Moonlighting Proteins Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections Edited by Brian Henderson Division of Infection and Immunity, University College London, London, UK Copyright © 2017 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750‐8400, fax (978) 750‐4470, or on the web at www.copyright.com. 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Identifiers: LCCN 2016049475 (print) | LCCN 2016051302 (ebook) | ISBN 9781118951118 (cloth) | ISBN 9781118951125 (pdf) | ISBN 9781118951132 (epub) Subjects: | MESH: Bacterial Proteins–physiology | Virulence Factors | Bacterial Infections Classification: LCC RA644.B32 (print) | LCC RA644.B32 (ebook) | NLM QW 52 | DDC 614.5/7–dc23 LC record available at https://lccn.loc.gov/2016049475 Cover Image: © SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images Cover Design: Wiley Set in 10/12pt Warnock by SPi Global, Pondicherry, India 10 9 8 7 6 5 4 3 2 1 v Contents List of Contributors xv Preface xix About the Editor xxiii Part I Overview of Protein Moonlighting 1 1 What is Protein Moonlighting and Why is it Important? 3 Constance J. Jeffery 1.1 What is Protein Moonlighting? 3 1.2 Why is Moonlighting Important? 5 1.2.1 Many More Proteins Might Moonlight 5 1.2.2 Protein Structure/Evolution 5 1.2.3 Roles in Health and Disease 8 1.2.3.1 Humans 8 1.2.3.2 Bacteria 10 1.3 Current questions 11 1.3.1 How Many More Proteins Moonlight? 11 1.3.2 How Can We Identify Additional Proteins That Moonlight and all the Moonlighting Functions of Proteins? 11 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? 12 1.3.4 How do Moonlighting Proteins get Targeted to More Than One Location in the Cell? 12 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? 12 1.4 Conclusions 13 References 13 2 Exploring Structure–Function Relationships in Moonlighting Proteins 21 Sayoni Das, Ishita Khan, Daisuke Kihara, and Christine Orengo 2.1 Introduction 21 2.2 Multiple Facets of Protein Function 22 vi Contents 2.3 The Protein Structure–Function Paradigm 23 2.4 Computational Approaches for Identifying Moonlighting Proteins 25 2.5 Classification of Moonlighting Proteins 26 2.5.1 Proteins with Distinct Sites for Different Functions in the Same Domain 27 2.5.1.1 α‐Enolase, Streptococcus pneumonia 27 2.5.1.2 Albaflavenone monooxygenase, Streptomyces coelicolor A3(2) 29 2.5.1.3 MAPK1/ERK2, Homo sapiens 30 2.5.2 Proteins with Distinct Sites for Different Functions in More Than One Domain 30 2.5.2.1 Malate synthase, Mycobacterium tuberculosis 31 2.5.2.2 BirA, Escherichia coli 31 2.5.2.3 MRDI, Homo sapiens 33 2.5.3 Proteins Using the Same Residues for Different Functions 33 2.5.3.1 GAPDH E. coli 33 2.5.3.2 Leukotriene A4 hydrolase, Homo sapiens 33 2.5.4 Proteins Using Different Residues in the Same/Overlapping Site for Different Functions 34 2.5.4.1 Phosphoglucose isomerase, Oryctolagus cuniculus, Mus musculus, Homo sapiens 34 2.5.4.2 Aldolase, Plasmodium falciparum 36 2.5.5 Proteins with Different Structural Conformations for Different Functions 36 2.5.5.1 RfaH, E. coli 36 2.6 Conclusions 37 References 39 Part II Proteins Moonlighting in Prokarya 45 3 Overview of Protein Moonlighting in Bacterial Virulence 47 Brian Henderson 3.1 Introduction 47 3.2 The Meaning of Bacterial Virulence and Virulence Factors 47 3.3 Affinity as a Measure of the Biological Importance of Proteins 49 3.4 Moonlighting Bacterial Virulence Proteins 50 3.4.1 Bacterial Proteins Moonlighting as Adhesins 52 3.4.2 Bacterial Moonlighting Proteins That Act as Invasins 59 