Abstract
The human body is a complex biological machine with billions of cells and vast numbers of biochemical processes – but our genome only contains 22,000 protein-encoding genes. Moonlighting proteins provide one way to increase the number of cellular activities. Moonlighting proteins exhibit more than one physiologically relevant biochemical or biophysical function within one polypeptide chain. Already more than 300 moonlighting proteins have been identified, and they include a diverse set of proteins with a large variety of functions. This article discusses examples of moonlighting proteins, how one protein structure can perform two different functions, and how the multiple functions can be regulated. In addition to learning more about what our proteins do and how they work together in complex multilayered interaction networks and processes in our bodies, the study of moonlighting proteins can inform future synthetic biology projects in making proteins that perform new functions and new combinations of functions, for example, for synthesising new materials, delivering drugs into cells, and in bioremediation.
Keywords: moonlighting proteins, multifunctional proteins, protein structure and function
Full Text
The Full Text of this article is available as a PDF (1.4 MB).
6. References
- 1.Jeffery C.J. (1999) Moonlighting proteins. Trends Biochem. Sci., 24, 8–11. [DOI] [PubMed] [Google Scholar]
- 2.Mani M., Chen C., Amblee V., et al. (2015) MoonProt: a database for proteins that are known to moonlight. Nucleic Acids Res., 43, D277–282. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Jeffery C.J., Bahnson B.J., Chien W., et al. (2000) Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that moonlights as neuroleukin, autocrine motility factor, and differentiation mediator. Biochemistry, 39, 955–964. [DOI] [PubMed] [Google Scholar]
- 4.Chaput M., Claes V., Portetelle D., et al. (1988) The neurotrophic factor neuroleukin is 90% homologous with phosphohexose isomerase. Nature, 332, 454–455. [DOI] [PubMed] [Google Scholar]
- 5.Faik P., Walker J.I., Redmill A.A. and Morgan M.J. (1988) Mouse glucose-6-phosphate isomerase and neuroleukin have identical 3’ sequences. Nature, 332, 455–457. [DOI] [PubMed] [Google Scholar]
- 6.Watanabe H., Takehana K., Date M., et al. (1996) Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide. Cancer Res., 56, 2960–2963. [PubMed] [Google Scholar]
- 7.Xu W., Seiter K., Feldman E., et al. (1996) The differentiation and maturation mediator for human myeloid leukemia cells shares homology with neuroleukin or phosphoglucose isomerase. Blood, 87, 4502–4506. [PubMed] [Google Scholar]
- 8.Wistow G. and Piatigorsky J. (1987) Recruitment of enzymes as lens structural proteins. Science, 236, 1554–1556. [DOI] [PubMed] [Google Scholar]
- 9.Piatigorsky J. (1998) Multifunctional lens crystallins and corneal enzymes. More than meets the eye. Ann. N. Y. Acad. Sci., 842, 7–15. [DOI] [PubMed] [Google Scholar]
- 10.Hendriks W., Mulders J.W.M., Bibby M.A., et al. (1988) Duck lens epsilon-crystallin and lactate dehydrogenase B4 are identical: A single-copy gene product with two distinct functions. Proc. Natl Acad. Sci. USA, 85, 7114–7118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wistow G.J., Mulders J.W.M. and de Jong W.W. (1987) The enzyme lactate dehydrogenase as a structural protein in avian and crocodilian lenses. Nature, 326, 622–624. [DOI] [PubMed] [Google Scholar]
- 12.Rao P.V., Krishna C.M. and Zigler J.S. Jr. (1992) Identification and characterization of the enzymatic activity of zeta-crystallin from guinea pig lens. A novel NADPH:quinone oxidoreductase. J. Biol. Chem., 267, 96–102. [PubMed] [Google Scholar]
- 13.Rao P.V. and Zigler J.S. Jr. (1991) Zeta-crystallin from guinea pig lens is capable of functioning catalytically as an oxidoreductase. Arch. Biochem. Biophys., 284, 181–185. [DOI] [PubMed] [Google Scholar]
