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Moonlighting enzymes: when cellular context defines specificity

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Abstract

It is not often realized that the absolute protein specificity is an exception rather than a rule. Two major kinds of protein multi-specificities are promiscuity and moonlighting. This review discusses the idea of enzyme specificity and then focusses on moonlighting. Some important examples of protein moonlighting, such as crystallins, ceruloplasmin, metallothioniens, macrophage migration inhibitory factor, and enzymes of carbohydrate metabolism are discussed. How protein plasticity and intrinsic disorder enable the removing the distinction between enzymes and other biologically active proteins are outlined. Finally, information on important roles of moonlighting in human diseases is updated.

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References

  1. Gupta MN, Kapoor M, Majumder AB, Singh V (2011) Isozymes, moonlighting proteins and promiscous enzymes. Curr Sci 100:1152–1162

  2. Gupta MN, Alam A, Hasnain SE (2020) Protein promiscuity in drug discovery, drug-repurposing and antibiotic resistance. Biochimie 175:50–57. https://doi.org/10.1016/j.biochi.2020.05.004

    Article  CAS  PubMed  Google Scholar 

  3. Copley SD (2003) Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr Opin Chem Biol 7(2):265–272. https://doi.org/10.1016/s1367-5931(03)00032-2

    Article  CAS  PubMed  Google Scholar 

  4. Jeffery CJ (1999) Moonlighting proteins. Trends Biochem Sci 24(1):8–11. https://doi.org/10.1016/s0968-0004(98)01335-8

    Article  CAS  PubMed  Google Scholar 

  5. Prabantu VM, Yazhini A, Srinivasan N (2020) Manoeuvring protein functions and functional levels by structural excursions. Phenotypic switching. Elsevier, Amsterdam, pp 77–104

    Chapter  Google Scholar 

  6. Jeffery CJ (2019) An enzyme in the test tube, and a transcription factor in the cell: moonlighting proteins and cellular factors that affect their behavior. Protein Sci 28(7):1233–1238. https://doi.org/10.1002/pro.3645

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jeffery CJ (2003) Moonlighting proteins: old proteins learning new tricks. Trends Genet 19(8):415–417. https://doi.org/10.1016/S0168-9525(03)00167-7

    Article  CAS  PubMed  Google Scholar 

  8. Jeffery CJ (2004) Moonlighting proteins: complications and implications for proteomics research. Drug Discovery Today Targets 3(2):71–78

    Article  CAS  Google Scholar 

  9. Moore B (2004) Bifunctional and moonlighting enzymes: lighting the way to regulatory control. Trends Plant Sci 9(5):221–228. https://doi.org/10.1016/j.tplants.2004.03.005

    Article  CAS  PubMed  Google Scholar 

  10. Gancedo C, Flores CL (2008) Moonlighting proteins in yeasts. Microbiol Mol Biol Rev 72(1):197–210. https://doi.org/10.1128/MMBR.00036-07. (table of contents)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huberts DH, van der Klei IJ (2010) Moonlighting proteins: an intriguing mode of multitasking. Biochim Biophys Acta 1803(4):520–525. https://doi.org/10.1016/j.bbamcr.2010.01.022

    Article  CAS  PubMed  Google Scholar 

  12. Henderson B, Martin A (2011) Bacterial virulence in the moonlight: multitasking bacterial moonlighting proteins are virulence determinants in infectious disease. Infect Immun 79(9):3476–3491. https://doi.org/10.1128/IAI.00179-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Copley SD (2012) Moonlighting is mainstream: paradigm adjustment required. BioEssays 34(7):578–588. https://doi.org/10.1002/bies.201100191

    Article  CAS  PubMed  Google Scholar 

  14. Fares MA (2014) The evolution of protein moonlighting: adaptive traps and promiscuity in the chaperonins. Biochem Soc Trans 42(6):1709–1714. https://doi.org/10.1042/BST20140225

    Article  CAS  PubMed  Google Scholar 

  15. Fuxe K, Borroto-Escuela DO, Romero-Fernandez W, Palkovits M, Tarakanov AO, Ciruela F, Agnati LF (2014) Moonlighting proteins and protein-protein interactions as neurotherapeutic targets in the G protein-coupled receptor field. Neuropsychopharmacology 39(1):131–155. https://doi.org/10.1038/npp.2013.242

    Article  CAS  PubMed  Google Scholar 

  16. Ginger ML (2014) Protein moonlighting in parasitic protists. Biochem Soc Trans 42(6):1734–1739. https://doi.org/10.1042/BST20140215

