Protein moonlighting in biology and medicine

323 Pages·2017·3.227 MB·English

by  Brian Henderson, Mario A. Fares, Andrew C. R. Martin

Protein Moonlighting in Biology
and Medicine
Protein Moonlighting in Biology and Medicine
Brian Henderson
Division of Infection and Immunity, University College London, London, UK
Mario A. Fares
Institute of Integrative Systems Biology (CSIC‐UV), Valencia, Spain
Trinity College Dublin, Dublin, Ireland
Andrew C. R. Martin
Division of Biosciences, University College London, London, UK
Copyright © 2017 by John Wiley & Sons, Inc. All rights reserved
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Library of Congress Cataloging‐in‐Publication data applied for
9781118952085
Cover image: Gettyimages/StudioM1
Printed in the United States of America
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v
Contents
Preface xi
1 An Introduction to the Protein Molecule 1
1.1 Why Study Protein Moonlighting? 1
1.2 A Brief History of Proteins 2
1.3 Protein Biology 4
1.4 Protein Structure and Function 6
1.5 Protein Sequence Determination, Structures, and Bioinformatics 9
1.6 Regulation of Protein Synthesis 11
1.7 Conclusions 12
References 12
2 How Proteins Evolve? 15
2.1 Introduction 15
2.2 A Darwinian View of Molecular Evolution 16
2.3 The Neutral and Nearly Neutral Theories of Molecular Evolution 18
2.4 Mutation, Fitness, and Evolution 20
2.5 Proteins Evolve at Different Rates 24
2.6 Protein Evolution by Gene Duplication 25
2.7 Conclusions 26
References 26
3 A Brief History of Protein Moonlighting 31
3.1 Introduction 31
3.2 Protein Moonlighting: The Early Beginnings 31
3.3 Eye Lens Proteins and Gene Sharing 33
3.4 Multifunctional Metabolic Proteins and Molecular Chaperones 35
3.5 The Return of Moonlighting 37
3.6 A Current View of Protein Moonlighting 39
3.7 The Current Population of Moonlighting Proteins 40
3.8 Conclusions 40
References 40
vi Contents
4 The Structural Basis of Protein Moonlighting 45
4.1 Introduction 45
4.2 The Structural Biology of Protein Moonlighting 48
4.2.1 Exploiting Protein Bulk 49
4.2.2 Catalytic Promiscuity 49
4.2.3 Exploiting Separate Functional Sites 50
4.2.4 Exploiting Alternatively Folded Forms 55
4.2.5 Alternative Oligomerization 56
4.2.6 Posttranslational Modifications 57
4.3 Predicting and Engineering Moonlighting 57
4.4 Conclusions 58
References 60
5 Protein Moonlighting and New Thoughts about Protein Evolution 63
5.1 Introduction 63
5.2 A Darwinian Perspective of Protein Moonlighting 65
5.3 Origin and Evolutionary Stability of Protein Moonlighting 67
5.4 Mutational Robustness and the Persistence of Moonlighting Proteins 68
5.5 Proteins Robust to Mutations Are Highly Evolvable 70
5.6 Moonlighting Proteins and the Rate of Protein Evolution 72
5.7 Molecular Chaperones Buffer the Effects of Mutations on Proteins,
Expediting Their Rate of Evolution and Enabling Moonlighting 74
5.8 Protein Moonlighting Can Lead to Functional Specialization 76
5.9 Conclusions 76
References 77
6 Biological Consequences of Protein Moonlighting 81
6.1 Introduction 81
6.2 The Human Genome, Protein‐Coding Genes, and Cellular Complexity 81
6.3 How Many Moonlighting Proteins Exist/What Proportion of the
Proteome Moonlights? 83
6.4 Secretion of Moonlighting Proteins: A Major Problem Seeking Solution 86
6.5 How Does Protein Moonlighting Influence Systems Biology? 90
6.5.1 Systems Biology and Protein Moonlighting 91
