electrochemical H+ Gradients Drive the Transport of Solutes in Plants, Fungi, and Bacteria  402
ION CHANNELS AND THE MEMBRANE POTENTIAL  403
Ion Channels Are Ion-selective and Gated  404
Membrane Potential Is Governed by the Permeability of a Membrane to Specific Ions  405
xxiv Contents

Ion Channels Randomly Snap Between Open and Closed States  407
Different Types of Stimuli Influence the Opening and Closing of Ion Channels  408
Voltage-gated Ion Channels Respond to the Membrane Potential  409
ION CHANNELS AND NERVE CELL SIGNALING  410
Action Potentials Allow Rapid Long-Distance Communication Along Axons  411
Action Potentials Are Mediated by Voltage-gated Cation Channels  411
Voltage-gated Ca2+ Channels in Nerve Terminals Convert an Electrical Signal into a Chemical
Signal 416
Transmitter-gated Ion Channels in the Postsynaptic Membrane Convert the Chemical Signal
Back into an Electrical Signal  417
Neurotransmitters Can Be Excitatory or Inhibitory  418
Most Psychoactive Drugs Affect Synaptic Signaling by Binding to Neurotransmitter
Receptors 419
The Complexity of Synaptic Signaling Enables Us to Think, Act, Learn, and Remember  420
Light-gated Ion Channels Can Be Used to Transiently Activate or Inactivate Neurons in Living
Animals 421
ESSENTIAL CONCEPTS  422
QUESTIONS  424

CHAPTER 13

How Cells Obtain Energy from Food  427

THE BREAKDOWN AND UTILIZATION OF SUGARS AND FATS  428
Food Molecules Are Broken Down in Three Stages  428
Glycolysis Extracts Energy from the Splitting of Sugar  430
Glycolysis Produces both ATP and NADH   431
Fermentations Can Produce ATP in the Absence of Oxygen  433
Glycolytic Enzymes Couple Oxidation to Energy Storage in Activated Carriers  434
Several Types of Organic Molecules Are Converted to Acetyl CoA
in the Mitochondrial Matrix  438
The Citric Acid Cycle Generates NADH by Oxidizing Acetyl Groups to CO2 438
Many Biosynthetic Pathways Begin with Glycolysis or the Citric Acid Cycle  441
Electron Transport Drives the Synthesis of the Majority of the ATP in Most Cells  446
REGULATION OF METABOLISM  447
Catabolic and Anabolic Reactions Are Organized and Regulated  447
Feedback Regulation Allows Cells to Switch from Glucose Breakdown to
Glucose Synthesis   447
Cells Store Food Molecules in Special Reservoirs to Prepare for Periods of Need  449
ESSENTIAL CONCEPTS  451
QUESTIONS  452
 Contents xxv

