I Overview of Protein Moonlighting

What is Protein Moonlighting and Why is it Important?

Constance J. Jeffery

Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, USA

What is Protein Moonlighting?

Moonlighting proteins exhibit more than one physiologically relevant biochemical or biophysical function within one polypeptide chain (Jeffery 1999). In this class of multifunctional proteins, the multiple functions are not due to gene fusions, multiple RNA splice variants or multiple proteolytic fragments. The moonlighting proteins do not include pleiotropic proteins, where a protein has multiple downstream cellular roles in different pathways or physiological processes that result from a single biochemical or biophysical function of a protein. Moonlighting proteins also do not include families of homologous proteins if the different functions are performed by different members of the protein family.

Some of the first moonlighting proteins to be identified were taxon-specific crystallins in the lens of the eye. These proteins, including the delta 2 crystallin/ arginosuccinate lyase in the duck (Wistow and Piatigorsky 1987), upsilon crys- tallin/lactate dehydrogenase A in the duckbill platypus (van Rheede et al. 2003), eta-crystallin/cytosolic aldehyde dehydrogenase (ALDH class 1) in the elephant shrew (Bateman et al. 2003), and several others, are ubiquitous soluble enzymes that were adopted as structural proteins in the lens. Other well-known moonlighting proteins include soluble enzymes in biochemical pathways that also bind to DNA or RNA to regulate transcription or translation. Human thymi- dylate synthase (TS), a cytosolic enzyme in the de novo synthesis of the DNA precursor thymidylate, also binds to mRNA encoding TS to inhibit translation (Chu et al. 1991). The Salmonella typhimurium PutA protein is an enzyme with proline dehydrogenase and proline oxidase pyrroline-5-carboxylic acid dehydrogenase activity when it is bound to the inner side of the plasma membrane (Menzel and Roth 1981a, b), but it also binds to DNA and moonlights as a transcriptional repressor of the put operon (Ostrovsky de Spicer et al. 1991; Ostrovsky de Spicer and Maloy 1993). The E. coli BirA biotin synthase is an enzyme in the biotin biosynthetic pathway that is also a bio operon suppressor

Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections, First Edition. Edited by Brian Henderson.

© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.

(Barker and Campbell 1981). Saccharomyces cerevisiae N-acetylglutamate kinase/N-acetylglutamyl-phosphate reductase (Arg5,6p) is an enzyme in the arginine biosynthetic pathway (Boonchird etal. 1991; Abadjieva et al. 2001) and also binds to mitochondrial and nuclear DNA to regulate expression of several genes (Hall et al. 2004). Kluyveromyces lactis galactokinase (GAL1) phosphoryl- ates galactose and is also a transcriptional activator of genes in the GAL operon (Meyer et al. 1991).

Perhaps even more surprising than the fact that some proteins can perform such different functions is that such a large variety of proteins moonlight. Over the past few decades, hundreds of proteins have been shown to moonlight (Mani et al. 2015; moonlightingproteins.org). They include many types of proteins: enzymes, scaffolds, receptors, adhesins, channels, transcription and translation regulators, extracellular matrix proteins, growth factors, and many others. They are active in a variety of physiological processes and biochemical pathways, are found in the cytoplasm, nucleus, mitochondria, on cell surface, and other cellular compartments, and some are secreted. They are also expressed in many different cell types within a species. They are found in a variety of species from throughout the evolutionary tree. They are common in eukaryotes in humans and other placental and monotreme (i.e., platypus) mammals, reptiles, birds, amphibians, fish, worms, insects, plants, fungi, and protozoans. A few are found in archea and many more have been identified in eubacteria, including pathogenic species (Clostridium difficile, Helicobacter pylori, Pseudomonas aeruginosa, Staphylococcus, etc.) as well as nonpathogenic, commensal bacteria, including health-promoting or “pro-biotic” species (Bifidobacterium). A few moonlighting proteins have even been found in viruses.

The variety also extends to the combinations of functions that are observed. Many of the known moonlighting proteins are cytosolic enzymes, chaperones, or other proteins that exhibit a second function in other cellular locations, for example as a receptor on the cell surface. Several proteins described in more detail in other chapters are cytosolic enzymes or chaperones that are secreted to serve as growth hormones or cytokines. For example, an enzymatic function and an extracellular cytokine function are found in phosphoglucose isomerase/autocrine motility factor (Gurney et al. 1986a, b; Chaput et al. 1988; Faik et al. 1988; Watanabe et al. 1996; Xu et al. 1996). Many of the moonlighting proteins have surprisingly unrelated functions, such as the PHGPx (glutathione peroxidase), a soluble enzyme that is also a sperm structural protein (Scheerer et al. 2007), adopted during evolution for its structural characteristics in the same way as taxon-specific crystallins above. Other proteins can exhibit two functions even within the same cellular compartment and may change function as cellular conditions change, for example changes in pH, or the concentration of a ligand, substrate, cofactor, or product. Still other moonlighting proteins have one function as a monomer or homo-multimer but interact with other proteins in a multiprotein complex, such as the proteasome or ribosome. Some proteins even have more than two functions, for example glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and enolase.

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