Skip to main content
SpringerLink
Log in

Multifunctional Proteins

  • MOLECULAR BIOPHYSICS
  • Published:
Biophysics Aims and scope Submit manuscript

Abstract

A surprisingly small number of human genes (19–20 thousand) is not consistent with a much larger number of proteins and the number of their functions. One of the factors of functional diversity is the multifunctionality of proteins. An important subclass of such proteins is moonlighting proteins, in which one polypeptide chain performs two or more functions under different conditions. Often, these are various housekeeping proteins – glycolytic, ribosomal, and others, which are abundant in the cell. In this review we consider the structures and functions of several such proteins – the rpS3 ribosomal protein, cytochrome c, glyceraldehyde-6-phosphate dehydrogenase (GAPDH), transcription factors STAT3, β-catenin and p53. A switching of their functions occurs due to violation of the balance between their synthesis, use, and degradation, intracellular relocalization, and post-translational modifications. A significant role of the internal disordered regions in the formation of intermolecular complexes with other proteins and nucleic acids is noted. The emergence of multifunctional proteins during evolution is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.

Similar content being viewed by others

REFERENCES

  1. G. W. Beadle and E. L.Tatum, Proc. Natl. Acad. Sci. U. S. A. 27, 499 (1941).

    ADS  Google Scholar 

  2. C. B. Anfinsen, Fed. Proc. 16, 783 (1957).

    Google Scholar 

  3. F. Moraes and A. Goes, Biochem. Mol. Biol. Educ. 44, 215 (2016).

    Google Scholar 

  4. UniProt Consortium. Nucleic Acids Res. 43 (Database issue), D204 (2015).

    Google Scholar 

  5. S. K. Burley, H. M. Berman, G. J. Kleywegt, et al., Methods Mol. Biol. 1607, 627 (2017).

    Google Scholar 

  6. F. E. Regnier and J. H. Kim, Anal. Chem. 90, 361 (2018).

    Google Scholar 

  7. O. I. Kiseleva, A. V. Lisitsa, and E. V. Poverennaya, Mol. Biol. (Moscow) 52, 394 (2018).

    Google Scholar 

  8. S. Y. Chen, C. Li, X. Jia, and S. J. Lai, Int. J. Mol. Sci. 20, E3834 (2019).

    Google Scholar 

  9. M. L. Tress, F. Abascal, and A. Valencia, Trends Biochem. Sci. 42, 98 (2017).

    Google Scholar 

  10. K. V. Nguyen, Biomol. Concepts 6, 11 (2015).

    Google Scholar 

  11. http://wallace.uab.es/multi

  12. M. Mani, C. Chen, V. Amblee, et al., Nucleic Acids Res. 43, D277 (2015).

    Google Scholar 

  13. C. J. Jeffery, Philos. Trans. R. Soc. Lond. B 373, 1738 (2018).

    Google Scholar 

  14. C. J. Jeffery, J. Proteomics 134, 19 (2016).

    Google Scholar 

  15. K. W. Min, S. H. Lee, and S. J. Baek, Cancer Lett. 370, 108 (2016).

    Google Scholar 

  16. S. D. Copley, Bioessays 34, 578, (2012).

    Google Scholar 

  17. B. Henderson and A. C. Martin, Biochem. Soc. Trans. 42, 1671 (2014).

    Google Scholar 

  18. C. E. Chapple and C. Brun, Oncotarget 6, 16812 (2015).

    Google Scholar 

  19. F. Wan, D. E. Anderson, R. A. Barnitz, et al., Cell 131, 9279 (2007).

    Google Scholar 

  20. 20. B. Pertschy, Microb. Cell 4, 140 (2017).