    Article  CAS  PubMed  Google Scholar 

  17. Karkowska-Kuleta J, Kozik A (2014) Moonlighting proteins as virulence factors of pathogenic fungi, parasitic protozoa and multicellular parasites. Mol Oral Microbiol 29(6):270–283. https://doi.org/10.1111/omi.12078

    Article  CAS  PubMed  Google Scholar 

  18. Khan IK, Kihara D (2014) Computational characterization of moonlighting proteins. Biochem Soc Trans 42(6):1780–1785. https://doi.org/10.1042/BST20140214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang G, Xia Y, Cui J, Gu Z, Song Y, Chen YQ, Chen H, Zhang H, Chen W (2014) The roles of moonlighting proteins in bacteria. Curr Issues Mol Biol 16:15–22

    PubMed  Google Scholar 

  20. Espinosa-Cantu A, Ascencio D, Barona-Gomez F, DeLuna A (2015) Gene duplication and the evolution of moonlighting proteins. Front Genet 6:227. https://doi.org/10.3389/fgene.2015.00227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Min KW, Lee SH, Baek SJ (2016) Moonlighting proteins in cancer. Cancer Lett 370(1):108–116. https://doi.org/10.1016/j.canlet.2015.09.022

    Article  CAS  PubMed  Google Scholar 

  22. Jeffery CJ (2016) Protein species and moonlighting proteins: Very small changes in a protein’s covalent structure can change its biochemical function. J Proteomics 134:19–24. https://doi.org/10.1016/j.jprot.2015.10.003

    Article  CAS  PubMed  Google Scholar 

  23. Gupta MN, Uversky VN (2023) Role of plasticity and disorder in protein moonlighting: blurring of lines between biocatalysts and other biologically active proteins. Structure and intrinsic disorder in enzymology. Elsevier, Amsterdam, pp 279–301

    Chapter  Google Scholar 

  24. Singh N, Bhalla N (2020) Moonlighting proteins. Annu Rev Genet 54:265–285. https://doi.org/10.1146/annurev-genet-030620-102906

    Article  CAS  PubMed  Google Scholar 

  25. Kapoor M, Gupta MN (2012) Lipase promiscuity and its biochemical applications. Process Biochem 47(4):555–569

    Article  CAS  Google Scholar 

  26. Gupta MN, Uversky VN (2023) The various facets of protein promiscuity: not just broad specificity of proteins. Structure and intrinsic disorder in enzymology. Elsevier, Amsterdam, pp 241–277

    Chapter  Google Scholar 

  27. Khersonsky O, Tawfik DS (2010) Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem 79:471–505. https://doi.org/10.1146/annurev-biochem-030409-143718

    Article  CAS  PubMed  Google Scholar 

  28. Nobeli I, Favia AD, Thornton JM (2009) Protein promiscuity and its implications for biotechnology. Nat Biotechnol 27(2):157–167. https://doi.org/10.1038/nbt1519

    Article  CAS  PubMed  Google Scholar 

  29. Jia B, Cheong GW, Zhang S (2013) Multifunctional enzymes in archaea: promiscuity and moonlight. Extremophiles 17(2):193–203. https://doi.org/10.1007/s00792-012-0509-1

    Article  CAS  PubMed  Google Scholar 

  30. Piatigorsky J (2007) Gene sharing and evolution: the diversity of protein functions. Harvard University Press, Cambridge

    Book  Google Scholar 

  31. Piatigorsky J, Wistow GJ (1989) Enzyme/crystallins: gene sharing as an evolutionary strategy. Cell 57(2):197–199. https://doi.org/10.1016/0092-8674(89)90956-2

    Article  CAS  PubMed  Google Scholar 

  32. Jeffery CJ (2003) Multifunctional proteins: examples of gene sharing. Ann Med 35(1):28–35. https://doi.org/10.1080/07853890310004101

    Article  CAS  PubMed  Google Scholar 

  33. Jeffery CJ (2004) Molecular mechanisms for multitasking: recent crystal structures of moonlighting proteins. Curr Opin Struct Biol 14(6):663–668. https://doi.org/10.1016/j.sbi.2004.10.001

    Article  CAS  PubMed  Google Scholar 

  34. Jeffery CJ (2005) Mass spectrometry and the search for moonlighting proteins. Mass Spectrom Rev 24(6):772–782. https://doi.org/10.1002/mas.20041

    Article  CAS  PubMed  Google Scholar 

  35. Jeffery CJ (2005) Moonlighting proteins: proteins with multiple functions. Molecular chaperones and cell signalling. Cambridge University Press, Cambridge, pp 61–77

