Moonlighting Proteins

Brian Henderson is Professor of Biochemistry in the Department of Microbial Diseases at the UCL-Eastman Dental Institute, University College London. He has worked in academia, both in the UK and North America, and also in the pharmaceutical and biopharmaceutical industry. He has been a cell biologist, immunologist and pharmacologist and over the past twenty years has focused on bacteria-host interactions in relation to human infection and the maintenance of the human microbiota. This is the discipline of Cellular Microbiology and Henderson published the first book on this subject in 1999. At the inception of his career as a cellular microbiologist he discovered a potent bone-destroying protein generated by a pathogenic bacterium. This protein, surprisingly, was the cell stress protein, heat shock protein (Hsp)60. This was one of the earliest bacterial moonlighting proteins discovered and is the reason that the editor has spent the last 20 years exploring the role of protein moonlighting in the life of the bacterium and its interactions with its human host. Henderson has written or edited 17 books and monographs and was the senior editor of the Cambridge University Press Monograph series: Advances in Molecular and Cellular Microbiology.

• List of Contributors xvPreface xixAbout the Editor xxiiiPart I Overview of Protein Moonlighting 11 What is Protein Moonlighting and Why is it Important? 3Constance J. Jeffery1.1 What is Protein Moonlighting? 31.2 Why is Moonlighting Important? 51.2.1 Many More Proteins Might Moonlight 51.2.2 Protein Structure/Evolution 51.2.3 Roles in Health and Disease 81.2.3.1 Humans 81.2.3.2 Bacteria 101.3 Current questions 111.3.1 How Many More Proteins Moonlight? 111.3.2 How Can We Identify Additional Proteins That Moonlight and all the Moonlighting Functions of Proteins? 111.3.3 In Developing Novel Therapeutics, How Can We Target the Appropriate Function of a Moonlighting Protein and Not Affect Other Functions of the Protein? 121.3.4 How do Moonlighting Proteins get Targeted to More Than One Location in the Cell? 121.3.5 What Changes in Expression Patterns Have Occurred to Enable the Protein to be Available in a New Time and Place to Perform a New Function? 121.4 Conclusions 13References 132 Exploring Structure–Function Relationships in Moonlighting Proteins 21Sayoni Das, Ishita Khan, Daisuke Kihara, and Christine Orengo2.1 Introduction 212.2 Multiple Facets of Protein Function 222.3 The Protein Structure–Function Paradigm 232.4 Computational Approaches for Identifying Moonlighting Proteins 252.5 Classification of Moonlighting Proteins 262.5.1 Proteins with Distinct Sites for Different Functions in the Same Domain 272.5.1.1 α‐Enolase, Streptococcus pneumonia 272.5.1.2 Albaflavenone monooxygenase, Streptomyces coelicolor A3(2) 292.5.1.3 MAPK1/ERK2, Homo sapiens 302.5.2 Proteins with Distinct Sites for Different Functions in More Than One Domain 302.5.2.1 Malate synthase, Mycobacterium tuberculosis 312.5.2.2 BirA, Escherichia coli 312.5.2.3 MRDI, Homo sapiens 332.5.3 Proteins Using the Same Residues for Different Functions 332.5.3.1 GAPDH E. coli 332.5.3.2 Leukotriene A4 hydrolase, Homo sapiens 332.5.4 Proteins Using Different Residues in the Same/Overlapping Site for Different Functions 342.5.4.1 Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens 342.5.4.2 Aldolase, Plasmodium