3.4.3 Bacterial Moonlighting Proteins Involved in Nutrient Acquisition 59 3.4.4 Bacterial Moonlighting Proteins Functioning as Evasins 60 3.4.5 Bacterial Moonlighting Proteins with Toxin‐like Actions 63 3.5 Bacterial Moonlighting Proteins Conclusively Shown to be Virulence Factors 64 3.6 Eukaryotic Moonlighting Proteins That Aid in Bacterial Virulence 66 3.7 Conclusions 67 References 68 Contents vii 4 Moonlighting Proteins as Cross‐Reactive Auto‐Antigens 81 Willem van Eden 4.1 Autoimmunity and Conservation 81 4.2 Immunogenicity of Conserved Proteins 82 4.3 HSP Co‐induction, Food, Microbiota, and T-cell Regulation 84 4.3.1 HSP as Targets for T‐Cell Regulation 85 4.4 The Contribution of Moonlighting Virulence Factors to Immunological Tolerance 87 References 88 Part III Proteins Moonlighting in Bacterial Virulence 93 Part 3.1 Chaperonins: A Family of Proteins with Widespread Virulence Properties 95 5 Chaperonin 60 Paralogs in Mycobacterium tuberculosis and Tubercle Formation 97 Brian Henderson 5.1 Introduction 97 5.2 Tuberculosis and the Tuberculoid Granuloma 97 5.3 Mycobacterial Factors Responsible for Granuloma Formation 98 5.4 Mycobacterium tuberculosis Chaperonin 60 Proteins, Macrophage Function, and Granuloma Formation 100 5.4.1 Mycobacterium tuberculosis has Two Chaperonin 60 Proteins 100 5.4.2 Moonlighting Actions of Mycobacterial Chaperonin 60 Proteins 101 5.4.3 Actions of Mycobacterial Chaperonin 60 Proteins Compatible with the Pathology of Tuberculosis 102 5.4.4 Identification of the Myeloid‐Cell‐Activating Site in M. tuberculosis Chaperonin 60.1 105 5.5 Conclusions 106 References 106 6 Legionella pneumophila Chaperonin 60, an Extra‐ and Intra‐Cellular Moonlighting Virulence‐Related Factor 111 Karla N. Valenzuela‐Valderas, Angela L. Riveroll, Peter Robertson, Lois E. Murray, and Rafael A. Garduño 6.1 Background 111 6.2 HtpB is an Essential Chaperonin with Protein‐folding Activity 112 6.3 Experimental Approaches to Elucidate the Functional Mechanisms of HtpB 112 6.3.1 The Intracellular Signaling Mechanism of HtpB in Yeast 113 6.3.2 Yeast Two‐Hybrid Screens 118 6.4 Secretion Mechanisms Potentially Responsible for Transporting HtpB to Extracytoplasmic Locations 120 6.4.1 Ability of GroEL and HtpB to Associate with Membranes 121 6.4.2 Ongoing Mechanistic Investigations on Chaperonins Secretion 122 viii Contents 6.5 Identifying Functionally Important Amino Acid Positions in HtpB 124 6.5.1 Site‐Directed Mutagenesis 125 6.6 Functional Evolution of HtpB 126 6.7 Concluding Remarks 127 References 129 Part 3.2 Peptidylprolyl Isomerases, Bacterial Virulence, and Targets for Therapy 135 7 An Overview of Peptidylprolyl Isomerases (PPIs) in Bacterial Virulence 137 Brian Henderson 7.1 Introduction 137 7.2 Proline and PPIs 137 7.3 Host PPIs and Responses to Bacteria and Bacterial Toxins 138 7.4 Bacterial PPIs as Virulence Factors 138 7.4.1 Proposed Mechanism of Virulence of Legionella pneumophila Mip 140 7.5 Other Bacterial PPIs Involved in Virulence 140 7.6 Conclusions 142 References 142 Part 3.3 Glyceraldehyde 3‐Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor 147 8 GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes 149 Michael A. Sirover 8.1 Introduction 149 8.2 GAPDH Membrane Function and Bacterial Virulence 150 8.2.1 Bacterial GAPDH Virulence 151 8.2.2 GAPDH and Iron Metabolism in Bacterial Virulence 153 8.3 Role of Nitric Oxide in GAPDH Bacterial Virulence 153 8.3.1 Nitric Oxide in Bacterial Virulence: Evasion of the Immune Response 154 8.3.2 Formation of