    Google Scholar 

  36. Jeffery CJ (2009) Moonlighting proteins—an update. Mol Biosyst 5(4):345–350. https://doi.org/10.1039/b900658n

    Article  CAS  PubMed  Google Scholar 

  37. Jeffery CJ (2011) Proteins with neomorphic moonlighting functions in disease. IUBMB Life 63(7):489–494. https://doi.org/10.1002/iub.504

    Article  CAS  PubMed  Google Scholar 

  38. Jeffery CJ (2014) An introduction to protein moonlighting. Biochem Soc Trans 42(6):1679–1683. https://doi.org/10.1042/BST20140226

    Article  CAS  PubMed  Google Scholar 

  39. Amblee V, Jeffery CJ (2015) Physical features of intracellular proteins that moonlight on the cell surface. PLoS ONE 10(6):e0130575. https://doi.org/10.1371/journal.pone.0130575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jeffery CJ (2015) Why study moonlighting proteins? Front Genet 6:211. https://doi.org/10.3389/fgene.2015.00211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang W, Jeffery CJ (2016) An analysis of surface proteomics results reveals novel candidates for intracellular/surface moonlighting proteins in bacteria. Mol Biosyst 12(5):1420–1431. https://doi.org/10.1039/c5mb00550g

    Article  CAS  PubMed  Google Scholar 

  42. Jeffery CJ (2017) Moonlighting proteins—nature’s Swiss army knives. Sci Prog 100(4):363–373. https://doi.org/10.3184/003685017X15063357842574

    Article  CAS  PubMed  Google Scholar 

  43. Jeffery CJ (2018) Protein moonlighting: what is it, and why is it important? Philos Trans R Soc Lond B Biol Sci. https://doi.org/10.1098/rstb.2016.0523

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jeffery CJ (2018) Protein moonlighting: what is it, and why is it important? Philos Trans R Soc B Biol Sci 373(1738):20160523

    Article  Google Scholar 

  45. Jeffery CJ (2019) Multitalented actors inside and outside the cell: recent discoveries add to the number of moonlighting proteins. Biochem Soc Trans 47(6):1941–1948. https://doi.org/10.1042/BST20190798

    Article  CAS  PubMed  Google Scholar 

  46. Jeffery CJ (2019) Intracellular/surface moonlighting proteins that aid in the attachment of gut microbiota to the host. AIMS Microbiol 5(1):77–86. https://doi.org/10.3934/microbiol.2019.1.77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jeffery CJ (2020) Enzymes, pseudoenzymes, and moonlighting proteins: diversity of function in protein superfamilies. FEBS J 287(19):4141–4149. https://doi.org/10.1111/febs.15446

    Article  CAS  PubMed  Google Scholar 

  48. Liu H, Jeffery CJ (2020) Moonlighting proteins in the fuzzy logic of cellular metabolism. Molecules. https://doi.org/10.3390/molecules25153440

    Article  PubMed  PubMed Central  Google Scholar 

  49. Curtis NJ, Jeffery CJ (2021) The expanding world of metabolic enzymes moonlighting as RNA binding proteins. Biochem Soc Trans 49(3):1099–1108. https://doi.org/10.1042/BST20200664

    Article  CAS  PubMed  Google Scholar 

  50. Radisky DC, Stallings-Mann M, Hirai Y, Bissell MJ (2009) Single proteins might have dual but related functions in intracellular and extracellular microenvironments. Nat Rev Mol Cell Biol 10(3):228–234. https://doi.org/10.1038/nrm2633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jeffery CJ, Bahnson BJ, Chien W, Ringe D, Petsko GA (2000) Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that moonlights as neuroleukin, autocrine motility factor, and differentiation mediator. Biochemistry 39(5):955–964. https://doi.org/10.1021/bi991604m

    Article  CAS  PubMed  Google Scholar 

  52. Sirover MA (2012) Subcellular dynamics of multifunctional protein regulation: mechanisms of GAPDH intracellular translocation. J Cell Biochem 113(7):2193–2200. https://doi.org/10.1002/jcb.24113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang Q, Raje V, Yakovlev VA, Yacoub A, Szczepanek K, Meier J, Derecka M, Chen Q, Hu Y, Sisler J, Hamed H, Lesnefsky EJ, Valerie K, Dent P, Larner AC (2013) Mitochondrial localized Stat3 promotes breast cancer growth via phosphorylation of serine 727. J Biol Chem 288(43):31280–31288. https://doi.org/10.1074/jbc.M113.505057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhang Y, Sampathkumar A, Kerber SM, Swart C, Hille C, Seerangan K, Graf A, Sweetlove L, Fernie AR (2020) A moonlighting role for enzymes of glycolysis in the co-localization of mitochondria and chloroplasts. Nat Commun 11(1):4509. https://doi.org/10.1038/s41467-020-18234-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Commichau FM, Stulke J (2008) Trigger enzymes: bifunctional proteins active in metabolism and in controlling gene expression. Mol Microbiol 67(4):692–702. https://doi.org/10.1111/j.1365-2958.2007.06071.x

