Molecular Biology of the Cell PDF 6th Edition

Molecular Biology of THE CELL Sixth Edition This page intentionally left blank to match pagination of print book Molecular Biology of THE CELL Sixth Edition Bruce Alberts Alexander Johnson Julian Lewis David Morgan Martin Ra...

Molecular Biology of THE CELL Sixth Edition This page intentionally left blank to match pagination of print book Molecular Biology of THE CELL Sixth Edition Bruce Alberts Alexander Johnson Julian Lewis David Morgan Martin Raff Keith Roberts Peter Walter With problems by John Wilson Tim Hunt Garland Science About the Authors Vice President: Denise Schanck Bruce Alberts received his PhD from Harvard University Associate Editor: Allie Bochicchio and is the Chancellor’s Leadership Chair in Biochemistry Production Editor and Layout: EJ Publishing Services and Biophysics for Science and Education, University of Senior Production Editor: Georgina Lucas California, San Francisco. He was the editor-in-chief of Science Text Editors: Sherry Granum Lewis and Elizabeth Zayatz magazine from 2008 until 2013, and for twelve years he served Illustrator: Nigel Orme as President of the U.S. National Academy of Sciences (1993– Structures: Tiago Barros 2005). Alexander Johnson received his PhD from Harvard Designer: Matthew McClements, Blink Studio, Ltd. University and is Professor of Microbiology and Immunology Copyeditor: Jo Clayton at the University of California, San Francisco. Julian Lewis Proofreader: Sally Huish (1946–2014) received his DPhil from the University of Oxford Indexer: Bill Johncocks and was an Emeritus Scientist at the London Research Institute Permissions Coordinator: Sheri Gilbert of Cancer Research UK. David Morgan received his PhD from Back Cover Photograph: Photography, Christophe Carlinet; the University of California, San Francisco, and is Professor of Design, Nigel Orme the Department of Physiology there as well as the Director of the Biochemistry, Cell Biology, Genetics, and Developmental Molecular Biology of the Cell Interactive Media: Biology Graduate Program. Martin Raff received his MD from Artistic and Scientific Direction: Peter Walter McGill University and is Emeritus Professor of Biology at the Narration: Julie Theriot Medical Research Council Laboratory for Molecular Cell Biology Director of Digital Publishing: Michael Morales at University College London. Keith Roberts received his PhD Editorial Assistant: Leah Christians from the University of Cambridge and was Deputy Director of Production Editor: Natasha Wolfe the John Innes Centre, Norwich. He is Emeritus Professor at the University of East Anglia. Peter Walter received his PhD from © 2015 by Bruce Alberts, Alexander Johnson, Julian Lewis, the Rockefeller University in New York and is Professor of the David Morgan, Martin Raff, Keith Roberts, and Peter Walter. Department of Biochemistry and Biophysics at the University of California, San Francisco, and an Investigator at the Howard This book contains information obtained from authentic Hughes Medical Institute. John Wilson received his PhD and highly regarded sources. Every effort has been made to from the California Institute of Technology and pursued his trace copyright holders and to obtain their permission for postdoctoral work at Stanford University. He is Distinguished the use of copyright material. Reprinted material is quoted Service Professor of Biochemistry and Molecular Biology at with permission, and sources are indicated. A wide variety of Baylor College of Medicine in Houston. Tim Hunt received references are listed. Reasonable efforts have been made to his PhD from the University of Cambridge where he taught publish reliable data and information, but the author and the biochemistry and cell biology for more than 20 years. He worked publisher cannot assume responsibility for the validity of all at Cancer Research UK until his retirement in 2010. He shared materials or for the consequences of their use. the 2001 Nobel Prize in Physiology or Medicine with Lee Hartwell and Paul Nurse. All rights reserved. No part of this book covered by the copyright Cover design: Cell biology is not only about the structure and herein may be reproduced or used in any format in any form or function of the myriad molecules that comprise a cell, but also by any means—graphic, electronic, or mechanical, including about how this complex chemistry is controlled. Understanding photocopying, recording, taping, or information storage and the cell’s elaborate regulatory feedback networks will require retrieval systems—without permission of the publisher. quantitative approaches. Library of Congress Cataloging-in-Publication Data Alberts, Bruce, author. Molecular biology of the cell / Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter ; with problems by John Wilson, Tim Hunt. -- Sixth edition. p. ; cm. Preceded by Molecular biology of the cell / Bruce Alberts... [et al.]. 5th ed. c2008. Includes bibliographical references and index. ISBN 978-0-8153-4432-2 (hardcover) -- ISBN 978-0-8153-4464-3 (paperback) I. Title. [DNLM: 1. Cells. 2. Molecular Biology. QU 300] QH581.2 572.8--dc23 2014031818 Published by Garland Science, Taylor & Francis Group, LLC, an informa business, 711 Third Avenue, New York, NY 10017, US 3 Park Square, Milton Park, Abingdon, OX14 4RN, UK Printed in the United States of America 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 Visit our website at http://www.garlandscience.com  Julian Hart Lewis August 12, 1946—April 30, 2014 This page intentionally left blank to match pagination of print book  vii Preface Since the last edition of this book appeared, more than five million scientific papers have been published. There has been a parallel increase in the quantity of digital information: new data on genome sequences, protein interactions, molecular struc- tures, and gene expression—all stored in vast databases. The challenge, for both sci- entists and textbook writers, is to convert this overwhelming amount of information into an accessible and up-to-date understanding of how cells work. Help comes from a large increase in the number of review articles that attempt to make raw material easier to digest, although the vast majority of these reviews are still quite narrowly focused. Meanwhile, a rapidly growing collection of online resources tries to convince us that understanding is only a few mouse-clicks away. In some areas this change in the way we access knowledge has been highly suc- cessful—in discovering the latest information about our own medical problems, for example. But to understand something of the beauty and complexity of how living cells work, one needs more than just a wiki- this or wiki- that; it is enormously hard to identify the valuable and enduring gems from so much confusing landfill. Much more effective is a carefully wrought narrative that leads logically and progressively through the key ideas, components, and experiments in such a way that readers can build for themselves a memorable, conceptual framework for cell biology— a framework that will allow them to critically evaluate all of the new science and, more importantly, to understand it. That is what we have tried to do in Molecular Biology of the Cell. In preparing this new edition, we have inevitably had to make some difficult decisions. In order to incorporate exciting new discoveries, while at the same time keeping the book portable, much has had to be excised. We have added new sec- tions, such as those on new RNA functions, advances in stem cell biology, new methods for studying proteins and genes and for imaging cells, advances in the genetics and treatment of cancer, and timing, growth control, and morphogenesis in development. The chemistry of cells is extremely complex, and any list of cell parts and their interactions—no matter how complete—will leave huge gaps in our understanding. We now realize that to produce convincing explanations of cell behavior will require quantitative information about cells that is coupled to sophisticated mathematical/ computational approaches—some not yet invented. As a consequence, an emerg- ing goal for cell biologists is to shift their studies more toward quantitative descrip- tion and mathematical deduction. We highlight this approach and some of its meth- ods in a new section at the end of Chapter 8. Faced with the immensity of what we have learned about cell biology, it might be tempting for a student to imagine that there is little left to discover. In fact, the more we find out about cells, the more new questions emerge. To emphasize that our understanding of cell biology is incomplete, we have highlighted some of the major gaps in our knowledge by including What We Don’t Know at the end of each chapter. These brief lists include only a tiny sample of the critical unanswered ques- tions and challenges for the next generation of scientists. We derive great pleasure from the knowledge that some of our readers will provide future answers. The more than 1500 illustrations have been designed to create a parallel narra- tive, closely interwoven with the text. We have increased their consistency between chapters, particularly in the use of color and of common icons; membrane pumps and channels are a good example. To avoid interruptions to the text, some material has been moved into new, readily accessible panels. Most of the important pro- tein structures depicted have now been redrawn and consistently colored. In each viii PREFACE case, we now provide the corresponding Protein Data Bank (PDB) code for the protein, which can be used to access online tools that provide more information about it, such as those on the RCSB PDB website (www.rcsb.org). These connec- tions allow readers of the book to explore more fully the proteins that lie at the core of cell biology. John Wilson and Tim Hunt have again contributed their distinctive and imagi- native problems to help students gain a more active understanding of the text. The problems emphasize quantitative approaches and encourage critical thinking about published experiments; they are now present at the end of all chapters. The answers to these problems, plus more