Of the two major products of the gene (proteins and microRNAs) it is the protein that is the 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. 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 million-fold. It can be a structural component acting as a tissue support or allowing the transmission of force. It can function as a binding protein, 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 haemoglobin, 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.
Not stated in the central dogma, but generally taken for granted, was that each protein product of the gene had one single biological function. This one-protein-one-function hypothesis was falsified by the first example of a protein exhibiting two functions. In addition, the transparency of a protein is not really a functional property but is a physical property of these molecules. So it was not until the 1990s that additional examples of proteins exhibiting more than one function were identified and another term to describe this phenomenon was introduced. Connie Jeffery, from the University of Chicago, introduced the term Protein Moonlighting 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 one hundred 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 proportion 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 significance in both biological and pathological/medical terms. Moonlighting proteins are known to be involved in human diseases such as 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 particular 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 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 the the biological and medical consequences of its occurrence. The book should be of interest to the widest range of biomedical scientists.