6.5.2 Analysis of the Systems Biology of the Moonlighting Protein Glycerol Kinase 95
6.6 Role of Moonlighting Proteins in the Control of the Biology
of the Healthy Cell 97
6.6.1 Do Moonlighting Protein Exhibit Novel Biological Functions? 97
6.6.2 Moonlighting Proteins and Normal Cellular Functions 104
6.6.2.1 Secreted Moonlighting Proteins 105
6.6.2.2 Moonlighting Proteins on the Plasma Membrane 106
6.6.2.3 Moonlighting Proteins in the Nucleus or Interacting with Nucleic Acids 110
6.6.2.4 Moonlighting Proteins in Cellular Vesicular Trafficking 113
6.6.2.5 Moonlighting in the Cell Cytoplasm 113
6.6.2.6 Ribosomal Moonlighting Proteins 115
6.6.2.7 Moonlighting in Cell Division 118
6.6.2.8 Moonlighting Proteins Existing in Multiple Cellular Compartments 118
Contents vii
6.7 Moonlighting Proteins in the Biology of Single‐Celled Eukaryotes 119
6.8 Moonlighting Proteins Interacting with Moonlighting Proteins 119
6.9 Moonlighting Proteins and Vision: Are Lens Proteins Moonlighting? 120
6.10 Conclusions 121
References 121
7 Protein Moonlighting and Human Health and Idiopathic Human Disease 143
7.1 Introduction 143
7.2 Mammalian Moonlighting Proteins Involved in the Biology of the Cell 143
7.3 Moonlighting Proteins and Human Physiology (Healthy Interactions
of Moonlighting Proteins) 144
7.3.1 Cellular Iron Uptake: GAPDH Binds to Iron‐Binding Proteins 144
7.3.2 Moonlighting Proteins Involved with the Vasculature 149
7.3.2.1 Thymidine Phosphorylase 149
7.3.2.2 Protein Disulfide Isomerase (PDI) 150
7.3.2.3 Mitochondrial Coupling Factor (Mcf)6 150
7.3.2.4 Miscellaneous Moonlighting Proteins 151
7.3.3 Secreted and Cell Surface Histones and Human Physiology 152
7.3.4 Moonlighting Proteins in Reproduction 154
7.3.4.1 Chaperonin (Hsp)10 and Pregnancy 154
7.3.4.2 Phosphoglucoisomerase and Implantation in the Ferret 155
7.3.4.3 Miscellaneous Moonlighting Proteins and Pregnancy 155
7.3.4.4 Moonlighting Proteins, Sperm, and Fertilization 156
7.3.5 Moonlighting Proteins Involved in Controlling Inflammation 157
7.3.5.1 Ubiquitin 158
7.3.5.2 Interferon‐Stimulated Gene 15 (ISG15) 159
7.3.5.3 Thioredoxin 159
7.3.5.4 TNF‐Stimulated Gene 6 (TSG‐6) 160
7.3.5.5 Ribosomal Protein L13a 161
7.3.5.6 Ribosomal Protein S19 161
7.3.5.7 Adiponectin and Inflammation 162
7.3.5.8 Miscellaneous Proteins 162
7.3.6 Moonlighting Proteins as Therapeutics 162
7.3.6.1 Hsp10 164
7.3.6.2 BiP 164
7.3.6.3 Ubiquitin 165
7.3.6.4 Moonlighting Proteins Involved in Wound Healing 165
7.4 Moonlighting Proteins in Human Pathology 166
7.4.1 Phosphoglucoisomerase as a Factor in Human Pathology 166
7.4.2 Moonlighting Proteins in Human Cancer 170
7.4.2.1 α‐Enolase 170
7.4.2.2 Aldolase 171
7.4.2.3 Phosphofructokinase 171
7.4.2.4 Triosephosphate Isomerase 172
7.4.2.5 GAPDH 172
7.4.2.6 Phosphoglycerate Kinase (PGK) 172
7.4.2.7 Pyruvate Kinase (PK) 173
viii Contents
7.4.2.8 BiP/Grp78 173
7.4.2.9 Hsp90 174
7.4.2.10 Hsp27 175
7.4.2.11 Cyclophilin A (CypA) 176
7.4.2.12 Miscellaneous Proteins 176
7.4.3 Molecular Chaperones and Protein‐Folding Catalysts in Human
Inflammatory Pathology 177
7.4.3.1 Chaperonin (Heat Shock Protein) 60 in Cardiovascular Disease 177
7.4.3.2 Hsp70 (HSPA1) in Cardiovascular Disease 178
7.4.3.3 Cyclophilin A 179
7.4.3.4 Thioredoxin and Thioredoxin‐80 180
7.4.3.5 Peroxiredoxins 181
7.4.4 DAMPs: Moonlighting Proteins in Human Inflammatory Pathology 181
7.4.4.1 S100 Proteins 182
7.4.4.2 High‐Mobility Group Box 1 Protein 182