than 1800 additional problems and solutions, all appear in the companion volume that John and Tim have written, Molecular Biology of the Cell, Sixth Edition: The Problems Book. We live in a world that presents us with many complex issues related to cell biology: biodiversity, climate change, food security, environmental degradation, resource depletion, and human disease. We hope that our textbook will help the reader better understand and possibly contribute to meeting these challenges. Knowledge and understanding bring the power to intervene. We are indebted to a large number of scientists whose generous help we men- tion separately in the detailed acknowledgments. Here we must mention some par- ticularly significant contributors. For Chapter 8, Hana El-Samad provided the core of the section on Mathematical Analysis of Cell Functions, and Karen Hopkin made valuable contributions to the section on Studying Gene Expression and Function. Werner Kuhlbrandt helped to reorganize and rewrite Chapter 14 (Energy Conver- sion: Mitochondria and Chloroplasts). Rebecca Heald did the same for Chapter 16 (The Cytoskeleton), as did Alexander Schier for Chapter 21 (Development of Mul- ticellular Organisms), and Matt Welch for Chapter 23 (Pathogens and Infection). Lewis Lanier aided in the writing of Chapter 24 (The Innate and Adaptive Immune Systems). Hossein Amiri generated the enormous online instructor’s question bank. Before starting out on the revision cycle for this edition, we asked a number of scientists who had used the last edition to teach cell biology students to meet with us and suggest improvements. They gave us useful feedback that has helped inform the new edition. We also benefited from the valuable input of groups of students who read most of the chapters in page proofs. Many people and much effort are needed to convert a long manuscript and a large pile of sketches into a finished textbook. The team at Garland Science that managed this conversion was outstanding. Denise Schanck, directing operations, displayed forbearance, insight, tact, and energy throughout the journey; she guided us all unerringly, ably assisted by Allie Bochicchio and Janette Scobie. Nigel Orme oversaw our revamped illustration program, put all the artwork into its final form, and again enhanced the back cover with his graphics skills. Tiago Barros helped us refresh our presentation of protein structures. Matthew McClements designed the book and its front cover. Emma Jeffcock again laid out the final pages, managing end- less rounds of proofs and last-minute changes with remarkable skill and patience; Georgina Lucas provided her with help. Michael Morales, assisted by Leah Chris- tians, produced and assembled the complex web of videos, animations, and other materials that form the core of the online resources that accompany the book. Adam Sendroff provided us with the valuable feedback from book users around the world that informed our revision cycle. Casting expert eyes over the manuscript, Eliza- beth Zayatz and Sherry Granum Lewis acted as development editors, Jo Clayton as copyeditor, and Sally Huish as proofreader. Bill Johncocks compiled the index. In London, Emily Preece fed us, while the Garland team’s professional help, skills, and energy, together with their friendship, nourished us in every other way throughout the revision, making the whole process a pleasure. The authors are extremely fortu- nate to be supported so generously. We thank our spouses, families, friends, and colleagues for their continuing sup- port, which has once again made the writing of this book possible. Just as we were completing this edition, Julian Lewis, our coauthor, friend, and colleague, finally succumbed to the cancer that he had fought so heroically for ten years. Starting in 1979, Julian made major contributions to all six editions, and, as our most elegant wordsmith, he elevated and enhanced both the style and tone of all the many chapters he touched. Noted for his careful scholarly approach, clarity and simplicity were at the core of his writing. Julian is irreplaceable, and we will all deeply miss his friendship and collaboration. We dedicate this Sixth Edition to his memory.  ix Note to the Reader Structure of the Book Although the chapters of this book can be read independently of one another, they are arranged in a logical sequence of five parts. The first three chapters of Part I cover elementary principles and basic biochemistry. They can serve either as an introduction for those who have not studied biochemistry or as a refresher course for those who have. Part II deals with the storage, expression, and transmission of genetic information. Part III presents the principles of the main experimental methods for investigating and analyzing cells; here, a new section entitled “Math- ematical Analysis of Cell Functions” in Chapter 8 provides an extra dimension in our understanding of cell regulation and function. Part IV describes the internal organization of the cell. Part V follows the behavior of cells in multicellular sys- tems, starting with development of multicellular organisms and concluding with chapters on pathogens and infection and on the innate and adaptive immune systems. End-of-Chapter Problems A selection of problems, written by John Wilson and Tim Hunt, appears in the text at the end of each chapter. New to this edition are problems for the last four chap- ters on multicellular organisms. The complete solutions to all of these problems can be found in Molecular Biology of the Cell, Sixth Edition: The Problems Book. References A concise list of selected references is included at the end of each chapter. These are arranged in alphabetical order under the main chapter section headings. These references sometimes include the original papers in which important dis- coveries were first reported. Glossary Terms Throughout the book, boldface type has been used to highlight key terms at the point in a chapter where the main discussion occurs. Italic type is used to set off important terms with a lesser degree of emphasis. At the end of the book is an expanded glossary, covering technical terms that are part of the common cur- rency of cell biology; it should be the first resort for a reader who encounters an unfamiliar term. The complete glossary as well as a set of flashcards is available on the Student Website. Nomenclature for Genes and Proteins Each species has its own conventions for naming genes; the only common fea- ture is that they are always set in italics. In some species (such as humans), gene names are spelled out all in capital letters; in other species (such as zebrafish), all in lowercase; in yet others (most mouse genes), with the first letter in uppercase and rest in lowercase; or (as in Drosophila) with different combinations of upper- case and lowercase, according to whether the first mutant allele to be discovered produced a dominant or recessive phenotype. Conventions for naming protein products are equally varied. This typographical chaos drives everyone crazy. It is not just tiresome and absurd; it is also unsustainable. We cannot independently define a fresh conven- tion for each of the next few million species whose genes we may wish to study. x NOTE TO THE READER Moreover, there are many occasions, especially in a book such as this, where we need to refer to a gene generically—without specifying the mouse version, the human version, the chick version, or the hippopotamus version—because they are all equivalent for the purposes of our discussion. What convention then should we use? We have decided in this book to cast aside the different conventions that are used in individual species and follow a uniform rule: we write all gene names, like the names of people and places, with the first letter in uppercase and the rest in lowercase, but all in italics, thus: Apc, Bazooka, Cdc2, Dishevelled, Egl1. The cor- responding protein, where it is named after the gene, will be written in the same way, but in roman rather than italic letters: Apc, Bazooka, Cdc2, Dishevelled, Egl1. When it is necessary to specify the organism, this can be done with a prefix to the gene name. For completeness, we list a few further details of naming rules that we shall follow. In some instances, an added letter in the gene name is traditionally used to distinguish between genes that are related by function or evolution; for those genes, we put that letter in uppercase if it is usual to do so (LacZ, RecA, HoxA4). We use no hyphen to separate added letters or numbers from the rest of the name. Proteins are more of a problem. Many of them have names in their own right, assigned to them before the gene was named. Such protein names take many forms, although most of them traditionally begin with a lowercase letter (actin, hemoglobin, catalase), like the names of ordinary substances (cheese, nylon), unless they are acronyms (such as GFP, for Green Fluorescent Protein, or BMP4, for Bone Morphogenetic Protein #4). To force all such protein names into a uni- form style would do too much violence to established usages, and we shall simply write them in the traditional way (actin, GFP, and so on). For the corresponding gene names in all these cases, we shall nevertheless follow our standard rule: Actin, Hemoglobin, Catalase, Bmp4, Gfp. Occasionally in our book we need to highlight a protein name by setting it in italics for emphasis; the intention will generally be clear from the context. For those who wish to know them, the table below shows some of the official conventions for individual species—conventions that we shall mostly violate in this book, in the manner shown. Species-Specific Convention Unified Convention Used in This Book Organism Gene Protein Gene Protein Mouse Hoxa4 Hoxa4 HoxA4 HoxA4 Bmp4 BMP4 Bmp4 BMP4 integrin α-1, Itgα1 integrin α1 Integrin α1, Itgα1 integrin α1 Human HOXA4 HOXA4 HoxA4 HoxA4 Zebrafish cyclops, cyc Cyclops, Cyc Cyclops, Cyc Cyclops, Cyc Caenorhabditis unc-6 UNC-6 Unc6 Unc6 Drosophila sevenless, sev (named Sevenless, SEV Sevenless, Sev Sevenless, Sev after recessive phenotype) Deformed, Dfd (named Deformed, DFD Deformed, Dfd Deformed, Dfd