Protein Moonlighting in Biology and Medicine

The past 25 years has seen the emergence of a wealth of data suggesting that novel biological functions of known proteins play important roles in biology and medicine.  This ability of proteins to exhibit more than one unique biological activity is known as protein moonlighting. Moonlighting proteins can exhibit novel biological functions, thus extending the function of the proteome, and are also implicated in the pathology of a growing number of idiopathic and infectious diseases. 

This book, written by a cell biologist, protein evolutionary biologist and protein bioinformatician, brings together the latest information on the structure, evolution and biological function of the growing numbers of moonlighting proteins that have been identified, and their roles in human health and disease.  This information is revealing the enormous importance protein moonlighting plays in the maintenance of human health and in the induction of disease pathology. 

Protein Moonlighting in Biology and Medicine will be of interest to a general readership in the biological and biomedical research community.

Brian Henderson is Professor of Biochemistry at University College London. He started his research career as a cell biologist, migrating to become an immunologist then pharmacologist with six years experience in the pharmaceutical industry. In the early 1990s studies of bacteria-host interactions identified a bacterial molecular chaperone, chaperonin 60, as a potent signalling molecule able to induce osteoclast formation and bone remodelling. This was Henderson’s introduction to protein moonlighting and he has spent the past twenty years exploring the roles of bacterial and human moonlighting proteins in human health and disease.

Mario Fares is a Principal Investogator in the Evolutionary Genetics and Bioinformatics Laboratory at Trinity College. His research is focused on the understanding of the selective forces shaping the evolution of proteins, proteomes and genomes. Most of the concepts dealt with in his laboratory are related to the field of molecular evolution and the complexity of mutations relationships. Taking these interests and concepts to the level of comparative genomics and proteomics adds the dimension of systems biology to his research.

Andrew Martin is a researcher in the Bloomsbury Center for Bioinformatics at University College, London. His research focuses on structural bioinformatics: developing tools to investigate and understand the relationship between protein sequence, structure and function. Within this general area, his main interests are protein modelling, structural analysis, structural immunology, effects of mutation on protein structure and disease, application of relational databases, automation and software development.

Preface xi

1 An Introduction to the Protein Molecule 1

1.1 Why Study Protein Moonlighting? 1

1.2 A Brief History of Proteins 2

1.3 Protein Biology 4

1.4 Protein Structure and Function 6

1.5 Protein Sequence Determination, Structures, and Bioinformatics 9

1.6 Regulation of Protein Synthesis 11

1.7 Conclusions 12

References 12

2 How Proteins Evolve? 15

2.1 Introduction 15

2.2 A Darwinian View of Molecular Evolution 16

2.3 The Neutral and Nearly Neutral Theories of Molecular Evolution 18

2.4 Mutation, Fitness, and Evolution 20

2.5 Proteins Evolve at Different Rates 24

2.6 Protein Evolution by Gene Duplication 25

2.7 Conclusions 26

References 26

3 A Brief History of Protein Moonlighting 31

3.1 Introduction 31

3.2 Protein Moonlighting: The Early Beginnings 31

3.3 Eye Lens Proteins and Gene Sharing 33

3.4 Multifunctional Metabolic Proteins and Molecular Chaperones 35

3.5 The Return of Moonlighting 37

3.6 A Current View of Protein Moonlighting 39

3.7 The Current Population of Moonlighting Proteins 40

3.8 Conclusions 40

References 40

4 The Structural Basis of Protein Moonlighting 45

4.1 Introduction 45

4.2 The Structural Biology of Protein Moonlighting 48

4.2.1 Exploiting Protein Bulk 49

4.2.2 Catalytic Promiscuity 49

4.2.3 Exploiting Separate Functional Sites 50

4.2.4 Exploiting Alternatively Folded Forms 55

4.2.5 Alternative Oligomerization 56

4.2.6 Posttranslational Modifications 57

4.3 Predicting and Engineering Moonlighting 57

4.4 Conclusions 58

References 60

5 Protein Moonlighting and New Thoughts about Protein Evolution 63

5.1 Introduction 63

5.2 A Darwinian Perspective of Protein Moonlighting 65

5.3 Origin and Evolutionary Stability of Protein Moonlighting 67

5.4 Mutational Robustness and the Persistence of Moonlighting Proteins 68

5.5 Proteins Robust to Mutations Are Highly Evolvable 70

5.6 Moonlighting Proteins and the Rate of Protein Evolution 72

5.7 Molecular Chaperones Buffer the Effects of Mutations on Proteins, Expediting Their Rate of Evolution and Enabling Moonlighting 74

