Why study moonlighting proteins?

Moonlighting proteins comprise a class of multifunctional proteins in which a single protein performs multiple physiologically relevant biochemical or biophysical functions that are not due to gene fusions, multiple RNA splice variants, or pleiotropic effects (Jeffery, 1999). Classic examples include soluble enzymes that also bind to DNA or RNA to regulate translation or transcription (Figure 1A) (reviewed in Commichau and Stulke, 2008) or have a second function as structural proteins in the lens of the eye (crystallins) (Figure 1B) (Wistow and Piatigorsky, 1987; Piatigorsky and Wistow, 1989). Other typical examples are cytosolic enzymes that moonlight as cytokines, chaperones, cytoskeletal components, DNA compactors, adhesins or scaffolds, as well as a chloride transporter that regulates the function of another transmembrane channel, ribosomal proteins that double as translation factors, and a DNA binding protein that becomes a component of the extracellular matrix (for reviews see Nobeli et al., 1996; Jeffery, 2003a,b, 2009, submitted; Piatigorsky, 2007; Gancedo and Flores, 2008; Huberts and van der Klei, 2010; Henderson and Martin, 2011, 2013; Guo and Schimmel, 2013). Moonlighting proteins are found in mammals, yeast, worms, bacteria, plants, viruses, archea and many other organisms. The online MoonProt Database, which includes information about those moonlighting proteins for which biochemical or biophysical evidence supports the presence of at least two biochemical functions in one polypeptide chain, includes over 270 proteins (Mani et al., 2015). It is likely that many other proteins also have additional functions that have not yet been found. In this opinion piece, I argue that there are currently many reasons for studying moonlighting proteins.