after dominant mutant phenotype) Yeast Saccharomyces cerevisiae CDC28 Cdc28, Cdc28p Cdc28 Cdc28 (budding yeast) Schizosaccharomyces Cdc2 Cdc2, Cdc2p Cdc2 Cdc2 pombe (fission yeast) Arabidopsis GAI GAI Gai GAI E. coli uvrA UvrA UvrA UvrA NOTE TO THE READER xi Molecular Biology of the Cell, Sixth Edition: The Problems Book by John Wilson and Tim Hunt (ISBN: 978-0-8153-4453-7) The Problems Book is designed to help students appreciate the ways in which experiments and simple calculations can lead to an understanding of how cells work. It provides problems to accompany Chapters 1–20 of Molecular Biology of the Cell. Each chapter of problems is divided into sections that correspond to those of the main textbook and review key terms, test for understanding basic concepts, pose research-based problems, and now include MCAT-style questions which help students to prepare for standardized medical school admission tests. Molecular Biology of the Cell, Sixth Edition: The Problems Book should be useful for homework assignments and as a basis for class discussion. It could even pro- vide ideas for exam questions. Solutions for all of the problems are provided in the book. Solutions for the end-of-chapter problems for Chapters 1–24 in the main textbook are also found in The Problems Book. RESOURCES FOR INSTRUCTORS AND STUDENTS The teaching and learning resources for instructors and students are available online. The instructor’s resources are password-protected and available only to adopting instructors. The student resources are available to everyone. We hope these resources will enhance student learning and make it easier for instructors to prepare dynamic lectures and activities for the classroom. Instructor Resources Instructor Resources are available on the Garland Science Instructor’s Resource Site, located at www.garlandscience.com/instructors. The website provides access not only to the teaching resources for this book but also to all other Garland Sci- ence textbooks. Adopting instructors can obtain access to the site from their sales representative or by emailing [email protected]. Art of Molecular Biology of the Cell, Sixth Edition The images from the book are available in two convenient formats: PowerPoint® and JPEG. They have been optimized for display on a computer. Figures are searchable by figure number, by figure name, or by keywords used in the figure legend from the book. Figure-Integrated Lecture Outlines The section headings, concept headings, and figures from the text have been inte- grated into PowerPoint presentations. These will be useful for instructors who would like a head start creating lectures for their course. Like all of our PowerPoint presentations, the lecture outlines can be customized. For example, the content of these presentations can be combined with videos and questions from the book or Question Bank, in order to create unique lectures that facilitate interactive learn- ing. Animations and Videos The 174 animations and videos that are available to students are also available on the Instructor’s Website in two formats. The WMV-formatted movies are created for instructors who wish to use the movies in PowerPoint presentations on Win- dows® computers; the QuickTime-formatted movies are for use in PowerPoint for Apple computers or Keynote® presentations. The movies can easily be down- loaded using the “download” button on the movie preview page. The movies are correlated to each chapter and callouts are highlighted in color. Media Guide This document provides an overview to the multimedia available for students and instructors and contains the text of the voice-over narration for all of the movies. Question Bank Written by Hossein Amiri, University of California, Santa Cruz, this greatly expanded question bank includes a variety of question formats: multiple choice, xii NOTE TO THE READER short answer, fill-in-the-blank, true-false, and matching. There are 35–60 ques- tions per chapter, and a large number of the multiple-choice questions will be suitable for use with personal response systems (that is, clickers). The Question Bank was created with the philosophy that a good exam should do much more than simply test students’ ability to memorize information; it should require them to reflect upon and integrate information as a part of a sound understanding. This resource provides a comprehensive sampling of questions that can be used either directly or as inspiration for instructors to write their own test questions. Diploma® Test Generator Software The questions from the Question Bank have been loaded into the Diploma Test Generator software. The software is easy to use and can scramble questions to cre- ate multiple tests. Questions are organized by chapter and type and can be addi- tionally categorized by the instructor according to difficulty or subject. Existing questions can be edited and new ones added. The Test Generator is compatible with several course management systems, including Blackboard®. Medical Topics Guide This document highlights medically relevant topics covered throughout Molecular Biology of the Cell and The Problems Book. It will be particularly useful for instruc- tors with a large number of premedical, health science, or nursing students. Blackboard and Learning Management System (LMS) Integration The movies, book images, and student assessments that accompany the book can be integrated into Blackboard or other LMSs. These resources are bundled into a “Common Cartridge” or “Upload Package” that facilitates bulk uploading of textbook resources into Blackboard and other LMSs. The LMS Common Cartridge can be obtained on a DVD from your sales representative or by emailing [email protected]. Resources for Students The resources for students are available on the Molecular Biology of the Cell Student Website, located at www.garlandscience.com/MBOC6-students. Animations and Videos There are 174 movies, covering a wide range of cell biology topics, which review key concepts in the book and illuminate subcellular processes. The movies are correlated to each chapter and callouts are highlighted in color. Cell Explorer Slides This application teaches cell morphology through interactive micrographs that highlight important cellular structures. Flashcards Each chapter contains a set of flashcards, built into the website, that allow stu- dents to review key terms from the text. Glossary The complete glossary from the book is available on the website and can be searched and browsed.  xiii Acknowledgments In writing this book we have benefited greatly from the advice of many biologists and biochemists. We would like to thank the following for their suggestions in preparing this edition, as well as those who helped in preparing the first, second, third, fourth, and fifth editions. (Those who helped on this edition are listed first, those who helped with the first, second, third, fourth, and fifth editions follow.) General: Research UK), Richard D. Wood (University of Pittsburgh Steven Cook (Imperial College London), Jose A. Costoya Cancer Institute) (Universidade de Santiago de Compostela), Arshad Desai Chapter 6: Briana Burton (Harvard University), Richard (University of California, San Diego), Susan K. Dutcher H. Ebright (Rutgers University), Daniel Finley (Harvard (Washington University, St. Louis), Michael Elowitz Medical School), Michael R. Green (University of (California Institute of Technology), Benjamin S. Glick Massachusetts Medical School), Christine Guthrie (University of Chicago), Gregory Hannon (Cold Spring (University of California, San Francisco), Art Horwich (Yale Harbor Laboratories), Rebecca Heald (University of School of Medicine), Harry Noller (University of California, California, Berkeley), Stefan Kanzok (Loyola University Santa Cruz), David Tollervey (University of Edinburgh), Chicago), Doug Kellogg (University of California, Santa Alexander J. Varshavsky (California Institute of Technology) Cruz), David Kimelman (University of Washington, Seattle), Chapter 7: Adrian Bird (The Wellcome Trust Centre, UK), Maria Krasilnikova (Pennsylvania State University), Werner Neil Brockdorff (University of Oxford), Christine Guthrie Kühlbrandt (Max Planck Institute of Biophysics), Lewis (University of California, San Francisco), Jeannie Lee Lanier (University of California, San Francisco), Annette (Harvard Medical School), Michael Levine (University Müller-Taubenberger (Ludwig Maximilians University), of California, Berkeley), Hiten Madhani (University Sandra Schmid (University of Texas Southwestern), Ronald of California, San Francisco), Duncan Odom (Cancer D. Vale (University of California, San Francisco), D. Eric Research UK), Kevin Struhl (Harvard Medical School), Walters (Chicago Medical School), Karsten Weis (Swiss Jesper Svejstrup (Cancer Research UK) Federal Institute of Technology) Chapter 8: Hana El-Samad [major contribution] Chapter 2: H. Lill (VU University) (University of California, San Francisco), Karen Hopkin Chapter 3: David S. Eisenberg (University of California, [major contribution], Donita Brady (Duke University), Los Angeles), F. Ulrich Hartl (Max Planck Institute of David Kashatus (University of Virginia), Melanie McGill Biochemistry), Louise Johnson (University of Oxford), (University of Toronto), Alex Mogilner (University of H. Lill (VU University), Jonathan Weissman (University of California, Davis), Richard Morris (John Innes Centre, UK), California, San Francisco) Prasanth Potluri (The Children’s Hospital of Philadelphia Chapter 4: Bradley E. Bernstein (Harvard Medical School), Research Institute), Danielle Vidaurre (University of Wendy Bickmore (MRC Human Genetics Unit, Edinburgh), Toronto), Carmen Warren (University of California, Los Jason Brickner (Northwestern University), Gary Felsenfeld Angeles), Ian Woods (Ithaca College) (NIH), Susan M. Gasser (University of Basel), Shiv Grewal Chapter 9: Douglas J. Briant (University of Victoria), (National Cancer Institute), Gary Karpen (University of Werner Kühlbrandt (Max Planck Institute of Biophysics), California, Berkeley), Eugene V. Koonin, (NCBI, NLM, Jeffrey Lichtman (Harvard University), Jennifer Lippincott- NIH), Hiten