Title Page

Copyright Page

Contents

List of Contributors

Preface

About the Editor

Part I Overview of Protein Moonlighting

Chapter 1 What is Protein Moonlighting and Why is it Important?

1.1 What is Protein Moonlighting?

1.2 Why is Moonlighting Important?

1.2.1 Many More Proteins Might Moonlight

1.2.2 Protein Structure/Evolution

1.2.3 Roles in Health and Disease

1.2.3.1 Humans

1.2.3.2 Bacteria

1.3 Current questions

1.3.1 How Many More Proteins Moonlight?

1.3.2 How Can We Identify Additional Proteins That Moonlight and all the Moonlighting Functions of Proteins?

1.3.3 In Developing Novel Therapeutics, How Can We Target the Appropriate Function of a Moonlighting Protein and Not Affect Other Functions of the Protein?

1.3.4 How do Moonlighting Proteins get Targeted to More Than One Location in the Cell?

1.3.5 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?

1.4 Conclusions

References

Chapter 2 Exploring Structure–Function Relationships in Moonlighting Proteins

2.1 Introduction

2.2 Multiple Facets of Protein Function

2.3 The Protein Structure–Function Paradigm

2.4 Computational Approaches for Identifying Moonlighting Proteins

2.5 Classification of Moonlighting Proteins

2.5.1 Proteins with Distinct Sites for Different Functions in the Same Domain

2.5.1.1 α-Enolase, Streptococcus pneumonia

2.5.1.2 Albaflavenone monooxygenase, Streptomyces coelicolor A3(2)

2.5.1.3 MAPK1/ERK2, Homo sapiens

2.5.2 Proteins with Distinct Sites for Different Functions in More Than One Domain

2.5.2.1 Malate synthase, Mycobacterium tuberculosis

2.5.2.2 BirA, Escherichia coli

2.5.2.3 MRDI, Homo sapiens

2.5.3 Proteins Using the Same Residues for Different Functions

2.5.3.1 GAPDH E. coli

2.5.3.2 Leukotriene A4 hydrolase, Homo sapiens

2.5.4 Proteins Using Different Residues in the Same/Overlapping Site for Different Functions

2.5.4.1 Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens

2.5.4.2 Aldolase, Plasmodium falciparum

2.5.5 Proteins with Different Structural Conformations for Different Functions

2.5.5.1 RfaH, E. coli

2.6 Conclusions

References

Part II Proteins Moonlighting in Prokarya

Chapter 3 Overview of Protein Moonlighting in Bacterial Virulence

3.1 Introduction

3.2 The Meaning of Bacterial Virulence and Virulence Factors

3.3 Affinity as a Measure of the Biological Importance of Proteins

3.4 Moonlighting Bacterial Virulence Proteins

3.4.1 Bacterial Proteins Moonlighting as Adhesins

3.4.2 Bacterial Moonlighting Proteins That Act as Invasins

3.4.3 Bacterial Moonlighting Proteins Involved in Nutrient Acquisition

3.4.4 Bacterial Moonlighting Proteins Functioning as Evasins

3.4.5 Bacterial Moonlighting Proteins with Toxin‐like Actions

3.5 Bacterial Moonlighting Proteins Conclusively Shown to be Virulence Factors

3.6 Eukaryotic Moonlighting Proteins That Aid in Bacterial Virulence

3.7 Conclusions

References

Chapter 4 Moonlighting Proteins as Cross-Reactive Auto-Antigens

4.1 Autoimmunity and Conservation

4.2 Immunogenicity of Conserved Proteins

4.3 HSP Co-induction, Food, Microbiota, and T-cell Regulation

4.3.1 HSP as Targets for T-Cell Regulation

4.4 The Contribution of Moonlighting Virulence Factors to Immunological Tolerance

References

Part III Proteins Moonlighting in Bacterial Virulence

Part 3.1 Chaperonins: A Family of Proteins with Widespread Virulence Properties

Chapter 5 Chaperonin 60 Paralogs in Mycobacterium tuberculosis and Tubercle Formation