7.4.4.3 Histones 183
7.4.5 Moonlighting Proteins and Vascular Pathology 183
7.4.5.1 Histones 183
7.4.5.2 Mitochondrial Coupling Factor 6 184
7.5 Neomorphic Moonlighting Proteins and Human Diseases 185
7.6 Moonlighting Proteins in Autoimmune Disease 185
7.7 Conclusions 188
References 188
8 Protein Moonlighting and Infectious Disease 223
8.1 Introduction 223
8.2 Microbial Colonization and Infection 224
8.3 Bacterial Virulence Mechanisms 224
8.4 Moonlighting Proteins in Bacterial Virulence 227
8.4.1 Affinities of Binding of Bacterial Moonlighting Proteins 227
8.4.2 Bacteria Utilizing Moonlighting Proteins 229
8.4.3 Identity of the Bacterial Proteins That Moonlight 232
8.5 B iological Activities of Bacterial Moonlighting Proteins as Virulence
Factors 237
8.5.1 Bacterial Moonlighting Proteins Acting as Adhesins 237
8.5.2 Bacterial Moonlighting Proteins Acting as Invasins 248
8.5.3 Bacterial Moonlighting Proteins Acting as Evasins 248
8.5.4 Bacterial Moonlighting Proteins with Activity Similar to Bacterial Toxins 252
8.5.5 Bacterial Moonlighting Proteins Acting as Receptors for Nutrients 256
8.5.6 Miscellaneous Actions of Moonlighting Proteins 256
8.5.7 Conclusions 257
8.6 E xamples of Bacterial Moonlighting Proteins in Human Infectious
Disease 257
8.7 Moonlighting Proteins in Fungi 259
8.8 Moonlighting Proteins in Protozoal Infections 260
8.9 Conclusions 262
References 262
Contents ix
9 Protein Moonlighting: The Future 281
9.1 Introduction 281
9.2 How Prevalent Is Protein Moonlighting? 282
9.3 Evolutionary Biology of Protein Moonlighting 284
9.3.1 Antibodies and Protein Moonlighting 285
9.4 Protein Posttranslational Modification and Protein Moonlighting 286
9.5 Genetics and Protein Moonlighting 287
9.6 Protein Moonlighting and Systems Biology 288
9.7 Moonlighting Proteins and the Response to Drugs 290
9.8 Moonlighting Proteins as Drug Targets 292
9.9 Conclusions 292
References 293
Index 297
xi
Preface
The DNA molecule is often termed the blueprint of life. However, you cannot cook
using the blueprint of a kitchen or bathe in the blueprint of a bathroom. Of the two
major products of the gene (proteins and miscellaneous RNAs), it is the protein that is
the main functional unit of biology. A combinatorial association of 20 amino acids in
linear chains of up to 30 000 residues generates, or can generate in theory, many more
proteins than there are stars in our universe or, indeed, atoms in our universe. The
protein molecule can be chemically active, in the form of an enzyme, whose catalytic
effect can speed up chemical reactions by a thousand‐ to a billion‐fold. It can be a struc-
tural component, acting as a tissue support or allowing the transmission of force. It can
function as a binding molecule, acting to transport other molecules or atoms, or act as
a receptor binding its ligand to transmit information into the cell. Proteins are vitally
important for life, and this is clearly indicated by the number of genetic diseases whose
symptoms are due to altered protein sequences. The classic example of this is sickle cell
disease, due to a single amino acid substitution in hemoglobin, resulting in a protein
that aggregates when deoxygenated, causing massive structural changes in circulating
erythrocytes. The function of proteins can be explained by the evolution in the protein
of a specific interaction between amino acids to generate what is termed an active site/
binding site.