5.8 Protein Moonlighting Can Lead to Functional Specialization 76

5.9 Conclusions 76

References 77

6 Biological Consequences of Protein Moonlighting 81

6.1 Introduction 81

6.2 The Human Genome, Protein�]Coding Genes, and Cellular Complexity 81

6.3 How Many Moonlighting Proteins Exist/What Proportion of the Proteome Moonlights? 83

6.4 Secretion of Moonlighting Proteins: A Major Problem Seeking Solution 86

6.5 How Does Protein Moonlighting Influence Systems Biology? 90

6.5.1 Systems Biology and Protein Moonlighting 91

6.5.2 Analysis of the Systems Biology of the Moonlighting Protein Glycerol Kinase 95

6.6 Role of Moonlighting Proteins in the Control of the Biology of the Healthy Cell 97

6.6.1 Do Moonlighting Protein Exhibit Novel Biological Functions? 97

6.6.2 Moonlighting Proteins and Normal Cellular Functions 104

6.6.2.1 Secreted Moonlighting Proteins 105

6.6.2.2 Moonlighting Proteins on the Plasma Membrane 106

6.6.2.3 Moonlighting Proteins in the Nucleus or Interacting with Nucleic Acids 110

6.6.2.4 Moonlighting Proteins in Cellular Vesicular Trafficking 113

6.6.2.5 Moonlighting in the Cell Cytoplasm 113

6.6.2.6 Ribosomal Moonlighting Proteins 115

6.6.2.7 Moonlighting in Cell Division 118

6.6.2.8 Moonlighting Proteins Existing in Multiple Cellular Compartments 118

6.7 Moonlighting Proteins in the Biology of Single�]Celled Eukaryotes 119

6.8 Moonlighting Proteins Interacting with Moonlighting Proteins 119

6.9 Moonlighting Proteins and Vision: Are Lens Proteins Moonlighting? 120

6.10 Conclusions 121

References 121

7 Protein Moonlighting and Human Health and Idiopathic Human Disease 143

7.1 Introduction 143

7.2 Mammalian Moonlighting Proteins Involved in the Biology of the Cell 143

7.3 Moonlighting Proteins and Human Physiology (Healthy Interactions of Moonlighting Proteins) 144

7.3.1 Cellular Iron Uptake: GAPDH Binds to Iron�]Binding Proteins 144

7.3.2 Moonlighting Proteins Involved with the Vasculature 149

7.3.2.1 Thymidine Phosphorylase 149

7.3.2.2 Protein Disulfide Isomerase (PDI) 150

7.3.2.3 Mitochondrial Coupling Factor (Mcf)6 150

7.3.2.4 Miscellaneous Moonlighting Proteins 151

7.3.3 Secreted and Cell Surface Histones and Human Physiology 152

7.3.4 Moonlighting Proteins in Reproduction 154

7.3.4.1 Chaperonin (Hsp)10 and Pregnancy 154

7.3.4.2 Phosphoglucoisomerase and Implantation in the Ferret 155

7.3.4.3 Miscellaneous Moonlighting Proteins and Pregnancy 155

7.3.4.4 Moonlighting Proteins, Sperm, and Fertilization 156

7.3.5 Moonlighting Proteins Involved in Controlling Inflammation 157

7.3.5.1 Ubiquitin 158

7.3.5.2 Interferon�]Stimulated Gene 15 (ISG15) 159

7.3.5.3 Thioredoxin 159

7.3.5.4 TNF�]Stimulated Gene 6 (TSG�]6) 160

7.3.5.5 Ribosomal Protein L13a 161

7.3.5.6 Ribosomal Protein S19 161

7.3.5.7 Adiponectin and Inflammation 162

7.3.5.8 Miscellaneous Proteins 162

7.3.6 Moonlighting Proteins as Therapeutics 162

7.3.6.1 Hsp10 164

7.3.6.2 BiP 164

7.3.6.3 Ubiquitin 165