CHAPTER 14

Energy Generation in Mitochondria

and Chloroplasts  455
Cells Obtain Most of Their Energy by a Membrane-based Mechanism  456
Chemiosmotic Coupling Is an Ancient Process, Preserved in Present-Day Cells  457
MITOCHONDRIA AND OXIDATIVE PHOSPHORYLATION  459
Mitochondria Are Dynamic in Structure, Location, and Number  459
A Mitochondrion Contains an Outer Membrane, an Inner Membrane,
and Two Internal Compartments  460
The Citric Acid Cycle Generates High-Energy Electrons Required for ATP Production  461
The Movement of Electrons Is Coupled to the Pumping of Protons  462
Electrons Pass Through Three Large Enzyme Complexes in the Inner
Mitochondrial Membrane  464
Proton Pumping Produces a Steep Electrochemical Proton Gradient
Across the Inner Mitochondrial Membrane  464
ATP Synthase Uses the Energy Stored in the Electrochemical Proton
Gradient to Produce ATP  465
The Electrochemical Proton Gradient Also Drives Transport Across
the Inner Mitochondrial Membrane  466
The Rapid Conversion of ADP to ATP in Mitochondria Maintains
a High ATP/ADP Ratio in Cells  467
Cell Respiration Is Amazingly Efficient  468
MOLECULAR MECHANISMS OF ELECTRON TRANSPORT AND PROTON PUMPING  469
Protons Are Readily Moved by the Transfer of Electrons  469
The Redox Potential Is a Measure of Electron Affinities  470
Electron Transfers Release Large Amounts of Energy  471
Metals Tightly Bound to Proteins Form Versatile Electron Carriers  471
Cytochrome c Oxidase Catalyzes the Reduction of Molecular Oxygen  474
CHLOROPLASTS AND PHOTOSYNTHESIS  478
Chloroplasts Resemble Mitochondria but Have an Extra Compartment—the Thylakoid  478
Photosynthesis Generates—and Then Consumes—ATP and NADPH  479
Chlorophyll Molecules Absorb the Energy of Sunlight  480
Excited Chlorophyll Molecules Funnel Energy into a Reaction Center  481
A Pair of Photosystems Cooperate to Generate both ATP and NADPH  482
Oxygen Is Generated by a Water-Splitting Complex Associated with Photosystem II  483
The Special Pair in Photosystem I Receives its Electrons from Photosystem II  484
Carbon Fixation Uses ATP and NADPH to Convert CO2 into Sugars  484
Sugars Generated by Carbon Fixation Can Be Stored as Starch or Consumed to Produce ATP  487
THE EVOLUTION OF ENERGY-GENERATING SYSTEMS  488
Oxidative Phosphorylation Evolved in Stages  488
Photosynthetic Bacteria Made Even Fewer Demands on Their Environment  489
The Lifestyle of Methanococcus Suggests That Chemiosmotic Coupling Is an Ancient Process  490
ESSENTIAL CONCEPTS  491
QUESTIONS  492
xxvi Contents

CHAPTER 15

Intracellular Compartments and Protein

Transport 495
MEMBRANE-ENCLOSED ORGANELLES  496
Eukaryotic Cells Contain a Basic Set of Membrane-enclosed Organelles  496
Membrane-enclosed Organelles Evolved in Different Ways  499
PROTEIN SORTING  500
Proteins Are Transported into Organelles by Three Mechanisms  500
Signal Sequences Direct Proteins to the Correct Compartment  502
Proteins Enter the Nucleus Through Nuclear Pores  503
Proteins Unfold to Enter Mitochondria and Chloroplasts  505
Proteins Enter Peroxisomes from both the Cytosol and the Endoplasmic Reticulum  506
Proteins Enter the Endoplasmic Reticulum While Being Synthesized  507
Soluble Proteins Made on the ER Are Released into the ER Lumen  508
Start and Stop Signals Determine the Arrangement of a Transmembrane Protein
in the Lipid Bilayer  509
VESICULAR TRANSPORT  511
Transport Vesicles Carry Soluble Proteins and Membrane Between Compartments  511
Vesicle Budding Is Driven by the Assembly of a Protein Coat  512
Vesicle Docking Depends on Tethers and SNAREs  514
SECRETORY PATHWAYS  515
Most Proteins Are Covalently Modified in the ER  516
Exit from the ER Is Controlled to Ensure Protein Quality  517
The Size of the ER Is Controlled by the Demand for Protein Folding  518
Proteins Are Further Modified and Sorted in the Golgi Apparatus  518
Secretory Proteins Are Released from the Cell by Exocytosis  519
ENDOCYTIC PATHWAYS  523
Specialized Phagocytic Cells Ingest Large Particles  523
Fluid and Macromolecules Are Taken Up by Pinocytosis  524
Receptor-mediated Endocytosis Provides a Specific Route into Animal Cells  525
Endocytosed Macromolecules Are Sorted in Endosomes  526
Lysosomes Are the Principal Sites of Intracellular Digestion   527
ESSENTIAL CONCEPTS  528
QUESTIONS  530
 Contents xxvii