falciparum 362.5.5 Proteins with Different Structural Conformations for Different Functions 362.5.5.1 RfaH, E. coli 362.6 Conclusions 37References 39Part II Proteins Moonlighting in Prokarya 453 Overview of Protein Moonlighting in Bacterial Virulence 47Brian Henderson3.1 Introduction 473.2 The Meaning of Bacterial Virulence and Virulence Factors 473.3 Affinity as a Measure of the Biological Importance of Proteins 493.4 Moonlighting Bacterial Virulence Proteins 503.4.1 Bacterial Proteins Moonlighting as Adhesins 523.4.2 Bacterial Moonlighting Proteins That Act as Invasins 593.4.3 Bacterial Moonlighting Proteins Involved in Nutrient Acquisition 593.4.4 Bacterial Moonlighting Proteins Functioning as Evasins 603.4.5 Bacterial Moonlighting Proteins with Toxin‐like Actions 633.5 Bacterial Moonlighting Proteins Conclusively Shown to be Virulence Factors 643.6 Eukaryotic Moonlighting Proteins That Aid in Bacterial Virulence 663.7 Conclusions 67References 684 Moonlighting Proteins as Cross‐Reactive Auto‐Antigens 81Willem van Eden4.1 Autoimmunity and Conservation 814.2 Immunogenicity of Conserved Proteins 824.3 HSP Co‐induction, Food, Microbiota, and T-cell Regulation 844.3.1 HSP as Targets for T‐Cell Regulation 854.4 The Contribution of Moonlighting Virulence Factors to Immunological Tolerance 87References 88Part III Proteins Moonlighting in Bacterial Virulence 93Part 3.1 Chaperonins: A Family of Proteins with Widespread Virulence Properties 955 Chaperonin 60 Paralogs in Mycobacterium tuberculosis and Tubercle Formation 97Brian Henderson5.1 Introduction 975.2 Tuberculosis and the Tuberculoid Granuloma 975.3 Mycobacterial Factors Responsible for Granuloma Formation 985.4 Mycobacterium tuberculosis Chaperonin 60 Proteins, Macrophage Function, and Granuloma Formation 1005.4.1 Mycobacterium tuberculosis has Two Chaperonin 60 Proteins 1005.4.2 Moonlighting Actions of Mycobacterial Chaperonin 60 Proteins 1015.4.3 Actions of Mycobacterial Chaperonin 60 Proteins Compatible with the Pathology of Tuberculosis 1025.4.4 Identification of the Myeloid‐Cell‐Activating Site in M. tuberculosis Chaperonin 60.1 1055.5 Conclusions 106References 1066 Legionella pneumophila Chaperonin 60, an Extra‐ and Intra‐Cellular Moonlighting Virulence‐Related Factor 111Karla N. Valenzuela‐Valderas, Angela L. Riveroll, Peter Robertson, Lois E. Murray, and Rafael A. Garduno6.1 Background 1116.2 HtpB is an Essential Chaperonin with Protein‐folding Activity 1126.3 Experimental Approaches to Elucidate the Functional Mechanisms of HtpB 1126.3.1 The Intracellular Signaling Mechanism of HtpB in Yeast 1136.3.2 Yeast Two‐Hybrid Screens 1186.4 Secretion Mechanisms Potentially Responsible for Transporting HtpB to Extracytoplasmic Locations 1206.4.1 Ability of GroEL and HtpB to Associate with Membranes 1216.4.2 Ongoing Mechanistic Investigations on Chaperonins Secretion 1226.5 Identifying Functionally Important Amino Acid Positions in HtpB 1246.5.1 Site‐Directed Mutagenesis 1256.6 Functional Evolution of HtpB 1266.7 Concluding Remarks 127References 129Part 3.2 Peptidylprolyl Isomerases, Bacterial Virulence, and Targets for Therapy 1357 An Overview of Peptidylprolyl Isomerases (PPIs) in Bacterial Virulence 137Brian Henderson7.1 Introduction 1377.2 Proline and PPIs 1377.3 Host PPIs and Responses to Bacteria and Bacterial Toxins 1387.4 Bacterial PPIs as Virulence Factors 1387.4.1 Proposed