- 14.Bateman O.A., Purkiss A.G., van Montfort R., et al. (2003) Crystal structure of eta-crystallin: adaptation of a class 1 aldehyde dehydrogenase for a new role in the eye lens. Biochemistry, 42, 4349–4356. [DOI] [PubMed] [Google Scholar]
- 15.Pancholi V. and Fischetti V.A. (1992) A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J. Exp. Med., 176, 415–426. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Petit F.M., Serres C., Bourgeon F., et al. (2013) Identification of sperm head proteins involved in zona pellucida binding. Hum. Reprod., 28, 852–865. [DOI] [PubMed] [Google Scholar]
- 17.Gopalakrishnan B., Aravinda S., Pawshe C.H., et al. (1998) Studies on glutathione S-transferases important for sperm function: evidence of catalytic activity-independent functions. Biochem. J., 329, 231–241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Auer J., Camoin L., Courtot A.M., et al. (2004) Evidence that P36, a human sperm acrosomal antigen involved in the fertilization process is triosephosphate isomerase. Mol. Reprod. Dev., 68, 515–552. [DOI] [PubMed] [Google Scholar]
- 19.Wu N. and Yu H. (2012) The Smc complexes in DNA damage response. Cell Biosci., 2, 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Darwiche N., Freeman L.A. and Strunnikov A. (1999) Characterization of the components of the putative mammalian sister chromatid cohesion complex. Gene, 233, 39–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Ghiselli G., Siracusa L.D. and Iozzo R.V. (1999) Complete cDNA cloning, genomic organization, chromosomal assignment, functional characterization of the promoter, and expression of the murine Bamacan gene. J. Biol. Chem., 274, 17384–17393. [DOI] [PubMed] [Google Scholar]
- 22.Couchman J.R., Kapoor R., Sthanam M. and Wu R.R. (1996) Perlecan and basement membrane-chondroitin sulfate proteoglycan (bamacan) are two basement membrane chondroitin/dermatan sulfate proteoglycans in the Engelbreth-Holm-Swarm tumor matrix. J. Biol. Chem., 271, 9595–9602. [DOI] [PubMed] [Google Scholar]
- 23.Ehinger S., Schubert W.D., Bergmann S., et al. (2004) Plasmin(ogen)-binding alpha-enolase from Streptococcus pneumoniae: crystal structure and evaluation of plasmin(ogen)-binding sites. J. Mol. Biol., 343, 997–1005. [DOI] [PubMed] [Google Scholar]
- 24.Walden W.E., Selezneva A.I., Dupuy J., et al. (2006) Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science, 314, 1903–1908. [DOI] [PubMed] [Google Scholar]
- 25.Kim T.S., Kim H.D. and Kim J. (2009) PKCdelta-dependent functional switch of rpS3 between translation and DNA repair. Biochim. Biophys. Acta, 1793, 395–405. [DOI] [PubMed] [Google Scholar]
- 26.Wan F., Weaver A., Gao X., et al. (2011) IKKbeta phosphorylation regulates RPS3 nuclear translocation and NF-kappaB function during infection with Escherichia coli strain O157:H7. Nat. Immunol., 12, 335–343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Mazumder B., Sampath P., Seshadri V., et al. (2003) Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control. Cell, 115, 187–198. [DOI] [PubMed] [Google Scholar]
- 28.Carvalho C.M., Santos A.A., Pires S.R., et al. (2008) Regulated nuclear trafficking of rpL10A mediated by NIK1 represents a defense strategy of plant cells against virus. PLoS Pathog., 4, E1000247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Rocha C.S., Santos A.A., Machado J.P. and Fontes E.P. (2008) The ribosomal protein L10/QM-like protein is a component of the NIK-mediated antiviral signaling. Virology, 380, 165–169. [DOI] [PubMed] [Google Scholar]
- 30.Adlanmerini M., Solinhac R., Abot A., et al. (2014) Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc. Natl Acad. Sci. USA, 111, E283–290. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Amblee V. and Jeffery C.J. (2015) Physical features of intracellular proteins that moonlight on the cell surface. PLoS One, 10, e0130575. [DOI] [PMC free article] [PubMed] [Google Scholar]