CHAPTER 16

Cell Signaling  533

GENERAL PRINCIPLES OF CELL SIGNALING  534
Signals Can Act over a Long or Short Range  534
A Limited Set of Extracellular Signals Can Produce a Huge Variety of Cell Behaviors  537
A Cell’s Response to a Signal Can Be Fast or Slow  538
Cell-Surface Receptors Relay Extracellular Signals via Intracellular Signaling Pathways  539
Some Intracellular Signaling Proteins Act as Molecular Switches  541
Cell-Surface Receptors Fall into Three Main Classes  543
Ion-Channel-Coupled Receptors Convert Chemical Signals into Electrical Ones  544
G-PROTEIN-COUPLED RECEPTORS  545
Stimulation of GPCRs Activates G-Protein Subunits  545
Some Bacterial Toxins Cause Disease by Altering the Activity of G Proteins  547
Some G Proteins Directly Regulate Ion Channels  548
Many G Proteins Activate Membrane-bound Enzymes That Produce Small
Messenger Molecules  549
The Cyclic AMP Signaling Pathway Can Activate Enzymes and Turn On Genes  549
The Inositol Phospholipid Pathway Triggers a Rise in Intracellular Ca2+ 552
A Ca2+ Signal Triggers Many Biological Processes  553
A GPCR Signaling Pathway Generates a Dissolved Gas That Carries a Signal to Adjacent Cells  554
GPCR-Triggered Intracellular Signaling Cascades Can Achieve Astonishing Speed,
Sensitivity, and Adaptability  555
ENZYME-COUPLED RECEPTORS  557
Activated RTKs Recruit a Complex of Intracellular Signaling Proteins  558
Most RTKs Activate the Monomeric GTPase Ras  559
RTKs Activate PI 3-Kinase to Produce Lipid Docking Sites in the Plasma Membrane  560
Some Receptors Activate a Fast Track to the Nucleus  565
Some Extracellular Signal Molecules Cross the Plasma Membrane and Bind to Intracellular Receptors  565
Plants Make Use of Receptors and Signaling Strategies That Differ from Those Used by Animals  567
Protein Kinase Networks Integrate Information to Control Complex Cell Behaviors  567
ESSENTIAL CONCEPTS  569
QUESTIONS  571
xxviii Contents

CHAPTER 17

Cytoskeleton 573
INTERMEDIATE FILAMENTS  575
Intermediate Filaments Are Strong and Ropelike  575
Intermediate Filaments Strengthen Cells Against Mechanical Stress  577
The Nuclear Envelope Is Supported by a Meshwork of Intermediate Filaments  578
Linker Proteins Connect Cytoskeletal Filaments and Bridge the Nuclear Envelope  579
MICROTUBULES   580
Microtubules Are Hollow Tubes with Structurally Distinct Ends   581
The Centrosome Is the Major Microtubule-organizing Center in Animal Cells  581
Microtubules Display Dynamic Instability  582
Dynamic Instability Is Driven by GTP Hydrolysis  583
Microtubule Dynamics Can Be Modified by Drugs  584
Microtubules Organize the Cell Interior  584
Motor Proteins Drive Intracellular Transport  586
Microtubules and Motor Proteins Position Organelles in the Cytoplasm  587
Cilia and Flagella Contain Stable Microtubules Moved by Dynein  590
ACTIN FILAMENTS  592
Actin Filaments Are Thin and Flexible  593
Actin and Tubulin Polymerize by Similar Mechanisms  593
Many Proteins Bind to Actin and Modify Its Properties  594
A Cortex Rich in Actin Filaments Underlies the Plasma Membrane of Most Eukaryotic
Cells 596
Cell Crawling Depends on Cortical Actin  596
Actin-binding Proteins Influence the Type of Protrusions Formed at the Leading Edge  598
Extracellular Signals Can Alter the Arrangement of Actin Filaments  598
Actin Associates with Myosin to Form Contractile Structures  599
MUSCLE CONTRACTION  600
Muscle Contraction Depends on Interacting Filaments of Actin and Myosin  600
Actin Filaments Slide Against Myosin Filaments During Muscle Contraction  601
Muscle Contraction Is Triggered by a Sudden Rise in Cytosolic Ca2+ 604
Different Types of Muscle Cells Perform Different Functions  605
ESSENTIAL CONCEPTS  606
QUESTIONS  607
 Contents xxix