Mechanism of Virulence of Legionella pneumophila Mip 1407.5 Other Bacterial PPIs Involved in Virulence 1407.6 Conclusions 142References 142Part 3.3 Glyceraldehyde 3‐Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor 1478 GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes 149Michael A. Sirover8.1 Introduction 1498.2 GAPDH Membrane Function and Bacterial Virulence 1508.2.1 Bacterial GAPDH Virulence 1518.2.2 GAPDH and Iron Metabolism in Bacterial Virulence 1538.3 Role of Nitric Oxide in GAPDH Bacterial Virulence 1538.3.1 Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response 1548.3.2 Formation of GAPDHcys‐NO by Bacterial NO Synthases 1558.3.3 GAPDHcys‐NO in Bacterial Virulence: Induction of Macrophage Apoptosis 1558.3.4 GAPDHcys‐NO in Bacterial Virulence: Inhibition of Macrophage iNOS Activity 1568.3.5 GAPDHcys‐NO in Bacterial Virulence: Transnitrosylation to Acceptor Proteins 1578.4 GAPDH Control of Gene Expression and Bacterial Virulence 1588.4.1 Bacterial GAPDH Virulence 1598.5 Discussion 160Acknowledgements 162References 1629 Streptococcus pyogenes GAPDH: A Cell‐Surface Major Virulence Determinant 169Vijay Pancholi9.1 Introduction and Early Discovery 1699.2 GAS GAPDH: A Major Surface Protein with Multiple Binding Activities 1709.3 AutoADP‐Ribosylation of SDH and Other Post‐Translational Modifications 1729.4 Implications of the Binding of SDH to Mammalian Proteins for Cell Signaling and Virulence Mechanisms 1739.5 Surface Export of SDH/GAPDH: A Cause or Effect? 1789.6 SDH: The GAS Virulence Factor‐Regulating Virulence Factor 1809.7 Concluding Remarks and Future Perspectives 183References 18310 Group B Streptococcus GAPDH and Immune Evasion 195Paula Ferreira and Patrick Trieu‐Cuot10.1 The Bacterium GBS 19510.2 Neonates are More Susceptible to GBS Infection than Adults 19510.3 IL‐10 Production Facilitates Bacterial Infection 19610.4 GBS Glyceraldehyde‐3‐Phosphate Dehydrogenase Induces IL‐10 Production 19710.5 Summary 199References 20011 Mycobacterium tuberculosis Cell‐Surface GAPDH Functions as a Transferrin Receptor 205Vishant M. Boradia, Manoj Raje, and Chaaya Iyengar Raje11.1 Introduction 20511.2 Iron Acquisition by Bacteria 20611.2.1 Heme Uptake 20611.2.2 Siderophore‐Mediated Uptake 20711.2.3 Transferrin Iron Acquisition 20711.3 Iron Acquisition by Intracellular Pathogens 20711.4 Iron Acquisition by M. tb 20811.4.1 Heme Uptake 20811.4.2 Siderophore‐Mediated Iron Acquisition 20911.4.3 Transferrin‐Mediated Iron Acquisition 20911.5 Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) 21011.6 Macrophage GAPDH and Iron Uptake 21011.6.1 Regulation 21011.6.2 Mechanism of Iron Uptake and Efflux 21111.6.3 Role of Post‐Translational Modifications 21111.7 Mycobacterial GAPDH and Iron Uptake 21211.7.1 Regulation 21211.7.2 Mechanism of Iron Uptake 21511.7.3 Uptake by Intraphagosomal M. tb 21611.8 Conclusions and Future Perspectives 216Acknowledgements 218References 21912 GAPDH and Probiotic Organisms 225Hideki Kinoshita12.1 Introduction 22512.2 Probiotics and Safety 22512.3 Potential Risk of Probiotics 22712.4 Plasminogen Binding and Enhancement of its Activation 22812.5 GAPDH as an Adhesin 22912.6 Binding Regions 23212.7 Mechanisms of Secretion and Surface Localization 23412.8 Other Functions 23512.9 Conclusion 236References 237Part 3.4 Cell‐Surface Enolase: A Complex Virulence Factor 24513 Impact of Streptococcal Enolase