The central dogma, formulated by Francis Crick (and following on from the work of
Beadle and Tatum), suggested the direction of information flow in biology was from
DNA to RNA to protein. This is now known to be wrong in several ways. Not stated in
the central dogma, but generally taken for granted, was that each protein product of the
gene had one single biological function. Like all good Popperian hypotheses, this one‐
protein‐one‐function hypothesis was falsified by the first example of a protein exhibiting
two functions. However, this finding failed to make much of an impact on science and it
was only in the 1980s, through the studies of Joram Piatigorsky on the composition of the
lenses of invertebrates and vertebrates, that it came to the attention of the scientific
community that many of the proteins in the lens were known metabolic enzymes and
molecular chaperones. Piatigorsky named this phenomenon, gene sharing, but the term
was overwhelmed by a welter of other similar terms from molecular biology and largely
became lost to view. In addition, it can be argued that the transparency of a protein is
not really a functional property, but is a bulk physical property of these molecules. So it
was not until the 1990s that additional examples of proteins exhibiting more than one
xii Preface
function were identified and another term to describe this phenomenon was introduced.
Connie Jeffery, from the University of Chicago, introduced the term protein moonlight-
ing in 1999 for the phenomenon of proteins having more than one unique biological
function. Since the introduction of the term, protein moonlighting, a slow trickle of
serendipitous discoveries of moonlighting proteins has been made such that, at the time
of writing, over 200 examples of such proteins have been made. While this is a small
number of examples, it is possibly only the tip of the iceberg that is the population of
moonlighting proteins in biology.
Protein moonlighting has only come to prominence in the last 15 years. Although
only a small number of protein families have been found to moonlight, the consequences
of such additional activities are already known to be of both biological and pathological/
medical significance. Moonlighting proteins are known to be involved in human dis-
eases such as atherosclerosis and cancer and there is rapidly emerging evidence for a
major role for protein moonlighting in the infectious diseases. Protein moonlighting
has potential consequences for various branches of biology. The most obvious is the
field of protein evolution. In moonlighting proteins not one but two or more active sites
have evolved. This calls into question our current models of protein evolution and
generates a range of questions as to the evolutionary mechanisms involved. Further, as
it is emerging that moonlighting protein homologues do not necessarily share specific
moonlighting activities, the level of evolutionary complexity in generating biologically
active sites seems much greater than was previously thought. Another area impacted
by protein moonlighting is the emerging field of systems biology. The complexity of
cellular systems with their multitudes of interacting networks of proteins is currently
predicated on each protein having one function. However, if a sizable proportion of
proteins moonlight, then this will dramatically increase cellular network complexity.
This book brings together a biochemist (Henderson), an evolutionary biologist
(Fares), and a protein bioinformaticist (Martin) who have had a long‐term interest in
protein moonlighting. The discussion covers all aspects of the phenomenon of protein
moonlighting from its evolution to structural biology and on to the biological and medi-
cal consequences of its occurrence. The book should be of interest to the widest range
of biomedical scientists.