Title Page

Copyright Page

Contents

Preface

Chapter 1 An Introduction to the Protein Molecule

1.1 Why Study Protein Moonlighting?

1.2 A Brief History of Proteins

1.3 Protein Biology

1.4 Protein Structure and Function

1.5 Protein Sequence Determination, Structures, and Bioinformatics

1.6 Regulation of Protein Synthesis

1.7 Conclusions

References

Chapter 2 How Proteins Evolve?

2.1 Introduction

2.2 A Darwinian View of Molecular Evolution

2.3 The Neutral and Nearly Neutral Theories of Molecular Evolution

2.4 Mutation, Fitness, and Evolution

2.5 Proteins Evolve at Different Rates

2.6 Protein Evolution by Gene Duplication

2.7 Conclusions

References

Chapter 3 A Brief History of Protein Moonlighting

3.1 Introduction

3.2 Protein Moonlighting: The Early Beginnings

3.3 Eye Lens Proteins and Gene Sharing

3.4 Multifunctional Metabolic Proteins and Molecular Chaperones

3.5 The Return of Moonlighting

3.6 A Current View of Protein Moonlighting

3.7 The Current Population of Moonlighting Proteins

3.8 Conclusions

References

Chapter 4 The Structural Basis of Protein Moonlighting

4.1 Introduction

4.2 The Structural Biology of Protein Moonlighting

4.2.1 Exploiting Protein Bulk

4.2.2 Catalytic Promiscuity

4.2.3 Exploiting Separate Functional Sites

4.2.4 Exploiting Alternatively Folded Forms

4.2.5 Alternative Oligomerization

4.2.6 Posttranslational Modifications

4.3 Predicting and Engineering Moonlighting

4.4 Conclusions

References

Chapter 5 Protein Moonlighting and New Thoughts about Protein Evolution

5.1 Introduction

5.2 A Darwinian Perspective of Protein Moonlighting

5.3 Origin and Evolutionary Stability of Protein Moonlighting

5.4 Mutational Robustness and the Persistence of Moonlighting Proteins

5.5 Proteins Robust to Mutations Are Highly Evolvable

5.6 Moonlighting Proteins and the Rate of Protein Evolution

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

5.8 Protein Moonlighting Can Lead to Functional Specialization

5.9 Conclusions

References

Chapter 6 Biological Consequences of Protein Moonlighting

6.1 Introduction

6.2 The Human Genome, Protein-Coding Genes, and Cellular Complexity

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

6.4 Secretion of Moonlighting Proteins: A Major Problem Seeking Solution

6.5 How Does Protein Moonlighting Influence Systems Biology?

6.5.1 Systems Biology and Protein Moonlighting

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

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

6.6.1 Do Moonlighting Protein Exhibit Novel Biological Functions?

6.6.2 Moonlighting Proteins and Normal Cellular Functions

6.6.2.1 Secreted Moonlighting Proteins

6.6.2.2 Moonlighting Proteins on the Plasma Membrane

6.6.2.3 Moonlighting Proteins in the Nucleus or Interacting with Nucleic Acids

6.6.2.4 Moonlighting Proteins in Cellular Vesicular Trafficking

6.6.2.5 Moonlighting in the Cell Cytoplasm

6.6.2.6 Ribosomal Moonlighting Proteins

6.6.2.7 Moonlighting in Cell Division

6.6.2.8 Moonlighting Proteins Existing in Multiple Cellular Compartments

6.7 Moonlighting Proteins in the Biology of Single-Celled Eukaryotes

6.8 Moonlighting Proteins Interacting with Moonlighting Proteins

6.9 Moonlighting Proteins and Vision: Are Lens Proteins Moonlighting?

6.10 Conclusions

References

Chapter 7 Protein Moonlighting and Human Health and Idiopathic Human Disease

7.1 Introduction

7.2 Mammalian Moonlighting Proteins Involved in the Biology of the Cell

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

7.3.1 Cellular Iron Uptake: GAPDH Binds to Iron-Binding Proteins

7.3.2 Moonlighting Proteins Involved with the Vasculature