Madhani (University of California, San Schwartz (NIH), Albert Pan (Georgia Regents University), Francisco), Tom Misteli (National Cancer Institute), Peter Shaw (John Innes Centre, UK), Robert H. Singer Geeta Narlikar (University of California, San Francisco), (Albert Einstein School of Medicine), Kurt Thorn Maynard Olson (University of Washington, Seattle), (University of California, San Francisco) Stephen Scherer (University of Toronto), Rolf Sternglanz Chapter 10: Ari Helenius (Swiss Federal Institute of (Stony Brook University), Chris L. Woodcock (University Technology), Werner Kühlbrandt (Max Planck Institute of Massachusetts, Amherst), Johanna Wysocka and lab of Biophysics), H. Lill (VU University), Satyajit Mayor members (Stanford School of Medicine) (National Centre for Biological Sciences, India), Kai Chapter 5: Oscar Aparicio (University of Southern Simons (Max Planck Institute of Molecular Cell Biology California), Julie P. Cooper (National Cancer Institute), Neil and Genetics), Gunnar von Heijne (Stockholm University), Hunter (Howard Hughes Medical Institute), Karim Labib Tobias Walther (Harvard University) (University of Manchester), Joachim Li (University Chapter 11: Graeme Davis (University of California, San of California, San Francisco), Stephen West (Cancer Francisco), Robert Edwards (University of California, San xiv ACKNOWLEDGMENTS Francisco), Bertil Hille (University of Washington, Seattle), (University of Colorado, Boulder), Maxence Nachury Lindsay Hinck (University of California, Santa Cruz), (Stanford School of Medicine), Eva Nogales (University Werner Kühlbrandt (Max Planck Institute of Biophysics), H. of California, Berkeley), Samara Reck-Peterson (Harvard Lill (VU University), Roger Nicoll (University of California, Medical School), Ronald D. Vale (University of California, San Francisco), Poul Nissen (Aarhus University), Robert San Francisco), Richard B. Vallee (Columbia University), Stroud (University of California, San Francisco), Karel Michael Way (Cancer Research UK), Orion Weiner Svoboda (Howard Hughes Medical Institute), Robert (University of California, San Francisco), Matthew Welch Tampé (Goethe-University Frankfurt) (University of California, Berkeley) Chapter 12: John Aitchison (Institute for System Biology, Chapter 17: Douglas J. Briant (University of Victoria, Seattle), Amber English (University of Colorado at Canada), Lindsay Hinck (University of California, Santa Boulder), Ralf Erdmann (Ruhr University of Bochum), Cruz), James A. McNew (Rice University) Larry Gerace (The Scripps Research Institute, La Jolla), Chapter 18: Emily D. Crawford (University of California, Ramanujan Hegde (MRC Laboratory of Molecular Biology, San Francisco), James A. McNew (Rice University), Cambridge, UK), Martin W. Hetzer (The Salk Institute), Shigekazu Nagata (Kyoto University), Jim Wells (University Lindsay Hinck (University of California, Santa Cruz), James of California, San Francisco) A. McNew (Rice University), Nikolaus Pfanner (University Chapter 19: Jeffrey Axelrod (Stanford University School of of Freiberg), Peter Rehling (University of Göttingen), Medicine), John Couchman (University of Copenhagen), Michael Rout (The Rockefeller University), Danny J. Schnell Johan de Rooij (The Hubrecht Institute, Utrecht), Benjamin (University of Massachusetts, Amherst), Sebastian Schuck Geiger (Weizmann Institute of Science, Israel), Andrew (University of Heidelberg), Suresh Subramani (University of P. Gilmore (University of Manchester), Tony Harris California, San Diego), Gia Voeltz (University of Colorado, (University of Toronto), Martin Humphries (University of Boulder), Susan R. Wente (Vanderbilt University School of Manchester), Andreas Prokop (University of Manchester), Medicine) Charles Streuli (University of Manchester), Masatoshi Chapter 13: Douglas J. Briant (University of Victoria, Takeichi (RIKEN Center for Developmental Biology, Japan), Canada), Scott D. Emr (Cornell University), Susan Barry Thompson (Cancer Research UK), Kenneth M. Ferro-Novick (University of California, San Diego), Yamada (NIH), Alpha Yap (The University of Queensland, Benjamin S. Glick (University of Chicago), Ari Helenius Australia) (Swiss Federal Institute of Technology), Lindsay Hinck Chapter 20: Anton Berns (Netherlands Cancer Institute), (University of California, Santa Cruz), Reinhard Jahn (Max J. Michael Bishop (University of California, San Francisco), Planck Institute for Biophysical Chemistry), Ira Mellman Trever Bivona (University of California, San Francisco), (Genentech), Peter Novick (University of California, San Fred Bunz (Johns Hopkins University), Paul Edwards Diego), Hugh Pelham (MRC Laboratory of Molecular (University of Cambridge), Ira Mellman (Genentech), Biology, Cambridge, UK), Graham Warren (Max F. Perutz Caetano Reis e Sousa (Cancer Research UK), Marc Shuman Laboratories, Vienna), Marino Zerial (Max Planck Institute (University of California, San Francisco), Mike Stratton of Molecular Cell Biology and Genetics) (Wellcome Trust Sanger Institute, UK), Ian Tomlinson Chapter 14: Werner Kühlbrandt [major contribution] (Max (Cancer Research UK) Planck Institute of Biophysics), Thomas D. Fox (Cornell Chapter 21: Alex Schier [major contribution] (Harvard University), Cynthia Kenyon (University of California, San University), Markus Affolter (University of Basel), Victor Francisco), Nils-Göran Larsson (Max Planck Institute for Ambros (University of Massachusetts, Worcester), James Biology of Aging), Jodi Nunnari (University of California, Briscoe (MRC National Institute for Medical Research, Davis), Patrick O’Farrell (University of California, San UK), Donald Brown (Carnegie Institution for Science, Francisco), Alastair Stewart (The Victor Chang Cardiac Baltimore), Steven Burden (New York University School Research Institute, Australia), Daniela Stock (The Victor of Medicine), Moses Chao (New York University School of Chang Cardiac Research Institute, Australia), Michael P. Medicine), Caroline Dean (John Innes Centre, UK), Chris Yaffe (California Institute for Regenerative Medicine) Doe (University of Oregon, Eugene), Uwe Drescher (King’s Chapter 15: Henry R. Bourne (University of California, College London), Gordon Fishell (New York University San Francisco), Dennis Bray (University of Cambridge), School of Medicine), Brigid Hogan (Duke University), Douglas J. Briant (University of Victoria, Canada), James Phil Ingham (Institute of Molecular and Cell Biology, Briscoe (MRC National Institute for Medical Research, Singapore), Laura Johnston (Columbia University), David UK), James Ferrell (Stanford University), Matthew Freeman Kingsley (Stanford University), Tom Kornberg (University (MRC Laboratory of Molecular Biology, Cambridge, UK), of California, San Francisco), Richard Mann (Columbia Alan Hall (Memorial Sloan Kettering Cancer Center), Carl- University), Andy McMahon (University of Southern Henrik Heldin (Uppsala University), James A. McNew (Rice California), Marek Mlodzik (Mount Sinai Hospital, New University), Roel Nusse (Stanford University), Julie Pitcher York), Patrick O’Farrell (University of California, San (University College London) Francisco), Duojia Pan (Johns Hopkins Medical School), Chapter 16: Rebecca Heald [major contribution] Olivier Pourquie (Harvard Medical School), Erez Raz (University of California, Berkeley), Anna Akhmanova (University of Muenster), Chris Rushlow (New York (Utrecht University), Arshad Desai (University of California, University), Stephen Small (New York University), Marc San Diego), Velia Fowler (The Scripps Research Institute, La Tessier-Lavigne (Rockefeller University) Jolla), Vladimir Gelfand (Northwestern University), Robert Chapter 22: Simon Hughes (King’s College London), Goldman (Northwestern University), Alan Rick Horwitz Rudolf Jaenisch (Massachusetts Institute of Technology), (University of Virginia), Wallace Marshall (University Arnold Kriegstein (University of California, San Francisco), of California, San Francisco), J. Richard McIntosh Doug Melton (Harvard University), Stuart Orkin (Harvard ACKNOWLEDGMENTS xv University), Thomas A. Reh (University of Washington, of Amsterdam), Henry Bourne (University of California, Seattle), Amy Wagers (Harvard University), Fiona M. Watt San Francisco), Alan Boyde (University College London), (Wellcome Trust Centre for Stem Cell Research, UK), Martin Brand (University of Cambridge), Carl Branden Douglas J. Winton (Cancer Research UK), Shinya Yamanaka (deceased), Andre Brandli (Swiss Federal Institute of (Kyoto University) Technology, Zurich), Dennis Bray (University of Chapter 23: Matthew Welch [major contribution] Cambridge), Mark Bretscher (MRC Laboratory of Molecular (University of California, Berkeley), Ari Helenius (Swiss Biology, Cambridge), James Briscoe (National Institute for Federal Institute of Technology), Dan Portnoy (University Medical Research, UK), Marianne Bronner-Fraser of California, Berkeley), David Sibley (Washington (California Institute of Technology), Robert Brooks (King’s University, St. Louis), Michael Way (Cancer Research UK) College London), Barry Brown (King’s College London), Chapter 24: Lewis Lanier (University of California, Michael Brown (University of Oxford), Michael Bulger San Francisco). (University of Rochester Medical Center), Fred Bunz (Johns Readers: Najla Arshad (Indian Institute of Science), Venice Hopkins University), Steve Burden (New York University of Chiueh (University of California, Berkeley), Quyen Huynh Medicine), Max Burger (University of Basel), Stephen (University of Toronto), Rachel Kooistra (Loyola University, Burley (SGX Pharmaceuticals), Keith Burridge (University Chicago), Wes Lewis (University of Alabama), Eric Nam of North Carolina, Chapel Hill), John Cairns (Radcliffe (University of Toronto), Vladimir Ryvkin (Stony Brook Infirmary, Oxford), Patricia Calarco (University of University), Laasya Samhita (Indian Institute of Science), California, San Francisco), Zacheus Cande (University of John Senderak (Jefferson Medical College), Phillipa California, Berkeley), Lewis Cantley (Harvard Medical Simons (Imperial College, UK), Anna Constance Vind School), Charles Cantor (Columbia