5.1 Introduction

5.2 Tuberculosis and the Tuberculoid Granuloma

5.3 Mycobacterial Factors Responsible for Granuloma Formation

5.4 Mycobacterium tuberculosis Chaperonin 60 Proteins, Macrophage Function, and Granuloma Formation

5.4.1 Mycobacterium tuberculosis has Two Chaperonin 60 Proteins

5.4.2 Moonlighting Actions of Mycobacterial Chaperonin 60 Proteins

5.4.3 Actions of Mycobacterial Chaperonin 60 Proteins Compatible with the Pathology of Tuberculosis

5.4.4 Identification of the Myeloid‐Cell‐Activating Site in M. tuberculosis Chaperonin 60.1

5.5 Conclusions

References

Chapter 6 Legionella pneumophila Chaperonin 60, an Extra- and Intra-Cellular Moonlighting Virulence-Related Factor

6.1 Background

6.2 HtpB is an Essential Chaperonin with Protein-folding Activity

6.3 Experimental Approaches to Elucidate the Functional Mechanisms of HtpB

6.3.1 The Intracellular Signaling Mechanism of HtpB in Yeast

6.3.2 Yeast Two-Hybrid Screens

6.4 Secretion Mechanisms Potentially Responsible for Transporting HtpB to Extracytoplasmic Locations

6.4.1 Ability of GroEL and HtpB to Associate with Membranes

6.4.2 Ongoing Mechanistic Investigations on Chaperonins Secretion

6.5 Identifying Functionally Important Amino Acid Positions in HtpB

6.5.1 Site-Directed Mutagenesis

6.6 Functional Evolution of HtpB

6.7 Concluding Remarks

References

Part 3.2 Peptidylprolyl Isomerases, Bacterial Virulence, and Targets for Therapy

Chapter 7 An Overview of Peptidylprolyl Isomerases (PPIs) in Bacterial Virulence

7.1 Introduction

7.2 Proline and PPIs

7.3 Host PPIs and Responses to Bacteria and Bacterial Toxins

7.4 Bacterial PPIs as Virulence Factors

7.4.1 Proposed Mechanism of Virulence of Legionella pneumophila Mip

7.5 Other Bacterial PPIs Involved in Virulence

7.6 Conclusions

References

Part 3.3 Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor

Chapter 8 GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes

8.1 Introduction

8.2 GAPDH Membrane Function and Bacterial Virulence

8.2.1 Bacterial GAPDH Virulence

8.2.2 GAPDH and Iron Metabolism in Bacterial Virulence

8.3 Role of Nitric Oxide in GAPDH Bacterial Virulence

8.3.1 Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response

8.3.2 Formation of GAPDHcys-NO by Bacterial NO Synthases

8.3.3 GAPDHcys-NO in Bacterial Virulence: Induction of Macrophage Apoptosis

8.3.4 GAPDHcys-NO in Bacterial Virulence: Inhibition of Macrophage iNOS Activity

8.3.5 GAPDHcys-NO in Bacterial Virulence: Transnitrosylation to Acceptor Proteins

8.4 GAPDH Control of Gene Expression and Bacterial Virulence

8.4.1 Bacterial GAPDH Virulence

8.5 Discussion

Acknowledgements

References

Chapter 9 Streptococcus pyogenes GAPDH: A Cell-Surface Major Virulence Determinant

9.1 Introduction and Early Discovery

9.2 GAS GAPDH: A Major Surface Protein with Multiple Binding Activities

9.3 AutoADP-Ribosylation of SDH and Other Post-Translational Modifications

9.4 Implications of the Binding of SDH to Mammalian Proteins for Cell Signaling and Virulence Mechanisms

9.5 Surface Export of SDH/GAPDH: A Cause or Effect?

9.6 SDH: The GAS Virulence Factor-Regulating Virulence Factor

9.7 Concluding Remarks and Future Perspectives

References

Chapter 10 Group B Streptococcus GAPDH and Immune Evasion

10.1 The Bacterium GBS

10.2 Neonates are More Susceptible to GBS Infection than Adults

10.3 IL-10 Production Facilitates Bacterial Infection

10.4 GBS Glyceraldehyde-3-Phosphate Dehydrogenase Induces IL-10 Production

10.5 Summary

References

Chapter 11 Mycobacterium tuberculosis Cell-Surface GAPDH Functions as a Transferrin Receptor

11.1 Introduction

11.2 Iron Acquisition by Bacteria

11.2.1 Heme Uptake

11.2.2 Siderophore-Mediated Uptake

11.2.3 Transferrin Iron Acquisition

11.3 Iron Acquisition by Intracellular Pathogens

11.4 Iron Acquisition by M. tb

11.4.1 Heme Uptake

11.4.2 Siderophore-Mediated Iron Acquisition

11.4.3 Transferrin-Mediated Iron Acquisition

11.5 Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH)