in Virulence 247Marcus Fulde and Simone Bergmann13.1 Introduction 24713.2 General Characteristics 24813.3 Expression and Surface Exposition of Enolase 24913.4 Streptococcal Enolase as Adhesion Cofactor 25213.4.1 Enolase as Plasminogen‐Binding Protein 25213.4.1.1 Plasminogen‐Binding Sites of Streptococcal Enolases 25313.4.2 Role of Enolase in Plasminogen‐Mediated Bacterial‐Host Cell Adhesion and Internalization 25413.4.3 Enolase as Plasminogen‐Binding Protein in Non‐Pathogenic Bacteria 25513.5 Enolase as Pro‐Fibrinolytic Cofactor 25613.5.1 Degradation of Fibrin Thrombi and Components of the Extracellular Matrix 25713.6 Streptococcal Enolase as Cariogenic Factor in Dental Disease 25813.7 Conclusion 258Acknowledgement 259References 25914 Streptococcal Enolase and Immune Evasion 269Masaya Yamaguchi and Shigetada Kawabata14.1 Introduction 26914.2 Localization and Crystal Structure 27114.3 Multiple Binding Activities of α‐Enolase 27314.4 Involvement of α‐Enolase in Gene Expression Regulation 27614.5 Role of Anti‐α‐Enolase Antibodies in Host Immunity 27714.6 α‐Enolase as Potential Therapeutic Target 27914.7 Questions Concerning α‐Enolase 281References 28115 Borrelia burgdorferi Enolase and Plasminogen Binding 291Catherine A. Brissette15.1 Introduction to Lyme Disease 29115.2 Life Cycle 29215.3 Borrelia Virulence Factors 29215.4 Plasminogen Binding by Bacteria 29315.5 B. burgdorferi and Plasminogen Binding 29415.6 Enolase 29515.7 B. burgdorferi Enolase and Plasminogen Binding 29715.8 Concluding Thoughts 301Acknowledgements 301References 301Part 3.5 Other Glycolytic Enzymes Acting as Virulence Factors 30916 Triosephosphate Isomerase from Staphylococcus aureus and Plasminogen Receptors on Microbial Pathogens 311Reiko Ikeda and Tomoe Ichikawa16.1 Introduction 31116.2 Identification of Triosephosphate Isomerase on S. aureusas a Molecule that Binds to the Pathogenic Yeast C. neoformans 31216.2.1 Co‐Cultivation of S. aureus and C. neoformans 31216.2.2 Identification of Adhesins on S. aureus and C. neoformans 31216.2.3 Mechanisms of C. neoformans Cell Death 31316.3 Binding of Triosephosphate Isomerase with Human Plasminogen 31416.4 Plasminogen‐Binding Proteins on Trichosporon asahii 31416.5 Plasminogen Receptors on C. neoformans 31616.6 Conclusions 316References 31717 Moonlighting Functions of Bacterial Fructose 1,6‐Bisphosphate Aldolases 321Neil J. Oldfield, Fariza Shams, Karl G. Wooldridge, and David P.J. Turner17.1 Introduction 32117.2 Fructose 1,6‐bisphosphate Aldolase in Metabolism 32117.3 Surface Localization of Streptococcal Fructose 1,6‐bisphosphate Aldolases 32217.4 Pneumococcal FBA Adhesin Binds Flamingo Cadherin Receptor 32317.5 FBA is Required for Optimal Meningococcal Adhesion to Human Cells 32417.6 Mycobacterium tuberculosis FBA Binds Human Plasminogen 32517.7 Other Examples of FBAs with Possible Roles in Pathogenesis 32617.8 Conclusions 327References 327Part 3.6 Other Metabolic Enzymes Functioning in Bacterial Virulence 33318 Pyruvate Dehydrogenase Subunit B and Plasminogen Binding in Mycoplasma 335Anne Gründel, Kathleen Friedrich, Melanie Pfeiffer, Enno Jacobs, and Roger Dumke18.1 Introduction 33518.2 Binding of Human Plasminogen to M. pneumoniae 33718.3 Localization of PDHB on the Surface of M. pneumoniae Cells 34018.4 Conclusions 343References 344Part 3.7 Miscellaneous Bacterial Moonlighting Virulence Proteins 34919 Unexpected