University), Roderick (University of Copenhagen), Steve Wellard (Pennsylvania Capaldi (University of Oregon), Mario Capecchi (University State University), Evan Whitehead (University of California, of Utah), Michael Carey (University of California, Los Berkeley), Carrie Wilczewski (Loyola University, Chicago), Angeles), Adelaide Carpenter (University of California, San Anna Wing (Pennsylvania State University), John Wright Diego), John Carroll (University College London), Tom (University of Alabama) Cavalier-Smith (King’s College London), Pierre Chambon (University of Strasbourg), Hans Clevers (Hubrecht First, second, third, fourth, and fifth editions: Institute, The Netherlands), Enrico Coen (John Innes Jerry Adams (The Walter and Eliza Hall Institute of Medical Institute, Norwich, UK), Philip Cohen (University of Research, Australia), Ralf Adams (London Research Dundee, Scotland), Robert Cohen (University of California, Institute), David Agard (University of California, San San Francisco), Stephen Cohen (EMBL Heidelberg, Francisco), Julie Ahringer (The Gurdon Institute, UK), Germany), Roger Cooke (University of California, San Michael Akam (University of Cambridge), David Allis (The Francisco), John Cooper (Washington University School of Rockefeller University), Wolfhard Almers (Oregon Health Medicine, St. Louis), Michael Cox (University of Wisconsin, and Science University), Fred Alt (CBR Institute for Madison), Nancy Craig (Johns Hopkins University), James Biomedical Research, Boston), Linda Amos (MRC Crow (University of Wisconsin, Madison), Stuart Cull- Laboratory of Molecular Biology, Cambridge), Raul Andino Candy (University College London), Leslie Dale (University (University of California, San Francisco), Clay Armstrong College London), Caroline Damsky (University of (University of Pennsylvania), Martha Arnaud (University of California, San Francisco), Johann De Bono (The Institute California, San Francisco), Spyros Artavanis-Tsakonas of Cancer Research, UK), Anthony DeFranco (University of (Harvard Medical School), Michael Ashburner (University California, San Francisco), Abby Dernburg (University of of Cambridge), Jonathan Ashmore (University College California, Berkeley), Arshad Desai (University of London), Laura Attardi (Stanford University), Tayna California, San Diego), Michael Dexter (The Wellcome Awabdy (University of California, San Francisco), Jeffrey Trust, UK), John Dick (University of Toronto, Canada), Axelrod (Stanford University Medical Center), Peter Baker Christopher Dobson (University of Cambridge), Russell (deceased), David Baldwin (Stanford University), Michael Doolittle (University of California, San Diego), W. Ford Banda (University of California, San Francisco), Cornelia Doolittle (Dalhousie University, Canada), Julian Downward Bargmann (The Rockefeller University), Ben Barres (Cancer Research UK), Keith Dudley (King’s College (Stanford University), David Bartel (Massachusetts Institute London), Graham Dunn (MRC Cell Biophysics Unit, of Technology), Konrad Basler (University of Zurich), London), Jim Dunwell (John Innes Institute, Norwich, UK), Wolfgang Baumeister (Max Planck Institute of Bruce Edgar (Fred Hutchinson Cancer Research Center, Biochemistry), Michael Bennett (Albert Einstein College of Seattle), Paul Edwards (University of Cambridge), Robert Medicine), Darwin Berg (University of California, San Edwards (University of California, San Francisco), David Diego), Anton Berns (Netherlands Cancer Institute), Eisenberg (University of California, Los Angeles), Sarah Merton Bernfield (Harvard Medical School), Michael Elgin (Washington University, St. Louis), Ruth Ellman Berridge (The Babraham Institute, Cambridge, UK), Walter (Institute of Cancer Research, Sutton, UK), Beverly Birchmeier (Max Delbrück Center for Molecular Medicine, Emerson (The Salk Institute), Charles Emerson (University Germany), Adrian Bird (Wellcome Trust Centre, UK), David of Virginia), Scott D. Emr (Cornell University), Sharyn Birk (UMDNJ—Robert Wood Johnson Medical School), Endow (Duke University), Lynn Enquist (Princeton Michael Bishop (University of California, San Francisco), University), Tariq Enver (Institute of Cancer Research, Elizabeth Blackburn (University of California, San London), David Epel (Stanford University), Gerard Evan Francisco), Tim Bliss (National Institute for Medical (University of California, Comprehensive Cancer Center), Research, London), Hans Bode (University of California, Ray Evert (University of Wisconsin, Madison), Matthias Irvine), Piet Borst (Jan Swammerdam Institute, University Falk (Lehigh University), Stanley Falkow (Stanford xvi ACKNOWLEDGMENTS University), Douglas Fearon (University of Cambridge), Scott Hawley (Stowers Institute for Medical Research, Gary Felsenfeld (NIH), Stuart Ferguson (University of Kansas City), Rebecca Heald (University of California, Oxford), James Ferrell (Stanford University), Christine Field Berkeley), John Heath (University of Birmingham, UK), (Harvard Medical School), Daniel Finley (Harvard Ramanujan Hegde (NIH), Carl-Henrik Heldin (Uppsala University), Gary Firestone (University of California, University), Ari Helenius (Swiss Federal Institute of Berkeley), Gerald Fischbach (Columbia University), Robert Technology), Richard Henderson (MRC Laboratory of Fletterick (University of California, San Francisco), Harvey Molecular Biology, Cambridge, UK), Glenn Herrick Florman (Tufts University), Judah Folkman (Harvard (University of Utah), Ira Herskowitz (deceased), Bertil Hille Medical School), Larry Fowke (University of Saskatchewan, (University of Washington, Seattle), Alan Hinnebusch Canada), Jennifer Frazier (Exploratorium®, San Francisco), (NIH, Bethesda), Brigid Hogan (Duke University), Nancy Matthew Freeman (Laboratory of Molecular Biology, UK), Hollingsworth (State University of New York, Stony Brook), Daniel Friend (University of California, San Francisco), Frank Holstege (University Medical Center, The Elaine Fuchs (University of Chicago), Joseph Gall (Carnegie Netherlands), Leroy Hood (Institute for Systems Biology, Institution of Washington), Richard Gardner (University of Seattle), John Hopfield (Princeton University), Robert Oxford), Anthony Gardner-Medwin (University College Horvitz (Massachusetts Institute of Technology), Art London), Peter Garland (Institute of Cancer Research, Horwich (Yale University School of Medicine), David London), David Garrod (University of Manchester, UK), Housman (Massachusetts Institute of Technology), Joe Susan M. Gasser (University of Basel), Walter Gehring Howard (Max Planck Institute of Molecular Cell Biology (Biozentrum, University of Basel), Benny Geiger and Genetics), Jonathan Howard (University of (Weizmann Institute of Science, Rehovot, Israel), Larry Washington, Seattle), James Hudspeth (The Rockefeller Gerace (The Scripps Research Institute), Holger Gerhardt University), Simon Hughes (King’s College London), Martin (London Research Institute), John Gerhart (University of Humphries (University of Manchester, UK), Tim Hunt California, Berkeley), Günther Gerisch (Max Planck (Cancer Research UK), Neil Hunter (University of Institute of Biochemistry), Frank Gertler (Massachusetts California, Davis), Laurence Hurst (University of Bath, UK), Institute of Technology), Sankar Ghosh (Yale University Jeremy Hyams (University College London), Tony Hyman School of Medicine), Alfred Gilman (The University of Texas (Max Planck Institute of Molecular Cell Biology and Southwestern Medical Center), Reid Gilmore (University of Genetics), Richard Hynes (Massachusetts Institute of Massachusetts, Amherst), Bernie Gilula (deceased), Technology), Philip Ingham (University of Sheffield, UK), Charles Gilvarg (Princeton University), Benjamin S. Glick Kenneth Irvine (Rutgers University), Robin Irvine (University of Chicago), Michael Glotzer (University of (University of Cambridge), Norman Iscove (Ontario Cancer Chicago), Larry Goldstein (University of California, San Institute, Toronto), David Ish-Horowicz (Cancer Research Diego), Bastien Gomperts (University College Hospital UK), Lily Jan (University of California, San Francisco), Medical School, London), Daniel Goodenough (Harvard Charles Janeway (deceased), Tom Jessell (Columbia Medical School), Jim Goodrich (University of Colorado, University), Arthur Johnson (Texas A&M University), Boulder), Jeffrey Gordon (Washington University, St. Louise Johnson (deceased), Andy Johnston (John Innes Louis), Peter Gould (Middlesex Hospital Medical School, Institute, Norwich, UK), E.G. Jordan (Queen Elizabeth London), Alan Grafen (University of Oxford), Walter College, London), Ron Kaback (University of California, Gratzer (King’s College London), Michael Gray (Dalhousie Los Angeles), Michael Karin (University of California, San University), Douglas Green (St. Jude Children’s Hospital), Diego), Eric Karsenti (European Molecular Biology Howard Green (Harvard University), Michael Green Laboratory, Germany), Ken Keegstra (Michigan State (University of Massachusetts, Amherst), Leslie Grivell University), Ray Keller (University of California, Berkeley), (University of Amsterdam), Carol Gross (University of Douglas Kellogg (University of California, Santa Cruz), California, San Francisco), Frank Grosveld (Erasmus Regis Kelly (University of California, San Francisco), John Universiteit, The Netherlands), Michael Grunstein Kendrick-Jones (MRC Laboratory of Molecular Biology, (University of California, Los Angeles), Barry Gumbiner Cambridge), Cynthia Kenyon (University of California, (Memorial Sloan Kettering Cancer Center), Brian Gunning San Francisco), Roger Keynes (University of Cambridge), (Australian National University, Canberra), Christine Judith Kimble (University of Wisconsin, Madison), Guthrie (University of California, San Francisco), James Robert Kingston (Massachusetts General Hospital), Marc Haber (Brandeis University), Ernst Hafen (Universitat Kirschner (Harvard University), Richard Klausner (NIH), Zurich), David Haig (Harvard University), Andrew Nancy Kleckner (Harvard University), Mike Klymkowsky Halestrap (University of Bristol, UK), Alan Hall (Memorial (University of Colorado, Boulder), Kelly