    Article  CAS  PubMed  Google Scholar 

  56. Cheng XY, Huang WJ, Hu SC, Zhang HL, Wang H, Zhang JX, Lin HH, Chen YZ, Zou Q, Ji ZL (2012) A global characterization and identification of multifunctional enzymes. PLoS ONE 7(6):e38979. https://doi.org/10.1371/journal.pone.0038979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Jiang CJ, Chen G, Huang J, Huang Q, Jin K, Shen PH, Li JF, Wu B (2011) A novel beta-glucosidase with lipolytic activity from a soil metagenome. Folia Microbiol (Praha) 56(6):563–570. https://doi.org/10.1007/s12223-011-0083-4

    Article  CAS  PubMed  Google Scholar 

  58. Shirafkan F, Gharaghani S, Rahimian K, Sajedi RH, Zahiri J (2021) Moonlighting protein prediction using physico-chemical and evolutional properties via machine learning methods. BMC Bioinform 22(1):261. https://doi.org/10.1186/s12859-021-04194-5

    Article  CAS  Google Scholar 

  59. Li Y, Zhao J, Liu Z, Wang C, Wei L, Han S, Du W (2021) De novo prediction of moonlighting proteins using multimodal deep ensemble learning. Front Genet 12:630379. https://doi.org/10.3389/fgene.2021.630379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fischer E (1894) Einfluss der configuration auf die wirkung derenzyme. Ber Dt Chem Ges 27:2985–2993

    Article  CAS  Google Scholar 

  61. Fersht AR (1985) Enzyme structure and mechanism, 2nd edn. W H Freeman and Co, New York

    Google Scholar 

  62. Szwajkajzer D, Carey J (1997) Molecular and biological constraints on ligand-binding affinity and specificity. Biopolymers 44(2):181–198. https://doi.org/10.1002/(SICI)1097-0282(1997)44:2%3c181::AID-BIP5%3e3.0.CO;2-R

    Article  CAS  PubMed  Google Scholar 

  63. Greenspan NS (2010) Cohen’s Conjecture, Howard’s Hypothesis, and Ptashne’s Ptruth: an exploration of the relationship between affinity and specificity. Trends Immunol 31(4):138–143. https://doi.org/10.1016/j.it.2010.01.001

    Article  CAS  PubMed  Google Scholar 

  64. Mammen M, Choi SK, Whitesides GM (1998) Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed Engl 37(20):2754–2794. https://doi.org/10.1002/(SICI)1521-3773(19981102)37:20%3c2754::AID-ANIE2754%3e3.0.CO;2-3

    Article  PubMed  Google Scholar 

  65. Kuznetsova IM, Zaslavsky BY, Breydo L, Turoverov KK, Uversky VN (2015) Beyond the excluded volume effects: mechanistic complexity of the crowded milieu. Molecules 20(1):1377–1409. https://doi.org/10.3390/molecules20011377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kuznetsova IM, Turoverov KK, Uversky VN (2014) What macromolecular crowding can do to a protein. Int J Mol Sci 15(12):23090–23140. https://doi.org/10.3390/ijms151223090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gupta MN, Uversky VN (2023) Macromolecular crowding: how it affects protein structure, disorder, and catalysis. Structure and intrinsic disorder in enzymology. Elsevier, Amsterdam, pp 353–376

    Chapter  Google Scholar 

  68. Schreiber G, Keating AE (2011) Protein binding specificity versus promiscuity. Curr Opin Struct Biol 21(1):50–61. https://doi.org/10.1016/j.sbi.2010.10.002

    Article  CAS  PubMed  Google Scholar 

  69. Alejo JL, Kempes CP, Adamala KP (2022) Diffusion control in biochemical specificity. Biophys J 121(8):1541–1548. https://doi.org/10.1016/j.bpj.2022.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ketudat Cairns JR, Mahong B, Baiya S, Jeon JS (2015) beta-Glucosidases: multitasking, moonlighting or simply misunderstood? Plant Sci 241:246–259. https://doi.org/10.1016/j.plantsci.2015.10.014

    Article  CAS  PubMed  Google Scholar 

  71. Peracchi A (2018) The limits of enzyme specificity and the evolution of metabolism. Trends Biochem Sci 43(12):984–996. https://doi.org/10.1016/j.tibs.2018.09.015