CHAPTER 18

The Cell-Division Cycle  609

OVERVIEW OF THE CELL CYCLE  610
The Eukaryotic Cell Cycle Usually Includes Four Phases  611
A Cell-Cycle Control System Triggers the Major Processes of the Cell Cycle  612
Cell-Cycle Control Is Similar in All Eukaryotes  613
THE CELL-CYCLE CONTROL SYSTEM  613
The Cell-Cycle Control System Depends on Cyclically Activated Protein
Kinases Called Cdks  613
Different Cyclin–Cdk Complexes Trigger Different Steps in the Cell Cycle  614
Cyclin Concentrations Are Regulated by Transcription and by Proteolysis  617
The Activity of Cyclin–Cdk Complexes Depends on Phosphorylation
and Dephosphorylation  618
Cdk Activity Can Be Blocked by Cdk Inhibitor Proteins  618
The Cell-Cycle Control System Can Pause the Cycle in Various Ways  618
G1 PHASE  620
Cdks Are Stably Inactivated in G1 620
Mitogens Promote the Production of the Cyclins That Stimulate Cell Division  620
DNA Damage Can Temporarily Halt Progression Through G1 621
Cells Can Delay Division for Prolonged Periods by Entering Specialized Nondividing States  621
S PHASE  623
S-Cdk Initiates DNA Replication and Blocks Re-Replication  623
Incomplete Replication Can Arrest the Cell Cycle in G2 623
M PHASE  624
M-Cdk Drives Entry into Mitosis  625
Cohesins and Condensins Help Configure Duplicated Chromosomes for Separation  625
Different Cytoskeletal Assemblies Carry Out Mitosis and Cytokinesis  626
M Phase Occurs in Stages  627
MITOSIS  627
Centrosomes Duplicate to Help Form the Two Poles of the Mitotic Spindle  627
The Mitotic Spindle Starts to Assemble in Prophase  630
Chromosomes Attach to the Mitotic Spindle at Prometaphase  630
Chromosomes Assist in the Assembly of the Mitotic Spindle  632
Chromosomes Line Up at the Spindle Equator at Metaphase  632
Proteolysis Triggers Sister-Chromatid Separation at Anaphase  633
Chromosomes Segregate During Anaphase  634
An Unattached Chromosome Will Prevent Sister-Chromatid Separation  634
The Nuclear Envelope Re-forms at Telophase  635
CYTOKINESIS  636
The Mitotic Spindle Determines the Plane of Cytoplasmic Cleavage  636
The Contractile Ring of Animal Cells Is Made of Actin and Myosin Filaments  637
Cytokinesis in Plant Cells Involves the Formation of a New Cell Wall  638
Membrane-enclosed Organelles Must Be Distributed to Daughter Cells When a Cell Divides  638
xxx Contents

CONTROL OF CELL NUMBERS AND CELL SIZE  639

Apoptosis Helps Regulate Animal Cell Numbers  640
Apoptosis Is Mediated by an Intracellular Proteolytic Cascade  640
The Intrinsic Apoptotic Death Program Is Regulated by the Bcl2 Family of Intracellular
Proteins   642
Apoptotic Signals Can Also Come from Other Cells  642
Animal Cells Require Extracellular Signals to Survive, Grow, and Divide  642
Survival Factors Suppress Apoptosis  643
Mitogens Stimulate Cell Division by Promoting Entry into S Phase  644
Growth Factors Stimulate Cells to Grow  644
Some Extracellular Signal Proteins Inhibit Cell Survival, Division, or Growth  645
ESSENTIAL CONCEPTS  646
QUESTIONS  648

CHAPTER 19

Sexual Reproduction and Genetics  651

THE BENEFITS OF SEX  652
Sexual Reproduction Involves both Diploid and Haploid Cells  652
Sexual Reproduction Generates Genetic Diversity  653
Sexual Reproduction Gives Organisms a Competitive Advantage
in a Changing Environment  654
MEIOSIS AND FERTILIZATION  654
Meiosis Involves One Round of DNA Replication Followed by Two Rounds
of Nuclear Division  655
Duplicated Homologous Chromosomes Pair During Meiotic Prophase  657
Crossing-Over Occurs Between the Duplicated Maternal and Paternal
Chromosomes in Each Bivalent  657
Chromosome Pairing and Crossing-Over Ensure the Proper Segregation of Homologs  659
The Second Meiotic Division Produces Haploid Daughter Nuclei  660
Haploid Gametes Contain Reassorted Genetic Information  660
Meiosis Is Not Flawless  662
Fertilization Reconstitutes a Complete Diploid Genome  663
MENDEL AND THE LAWS OF INHERITANCE  664
Mendel Studied Traits That Are Inherited in a Discrete Fashion  664
Mendel Disproved the Alternative Theories of Inheritance  664
Mendel’s Experiments Revealed the Existence of Dominant and Recessive Alleles  665
Each Gamete Carries a Single Allele for Each Character  666
Mendel’s Law of Segregation Applies to All Sexually Reproducing Organisms  667
Alleles for Different Traits Segregate Independently  668
The Behavior of Chromosomes During Meiosis Underlies Mendel’s Laws of Inheritance  669
Genes That Lie on the Same Chromosome Can Segregate Independently by
Crossing-Over 671
Mutations in Genes Can Cause a Loss of Function or a Gain of Function  672
Each of Us Carries Many Potentially Harmful Recessive Mutations  673
 Contents xxxi