Komachi Sloan Kettering Cancer Center), Jeffrey Hall (Brandeis (University of California, San Francisco), Eugene Koonin University), John Hall (University of Southampton, UK), (NIH), Juan Korenbrot (University of California, San Zach Hall (University of California, San Francisco), Douglas Francisco), Roger Kornberg (Stanford University), Tom Hanahan (University of California, San Francisco), David Kornberg (University of California, San Francisco), Stuart Hanke (University of Cambridge), Nicholas Harberd Kornfeld (Washington University, St. Louis), Daniel (University of Oxford), Graham Hardie (University of Koshland (University of California, Berkeley), Douglas Dundee, Scotland), Richard Harland (University of Koshland (Carnegie Institution of Washington, Baltimore), California, Berkeley), Adrian Harris (Cancer Research UK), Marilyn Kozak (University of Pittsburgh), Mark Krasnow John Harris (University of Otago, New Zealand), Stephen (Stanford University), Werner Kühlbrandt (Max Planck Harrison (Harvard University), Leland Hartwell (University Institute for Biophysics), John Kuriyan (University of of Washington, Seattle), Adrian Harwood (MRC Laboratory California, Berkeley), Robert Kypta (MRC Laboratory for for Molecular Cell Biology and Cell Biology Unit, London), Molecular Cell Biology, London), Peter Lachmann ACKNOWLEDGMENTS xvii (MRC Centre, Cambridge), Ulrich Laemmli (University of Nagata (Kyoto University, Japan), Geeta Narlikar Geneva, Switzerland), Trevor Lamb (University of (University of California, San Francisco), Kim Nasmyth Cambridge), Hartmut Land (Cancer Research UK), David (University of Oxford), Mark E. Nelson (University of Lane (University of Dundee, Scotland), Jane Langdale Illinois, Urbana-Champaign), Michael Neuberger (University of Oxford), Lewis Lanier (University of (deceased), Walter Neupert (University of Munich, California, San Francisco), Jay Lash (University of Germany), David Nicholls (University of Dundee, Pennsylvania), Peter Lawrence (MRC Laboratory of Scotland), Roger Nicoll (University of California, San Molecular Biology, Cambridge), Paul Lazarow (Mount Sinai Francisco), Suzanne Noble (University of California, San School of Medicine), Robert J. Lefkowitz (Duke University), Francisco), Harry Noller (University of California, Santa Michael Levine (University of California, Berkeley), Warren Cruz), Jodi Nunnari (University of California, Davis), Paul Levinson (University of California, San Francisco), Alex Nurse (Francis Crick Institute), Roel Nusse (Stanford Levitzki (Hebrew University, Israel), Ottoline Leyser University), Michael Nussenzweig (Rockefeller University), (University of York, UK), Joachim Li (University of Duncan O’Dell (deceased), Patrick O’Farrell (University of California, San Francisco), Tomas Lindahl (Cancer California, San Francisco), Bjorn Olsen (Harvard Medical Research UK), Vishu Lingappa (University of California, School), Maynard Olson (University of Washington, San Francisco), Jennifer Lippincott-Schwartz (NIH), Joseph Seattle), Stuart Orkin (Harvard University), Terry Lipsick (Stanford University School of Medicine), Dan Orr-Weaver (Massachusetts Institute of Technology), Erin Littman (New York University School of Medicine), Clive O’Shea (Harvard University), Dieter Osterhelt (Max Planck Lloyd (John Innes Institute, Norwich, UK), Richard Institute of Biochemistry), William Otto (Cancer Research Locksley (University of California, San Francisco), Richard UK), John Owen (University of Birmingham, UK), Dale Losick (Harvard University), Daniel Louvard (Institut Curie, Oxender (University of Michigan), George Palade France), Robin Lovell-Badge (National Institute for Medical (deceased), Barbara Panning (University of California, San Research, London), Scott Lowe (Cold Spring Harbor Francisco), Roy Parker (University of Arizona, Tucson), Laboratory), Shirley Lowe (University of California, San William W. Parson (University of Washington, Seattle), Francisco), Reinhard Lührman (Max Planck Institute of Terence Partridge (MRC Clinical Sciences Centre, London), Biophysical Chemistry), Michael Lynch (Indiana William E. Paul (NIH), Tony Pawson (deceased), Hugh University), Laura Machesky (University of Birmingham, Pelham (MRC, UK), Robert Perry (Institute of Cancer UK), Hiten Madhani (University of California, San Research, Philadelphia), Gordon Peters (Cancer Research Francisco), James Maller (University of Colorado Medical UK), Greg Petsko (Brandeis University), Nikolaus Pfanner School), Tom Maniatis (Harvard University), Colin Manoil (University of Freiburg, Germany), David Phillips (Harvard Medical School), Elliott Margulies (NIH), Philippa (The Rockefeller University), Jeremy Pickett-Heaps Marrack (National Jewish Medical and Research Center, (The University of Melbourne, Australia), Jonathan Pines Denver), Mark Marsh (Institute of Cancer Research, (Gurdon Institute, Cambridge), Julie Pitcher (University London), Wallace Marshall (University of California, San College London), Jeffrey Pollard (Albert Einstein College Francisco), Gail Martin (University of California, San of Medicine), Tom Pollard (Yale University), Bruce Ponder Francisco), Paul Martin (University College London), (University of Cambridge), Daniel Portnoy (University of Joan Massagué (Memorial Sloan Kettering Cancer Center), California, Berkeley), James Priess (University of Christopher Mathews (Oregon State University), Brian Washington, Seattle), Darwin Prockop (Tulane University), McCarthy (University of California, Irvine), Richard Mark Ptashne (Memorial Sloan Kettering Cancer Center), McCarty (Cornell University), William McGinnis Dale Purves (Duke University), Efraim Racker (Cornell (University of California, San Diego), Anne McLaren University), Jordan Raff (University of Oxford), Klaus (Wellcome/Cancer Research Campaign Institute, Rajewsky (Max Delbrück Center for Molecular Medicine, Cambridge), Frank McNally (University of California, Germany), George Ratcliffe (University of Oxford), Elio Davis), Freiderick Meins (Freiderich Miescher Institut, Raviola (Harvard Medical School), Martin Rechsteiner Basel), Stephanie Mel (University of California, San Diego), (University of Utah, Salt Lake City), David Rees (National Ira Mellman (Genentech), Barbara Meyer (University of Institute for Medical Research, London), Thomas A. Reh California, Berkeley), Elliot Meyerowitz (California Institute (University of Washington, Seattle), Louis Reichardt of Technology), Chris Miller (Brandeis University), Robert (University of California, San Francisco), Renee Reijo Mishell (University of Birmingham, UK), Avrion Mitchison (University of California, San Francisco), Caetano Reis e (University College London), N.A. Mitchison (University Sousa (Cancer Research UK), Fred Richards (Yale College London), Timothy Mitchison (Harvard Medical University), Conly Rieder (Wadsworth Center, Albany), School), Quinn Mitrovich (University of California, San Phillips Robbins (Massachusetts Institute of Technology), Francisco), Peter Mombaerts (The Rockefeller University), Elizabeth Robertson (The Wellcome Trust Centre for Mark Mooseker (Yale University), David Morgan Human Genetics, UK), Elaine Robson (University of (University of California, San Francisco), Michelle Moritz Reading, UK), Robert Roeder (The Rockefeller University), (University of California, San Francisco), Montrose Moses Joel Rosenbaum (Yale University), Janet Rossant (Mount (Duke University), Keith Mostov (University of California, Sinai Hospital, Toronto), Jesse Roth (NIH), Jim Rothman San Francisco), Anne Mudge (University College London), (Memorial Sloan Kettering Cancer Center), Rodney Hans Müller-Eberhard (Scripps Clinic and Research Rothstein (Columbia University), Erkki Ruoslahti Institute), Alan Munro (University of Cambridge), (La Jolla Cancer Research Foundation), Gary Ruvkun J. Murdoch Mitchison (Harvard University), Richard Myers (Massachusetts General Hospital), David Sabatini (New (Stanford University), Diana Myles (University of California, York University), Alan Sachs (University of California, Davis), Andrew Murray (Harvard University), Shigekazu Berkeley), Edward Salmon (University of North Carolina, xviii ACKNOWLEDGMENTS Chapel Hill), Aziz Sancar (University of North Carolina, Roger Thomas (University of Bristol, UK), Craig Thompson Chapel Hill), Joshua Sanes (Harvard University), Peter (Memorial Sloan Kettering Cancer Center), Janet Thornton Sarnow (Stanford University), Lisa Satterwhite (European Bioinformatics Institute, UK), Vernon Thornton (Duke University Medical School), Robert Sauer (King’s College London), Cheryll Tickle (University of (Massachusetts Institute of Technology), Ken Sawin Dundee, Scotland), Jim Till (Ontario Cancer Institute, (The Wellcome Trust Centre for Cell Biology, UK), Howard Toronto), Lewis Tilney (University of Pennsylvania), David Schachman (University of California, Berkeley), Gerald Tollervey (University of Edinburgh, UK), Ian Tomlinson Schatten (Pittsburgh Development Center), Gottfried (Cancer Research UK), Nick Tonks (Cold Spring Harbor Schatz (Biozentrum, University of Basel), Randy Schekman Laboratory), Alain Townsend (Institute of Molecular (University of California, Berkeley), Richard Scheller Medicine, John Radcliffe Hospital, Oxford), Paul Travers (Stanford University), Giampietro Schiavo (Cancer (Scottish Institute for Regeneration Medicine), Robert Research UK), Ueli Schibler (University of Geneva, Trelstad (UMDNJ—Robert Wood Johnson Medical School), Switzerland), Joseph Schlessinger (New York University Anthony Trewavas (Edinburgh University, Scotland), Nigel Medical Center), Danny J. Schnell (University of Unwin (MRC Laboratory of Molecular Biology, Cambridge), Massachusetts, Amherst), Michael Schramm (Hebrew Victor Vacquier (University of California, San Diego), University, Israel), Robert Schreiber (Washington Ronald D. Vale (University of California, San Francisco), University School of Medicine), James Schwartz (Columbia Tom Vanaman (University of Kentucky), Harry van der University), Ronald Schwartz (NIH), François Schweisguth Westen (Wageningen, The Netherlands), Harold Varmus (Institut