    Article  CAS  PubMed  Google Scholar 

  72. Tawfik DS (2014) Accuracy-rate tradeoffs: how do enzymes meet demands of selectivity and catalytic efficiency? Curr Opin Chem Biol 21:73–80. https://doi.org/10.1016/j.cbpa.2014.05.008

    Article  CAS  PubMed  Google Scholar 

  73. Goldsmith M, Tawfik DS (2017) Enzyme engineering: reaching the maximal catalytic efficiency peak. Curr Opin Struct Biol 47:140–150. https://doi.org/10.1016/j.sbi.2017.09.002

    Article  CAS  PubMed  Google Scholar 

  74. Pauling L (1957) The probability of errors in the process of synthesis of protein molecules. Festschrift fur Prof. Dr. Arthur Stoll. Birkhauser Verlag, Basel, pp 597–602

    Google Scholar 

  75. Gupta MN (1992) Enzyme function in organic solvents. Eur J Biochem 203(1–2):25–32. https://doi.org/10.1111/j.1432-1033.1992.tb19823.x

    Article  CAS  PubMed  Google Scholar 

  76. Braco L, Dabulis K, Klibanov AM (1990) Production of abiotic receptors by molecular imprinting of proteins. Proc Natl Acad Sci USA 87(1):274–277. https://doi.org/10.1073/pnas.87.1.274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Mukherjee J, Gupta MN (2016) Dual bioimprinting of Thermomyces lanuginosus lipase for synthesis of biodiesel. Biotechnol Rep (Amst) 10:38–43. https://doi.org/10.1016/j.btre.2016.02.005

    Article  PubMed  Google Scholar 

  78. Mukherjee J, Gupta MN (2015) Molecular bioimprinting of lipases with surfactants and its functional consequences in low water media. Int J Biol Macromol 81:544–551. https://doi.org/10.1016/j.ijbiomac.2015.08.033

    Article  CAS  PubMed  Google Scholar 

  79. Mukherjee J, Gupta MN (2015) Enhancing the catalytic efficiency of subtilisin for transesterification by dual bioimprinting. Tetrahedron Lett 56(29):4397–4401

    Article  CAS  Google Scholar 

  80. James LC, Tawfik DS (2003) Conformational diversity and protein evolution–a 60-year-old hypothesis revisited. Trends Biochem Sci 28(7):361–368. https://doi.org/10.1016/S0968-0004(03)00135-X

    Article  CAS  PubMed  Google Scholar 

  81. Tokuriki N, Tawfik DS (2009) Protein dynamism and evolvability. Science 324(5924):203–207. https://doi.org/10.1126/science.1169375

    Article  CAS  PubMed  Google Scholar 

  82. Plattner N, Noe F (2015) Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models. Nat Commun 6:7653. https://doi.org/10.1038/ncomms8653

    Article  PubMed  Google Scholar 

  83. Mukherjee J, Gupta MN (2015) Increasing importance of protein flexibility in designing biocatalytic processes. Biotechnol Rep (Amst) 6:119–123. https://doi.org/10.1016/j.btre.2015.04.001

    Article  PubMed  Google Scholar 

  84. Zou T, Risso VA, Gavira JA, Sanchez-Ruiz JM, Ozkan SB (2015) Evolution of conformational dynamics determines the conversion of a promiscuous generalist into a specialist enzyme. Mol Biol Evol 32(1):132–143. https://doi.org/10.1093/molbev/msu281

    Article  CAS  PubMed  Google Scholar 

  85. Sundberg EJ, Mariuzza RA (2000) Luxury accommodations: the expanding role of structural plasticity in protein-protein interactions. Structure 8(7):R137-142. https://doi.org/10.1016/s0969-2126(00)00167-2

    Article  CAS  PubMed  Google Scholar 

  86. DeLano WL, Ultsch MH, de Vos AM, Wells JA (2000) Convergent solutions to binding at a protein-protein interface. Science 287(5456):1279–1283. https://doi.org/10.1126/science.287.5456.1279

    Article  CAS  PubMed  Google Scholar 

  87. Mariuzza RA (2006) Multiple paths to multispecificity. Immunity 24(4):359–361. https://doi.org/10.1016/j.immuni.2006.03.009

    Article  CAS  PubMed  Google Scholar 

  88. Crean RM, Gardner JM, Kamerlin SCL (2020) Harnessing conformational plasticity to generate designer enzymes. J Am Chem Soc 142(26):11324–11342. https://doi.org/10.1021/jacs.0c04924

