Cellular and Molecular Life Sciences

, Volume 76, Issue 22, pp 4407–4412 | Cite as

Understanding protein multifunctionality: from short linear motifs to cellular functions

  • Andreas Zanzoni
  • Diogo M. Ribeiro
  • Christine BrunEmail author


Moonlighting proteins perform multiple unrelated functions without any change in polypeptide sequence. They can coordinate cellular activities, serving as switches between pathways and helping to respond to changes in the cellular environment. Therefore, regulation of the multiple protein activities, in space and time, is likely to be important for the homeostasis of biological systems. Some moonlighting proteins may perform their multiple functions simultaneously while others alternate between functions due to certain triggers. The switch of the moonlighting protein’s functions can be regulated by several distinct factors, including the binding of other molecules such as proteins. We here review the approaches used to identify moonlighting proteins and existing repositories. We particularly emphasise the role played by short linear motifs and PTMs as regulatory switches of moonlighting functions.


Moonlighting proteins Multifunctional proteins Cell signalling regulation Short linear motifs Molecular switch Protein interaction networks Bioinformatics 



The project leading to this publication has received funding from Excellence Initiative of Aix-Marseille University - A*MIDEX, a French “Investissements d’Avenir” programme (to CB).


  1. 1.
    Beadle GW, Tatum EL (1941) Genetic control of biochemical reactions in neurospora. Proc Natl Acad Sci USA 27:499–506CrossRefGoogle Scholar
  2. 2.
    Piatigorsky J, Wistow GJ (1989) Enzyme/crystallins: gene sharing as an evolutionary strategy. Cell 57:197–199CrossRefGoogle Scholar
  3. 3.
    Jeffery CJ (1999) Moonlighting proteins. Trends Biochem Sci 24:8–11CrossRefGoogle Scholar
  4. 4.
    Huberts DHEW, van der Klei IJ (2010) Moonlighting proteins: an intriguing mode of multitasking. Biochim Biophys Acta 1803:520–525. CrossRefPubMedGoogle Scholar
  5. 5.
    Chapple CE, Robisson B, Spinelli L et al (2015) Extreme multifunctional proteins identified from a human protein interaction network. Nat Commun 6:7412. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chapple CE, Brun C (2015) Redefining protein moonlighting. Oncotarget 6:16812–16813. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Franco-Serrano L, Hernández S, Calvo A et al (2018) MultitaskProtDB-II: an update of a database of multitasking/moonlighting proteins. Nucleic Acids Res 46:D645–D648. CrossRefPubMedGoogle Scholar
  8. 8.
    Copley SD (2012) Moonlighting is mainstream: paradigm adjustment required. BioEssays 34:578–588. CrossRefPubMedGoogle Scholar
  9. 9.
    Jeffery CJ (2018) Protein moonlighting: what is it, and why is it important? Philos Trans R Soc Lond BBiol Sci. CrossRefGoogle Scholar
  10. 10.
    Jeffery CJ (2014) An introduction to protein moonlighting. Biochem Soc Trans 42:1679–1683. CrossRefPubMedGoogle Scholar
  11. 11.
    Gancedo C, Flores C-L, Gancedo JM (2016) The expanding landscape of moonlighting proteins in yeasts. Microbiol Mol Biol Rev 80:765–777. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Espinosa-Cantú A, Ascencio D, Herrera-Basurto S et al (2018) Protein moonlighting revealed by noncatalytic phenotypes of yeast enzymes. Genetics 208:419–431. CrossRefPubMedGoogle Scholar
  13. 13.
    Khan I, Chitale M, Rayon C, Kihara D (2012) Evaluation of function predictions by PFP, ESG, and PSI-BLAST for moonlighting proteins. BMC Proc 6(Suppl 7):S5. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Khan IK, Bhuiyan M, Kihara D (2017) DextMP: deep dive into text for predicting moonlighting proteins. Bioinformatics 33:i83–i91. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Khan IK, Kihara D (2016) Genome-scale prediction of moonlighting proteins using diverse protein association information. Bioinformatics 32:2281–2288. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Maxwell CA, McCarthy J, Turley E (2008) Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? J Cell Sci 121:925–932. CrossRefPubMedGoogle Scholar
  17. 17.
    Becker E, Robisson B, Chapple CE et al (2012) Multifunctional proteins revealed by overlapping clustering in protein interaction network. Bioinformatics 28:84–90. CrossRefPubMedGoogle Scholar
  18. 18.
    Chapple CE, Herrmann C, Brun C (2015) PrOnto database: GO term functional dissimilarity inferred from biological data. Front Genet 6:200. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Davey NE, Van Roey K, Weatheritt RJ et al (2012) Attributes of short linear motifs. Mol BioSyst 8:268–281. CrossRefPubMedGoogle Scholar
  20. 20.
    Gouw M, Michael S, Sámano-Sánchez H et al (2018) The eukaryotic linear motif resource—2018 update. Nucleic Acids Res 46:D428–D434. CrossRefPubMedGoogle Scholar
  21. 21.
    Deribe YL, Pawson T, Dikic I (2010) Post-translational modifications in signal integration. Nat Struct Mol Biol 17:666–672. CrossRefPubMedGoogle Scholar
  22. 22.
    Perkins JR, Diboun I, Dessailly BH et al (2010) Transient protein-protein interactions: structural, functional, and network properties. Structure 18:1233–1243. CrossRefPubMedGoogle Scholar