7.3.6.4 Moonlighting Proteins Involved in Wound Healing 165

7.4 Moonlighting Proteins in Human Pathology 166

7.4.1 Phosphoglucoisomerase as a Factor in Human Pathology 166

7.4.2 Moonlighting Proteins in Human Cancer 170

7.4.2.1 α�]Enolase 170

7.4.2.2 Aldolase 171

7.4.2.3 Phosphofructokinase 171

7.4.2.4 Triosephosphate Isomerase 172

7.4.2.5 GAPDH 172

7.4.2.6 Phosphoglycerate Kinase (PGK) 172

7.4.2.7 Pyruvate Kinase (PK) 173

7.4.2.8 BiP/Grp78 173

7.4.2.9 Hsp90 174

7.4.2.10 Hsp27 175

7.4.2.11 Cyclophilin A (CypA) 176

7.4.2.12 Miscellaneous Proteins 176

7.4.3 Molecular Chaperones and Protein�]Folding Catalysts in Human Inflammatory Pathology 177

7.4.3.1 Chaperonin (Heat Shock Protein) 60 in Cardiovascular Disease 177

7.4.3.2 Hsp70 (HSPA1) in Cardiovascular Disease 178

7.4.3.3 Cyclophilin A 179

7.4.3.4 Thioredoxin and Thioredoxin�]80 180

7.4.3.5 Peroxiredoxins 181

7.4.4 DAMPs: Moonlighting Proteins in Human Inflammatory Pathology 181

7.4.4.1 S100 Proteins 182

7.4.4.2 High�]Mobility Group Box 1 Protein 182

7.4.4.3 Histones 183

7.4.5 Moonlighting Proteins and Vascular Pathology 183

7.4.5.1 Histones 183

7.4.5.2 Mitochondrial Coupling Factor 6 184

7.5 Neomorphic Moonlighting Proteins and Human Diseases 185

7.6 Moonlighting Proteins in Autoimmune Disease 185

7.7 Conclusions 188

References 188

8 Protein Moonlighting and Infectious Disease 223

8.1 Introduction 223

8.2 Microbial Colonization and Infection 224

8.3 Bacterial Virulence Mechanisms 224

8.4 Moonlighting Proteins in Bacterial Virulence 227

8.4.1 Affinities of Binding of Bacterial Moonlighting Proteins 227

8.4.2 Bacteria Utilizing Moonlighting Proteins 229

8.4.3 Identity of the Bacterial Proteins That Moonlight 232

8.5 Biological Activities of Bacterial Moonlighting Proteins as Virulence Factors 237

8.5.1 Bacterial Moonlighting Proteins Acting as Adhesins 237

8.5.2 Bacterial Moonlighting Proteins Acting as Invasins 248

8.5.3 Bacterial Moonlighting Proteins Acting as Evasins 248

8.5.4 Bacterial Moonlighting Proteins with Activity Similar to Bacterial Toxins 252

8.5.5 Bacterial Moonlighting Proteins Acting as Receptors for Nutrients 256

8.5.6 Miscellaneous Actions of Moonlighting Proteins 256

8.5.7 Conclusions 257

8.6 Examples of Bacterial Moonlighting Proteins in Human Infectious Disease 257

8.7 Moonlighting Proteins in Fungi 259

8.8 Moonlighting Proteins in Protozoal Infections 260

8.9 Conclusions 262

References 262

9 Protein Moonlighting: The Future 281

9.1 Introduction 281

9.2 How Prevalent Is Protein Moonlighting? 282

9.3 Evolutionary Biology of Protein Moonlighting 284

9.3.1 Antibodies and Protein Moonlighting 285

9.4 Protein Posttranslational Modification and Protein Moonlighting 286

9.5 Genetics and Protein Moonlighting 287

9.6 Protein Moonlighting and Systems Biology 288

9.7 Moonlighting Proteins and the Response to Drugs 290

9.8 Moonlighting Proteins as Drug Targets 292

9.9 Conclusions 292

References 293

Index 297

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