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Domnauer M, Zheng F, Li L, Zhang Y, Chang CE, Unruh JR, Conkright-Fincham J, McCroskey S, Florens L, Zhang Y, Seidel C, Fong B, Schilling B, Sharma R, Ramanathan A, Si K, Zhou C (2021) Proteome plasticity in response to persistent environmental change. Mol Cell 81(16):3294-3309 e3212. https://doi.org/10.1016/j.molcel.2021.06.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Porter LL, Looger LL (2018) Extant fold-switching proteins are widespread. Proc Natl Acad Sci USA 115(23):5968–5973. https://doi.org/10.1073/pnas.1800168115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Madhurima K, Nandi B, Sekhar A (2021) Metamorphic proteins: the Janus proteins of structural biology. Open Biol 11(4):210012. https://doi.org/10.1098/rsob.210012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lopez-Pelegrin M, Cerda-Costa N, Cintas-Pedrola A, Herranz-Trillo F, Bernado P, Peinado JR, Arolas JL, Gomis-Ruth FX (2014) Multiple stable conformations account for reversible concentration-dependent oligomerization and autoinhibition of a metamorphic metallopeptidase. Angew Chem Int Ed Engl 53(40):10624–10630. https://doi.org/10.1002/anie.201405727

    Article  CAS  PubMed  Google Scholar 

  93. London RE (2019) HIV-1 reverse transcriptase: a metamorphic protein with three stable states. Structure 27(3):420–426. https://doi.org/10.1016/j.str.2018.11.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Majumder AB, Gupta MN (2014) Lipase-catalyzed condensation reaction of 4-nitrobenzaldehyde with acetyl acetone in aqueous-organic cosolvent mixtures and in nearly anhydrous media. Synth Commun 44(6):818–826

    Article  CAS  Google Scholar 

  95. Gupta MN, Uversky VN (2023) Structure and disorder: protein functions depend on this new binary transforming lock-and-key into structure-function continuum. Structure and intrinsic disorder in enzymology. Elsevier, Amsterdam, pp 127–148

    Chapter  Google Scholar 

  96. Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41(3):415–427. https://doi.org/10.1002/1097-0134(20001115)41:3%3c415::aid-prot130%3e3.0.co;2-7

    Article  CAS  PubMed  Google Scholar 

  97. Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001) Intrinsically disordered protein. J Mol Graph Model 19(1):26–59. https://doi.org/10.1016/s1093-3263(00)00138-8

    Article  CAS  PubMed  Google Scholar 

  98. Dunker AK, Obradovic Z (2001) The protein trinity–linking function and disorder. Nat Biotechnol 19(9):805–806. https://doi.org/10.1038/nbt0901-805

    Article  CAS  PubMed  Google Scholar 

  99. Tompa P (2002) Intrinsically unstructured proteins. Trends Biochem Sci 27(10):527–533. https://doi.org/10.1016/s0968-0004(02)02169-2

    Article  CAS  PubMed  Google Scholar 

  100. Uversky VN (2002) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11(4):739–756. https://doi.org/10.1110/ps.4210102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Uversky VN (2002) What does it mean to be natively unfolded? Eur J Biochem 269(1):2–12. https://doi.org/10.1046/j.0014-2956.2001.02649.x

    Article  CAS  PubMed  Google Scholar 

  102. Uversky VN (2003) Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol Life Sci 60(9):1852–1871. https://doi.org/10.1007/s00018-003-3096-6

    Article  CAS  PubMed  Google Scholar 

  103. Dunker AK, Silman I, Uversky VN, Sussman JL (2008) Function and structure of inherently disordered proteins. Curr Opin Struct Biol 18(6):756–764. https://doi.org/10.1016/j.sbi.2008.10.002

    Article  CAS  PubMed  Google Scholar 

  104. Uversky VN, Dunker AK (2010) Understanding protein non-folding. Biochim Biophys Acta 1804(6):1231–1264. https://doi.org/10.1016/j.bbapap.2010.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Uversky VN (2013) Unusual biophysics of intrinsically disordered proteins. Biochim Biophys Acta 1834(5):932–951. https://doi.org/10.1016/j.bbapap.2012.12.008

    Article  CAS  PubMed  Google Scholar 

  106. van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM, Kriwacki RW, Oldfield CJ, Pappu RV, Tompa P, Uversky VN, Wright PE, Babu MM (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114(13):6589–6631. https://doi.org/10.1021/cr400525m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Oldfield CJ, Cheng Y, Cortese MS, Romero P, Uversky VN, Dunker AK (2005) Coupled folding and binding with alpha-helix-forming molecular recognition elements. Biochemistry 44(37):12454–12470. https://doi.org/10.1021/bi050736e