    Google Scholar 

  21. X. Gao and P. R. Hardwidge, Front. Microbiol. 2, 137 (2011).

    Google Scholar 

  22. T. H. Kim, P. Leslie, and Y. Zhang, Oncotarget 5, 860 (2014).

    Google Scholar 

  23. D. Alvarez-Paggi, L. Hannibal, M. Castro, et al., Chem. Rev. 117, 13382 (2017).

    Google Scholar 

  24. M. Zhou, Y. Li, Q. Hu, et al., Genes Dev. 29, 2349 (2015).

    Google Scholar 

  25. L. Dorstyn, C. W. Akey, and S. Kumar, Cell Death Differ. 25, 1194 (2018).

    Google Scholar 

  26. Y. P. Ow, D. R. Green, Z. Hao, and T. W. Mak, Nat. Rev. Mol. Cell. Biol. 9, 532 (2008).

    Google Scholar 

  27. A. Oberst, C. Bender, and D. R. Green, Cell Death Differ. 15, 1139 (2008).

    Google Scholar 

  28. H-X. Zhou, S. T. Wlodek, and J. A. McCammon, Proc. Natl. Acad. Sci. U. S. A. 95, 9280 (1998).

    ADS  Google Scholar 

  29. H.-X. Zhou and J. A. McCammon, Trends Biochem. Sci. 35, 179.10.007 (2010).

  30. F. M. Raushel, J. B. Thoden, and H. M. Holden, Acc. Chem. Res. 36, 539 (2003).

    Google Scholar 

  31. N. K. Nagradova, FEBS Lett. 487, 327 (2001).

    Google Scholar 

  32. N. Nagradova, IUBMB Life 55, 459 (2003).

    Google Scholar 

  33. S. C. Goodchild, P. M. G. Curmi, and L. J. Brown, Biophys Rev. 3, 143 (2011).

    Google Scholar 

  34. M. A. Sirover, Biochim. Biophys. Acta – Gen. Subj. 1810, 741 (2011).

    Google Scholar 

  35. M. A. Sirover, Cancer Metastasis Rev. 37, 665 (2018).

    Google Scholar 

  36. H. He, M. Lee, L. L. Zheng, et al., Biosci. Rep. 33, e00018 (2013).

    Google Scholar 

  37. M. R. White and E. D. Garcin, Subcell. Biochem. 83, 413 (2017).

    Google Scholar 

  38. V. M. Boradia, M. Raje, and C. I. Raje, Biochem. Soc. Trans. 42, 1796 (2014).

    Google Scholar 

  39. M. Schneider, J. Knuesting, O. Birkholz, et al., BMC Plant Biol. 18, 184 (2018).

    Google Scholar 

  40. T. Hildebrandt, J. Knuesting, C. Berndt, et al., Biol. Chem. 396, 523 (2015).

    Google Scholar 

  41. M. A. Sirover, J. Biochem. Cell Biol. 57, 20 (2014).

    Google Scholar 

  42. P. S. Knoepfler, Cancer Res. 67, 5061 (2007).

    Google Scholar 

  43. M. Fisher, Oncogen 36, 3943 (2017).

    Google Scholar 

  44. M. G. Myers, Science 323, 723 (2009).

    Google Scholar 

  45. A. Subramaniam, M. K. Shanmugam, E. Perumal, et al., Biochim. Biophys. Acta 1835, 46 (2013).

    Google Scholar 

  46. J. Sgrignani, M. Garofalo, M. Matkovic, et al., Int. J. Mol. Sci. 19, E1591 (2018). https://doi.org/10.3390/ijms19061591

