Protein Moonlighting in Biology and Medicine

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 xi1 An Introduction to the Protein Molecule 11.1 Why Study Protein Moonlighting? 11.2 A Brief History of Proteins 21.3 Protein Biology 41.4 Protein Structure and Function 61.5 Protein Sequence Determination, Structures, and Bioinformatics 91.6 Regulation of Protein Synthesis 111.7 Conclusions 12References 122 How Proteins Evolve? 152.1 Introduction 152.2 A Darwinian View of Molecular Evolution 162.3 The Neutral and Nearly Neutral Theories of Molecular Evolution 182.4 Mutation, Fitness, and Evolution 202.5 Proteins Evolve at Different Rates 242.6 Protein Evolution by Gene Duplication 252.7 Conclusions 26References 263 A Brief History of Protein Moonlighting 313.1 Introduction 313.2 Protein Moonlighting: The Early Beginnings 313.3 Eye Lens Proteins and Gene Sharing 333.4 Multifunctional Metabolic Proteins and Molecular Chaperones 353.5 The Return of Moonlighting 373.6 A Current View of Protein Moonlighting 393.7 The Current Population of Moonlighting Proteins 403.8 Conclusions 40References 404 The Structural Basis of Protein Moonlighting 454.1 Introduction 454.2 The Structural Biology of Protein Moonlighting 484.2.1 Exploiting Protein Bulk 494.2.2 Catalytic Promiscuity 494.2.3 Exploiting Separate Functional Sites 504.2.4 Exploiting Alternatively Folded Forms 554.2.5 Alternative Oligomerization 564.2.6 Posttranslational Modifications 574.3 Predicting and Engineering Moonlighting 574.4 Conclusions 58References 605 Protein Moonlighting and New Thoughts about Protein Evolution 635.1 Introduction 635.2 A Darwinian Perspective of Protein Moonlighting 655.3 Origin and Evolutionary Stability of Protein Moonlighting 675.4 Mutational Robustness and the Persistence of Moonlighting Proteins 685.5 Proteins Robust to Mutations Are Highly Evolvable 705.6 Moonlighting Proteins and the Rate of Protein Evolution 725.7 Molecular Chaperones Buffer the Effects of Mutations on Proteins, Expediting Their Rate of Evolution and Enabling Moonlighting 745.8 Protein Moonlighting Can Lead to Functional Specialization 765.9 Conclusions 76References 776 Biological Consequences of Protein Moonlighting 816.1 Introduction 816.2 The Human Genome, Protein]Coding Genes, and Cellular Complexity 816.3 How Many Moonlighting Proteins Exist/What Proportion of the Proteome Moonlights? 836.4 Secretion of Moonlighting Proteins: A Major Problem Seeking Solution 866.5 How Does Protein Moonlighting Influence Systems Biology? 906.5.1 Systems Biology and Protein Moonlighting 916.5.2 Analysis of the Systems Biology of the Moonlighting Protein Glycerol Kinase 956.6 Role of Moonlighting Proteins in the Control of the Biology of the Healthy Cell 976.6.1 Do Moonlighting Protein Exhibit Novel Biological Functions? 976.6.2 Moonlighting Proteins and Normal Cellular Functions 1046.6.2.1 Secreted Moonlighting Proteins 1056.6.2.2 Moonlighting Proteins on the Plasma Membrane 1066.6.2.3 Moonlighting Proteins in the Nucleus or Interacting with Nucleic Acids 1106.6.2.4 Moonlighting Proteins in Cellular Vesicular Trafficking 1136.6.2.5 Moonlighting in the Cell Cytoplasm 1136.6.2.6 Ribosomal Moonlighting Proteins 1156.6.2.7 Moonlighting in Cell Division 1186.6.2.8 Moonlighting Proteins Existing in Multiple Cellular Compartments 1186.7 Moonlighting Proteins in the Biology of Single]Celled Eukaryotes 1196.8 Moonlighting Proteins Interacting with Moonlighting Proteins 1196.9 Moonlighting Proteins and Vision: Are Lens Proteins Moonlighting? 1206.10 Conclusions 121References 1217 Protein Moonlighting and Human Health and Idiopathic Human Disease 1437.1 Introduction 1437.2 Mammalian Moonlighting Proteins Involved in the Biology of the Cell 1437.3 Moonlighting Proteins and Human Physiology (Healthy Interactions of Moonlighting Proteins) 1447.3.1 Cellular Iron Uptake: GAPDH Binds to Iron]Binding Proteins 1447.3.2 Moonlighting Proteins Involved with the Vasculature 1497.3.2.1 Thymidine Phosphorylase 1497.3.2.2 Protein Disulfide Isomerase (PDI) 1507.3.2.3 Mitochondrial Coupling Factor (Mcf)6 1507.3.2.4 Miscellaneous Moonlighting Proteins 1517.3.3 Secreted and Cell Surface Histones and Human Physiology 1527.3.4 Moonlighting Proteins in Reproduction 1547.3.4.1 Chaperonin (Hsp)10 and Pregnancy 1547.3.4.2 Phosphoglucoisomerase and Implantation in the Ferret 1557.3.4.3 Miscellaneous Moonlighting Proteins and Pregnancy 1557.3.4.4 