Pasteur, France), John Scott (University of (National Cancer Institute, United States), Alexander J. Manchester, UK), John Sedat (University of California, San Varshavsky (California Institute of Technology), Donald Francisco), Peter Selby (Cancer Research UK), Zvi Sellinger Voet (University of Pennsylvania), Harald von Boehmer (Hebrew University, Israel), Gregg Semenza (Johns (Harvard Medical School), Madhu Wahi (University of Hopkins University), Philippe Sengel (University of California, San Francisco), Virginia Walbot (Stanford Grenoble, France), Peter Shaw (John Innes Institute, University), Frank Walsh (GlaxoSmithKline, UK), Trevor Norwich, UK), Michael Sheetz (Columbia University), Wang (John Innes Institute, Norwich, UK), Xiaodong Wang Morgan Sheng (Massachusetts Institute of Technology), (The University of Texas Southwestern Medical School), Charles Sherr (St. Jude Children’s Hospital), David Shima Yu-Lie Wang (Worcester Foundation for Biomedical (Cancer Research UK), Samuel Silverstein (Columbia Research, MA), Gary Ward (University of Vermont), Anne University), Melvin I. Simon (California Institute of Warner (University College London), Graham Warren (Yale Technology), Kai Simons (Max Planck Institute of University School of Medicine), Paul Wassarman (Mount Molecular Cell Biology and Genetics), Jonathan Slack Sinai School of Medicine), Clare Waterman-Storer (The (Cancer Research UK), Alison Smith (John Innes Institute, Scripps Research Institute), Fiona Watt (Cancer Research Norfolk, UK), Austin Smith (University of Edinburgh, UK), UK), John Watts (John Innes Institute, Norwich, UK), Klaus Jim Smith (The Gurdon Institute, UK), John Maynard Smith Weber (Max Planck Institute for Biophysical Chemistry), (University of Sussex, UK), Mitchell Sogin (Woods Hole Martin Weigert (Institute of Cancer Research, Institute), Frank Solomon (Massachusetts Institute of Philadelphia), Robert Weinberg (Massachusetts Institute of Technology), Michael Solursh (University of Iowa), Bruce Technology), Harold Weintraub (deceased), Karsten Weis Spiegelman (Harvard Medical School), Timothy Springer (Swiss Federal Institute of Technology), Irving Weissman (Harvard Medical School), Mathias Sprinzl (University of (Stanford University), Jonathan Weissman (University of Bayreuth, Germany), Scott Stachel (University of California, California, San Francisco), Susan R. Wente (Vanderbilt Berkeley), Andrew Staehelin (University of Colorado, University School of Medicine), Norman Wessells Boulder), David Standring (University of California, San (University of Oregon, Eugene), Stephen West (Cancer Francisco), Margaret Stanley (University of Cambridge), Research UK), Judy White (University of Virginia), William Martha Stark (University of California, San Francisco), Wickner (Dartmouth College), Michael Wilcox (deceased), Wilfred Stein (Hebrew University, Israel), Malcolm Lewis T. Williams (Chiron Corporation), Patrick Williamson Steinberg (Princeton University), Ralph Steinman (University of Massachusetts, Amherst), Keith Willison (deceased), Len Stephens (The Babraham Institute, UK), (Chester Beatty Laboratories, London), John Wilson (Baylor Paul Sternberg (California Institute of Technology), Chuck University), Alan Wolffe (deceased), Richard Wolfenden Stevens (The Salk Institute), Murray Stewart (MRC (University of North Carolina, Chapel Hill), Sandra Wolin Laboratory of Molecular Biology, Cambridge), Bruce (Yale University School of Medicine), Lewis Wolpert Stillman (Cold Spring Harbor Laboratory), Charles Streuli (University College London), Richard D. Wood (University (University of Manchester, UK), Monroe Strickberger of Pittsburgh Cancer Institute), Abraham Worcel (University of Missouri, St. Louis), Robert Stroud (University of Rochester), Nick Wright (Cancer Research (University of California, San Francisco), Michael Stryker UK), John Wyke (Beatson Institute for Cancer Research, (University of California, San Francisco), William Sullivan Glasgow), Michael P. Yaffe (California Institute for (University of California, Santa Cruz), Azim Surani (The Regenerative Medicine), Kenneth M. Yamada (NIH), Keith Gurdon Institute, University of Cambridge), Daniel Szollosi Yamamoto (University of California, San Francisco), (Institut National de la Recherche Agronomique, France), Charles Yocum (University of Michigan, Ann Arbor), Peter Jack Szostak (Harvard Medical School), Clifford Tabin Yurchenco (UMDNJ—Robert Wood Johnson Medical (Harvard Medical School), Masatoshi Takeichi (RIKEN School), Rosalind Zalin (University College London), Center for Developmental Biology, Japan), Nicolas Tapon Patricia Zambryski (University of California, Berkeley), (London Research Institute), Diethard Tautz (University of Marino Zerial (Max Planck Institute of Molecular Cell Cologne, Germany), Julie Theriot (Stanford University), Biology and Genetics).  xix Contents PART I INTRODUCTION TO THE CELL 1 Chapter 1 Cells and Genomes 1 Chapter 2 Cell Chemistry and Bioenergetics 43 Chapter 3 Proteins 109 PART II BASIC GENETIC MECHANISMS 173 Chapter 4 DNA, Chromosomes, and Genomes 173 Chapter 5 DNA Replication, Repair, and Recombination 237 Chapter 6 How Cells Read the Genome: From DNA to Protein 299 Chapter 7 Control of Gene Expression 369 PART III WAYS OF WORKING WITH CELLS 439 Chapter 8 Analyzing Cells, Molecules, and Systems 439 Chapter 9 Visualizing Cells 529 PART IV INTERNAL ORGANIZATION OF THE CELL 565 Chapter 10 Membrane Structure 565 Chapter 11 Membrane Transport of Small Molecules and the Electrical Properties of Membranes 597 Chapter 12 Intracellular Compartments and Protein Sorting 641 Chapter 13 Intracellular Membrane Traffic 695 Chapter 14 Energy Conversion: Mitochondria and Chloroplasts 753 Chapter 15 Cell Signaling 813 Chapter 16 The Cytoskeleton 889 Chapter 17 The Cell Cycle 963 Chapter 18 Cell Death 1021 PART V CELLS IN THEIR SOCIAL CONTEXT 1035 Chapter 19 Cell Junctions and the Extracellular Matrix 1035 Chapter 20 Cancer 1091 Chapter 21 Development of Multicellular Organisms 1145 Chapter 22 Stem Cells and Tissue Renewal 1217 Chapter 23 Pathogens and Infection 1263 Chapter 24 The Innate and Adaptive Immune Systems 1297 Glossary G: 1 Index I: 1 Tables The Genetic Code, Amino Acids T: 1 xx Special Features Table 1–2 Some Model Organisms and Their Genomes 29 Table 2–1 Covalent and Noncovalent Chemical Bonds 45 Table 2–2 Relationship Between the Standard Free-Energy Change, ΔG°, and the Equilibrium Constant 63 PANEL 2–1 Chemical Bonds and Groups Commonly Encountered in Biological Molecules 90 PANEL 2–2 Water and Its Influence on the Behavior of Biological Molecules 92 PANEL 2–3 The Principal Types of Weak Noncovalent Bonds that Hold Macromolecules Together 94 PANEL 2–4 An Outline of Some of the Types of Sugars Commonly Found in Cells 96 PANEL 2–5 Fatty Acids and Other Lipids 98 PANEL 2–6 A Survey of the Nucleotides 100 PANEL 2–7 Free Energy and Biological Reactions 102 PANEL 2–8 Details of the 10 Steps of Glycolysis 104 PANEL 2–9 The Complete Citric Acid Cycle 106 Panel 3–1 The 20 Amino Acids Found in Proteins 112 Table 3–3 Some Molecules Covalently Attached to Proteins Regulate Protein Function 165 Table 4–1 Some Vital Statistics for the Human Genome 184 Table 5–4 Three Major Classes of Transposable Elements 288 Table 6–1 Principal Types of RNAs Produced in Cells 305 PANEL 7–1 Common Structural Motifs in Transcription Regulators 376 PANEL 8–1 DNA Sequencing Methods 478 PANEL 8–2 Review of Classical Genetics 486 Table 11–1 A Comparison of Inorganic Ion Concentrations Inside and Outside a Typical Mammalian Cell 598 PANEL 11–1 The Derivation of the Nernst Equation 616 Table 12–1 Relative Volumes Occupied by the Major Intracellular Compartments in a Liver Cell (Hepatocyte) 643 PANEL 14–1 Redox Potentials 765 Table 14–1 Product Yields from the Oxidation of Sugars and Fats 775 Table 15–3 Four Major Families of Trimeric G Proteins 846 Table 15–4 Some Signal Proteins That Act Via RTKs 850 Table 15–5 The Ras Superfamily of Monomeric GTPases 854 Table 15–6 Some Extracellular Signal Proteins That Act Through Cytokine Receptors and the JAK–STAT Signaling Pathway 864 PANEL 16–2 The Polymerization of Actin and Tubulin 902 Table 16–1 Chemical Inhibitors of Actin and Microtubules 904 PANEL 16–3 Actin Filaments 905 PANEL 16–4 Microtubules 933 Table 16–2 Major Types of Intermediate Filament Proteins in Vertebrate Cells 944 Table 17–1 The Major Cyclins and Cdks of Vertebrates and Budding Yeast 969 Table 17–2 Summary of the Major Cell Cycle Regulatory Proteins 973 PANEL 17–1 The Principle Stages of M Phase (Mitosis and Cytokinesis) in an Animal Cell 980 Table 19–1 Anchoring Junctions 1037 Table 19–2 Some Types of Collagen and Their Properties 1063 Table 19–3 Some Types of Integrins 1076 Table 22–1 Blood Cells 1241 Table 24–2 Properties of the Major Classes of Antibodies in Humans 1318 Table 24–3 Properties of Human Class I and Class II MHC Proteins 1330  xxi Detailed Contents Chapter 1 Cells and Genomes 1 The Frog and the Zebrafish Provide Accessible Models for Vertebrate Development 35 The Universal Features of Cells on Earth 2 The Mouse Is the Predominant Mammalian Model Organism 35 All Cells Store Their Hereditary Information in the Same Linear Humans Report on Their Own Peculiarities 36 Chemical Code: DNA 2 We Are All Different in Detail 38 All Cells Replicate Their Hereditary Information by Templated To Understand Cells and Organisms Will Require Mathematics, Polymerization 3 Computers, and Quantitative Information 38 All Cells Transcribe Portions of Their Hereditary Information into Summary 39 the Same Intermediary Form: RNA 4 Problems 39 All Cells Use Proteins as Catalysts 5 References 41 All Cells Translate RNA into Protein in the Same Way 6 Each Protein Is Encoded by a Specific Gene 7 Chapter 2 Cell Chemistry and Bioenergetics 43 Life Requires Free Energy 8 All Cells Function as Biochemical Factories Dealing with the Same The Chemical Components of a Cell 43 Basic Molecular Building Blocks 8 Water Is Held Together by Hydrogen Bonds 44 All Cells Are Enclosed in a Plasma Membrane Across Which Four Types of Noncovalent Attractions Help Bring Molecules Nutrients and Waste Materials Must Pass 8 Together