    Article  Google Scholar 

  47. B. T. MacDonald, K. Tamai, and X. He, Dev. Cell 17, 9 (2009).

    Google Scholar 

  48. Y. Xing, K. Takemaru, J. Liu, et al., Structure 16, 478 (2008).

    Google Scholar 

  49. C. J. Gottardi and M. Peifer, Structure 16, 336 (2008).

    Google Scholar 

  50. M. Napoli and E. R. Flores. Br. J. Cancer 116, 149 (2017).

    Google Scholar 

  51. V. Marcel, F. Nguyen Van Long, and J. J. Diaz, Cancers (Basel) 10, E152 (2018).

    Google Scholar 

  52. F. M. Simabuco, M. G. Morale, I. C. B. Pavan, et al., Oncotarget 9, 23780 (2018).

    Google Scholar 

  53. K. D. Sullivan, M. D. Galbraith, Z. Andrysik, and J. M. Espinosa, Cell Death Differ. 25, 133 (2018).

    Google Scholar 

  54. B. J. Aubrey, G. L. Kelly, A. Janic, et al., Cell Death Differ. 25, 104 (2018).

    Google Scholar 

  55. S. Nicolai, A. Rossi, N. Di Daniele, et al., Aging (NY) 7, 1050 (2015).

    Google Scholar 

  56. L. J. Hofseth, S. P. Hussain, and C. C. Harris, Trends Pharmacol. Sci. 25, 177 (2004).

    Google Scholar 

  57. C. Culmsee and M. P. Mattson, Biochem. Biophys. Res. Commun. 331, 761 (2005).

    Google Scholar 

  58. C. Wan, X. Ma, S. Shi, et al., Toxicol. Appl. Pharmacol. 281, 294 (2014).

    Google Scholar 

  59. D. B. Wang, C. Kinoshita, Y. Kinoshita, and R. S.Morrison, Biochim. Biophys. Acta 1842, 1186 (2014).

    Google Scholar 

  60. Q. Dai, T. T. Luo, S. C. Luo, et al., J. Bioenerg. Biomembr. 48, 337 (2016)

    Google Scholar 

  61. E. Aberg, F. Saccoccia, M. Grabherr, et al., BMC Evol. Biol. 17, 177 (2017).

    Google Scholar 

  62. A. C. Joerger and A. R. Fersht, Annu. Rev. Biochem. 85, 375 (2016).

    Google Scholar 

  63. V. Gottifredi and C. Prives, Science 292, 1851 (2001).

    Google Scholar 

  64. P. Bonini, S. Cicconi, A. Cardinale, et al., J. Neurosci. Res. 75, 83 (2004).

    Google Scholar 

  65. S. Rashi-Elkeles, R. Elkon, S. Shavit, et al., Mol. Oncol. 5, 336 (2011).

    Google Scholar 

  66. R. Parlato and G. Kreiner, J. Mol. Med. (Berl.) 91, 541 (2013).

    Google Scholar 

  67. S. J. Woods, K. M. Hannan, R. B. Pearson, and R. D. Hannan, Biochim. Biophys. Acta – Gene Regul. Mech. 1849, 821 (2015).

    Google Scholar 

  68. M. Kitayner, H. Rozenberg, N. Kessler, et al., Mol. Cell. 22, 741 (2006).

    Google Scholar 

  69. E. Fadda and M. G. Nixon, Phys. Chem. Chem. Phys. 19, 21287 (2017).

    Google Scholar 

  70. A. C. Joerger and A. R. Fersht, Cold Spring Harb. Perspect. Biol. 2, a000919 (2010). https://doi.org/10.1101/cshperspect.a000919