  23. 23.
    Gibson TJ (2009) Cell regulation: determined to signal discrete cooperation. Trends Biochem Sci 34:471–482. CrossRefPubMedGoogle Scholar
  24. 24.
    Neduva V, Russell RB (2005) Linear motifs: evolutionary interaction switches. FEBS Lett 579:3342–3345. CrossRefPubMedGoogle Scholar
  25. 25.
    Van Roey K, Gibson TJ, Davey NE (2012) Motif switches: decision-making in cell regulation. Curr Opin Struct Biol 22:378–385. CrossRefPubMedGoogle Scholar
  26. 26.
    Brooks CL, Li M, Hu M et al (2007) The p53–Mdm2–HAUSP complex is involved in p53 stabilization by HAUSP. Oncogene 26:7262–7266. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Van Roey K, Dinkel H, Weatheritt RJ et al (2013) The switches.ELM resource: a compendium of conditional regulatory interaction interfaces. Sci Signal 6:rs7. CrossRefPubMedGoogle Scholar
  28. 28.
    Tristan C, Shahani N, Sedlak TW, Sawa A (2011) The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal 23:317–323. CrossRefPubMedGoogle Scholar
  29. 29.
    Hara MR, Agrawal N, Kim SF et al (2005) S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7:665–674. CrossRefGoogle Scholar
  30. 30.
    Sen N, Hara MR, Kornberg MD et al (2008) Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol 10:866–873. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Volz K (2008) The functional duality of iron regulatory protein 1. Curr Opin Struct Biol 18:106–111. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Fillebeen C, Caltagirone A, Martelli A et al (2005) IRP1 Ser-711 is a phosphorylation site, critical for regulation of RNA-binding and aconitase activities. Biochem J 388:143–150. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Clarke SL, Vasanthakumar A, Anderson SA et al (2006) Iron-responsive degradation of iron-regulatory protein 1 does not require the Fe–S cluster. EMBO J 25:544–553. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Deck KM, Vasanthakumar A, Anderson SA et al (2009) Evidence that phosphorylation of iron regulatory protein 1 at Serine 138 destabilizes the [4Fe–4S] cluster in cytosolic aconitase by enhancing 4Fe–3Fe cycling. J Biol Chem 284:12701–12709. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lay AJ, Jiang XM, Kisker O et al (2000) Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase. Nature 408:869–873. CrossRefPubMedGoogle Scholar
  36. 36.
    Shetty P, Velusamy T, Bhandary YP et al (2010) Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase. Mol Cell Biochem 335:235–247. CrossRefPubMedGoogle Scholar
  37. 37.
    Royle SJ (2011) Mitotic moonlighting functions for membrane trafficking proteins. Traffic 12:791–798. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Smith CM, Chircop M (2012) Clathrin-mediated endocytic proteins are involved in regulating mitotic progression and completion. Traffic 13:1628–1641. CrossRefPubMedGoogle Scholar
  39. 39.
    Ferguson SM, De Camilli P (2012) Dynamin, a membrane-remodelling GTPase. Nat Rev Mol Cell Biol 13:75–88. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Thompson HM, Skop AR, Euteneuer U et al (2002) The large GTPase dynamin associates with the spindle midzone and is required for cytokinesis. Curr Biol 12:2111–2117CrossRefGoogle Scholar
  41. 41.
    Chircop M, Sarcevic B, Larsen MR et al (2011) Phosphorylation of dynamin II at serine-764 is associated with cytokinesis. Biochim Biophys Acta 1813:1689–1699. CrossRefPubMedGoogle Scholar
  42. 42.
    Monaghan RM, Whitmarsh AJ (2015) Mitochondrial proteins moonlighting in the nucleus. Trends Biochem Sci 40:728–735. CrossRefPubMedGoogle Scholar
  43. 43.
    Chen L-Y, Liu D, Songyang Z (2007) Telomere maintenance through spatial control of telomeric proteins. Mol Cell Biol 27:5898–5909. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Chen L-Y, Zhang Y, Zhang Q et al (2012) Mitochondrial localization of telomeric protein TIN2 links telomere regulation to metabolic control. Mol Cell 47:839–850. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Chen C, Zabad S, Liu H et al (2018) MoonProt 2.0: an expansion and update of the moonlighting proteins database. Nucleic Acids Res 46:D640–D644. CrossRefPubMedGoogle Scholar
  46. 46.
    Amberger JS, Bocchini CA, Schiettecatte F et al (2015) online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res 43:D789–D798. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    wwPDB consortium (2018) Protein data bank: the single global archive for 3D macromolecular structure data. Nucleic Acids Res. CrossRefGoogle Scholar
  48. 48.
    Ribeiro DM, Briere G, Bely B et al (2019) MoonDB 2.0: an updated database of extreme multifunctional and moonlighting proteins. Nucleic Acids Res. CrossRefPubMedGoogle Scholar
  49. 49.
    Zanzoni A, Chapple CE, Brun C (2015) Relationships between predicted moonlighting proteins, human diseases, and comorbidities from a network perspective. Front Physiol 6:171. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Corbi-Verge C, Kim PM (2016) Motif mediated protein-protein interactions as drug targets. Cell Commun Signal 14:8. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Aix Marseille Univ, INSERM, TAGC, UMR_S1090MarseilleFrance
  2. 2.CNRSMarseilleFrance

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