Moonlighting Proteins, Sperm, and Fertilization 1567.3.5 Moonlighting Proteins Involved in Controlling Inflammation 1577.3.5.1 Ubiquitin 1587.3.5.2 Interferon]Stimulated Gene 15 (ISG15) 1597.3.5.3 Thioredoxin 1597.3.5.4 TNF]Stimulated Gene 6 (TSG]6) 1607.3.5.5 Ribosomal Protein L13a 1617.3.5.6 Ribosomal Protein S19 1617.3.5.7 Adiponectin and Inflammation 1627.3.5.8 Miscellaneous Proteins 1627.3.6 Moonlighting Proteins as Therapeutics 1627.3.6.1 Hsp10 1647.3.6.2 BiP 1647.3.6.3 Ubiquitin 1657.3.6.4 Moonlighting Proteins Involved in Wound Healing 1657.4 Moonlighting Proteins in Human Pathology 1667.4.1 Phosphoglucoisomerase as a Factor in Human Pathology 1667.4.2 Moonlighting Proteins in Human Cancer 1707.4.2.1 α]Enolase 1707.4.2.2 Aldolase 1717.4.2.3 Phosphofructokinase 1717.4.2.4 Triosephosphate Isomerase 1727.4.2.5 GAPDH 1727.4.2.6 Phosphoglycerate Kinase (PGK) 1727.4.2.7 Pyruvate Kinase (PK) 1737.4.2.8 BiP/Grp78 1737.4.2.9 Hsp90 1747.4.2.10 Hsp27 1757.4.2.11 Cyclophilin A (CypA) 1767.4.2.12 Miscellaneous Proteins 1767.4.3 Molecular Chaperones and Protein]Folding Catalysts in Human Inflammatory Pathology 1777.4.3.1 Chaperonin (Heat Shock Protein) 60 in Cardiovascular Disease 1777.4.3.2 Hsp70 (HSPA1) in Cardiovascular Disease 1787.4.3.3 Cyclophilin A 1797.4.3.4 Thioredoxin and Thioredoxin]80 1807.4.3.5 Peroxiredoxins 1817.4.4 DAMPs: Moonlighting Proteins in Human Inflammatory Pathology 1817.4.4.1 S100 Proteins 1827.4.4.2 High]Mobility Group Box 1 Protein 1827.4.4.3 Histones 1837.4.5 Moonlighting Proteins and Vascular Pathology 1837.4.5.1 Histones 1837.4.5.2 Mitochondrial Coupling Factor 6 1847.5 Neomorphic Moonlighting Proteins and Human Diseases 1857.6 Moonlighting Proteins in Autoimmune Disease 1857.7 Conclusions 188References 1888 Protein Moonlighting and Infectious Disease 2238.1 Introduction 2238.2 Microbial Colonization and Infection 2248.3 Bacterial Virulence Mechanisms 2248.4 Moonlighting Proteins in Bacterial Virulence 2278.4.1 Affinities of Binding of Bacterial Moonlighting Proteins 2278.4.2 Bacteria Utilizing Moonlighting Proteins 2298.4.3 Identity of the Bacterial Proteins That Moonlight 2328.5 Biological Activities of Bacterial Moonlighting Proteins as Virulence Factors 2378.5.1 Bacterial Moonlighting Proteins Acting as Adhesins 2378.5.2 Bacterial Moonlighting Proteins Acting as Invasins 2488.5.3 Bacterial Moonlighting Proteins Acting as Evasins 2488.5.4 Bacterial Moonlighting Proteins with Activity Similar to Bacterial Toxins 2528.5.5 Bacterial Moonlighting Proteins Acting as Receptors for Nutrients 2568.5.6 Miscellaneous Actions of Moonlighting Proteins 2568.5.7 Conclusions 2578.6 Examples of Bacterial Moonlighting Proteins in Human Infectious Disease 2578.7 Moonlighting Proteins in Fungi 2598.8 Moonlighting Proteins in Protozoal Infections 2608.9 Conclusions 262References 2629 Protein Moonlighting: The Future 2819.1 Introduction 2819.2 How Prevalent Is Protein Moonlighting? 2829.3 Evolutionary Biology of Protein Moonlighting 2849.3.1 Antibodies and Protein Moonlighting 2859.4 Protein Posttranslational Modification and Protein Moonlighting 2869.5 Genetics and Protein Moonlighting 2879.6 Protein Moonlighting and Systems Biology 2889.7 Moonlighting Proteins and the Response to Drugs 2909.8 Moonlighting Proteins as Drug Targets 2929.9 Conclusions 292References 293Index 297

'The “Protein Moonlighting in Biology and Medicine” book presents a very well-designed, comprehensive account of the basic knowledge and practical aspects of moonlighting proteins that have been culminating over the last two decades. Written by a cell biologist teaming up with two protein evolution and bioinformatics experts, this title provides a very useful digestible read on the structure, function, evolution, and bioinformatics of moonlighting proteins. Readers are oriented to these topics by two relevant introductory chapters. The book also addresses the diverse involvement of moonlighting proteins in cell biology, health maintenance, and idiopathic and infectious diseases. A very useful feature in this book, which is not frequently considered in other multi-authored titles, is the authors’ effort to present a coherent story by bridging chapters together incorporating an ‘introduction’ section at the beginning of each one. It is a very useful, contemporary book for students and researchers in biology, biomedicine and protein science.' Science Progress, 100:4 (2017)