    Article  Google Scholar 

  71. A. C. Joerger and A. R. Fersht, Annu. Rev. Biochem. 77, 557 (2008).

    Google Scholar 

  72. Y. Pan and R. Nussinov, J. Biol. Chem. 282, 691(2007).

    Google Scholar 

  73. Y. S. Tan, Y. Mhoumad, and C. S. Verma. J. Mol. Cell Biol. 11, 306 (2019).

    Google Scholar 

  74. Y. Pan and R. Nussino, J. Mol. Recognit. 23, 232 (2010).

    Google Scholar 

  75. K. McKinney, M. Mattia, V. Gottifredi, and C. Prives, Mol. Cell. 16, 413 (2004).

    Google Scholar 

  76. A. Tafvizi, F. Huang, A. R. Fersht, et al., Proc. Natl. Acad. Sci. U. S. A. 108, 563 (2011).

    ADS  Google Scholar 

  77. A. Murata, Y. Itoh, E. Mano, et al., Biophys. J. 112, 2301 (2017).

    ADS  Google Scholar 

  78. N. E. Lidor, Y. Field, Y. Lubling, et al., Genome Res. 20, 1361 (2010).

    Google Scholar 

  79. F. Cui and V. B. Zhurkin, Nucleic Acids Res. 42, 836 (2014).

    Google Scholar 

  80. Y. Pan, C. J. Tsai, B. Ma, and R. Nussinov, Trends Genet. 26, 75 (2010).

    Google Scholar 

  81. J. Liu, N. B. Perumal, C. J. Oldfield, et al., Biochemistry 45, 6873 (2006).

    Google Scholar 

  82. J. P. Kruse and W. Gu, Cell 137, 609 (2009).

    Google Scholar 

  83. S. D. Copley, Biochem. Soc. Trans. 42, 1684 (2014).

    Google Scholar 

  84. W. Lu, V.I. Gelfand. Trends Cell Biol. 27, 505 (2017).

    Google Scholar 

  85. B. Henderson, Biochem. Soc. Trans. 42, 1720 (2014).

    Google Scholar 

  86. C. Gancedo, C. L. Flores, and J. M. Gancedo, Biochem. Soc. Trans. 42, 1715 (2014).

    Google Scholar 

  87. M. A. Fares, Biochem. Soc. Trans. 42, 1709. (2014).

    Google Scholar 

  88. C. E. Chapple, B. Robisson, L. Spinelli, et al., Nat. Commun. 6, 7412 (2015).

    ADS  Google Scholar 

  89. G. Hu, Z. Wu, V. N. Uversky, and L. Kurgan, Int. J. Mol. Sci. 18, 2761 (2017).

    Google Scholar 

  90. L. M. Iakoucheva, C. J. Brown, J. D. Lawson, et al., J. Mol. Biol. 323, 573 (2002)

    Google Scholar 

  91. R. van der Lee, M. Buljan, B. Lang, et al., Chem. Rev. 114, 6589 (2014).

    Google Scholar 

  92. N. S. Latysheva, T. Flock, R. J. Weatheritt, et al., Prot. Sci. 24, 909 (2015).

    Google Scholar 

  93. A. Balcerak, A. Trebinska-Stryjewska, R. Konopinski, et al., Open Biol. 9,190096 (2019). https://doi.org/10.1098/rsob.190096

    Article  Google Scholar 

  94. E. A. Lemke, J. Mol. Biol. 428 (10, Pt. A), 2011 (2016).

    Google Scholar 

  95. N. N. Sluchanko and D. M. Bustos. Prog. Mol. Biol. Transl. Sci. 166, 19 (2019).

    Google Scholar 

  96. A. Zanzoni, D. M. Ribeiro, and C. Brun, Cell Mol. Life Sci. 76, 4407 (2019).

    Google Scholar 

  97. R. J. Weatheritt, N. E. Davey, and T. J. Gibson, Nucleic Acids Res. 40, 7123 (2012).

    Google Scholar 

  98. K. Van Roey, B. Uyar, R. J. Weatheritt, et al., Chem. Rev. 114, 6733 (2014).

    Google Scholar 

Download references

Funding

The work was supported by the Ministry of Science and Higher Education of Russian Federation (grant 0852-2020-0028).

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neurobiology, Academy of Biology and Biotechnology, Southern Federal University, 344090, Rostov-on-Don, Russia

    A. B. Uzdensky

Authors
  1. A. B. Uzdensky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. B. Uzdensky.

Additional information

Abbreviations: P—platform; PTM—posttranslational modification; E—enzyme; Apaf-1—Apoptotic protease-activating factor 1; CTD—C-terminal domain; DBD—DNA-binding domain; GAPDH—glyceraldehyde-6-phosphate dehydrogenase; IDR—intrinsically disordered region; MLP—moonlighting proteins; NLS—nuclear localization sequence; p53RE— p53-response element; SLiM—short linear motif; SNP—single nucleotide polymorphism; STAT3—signal transducer and activator of transcription 3; TAD—transactivation domain; TET— tetramerization domain.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Uzdensky, A.B. Multifunctional Proteins. BIOPHYSICS 65, 390–403 (2020). https://doi.org/10.1134/S0006350920030227

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006350920030227

Keywords:

Search

Navigation