Interactions of Leptospiral Ef‐Tu and Enolase 351Natália Salazar and Angela Barbosa19.1 Leptospira –Host Interactions 35119.2 Leptospira Ef‐Tu 35219.3 Leptospira Enolase 35319.4 Conclusions 354References 35420 Mycobacterium tuberculosis Antigen 85 Family Proteins: Mycolyl Transferases and Matrix‐Binding Adhesins 357Christopher P. Ptak, Chih‐Jung Kuo, and Yung‐Fu Chang20.1 Introduction 35720.2 Identification of Antigen 85 35820.3 Antigen 85 Family Proteins: Mycolyl Transferases 35920.3.1 Role of the Mycomembrane 35920.3.2 Ag85 Family of Homologous Proteins 35920.3.3 Inhibition and Knockouts of Ag85 36020.4 Antigen 85 Family Proteins: Matrix‐Binding Adhesins 36120.4.1 Abundance and Location 36120.4.2 Ag85 a Fibronectin‐Binding Adhesin 36220.4.3 Ag85 an Elastin‐Binding Adhesin 36320.4.4 Implication in Disease 36420.5 Conclusion 365Acknowledgement 365References 365Part 3.8 Bacterial Moonlighting Proteins that Function as Cytokine Binders/Receptors 37121 Miscellaneous IL‐1β‐Binding Proteins of Aggregatibacter actinomycetemcomitans 373Riikka Ihalin21.1 Introduction 37321.2 A. actinomycetemcomitans Biofilms Sequester IL‐1β 37421.3 A. actinomycetemcomitans Cells Take in IL‐1β 37521.3.1 Novel Outer Membrane Lipoprotein of A. actinomycetemcomitans Binds IL‐1β 37521.3.2 IL‐1β Localizes to the Cytosolic Face of the Inner Membrane and in the Nucleoids of A. actinomycetemcomitans 37721.3.3 Inner Membrane Protein ATP Synthase Subunit β Binds IL‐1β 37721.3.4 DNA‐Binding Histone‐Like Protein HU Interacts with IL‐1β 37821.4 The Potential Effects of IL‐1β on A. actinomycetemcomitans 37921.4.1 Biofilm Amount Increases and Metabolic Activity Decreases 37921.4.2 Potential Changes in Gene Expression 38021.5 Conclusions 381References 382Part 3.9 Moonlighting Outside of the Box 38722 Bacteriophage Moonlighting Proteins in the Control of Bacterial Pathogenicity 389Janine Z. Bowring, Alberto Marina, José R. Penadés, and Nuria Quiles‐Puchalt22.1 Introduction 38922.2 Bacteriophage T4 I‐TevI Homing Endonuclease Functions as a Transcriptional Autorepressor 39122.3 Capsid Psu Protein of Bacteriophage P4 Functions as a Rho Transcription Antiterminator 39422.4 Bacteriophage Lytic Enzymes Moonlight as Structural Proteins 39822.5 Moonlighting Bacteriophage Proteins De‐Repressing Phage‐Inducible Chromosomal Islands 39822.6 dUTPase, a Metabolic Enzyme with a Moonlighting Signalling Role 40122.7 Escherichia coli Thioredoxin Protein Moonlights with T7 DNA Polymerase for Enhanced T7 DNA Replication 40422.8 Discussion 404References 40623 Viral Entry Glycoproteins and Viral Immune Evasion 413Jonathan D. Cook and Jeffrey E. Lee23.1 Introduction 41323.2 Enveloped Viral Entry 41423.3 Moonlighting Activities of Viral Entry Glycoproteins 41523.3.1 Viral Entry Glycoproteins Moonlighting as Evasins 41623.3.2 Evading the Complement System 41723.3.3 Evading Antibody Surveillance 41923.3.3.1 The Viral Glycan Shield 41923.3.3.2 Shed Viral Glycoproteins: An Antibody Decoy 42123.3.3.3 Antigenic Variations in Viral Glycoproteins 42123.3.3.4 Shed Viral Glycoproteins and Immune Signal Modulation 42323.3.4 Evading Host Restriction Factors 42323.3.5 Modulation of Other Immune Pathways 42423.4 Viral Entry Proteins Moonlighting as Saboteurs of Cellular Pathways 42723.4.1 Sabotaging Signal Transduction Cascades 42723.4.2 Host Surface Protein Sabotage 42823.5 Conclusions 429References 429Index 439