    Article  CAS  PubMed  Google Scholar 

  108. Mohan A, Oldfield CJ, Radivojac P, Vacic V, Cortese MS, Dunker AK, Uversky VN (2006) Analysis of molecular recognition features (MoRFs). J Mol Biol 362(5):1043–1059. https://doi.org/10.1016/j.jmb.2006.07.087

    Article  CAS  PubMed  Google Scholar 

  109. Cheng Y, Oldfield CJ, Meng J, Romero P, Uversky VN, Dunker AK (2007) Mining alpha-helix-forming molecular recognition features with cross species sequence alignments. Biochemistry 46(47):13468–13477. https://doi.org/10.1021/bi7012273

    Article  CAS  PubMed  Google Scholar 

  110. Vacic V, Oldfield CJ, Mohan A, Radivojac P, Cortese MS, Uversky VN, Dunker AK (2007) Characterization of molecular recognition features, MoRFs, and their binding partners. J Proteome Res 6(6):2351–2366. https://doi.org/10.1021/pr0701411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tompa P, Fuxreiter M, Oldfield CJ, Simon I, Dunker AK, Uversky VN (2009) Close encounters of the third kind: disordered domains and the interactions of proteins. BioEssays 31(3):328–335. https://doi.org/10.1002/bies.200800151

    Article  CAS  PubMed  Google Scholar 

  112. Hsu WL, Oldfield C, Meng J, Huang F, Xue B, Uversky VN, Romero P, Dunker AK (2012) Intrinsic protein disorder and protein-protein interactions. Pac Symp Biocomput:116–127 https://doi.org/10.1142/9789814366496_0012

  113. Uversky VN (2015) Functional roles of transiently and intrinsically disordered regions within proteins. FEBS J 282(7):1182–1189. https://doi.org/10.1111/febs.13202

    Article  CAS  PubMed  Google Scholar 

  114. Alterovitz WL, Faraggi E, Oldfield CJ, Meng J, Xue B, Huang F, Romero P, Kloczkowski A, Uversky VN, Dunker AK (2020) Many-to-one binding by intrinsically disordered protein regions. Pac Symp Biocomput 25:159–170

    PubMed  Google Scholar 

  115. Dunker AK, Garner E, Guilliot S, Romero P, Albrecht K, Hart J, Obradovic Z, Kissinger C, Villafranca JE (1998) Protein disorder and the evolution of molecular recognition: theory, predictions and observations. Pac Symp Biocomput:473–484

  116. Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293(2):321–331. https://doi.org/10.1006/jmbi.1999.3110

    Article  CAS  PubMed  Google Scholar 

  117. Wright PE, Dyson HJ (2015) Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol 16(1):18–29. https://doi.org/10.1038/nrm3920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Borgia A, Borgia MB, Bugge K, Kissling VM, Heidarsson PO, Fernandes CB, Sottini A, Soranno A, Buholzer KJ, Nettels D, Kragelund BB, Best RB, Schuler B (2018) Extreme disorder in an ultrahigh-affinity protein complex. Nature 555(7694):61–66. https://doi.org/10.1038/nature25762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Uversky VN (2019) Intrinsically disordered proteins and their “mysterious”(meta) physics. Front Phys 7:10

    Article  Google Scholar 

  120. Uversky VN, Dunker AK (2013) The case for intrinsically disordered proteins playing contributory roles in molecular recognition without a stable 3D structure. F1000 Biol Rep 5:1. https://doi.org/10.3410/B5-1

    Article  PubMed  PubMed Central  Google Scholar 

  121. Uversky VN (2013) A decade and a half of protein intrinsic disorder: biology still waits for physics. Protein Sci 22(6):693–724. https://doi.org/10.1002/pro.2261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Jakob U, Kriwacki R, Uversky VN (2014) Conditionally and transiently disordered proteins: awakening cryptic disorder to regulate protein function. Chem Rev 114(13):6779–6805. https://doi.org/10.1021/cr400459c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chapple CE, Robisson B, Spinelli L, Guien C, Becker E, Brun C (2015) Extreme multifunctional proteins identified from a human protein interaction network. Nat Commun 6:7412. https://doi.org/10.1038/ncomms8412

    Article  PubMed  Google Scholar 

  124. Hernandez S, Amela I, Cedano J, Piñol J, Perez-Pons JA, Mozo-Villarias A, Querol E (2012) Do moonlighting proteins belong to the intrinsically disordered protein class? J Proteom Bioinform 5(11):262–264