11.6 Macrophage GAPDH and Iron Uptake

11.6.1 Regulation

11.6.2 Mechanism of Iron Uptake and Efflux

11.6.3 Role of Post-Translational Modifications

11.7 Mycobacterial GAPDH and Iron Uptake

11.7.1 Regulation

11.7.2 Mechanism of Iron Uptake

11.7.3 Uptake by Intraphagosomal M. tb

11.8 Conclusions and Future Perspectives

Acknowledgements

References

Chapter 12 GAPDH and Probiotic Organisms

12.1 Introduction

12.2 Probiotics and Safety

12.3 Potential Risk of Probiotics

12.4 Plasminogen Binding and Enhancement of its Activation

12.5 GAPDH as an Adhesin

12.6 Binding Regions

12.7 Mechanisms of Secretion and Surface Localization

12.8 Other Functions

12.9 Conclusion

References

Part 3.4 Cell-Surface Enolase: A Complex Virulence Factor

Chapter 13 Impact of Streptococcal Enolase in Virulence

13.1 Introduction

13.2 General Characteristics

13.3 Expression and Surface Exposition of Enolase

13.4 Streptococcal Enolase as Adhesion Cofactor

13.4.1 Enolase as Plasminogen‐Binding Protein

13.4.1.1 Plasminogen-Binding Sites of Streptococcal Enolases

13.4.2 Role of Enolase in Plasminogen-Mediated Bacterial-Host Cell Adhesion and Internalization

13.4.3 Enolase as Plasminogen-Binding Protein in Non-Pathogenic Bacteria

13.5 Enolase as Pro-Fibrinolytic Cofactor

13.5.1 Degradation of Fibrin Thrombi and Components of the Extracellular Matrix

13.6 Streptococcal Enolase as Cariogenic Factor in Dental Disease

13.7 Conclusion

Acknowledgement

References

Chapter 14 Streptococcal Enolase and Immune Evasion

14.1 Introduction

14.2 Localization and Crystal Structure

14.3 Multiple Binding Activities of α-Enolase

14.4 Involvement of α-Enolase in Gene Expression Regulation

14.5 Role of Anti-α-Enolase Antibodies in Host Immunity

14.6 α-Enolase as Potential Therapeutic Target

14.7 Questions Concerning α-Enolase

References

Chapter 15 Borrelia burgdorferi Enolase and Plasminogen Binding

15.1 Introduction to Lyme Disease

15.2 Life Cycle

15.3 Borrelia Virulence Factors

15.4 Plasminogen Binding by Bacteria

15.5 B. burgdorferi and Plasminogen Binding

15.6 Enolase

15.7 B. burgdorferi Enolase and Plasminogen Binding

15.8 Concluding Thoughts

Acknowledgements

References

Part 3.5 Other Glycolytic Enzymes Acting as Virulence Factors

Chapter 16 Triosephosphate Isomerase from Staphylococcus aureus and Plasminogen Receptors on Microbial Pathogens

16.1 Introduction

16.2 Identification of Triosephosphate Isomerase on S. aureus as a Molecule that Binds to the Pathogenic Yeast C. neoformans

16.2.1 Co-Cultivation of S. aureus and C. neoformans

16.2.2 Identification of Adhesins on S. aureus and C. neoformans

16.2.3 Mechanisms of C. neoformans Cell Death

16.3 Binding of Triosephosphate Isomerase with Human Plasminogen

16.4 Plasminogen-Binding Proteins on Trichosporon asahii

16.5 Plasminogen Receptors on C. neoformans

16.6 Conclusions

References

Chapter 17 Moonlighting Functions of Bacterial Fructose 1,6-Bisphosphate Aldolases

17.1 Introduction

17.2 Fructose 1,6-bisphosphate Aldolase in Metabolism

17.3 Surface Localization of Streptococcal Fructose 1,6-bisphosphate Aldolases

17.4 Pneumococcal FBA Adhesin Binds Flamingo Cadherin Receptor

17.5 FBA is Required for Optimal Meningococcal Adhesion to Human Cells

17.6 Mycobacterium tuberculosis FBA Binds Human Plasminogen

17.7 Other Examples of FBAs with Possible Roles in Pathogenesis

17.8 Conclusions

References

Part 3.6 Other Metabolic Enzymes Functioning in Bacterial Virulence

Chapter 18 Pyruvate Dehydrogenase Subunit B and Plasminogen Binding in Mycoplasma