7.3.2.1 Thymidine Phosphorylase

7.3.2.2 Protein Disulfide Isomerase (PDI)

7.3.2.3 Mitochondrial Coupling Factor (Mcf)6

7.3.2.4 Miscellaneous Moonlighting Proteins

7.3.3 Secreted and Cell Surface Histones and Human Physiology

7.3.4 Moonlighting Proteins in Reproduction

7.3.4.1 Chaperonin (Hsp)10 and Pregnancy

7.3.4.2 Phosphoglucoisomerase and Implantation in the Ferret

7.3.4.3 Miscellaneous Moonlighting Proteins and Pregnancy

7.3.4.4 Moonlighting Proteins, Sperm, and Fertilization

7.3.5 Moonlighting Proteins Involved in Controlling Inflammation

7.3.5.1 Ubiquitin

7.3.5.2 Interferon-Stimulated Gene 15 (ISG15)

7.3.5.3 Thioredoxin

7.3.5.4 TNF-Stimulated Gene 6 (TSG-6)

7.3.5.5 Ribosomal Protein L13a

7.3.5.6 Ribosomal Protein S19

7.3.5.7 Adiponectin and Inflammation

7.3.5.8 Miscellaneous Proteins

7.3.6 Moonlighting Proteins as Therapeutics

7.3.6.1 Hsp10

7.3.6.2 BiP

7.3.6.3 Ubiquitin

7.3.6.4 Moonlighting Proteins Involved in Wound Healing

7.4 Moonlighting Proteins in Human Pathology

7.4.1 Phosphoglucoisomerase as a Factor in Human Pathology

7.4.2 Moonlighting Proteins in Human Cancer

7.4.2.1 α-Enolase

7.4.2.2 Aldolase

7.4.2.3 Phosphofructokinase

7.4.2.4 Triosephosphate Isomerase

7.4.2.5 GAPDH

7.4.2.6 Phosphoglycerate Kinase (PGK)

7.4.2.7 Pyruvate Kinase (PK)

7.4.2.8 BiP/Grp78

7.4.2.9 Hsp90

7.4.2.10 Hsp27

7.4.2.11 Cyclophilin A (CypA)

7.4.2.12 Miscellaneous Proteins

7.4.3 Molecular Chaperones and Protein-Folding Catalysts in Human Inflammatory Pathology

7.4.3.1 Chaperonin (Heat Shock Protein) 60 in Cardiovascular Disease

7.4.3.2 Hsp70 (HSPA1) in Cardiovascular Disease

7.4.3.3 Cyclophilin A

7.4.3.4 Thioredoxin and Thioredoxin-80

7.4.3.5 Peroxiredoxins

7.4.4 DAMPs: Moonlighting Proteins in Human Inflammatory Pathology

7.4.4.1 S100 Proteins

7.4.4.2 High-Mobility Group Box 1 Protein

7.4.4.3 Histones

7.4.5 Moonlighting Proteins and Vascular Pathology

7.4.5.1 Histones

7.4.5.2 Mitochondrial Coupling Factor 6

7.5 Neomorphic Moonlighting Proteins and Human Diseases

7.6 Moonlighting Proteins in Autoimmune Disease

7.7 Conclusions

References

Chapter 8 Protein Moonlighting and Infectious Disease

8.1 Introduction

8.2 Microbial Colonization and Infection

8.3 Bacterial Virulence Mechanisms

8.4 Moonlighting Proteins in Bacterial Virulence

8.4.1 Affinities of Binding of Bacterial Moonlighting Proteins

8.4.2 Bacteria Utilizing Moonlighting Proteins

8.4.3 Identity of the Bacterial Proteins That Moonlight

8.5 Biological Activities of Bacterial Moonlighting Proteins as Virulence Factors

8.5.1 Bacterial Moonlighting Proteins Acting as Adhesins

8.5.2 Bacterial Moonlighting Proteins Acting as Invasins

8.5.3 Bacterial Moonlighting Proteins Acting as Evasins

8.5.4 Bacterial Moonlighting Proteins with Activity Similar to Bacterial Toxins

8.5.5 Bacterial Moonlighting Proteins Acting as Receptors for Nutrients

8.5.6 Miscellaneous Actions of Moonlighting Proteins

8.5.7 Conclusions

8.6 Examples of Bacterial Moonlighting Proteins in Human Infectious Disease

8.7 Moonlighting Proteins in Fungi

8.8 Moonlighting Proteins in Protozoal Infections

8.9 Conclusions

References

Chapter 9 Protein Moonlighting: The Future

9.1 Introduction

9.2 How Prevalent Is Protein Moonlighting?

9.3 Evolutionary Biology of Protein Moonlighting

9.3.1 Antibodies and Protein Moonlighting

9.4 Protein Posttranslational Modification and Protein Moonlighting

9.5 Genetics and Protein Moonlighting

9.6 Protein Moonlighting and Systems Biology

9.7 Moonlighting Proteins and the Response to Drugs

9.8 Moonlighting Proteins as Drug Targets

9.9 Conclusions

References

Index

Supplemental Images

EULA