Introduction

Moonlighting proteins, also referred to as ‘gene sharing’, refer to a subset of multifunctional proteins in which two or more different functions are performed by one polypeptide chain, and the multiple functions are not a result of splice variants, gene fusions, or multiple isoforms [1]. In addition, they do not include proteins with the same function in multiple locations or protein families in which different members have different functions, if each individual member has only one function. A single protein with multiple functions may seem surprising, but there are actually many cases of proteins that ‘moonlight’.

Examples and mechanisms of combining two functions in one protein

The current examples of moonlighting proteins include enzymes, DNA binding proteins, receptors, transmembrane channels, chaperones and ribosomal proteins (Table 4.1). In general, there are several different methods by which a moonlighting protein can combine two functions within one polypeptide chain. A single protein can have a second function when it moves to a different cellular location; when it is expressed in a different cell type; when it binds a substrate, product, or cofactor; when it interacts with another protein to form a multimer, or when it interacts with a large multiprotein complex. In addition, a few enzymes have two active sites for different substrates (Figure 4.1). The methods are not mutually exclusive and sometimes a combination of methods is employed.

Cellular location: Several cytosolic or nuclear enzymes have a second function outside of the cell.