18.1 Introduction

18.2 Binding of Human Plasminogen to M. pneumoniae

18.3 Localization of PDHB on the Surface of M. pneumoniae Cells

18.4 Conclusions

References

Part 3.7 Miscellaneous Bacterial Moonlighting Virulence Proteins

Chapter 19 Unexpected Interactions of Leptospiral Ef-Tu and Enolase

19.1 Leptospira –Host Interactions

19.2 Leptospira Ef-Tu

19.3 Leptospira Enolase

19.4 Conclusions

References

Chapter 20 Mycobacterium tuberculosis Antigen 85 Family Proteins: Mycolyl Transferases and Matrix-Binding Adhesins

20.1 Introduction

20.2 Identification of Antigen 85

20.3 Antigen 85 Family Proteins: Mycolyl Transferases

20.3.1 Role of the Mycomembrane

20.3.2 Ag85 Family of Homologous Proteins

20.3.3 Inhibition and Knockouts of Ag85

20.4 Antigen 85 Family Proteins: Matrix-Binding Adhesins

20.4.1 Abundance and Location

20.4.2 Ag85 a Fibronectin-Binding Adhesin

20.4.3 Ag85 an Elastin-Binding Adhesin

20.4.4 Implication in Disease

20.5 Conclusion

Acknowledgement

References

Part 3.8 Bacterial Moonlighting Proteins that Function as Cytokine Binders/Receptors

Chapter 21 Miscellaneous IL-1β-Binding Proteins of Aggregatibacter actinomycetemcomitans

21.1 Introduction

21.2 A. actinomycetemcomitans Biofilms Sequester IL-1β

21.3 A. actinomycetemcomitans Cells Take in IL-1β

21.3.1 Novel Outer Membrane Lipoprotein of  A. actinomycetemcomitans Binds IL-1β

21.3.2 IL-1β Localizes to the Cytosolic Face of the Inner Membrane and in the Nucleoids of  A. actinomycetemcomitans

21.3.3 Inner Membrane Protein ATP Synthase Subunit β Binds IL-1β

21.3.4 DNA-Binding Histone-Like Protein HU Interacts with IL-1β

21.4 The Potential Effects of IL-1β on A. actinomycetemcomitans

21.4.1 Biofilm Amount Increases and Metabolic Activity Decreases

21.4.2 Potential Changes in Gene Expression

21.5 Conclusions

References

Part 3.9 Moonlighting Outside of the Box

Chapter 22 Bacteriophage Moonlighting Proteins in the Control of Bacterial Pathogenicity

22.1 Introduction

22.2 Bacteriophage T4 I-TevI Homing Endonuclease Functions as a Transcriptional Autorepressor

22.3 Capsid Psu Protein of Bacteriophage P4 Functions as a Rho Transcription Antiterminator

22.4 Bacteriophage Lytic Enzymes Moonlight as Structural Proteins

22.5 Moonlighting Bacteriophage Proteins De-Repressing Phage-Inducible Chromosomal Islands

22.6 dUTPase, a Metabolic Enzyme with a Moonlighting Signalling Role

22.7 Escherichia coli Thioredoxin Protein Moonlights with T7 DNA Polymerase for Enhanced T7 DNA Replication

22.8 Discussion

References

Chapter 23 Viral Entry Glycoproteins and Viral Immune Evasion

23.1 Introduction

23.2 Enveloped Viral Entry

23.3 Moonlighting Activities of Viral Entry Glycoproteins

23.3.1 Viral Entry Glycoproteins Moonlighting as Evasins

23.3.2 Evading the Complement System

23.3.3 Evading Antibody Surveillance

23.3.3.1 The Viral Glycan Shield

23.3.3.2 Shed Viral Glycoproteins: An Antibody Decoy

23.3.3.3 Antigenic Variations in Viral Glycoproteins

23.3.3.4 Shed Viral Glycoproteins and Immune Signal Modulation

23.3.4 Evading Host Restriction Factors

23.3.5 Modulation of Other Immune Pathways

23.4 Viral Entry Proteins Moonlighting as Saboteurs of Cellular Pathways

23.4.1 Sabotaging Signal Transduction Cascades

23.4.2 Host Surface Protein Sabotage

23.5 Conclusions

References

Index

Supplemental Images

EULA