Protein Moonlighting in Biology and Medicine

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

• Publisher: Wiley-Blackwell
• Year: 2016
• Print ISBN: 9781118952085
• eBook ISBN: 9781118952894
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biotechnology
• Index: Biological Sciences

The past 25 years has seen the emergence of a wealth of data suggesting that novel biological functions of known proteins play important roles in biology and medicine. This ability of proteins to exhibit more than one unique biological activity is known as protein moonlighting. Moonlighting proteins can exhibit novel biological functions, thus extending the function of the proteome, and are also implicated in the pathology of a growing number of idiopathic and infectious diseases.

This book, written by a cell biologist, protein evolutionary biologist and protein bioinformatician, brings together the latest information on the structure, evolution and biological function of the growing numbers of moonlighting proteins that have been identified, and their roles in human health and disease. This information is revealing the enormous importance protein moonlighting plays in the maintenance of human health and in the induction of disease pathology.

Protein Moonlighting in Biology and Medicine will be of interest to a general readership in the biological and biomedical research community.

1
An Introduction to the Protein Molecule

1.1 Why Study Protein Moonlighting?

It is a mitochondrial protein essential for energy production. It is also a key controller of the essential process of apoptosis. It is the second enzyme of the glycolytic pathway and a secreted pro‐cancer signal important in breast cancer. It is the central enzyme of glycolysis, which also performs the functions of the major bacterial virulence factors.

These seemingly paradoxical statements encapsulate what is an emerging story in the biology of the protein molecule. A growing number of prokaryotic and eukaryotic proteins have been found to exhibit more than one unique biological function. The number of such multifunctional, or moonlighting, proteins being discovered is increasing, and reviews of the literature, such as this book, are also identifying historical reports of protein moonlighting. A number of databases that encapsulate the data on the known moonlighting proteins are now available online (Hernandez et al. 2014; Mani et al. 2015). It is estimated that up to 300 proteins have protein moonlighting behavior. As will be discussed in later chapters of this book, this is likely to be only a small proportion of the total number of proteins that can moonlight. Indeed, this is one of the key questions that need to be addressed in the field of protein biology. It is recognized that multicellular eukaryotes have low numbers of protein‐coding genes. For example, Homo sapiens seems to be able to control its 10¹³ cells with only 19 000 protein‐coding genes (Ezkurdia et al. 2014). This seems a very low number of genes to generate the human functional proteome. Protein moonlighting might be one phenomenon that could account for the needs for such small numbers of proteins to be able to “run a human.”

The three examples of moonlighting proteins that began this discussion are the very well‐known proteins: cytochrome C (Cyt C), phosphoglucoisomerase (PGI), and glyceraldehyde 3‐phosphate dehydrogenase (GAPDH). In addition to their established enzymatic functions, these three proteins have completely distinct and novel functions important in both physiological and pathological processes. At the current time, Cyt C appears only to have actions revolving around the control of apoptosis. The PGI protein has five distinct biological functions (see Chapter 3), and the family of GAPDH proteins has a bewilderingly large number of biological functions in both prokaryotes and eukaryotes (Sirover 2014). Surprisingly, as will be discussed in Chapter 8, GAPDH proteins from a number of pathogenic bacteria can function as so‐called virulence factors mimicking the actions of bacterial toxins, adhesins, invasins, evasins, and iron‐binding proteins. Indeed, one of the many surprises in the protein moonlighting literature is that both human GAPDH (Sheokand et al. 2013) and the GAPDH from some bacteria like the major human pathogen, Mycobacterium tuberculosis (Boradia et al. 2014), function as cell surface and secreted binding proteins for the iron‐carrying protein, transferrin. It would appear that the same moonlighting protein is important in iron sequestration in humans and mycobacteria and are likely to be pitted against each other in the ancient scourge, tuberculosis. This example of GAPDH exemplifies the finding that a proportion of moonlighting proteins can exhibit multiple functions. For example, the molecular chaperone, chaperonin (Cpn) or heat shock protein (Hsp)60 family of proteins, exhibits over 40 different biological functions (Henderson et al. 2013). It is not known if all moonlighting proteins have this capacity for multiple functionality.

Moonlighting proteins are now firmly established as participants in normal cellular, tissue, and organismal homeostasis as well as being parts of the mechanisms of tissue pathology and infectious disease. This book, written by a cellular biologist (Henderson), a protein bioinformaticist (Martin), and an evolutionary biologist (Fares), brings together the literature on protein moonlighting to provide a current overview of this new area of biology. To get the story started, this first chapter will introduce the reader to the world of the protein molecule.

1.2 A Brief History of Proteins

The concept of proteins first entered science in the eighteenth century. The French chemist, Antoine Fourcroy, in 1789, identified three different categories of what we now know are “proteins” from animal sources—albumin, fibrin, and gelatin—in addition to at least two classes in plants. Indeed, the name “albumins” was used as a generic term to describe all proteins at this time. The term “protein” emerges from the studies of two chemists, the world‐renowned Swedish chemist, Jacob Berzelius, and the less well‐known Dutch physician and chemist, Gerrit Mulder. Mulder was exploring the composition of natural products using newly developed methods of compositional analysis. Analyzing various “albumins,” he was surprised to find that they all had virtually the same atomic composition (Mulder 1838). This led Mulder to speculate that all the albumins he had been studying might be composed of the same substance that he termed “Grundstoff.” Mulder was in correspondence with Berzelius, who thought that this result should be noted with a specific name for the generic material composing all the albumins examined. The name he suggested was “protein,” derived from the Greek word proteos, meaning “standing in front” or “in the lead” (Tanford and Reynolds 2003).

Soon after Mulder’s paper was published, the influential scientist, Justus Liebig, entered the story. In 1841, he praised the work of Mulder and concluded that only four proteins existed in plants, while in animals he concluded that albumin and fibrin could be converted into blood. While not directly true, of course, we now know that these proteins are formed of the same 20 amino acids, which can be assembled in different ways. Gradually, the truth started to unfold. While “Grundstoff” was thought only to contain carbon, hydrogen, oxygen, and nitrogen in a fixed ratio, and sometimes was associated with sulfur, Liebig found that the sulfur could not always be separated; we now know that two amino acids (cysteine and methionine) contain sulfur. J.B. Dumas showed in 1842 that the ratio of carbon, hydrogen, oxygen, and nitrogen was not fixed, as thought by Mulder, showing that “Grundstoff” was much more varied than previously thought.

By 1900, it was realized that proteins are in fact made up of amino acid building blocks; and in 1902, ...

Table of contents

• Cover
• Title Page
• Table of Contents
• Preface
• 1 An Introduction to the Protein Molecule
• 2 How Proteins Evolve?
• 3 A Brief History of Protein Moonlighting
• 4 The Structural Basis of Protein Moonlighting
• 5 Protein Moonlighting and New Thoughts about Protein Evolution
• 6 Biological Consequences of Protein Moonlighting
• 7 Protein Moonlighting and Human Health and Idiopathic Human Disease
• 8 Protein Moonlighting and Infectious Disease
• 9 Protein Moonlighting
• Index
• End User License Agreement