FAQs about Moonlighting Proteins


What are moonlighting proteins?

A moonlighting protein is a single protein that has multiple functions that are not due to gene fusions, multiple RNA splice variants or multiple proteolytic fragments. Moonlighting proteins do not include families of homologous proteins if the different functions are performed by different proteins in the protein family, or proteins that have multiple cellular roles that involve the same biochemical function in different locations.

A classic example is phosphoglucose isomerase/autocrine motility factor, neuroleukin/differentiation and maturation mediator. It is both a cytosolic enzyme in glycolysis and an extracellular cytokine and growth factor.

Cytosolic Enzyme                       Extracellular Growth Factor

How common are moonlighting proteins?

It's not clear how common moonlighting is. The literature contains approximately 200 proteins for which there is biochemical and/or biophysical evidence of two different functions performed by one polypeptide chain. The known examples of moonlighting proteins include many types of proteins, including receptors, enzymes, transcription factors, adhesins and scaffolds. Moonlighting proteins are found in mammals, yeast, bacteria, plants, and many other organisms. Different combinations of biochemical functions are found, for example, an enzymatic function and a receptor-binding function found in phosphoglucose isomerase/autocrine motiility factor. Diverse methods are used to switch between functions: binding a small molecule, joining a multiprotein complex, binding to DNA, etc. Two proposed mechanisms/models for evolution of a moonlighting function make use of general features of protein structure and could apply to many protein types, potentially resulting in a large number of proteins that moonlight.

Are any moonlighting proteins involved in disease?

Already moonlighting proteins have been found to be involved in cancer cell motility, angiogenesis, DNA synthesis or repair, and chromatin and cytoskeleton structure. The ability of a protein to moonlight can complicate the elucidation of molecular mechanisms of disease, the identification of biomarkers of disease progression, and the development of novel therapeutics.

How did moonlighting proteins evolve?

Two general methods have been suggested for evolving a moonlighting function. Some proteins appear to have been recruited for a new function when new cell types or organs evolved, but without significant modification of the protein structure, for example, the taxon specific crystallins. In these cases, the new function probably makes use of overall structural or physical features of the protein. A second method is illustrated by the case of PGI/AMF, an ancient enzyme that evolved a protein–protein interaction surface in addition to its active site pocket. The PGI active site pocket is a relatively small part of the protein structure, and there is a lot of solvent-exposed surface area that can undergo changes without adversely affecting catalysis. Because PGI is found in almost all species, it apparently first evolved over three billion years ago. A comparison of the rabbit and bacterial PGI structures showed that the active site has been conserved, but many surface features have changed during evolution. It is possible that the random accumulation of mutations on the surface might have resulted in an additional binding site that enables PGI to bind to a receptor.

I have a protein that is a moonlighting protein. How can I have it added to the MoonProt database?

Please contact us at protein@moonlightingproteins.org if you have another protein to suggest for including in MoonProt database.

I would like to use the MoonProt database in a project to analyze the amino acid sequences or structures using bioinformatics.

Please contact us at bioinformatics@moonlightingproteins.org if you are interested in using MoonProt database for analysis of sequences and/or structures of moonlighting proteins.

Jeffery Lab
University of Illinois at Chicago
MBRB Rm. 4260