GENETICS AS AN EXPERIMENTAL TOOL  674

The Classical Genetic Approach Begins with Random Mutagenesis  674
Genetic Screens Identify Mutants Deficient in Specific Cell Processes  676
Conditional Mutants Permit the Study of Lethal Mutations  676
A Complementation Test Reveals Whether Two Mutations Are in the Same Gene  678
EXPLORING HUMAN GENETICS  678
Linked Blocks of Polymorphisms Have Been Passed Down from Our Ancestors  679
Polymorphisms Provide Clues to Our Evolutionary History  679
Genetic Studies Aid in the Search for the Causes of Human Diseases  680
Many Severe, Rare Human Diseases Are Caused by Mutations in Single Genes  681
Common Human Diseases Are Often Influenced by Multiple Mutations and Environmental Factors  682
Genome-wide Association Studies Can Aid the Search for Mutations Associated with Disease  683
We Still Have Much to Learn about the Genetic Basis of Human Variation and Disease  686
ESSENTIAL CONCEPTS  687
QUESTIONS  688

CHAPTER 20

Cell Communities: Tissues, Stem Cells,

and Cancer  691
EXTRACELLULAR MATRIX AND CONNECTIVE TISSUES  692
Plant Cells Have Tough External Walls  693
Cellulose Microfibrils Give the Plant Cell Wall Its Tensile Strength  694
Animal Connective Tissues Consist Largely of Extracellular Matrix  695
Collagen Provides Tensile Strength in Animal Connective Tissues  696
Cells Organize the Collagen They Secrete  697
Integrins Couple the Matrix Outside a Cell to the Cytoskeleton Inside It  698
Gels of Polysaccharides and Proteins Fill Spaces and Resist Compression  700
EPITHELIAL SHEETS AND CELL JUNCTIONS  701
Epithelial Sheets Are Polarized and Rest on a Basal Lamina  702
Tight Junctions Make an Epithelium Leakproof and Separate Its Apical
and Basolateral Surfaces  703
Cytoskeleton-linked Junctions Bind Epithelial Cells Robustly to One Another
and to the Basal Lamina  704
Gap Junctions Allow Cytosolic Inorganic Ions and Small Molecules to Pass from Cell to Cell  707
STEM CELLS AND TISSUE RENEWAL  709
Tissues Are Organized Mixtures of Many Cell Types  710
Different Tissues Are Renewed at Different Rates  711
Stem Cells and Proliferating Precursor Cells Generate a Continuous Supply of Terminally Differentiated Cells  712
Specific Signals Maintain Stem-Cell Populations  714
Stem Cells Can Be Used to Repair Lost or Damaged Tissues  715
Induced Pluripotent Stem Cells Provide a Convenient Source of Human ES-like Cells  716
Mouse and Human Pluripotent Stem Cells Can Form Organoids in Culture  717
xxxii Contents

CANCER  718
Cancer Cells Proliferate Excessively and Migrate Inappropriately  718
Epidemiological Studies Identify Preventable Causes of Cancer  719
Cancers Develop by an Accumulation of Somatic Mutations  720
Cancer Cells Evolve, Acquiring an Increasing Competitive Advantage  721
Two Main Classes of Genes Are Critical for Cancer: Oncogenes and Tumor Suppressor Genes  723
Cancer-critical Mutations Cluster in a Few Fundamental Pathways  725
Colorectal Cancer Illustrates How Loss of a Tumor Suppressor Gene Can Lead to Cancer  726
An Understanding of Cancer Cell Biology Opens the Way to New Treatments  727
ESSENTIAL CONCEPTS  729
QUESTIONS  733

ANSWERS A:1

GLOSSARY G:1

INDEX I:1