in Cells 44 A Living Cell Can Exist with Fewer Than 500 Genes 9 Some Polar Molecules Form Acids and Bases in Water 45 A Cell Is Formed from Carbon Compounds 47 Summary 10 Cells Contain Four Major Families of Small Organic Molecules 47 The Diversity of Genomes and the Tree of Life 10 The Chemistry of Cells Is Dominated by Macromolecules with Cells Can Be Powered by a Variety of Free-Energy Sources 10 Remarkable Properties 47 Some Cells Fix Nitrogen and Carbon Dioxide for Others 12 Noncovalent Bonds Specify Both the Precise Shape of a The Greatest Biochemical Diversity Exists Among Prokaryotic Cells 12 Macromolecule and Its Binding to Other Molecules 49 The Tree of Life Has Three Primary Branches: Bacteria, Archaea, Summary 50 and Eukaryotes 14 Catalysis and the Use of Energy by Cells 51 Some Genes Evolve Rapidly; Others Are Highly Conserved 15 Cell Metabolism Is Organized by Enzymes 51 Most Bacteria and Archaea Have 1000–6000 Genes 16 Biological Order Is Made Possible by the Release of Heat Energy New Genes Are Generated from Preexisting Genes 16 from Cells 52 Gene Duplications Give Rise to Families of Related Genes Within Cells Obtain Energy by the Oxidation of Organic Molecules 54 a Single Cell 17 Oxidation and Reduction Involve Electron Transfers 55 Genes Can Be Transferred Between Organisms, Both in the Enzymes Lower the Activation-Energy Barriers That Block Laboratory and in Nature 18 Chemical Reactions 57 Sex Results in Horizontal Exchanges of Genetic Information Enzymes Can Drive Substrate Molecules Along Specific Reaction Within a Species 19 Pathways 58 The Function of a Gene Can Often Be Deduced from Its Sequence 20 How Enzymes Find Their Substrates: The Enormous Rapidity of More Than 200 Gene Families Are Common to All Three Primary Molecular Motions 59 Branches of the Tree of Life 20 The Free-Energy Change for a Reaction, ∆G, Determines Whether Mutations Reveal the Functions of Genes 21 It Can Occur Spontaneously 60 Molecular Biology Began with a Spotlight on E. coli 22 The Concentration of Reactants Influences the Free-Energy Summary 22 Change and a Reaction’s Direction 61 The Standard Free-Energy Change, ∆G°, Makes It Possible Genetic Information in Eukaryotes 23 to Compare the Energetics of Different Reactions 61 Eukaryotic Cells May Have Originated as Predators 24 The Equilibrium Constant and ∆G° Are Readily Derived from Modern Eukaryotic Cells Evolved from a Symbiosis 25 Each Other 62 Eukaryotes Have Hybrid Genomes 27 The Free-Energy Changes of Coupled Reactions Are Additive 63 Eukaryotic Genomes Are Big 28 Activated Carrier Molecules Are Essential for Biosynthesis 63 Eukaryotic Genomes Are Rich in Regulatory DNA 29 The Formation of an Activated Carrier Is Coupled to an The Genome Defines the Program of Multicellular Development 29 Energetically Favorable Reaction 64 Many Eukaryotes Live as Solitary Cells 30 ATP Is the Most Widely Used Activated Carrier Molecule 65 A Yeast Serves as a Minimal Model Eukaryote 30 Energy Stored in ATP Is Often Harnessed to Join Two Molecules The Expression Levels of All the Genes of An Organism Together 65 Can Be Monitored Simultaneously 32 NADH and NADPH Are Important Electron Carriers 67 Arabidopsis Has Been Chosen Out of 300,000 Species There Are Many Other Activated Carrier Molecules in Cells 68 As a Model Plant 32 The Synthesis of Biological Polymers Is Driven by ATP Hydrolysis 70 The World of Animal Cells Is Represented By a Worm, a Fly, Summary 73 a Fish, a Mouse, and a Human 33 HOW CELLS OBTAIN ENERGY FROM FOOD 73 Studies in Drosophila Provide a Key to Vertebrate Development 33 Glycolysis Is a Central ATP-Producing Pathway 74 The Vertebrate Genome Is a Product of Repeated Duplications 34 Fermentations Produce ATP in the Absence of Oxygen 75 xxii DETAILED CONTENTS Glycolysis Illustrates How Enzymes Couple Oxidation to Energy The Regulation of the Src Protein Kinase Reveals How a Protein Storage 76 Can Function as a Microprocessor 155 Organisms Store Food Molecules in Special Reservoirs 78 Proteins That Bind and Hydrolyze GTP Are Ubiquitous Cell Most Animal Cells Derive Their Energy from Fatty Acids Between Regulators 156 Meals 81 Regulatory Proteins GAP and GEF Control the Activity of GTP- Sugars and Fats Are Both Degraded to Acetyl CoA in Mitochondria 81 Binding Proteins by Determining Whether GTP or GDP The Citric Acid Cycle Generates NADH by Oxidizing Acetyl Is Bound 157 Groups to CO2 82 Proteins Can Be Regulated by the Covalent Addition of Other Electron Transport Drives the Synthesis of the Majority of the ATP Proteins 157 in Most Cells 84 An Elaborate Ubiquitin-Conjugating System Is Used to Mark Amino Acids and Nucleotides Are Part of the Nitrogen Cycle 85 Proteins 158 Metabolism Is Highly Organized and Regulated 87 Protein Complexes with Interchangeable Parts Make Efficient Summary 88 Use of Genetic Information 159 Problems 88 A GTP-Binding Protein Shows How Large Protein Movements References 108 Can Be Generated 160 Motor Proteins Produce Large Movements in Cells 161 Chapter 3 Proteins 109 Membrane-Bound Transporters Harness Energy to Pump Molecules Through Membranes 163 THE SHAPE AND STRUCTURE OF PROTEINS 109 Proteins Often Form Large Complexes That Function as Protein The Shape of a Protein Is Specified by Its Amino Acid Sequence 109 Machines 164 Proteins Fold into a Conformation of Lowest Energy 114 Scaffolds Concentrate Sets of Interacting Proteins 164 The α Helix and the β Sheet Are Common Folding Patterns 115 Many Proteins Are Controlled by Covalent Modifications That Protein Domains Are Modular Units from Which Larger Proteins Direct Them to Specific Sites Inside the Cell 165 Are Built 117 A Complex Network of Protein Interactions Underlies Cell Function 166 Few of the Many Possible Polypeptide Chains Will Be Useful Summary 169 to Cells 118 Problems 170 Proteins Can Be Classified into Many Families 119 References 172 Some Protein Domains Are Found in Many Different Proteins 121 Certain Pairs of Domains Are Found Together in Many Proteins 122 The Human Genome Encodes a Complex Set of Proteins, Chapter 4 DNA, Chromosomes, and Genomes 173 Revealing That Much Remains Unknown 122 THE STRUCTURE AND FUNCTION OF DNA 173 Larger Protein Molecules Often Contain More Than One A DNA Molecule Consists of Two Complementary Chains of Polypeptide Chain 123 Nucleotides 175 Some Globular Proteins Form Long Helical Filaments 123 The Structure of DNA Provides a Mechanism for Heredity 177 Many Protein Molecules Have Elongated, Fibrous Shapes 124 In Eukaryotes, DNA Is Enclosed in a Cell Nucleus 178 Proteins Contain a Surprisingly Large Amount of Intrinsically Summary 179 Disordered Polypeptide Chain 125 Covalent Cross-Linkages Stabilize Extracellular Proteins 127 CHROMOSOMAL DNA AND ITS PACKAGING IN THE Protein Molecules Often Serve as Subunits for the Assembly CHROMATIN FIBER 179 of Large Structures 127 Eukaryotic DNA Is Packaged into a Set of Chromosomes 180 Many Structures in Cells Are Capable of Self-Assembly 128 Chromosomes Contain Long Strings of Genes 182 Assembly Factors Often Aid the Formation of Complex Biological The Nucleotide Sequence of the Human Genome Shows How Structures 130 Our Genes Are Arranged 183 Amyloid Fibrils Can Form from Many Proteins 130 Each DNA Molecule That Forms a Linear Chromosome Must Amyloid Structures Can Perform Useful Functions in Cells 132 Contain a Centromere, Two Telomeres, and Replication Many Proteins Contain Low-complexity Domains that Can Form Origins 185 “Reversible Amyloids” 132 DNA Molecules Are Highly Condensed in Chromosomes 187 Summary 134 Nucleosomes Are a Basic Unit of Eukaryotic Chromosome PROTEIN FUNCTION 134 Structure 187 All Proteins Bind to Other Molecules 134 The Structure of the Nucleosome Core Particle Reveals How The Surface Conformation of a Protein Determines Its Chemistry 135 DNA Is Packaged 188 Sequence Comparisons Between Protein Family Members Nucleosomes Have a Dynamic Structure, and Are Frequently Highlight Crucial Ligand-Binding Sites 136 Subjected to Changes Catalyzed by ATP-Dependent Proteins Bind to Other Proteins Through Several Types of Chromatin Remodeling Complexes 190 Interfaces 137 Nucleosomes Are Usually Packed Together into a Compact Antibody Binding Sites Are Especially Versatile 138 Chromatin Fiber 191 The Equilibrium Constant Measures Binding Strength 138 Summary 193 Enzymes Are Powerful and Highly Specific Catalysts 140 CHROMATIN STRUCTURE AND FUNCTION 194 Substrate Binding Is the First Step in Enzyme Catalysis 141 Heterochromatin Is Highly Organized and Restricts Gene Enzymes Speed Reactions by Selectively Stabilizing Transition Expression 194 States 141 The Heterochromatic State Is Self-Propagating 194 Enzymes Can Use Simultaneous Acid and Base Catalysis 144 Lysozyme Illustrates How an Enzyme Works 144 The Core Histones Are Covalently Modified at Many Different Sites 196 Tightly Bound Small Molecules Add Extra Functions to Proteins 146 Chromatin Acquires Additional Variety Through the Site-Specific Multienzyme Complexes Help to Increase the Rate of Cell Insertion of a Small Set of Histone Variants 198 Metabolism 148 Covalent Modifications and Histone Variants Act in Concert to The Cell Regulates the Catalytic Activities of Its Enzymes 149 Control Chromosome Functions 198 Allosteric Enzymes Have Two or More Binding Sites That Interact 151 A Complex of Reader and Writer Proteins Can Spread Specific Two Ligands Whose Binding Sites Are Coupled Must Reciprocally Chromatin Modifications Along a Chromosome 199 Affect Each Other’s Binding 151 Barrier DNA Sequences Block the Spread of Reader–Writer Symmetric Protein Assemblies Produce Cooperative Allosteric Complexes and thereby Separate Neighboring Chromatin Transitions 152 Domains 202 Many Changes in Proteins Are Driven by Protein Phosphorylation 153 The Chromatin in Centromeres Reveals How Histone Variants A Eukaryotic Cell Contains a Large Collection of Protein Kinases Can Create Special Structures 203 and Protein Phosphatases 154 Some Chromatin Structures Can Be Directly Inherited 204 DETAILED CONTENTS xxiii Experiments with Frog Embryos Suggest that both Activating The Proteins at a Replication Fork Cooperate to Form a and Repressive Chromatin Structures Can