    Article  CAS  Google Scholar 

  125. Tompa P, Szasz C, Buday L (2005) Structural disorder throws new light on moonlighting. Trends Biochem Sci 30(9):484–489. https://doi.org/10.1016/j.tibs.2005.07.008

    Article  CAS  PubMed  Google Scholar 

  126. Uversky VN (2016) p53 proteoforms and intrinsic disorder: an illustration of the protein structure-function continuum concept. Int J Mol Sci. https://doi.org/10.3390/ijms17111874

    Article  PubMed  PubMed Central  Google Scholar 

  127. Rajagopalan K, Mooney SM, Parekh N, Getzenberg RH, Kulkarni P (2011) A majority of the cancer/testis antigens are intrinsically disordered proteins. J Cell Biochem 112(11):3256–3267. https://doi.org/10.1002/jcb.23252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wool IG (1996) Extraribosomal functions of ribosomal proteins. Trends Biochem Sci 21(5):164–165

    Article  CAS  PubMed  Google Scholar 

  129. Chavez-Rios R, Arias-Romero LE, Almaraz-Barrera Mde J, Hernandez-Rivas R, Guillen N, Vargas M (2003) L10 ribosomal protein from Entamoeba histolytica share structural and functional homologies with QM/Jif-1: proteins with extraribosomal functions. Mol Biochem Parasitol 127(2):151–160. https://doi.org/10.1016/s0166-6851(02)00332-8

    Article  CAS  PubMed  Google Scholar 

  130. Warner JR, McIntosh KB (2009) How common are extraribosomal functions of ribosomal proteins? Mol Cell 34(1):3–11. https://doi.org/10.1016/j.molcel.2009.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Aseev LV, Boni IV (2011) Extraribosomal functions of bacterial ribosomal proteins. Mol Biol (Mosk) 45(5):805–816

    Article  CAS  PubMed  Google Scholar 

  132. Lu H, Zhu YF, Xiong J, Wang R, Jia Z (2015) Potential extra-ribosomal functions of ribosomal proteins in Saccharomyces cerevisiae. Microbiol Res 177:28–33. https://doi.org/10.1016/j.micres.2015.05.004

    Article  CAS  PubMed  Google Scholar 

  133. Xiong W, Lan T, Mo B (2021) Extraribosomal functions of cytosolic ribosomal proteins in plants. Front Plant Sci 12:607157. https://doi.org/10.3389/fpls.2021.607157

    Article  PubMed  PubMed Central  Google Scholar 

  134. Peng Z, Oldfield CJ, Xue B, Mizianty MJ, Dunker AK, Kurgan L, Uversky VN (2014) A creature with a hundred waggly tails: intrinsically disordered proteins in the ribosome. Cell Mol Life Sci 71(8):1477–1504. https://doi.org/10.1007/s00018-013-1446-6

    Article  CAS  PubMed  Google Scholar 

  135. Hurtado-Rios JJ, Carrasco-Navarro U, Almanza-Perez JC, Ponce-Alquicira E (2022) Ribosomes: the new role of ribosomal proteins as natural antimicrobials. Int J Mol Sci. https://doi.org/10.3390/ijms23169123

    Article  PubMed  PubMed Central  Google Scholar 

  136. Balcerak A, Trebinska-Stryjewska A, Konopinski R, Wakula M, Grzybowska EA (2019) RNA-protein interactions: disorder, moonlighting and junk contribute to eukaryotic complexity. Open Biol 9(6):190096. https://doi.org/10.1098/rsob.190096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Ottoz DSM, Berchowitz LE (2020) The role of disorder in RNA binding affinity and specificity. Open Biol 10(12):200328. https://doi.org/10.1098/rsob.200328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Meng F, Kurgan L (2018) High-throughput prediction of disordered moonlighting regions in protein sequences. Proteins 86(10):1097–1110. https://doi.org/10.1002/prot.25590

    Article  CAS  PubMed  Google Scholar 

  139. Moore BE, Perez VJ (1967) Specific acidic proteino of the nervous system. In: Carlson FD (ed) Physiological and biochemical aspects of nervous integration. Prentice-Hall, Englewood Cliffs, pp 343–359

    Google Scholar 

  140. Mhawech P (2005) 14–3-3 proteins–an update. Cell Res 15(4):228–236. https://doi.org/10.1038/sj.cr.7290291

    Article  CAS  PubMed  Google Scholar 

  141. Bustos DM, Iglesias AA (2006) Intrinsic disorder is a key characteristic in partners that bind 14–3-3 proteins. Proteins 63(1):35–42. https://doi.org/10.1002/prot.20888

    Article  CAS  PubMed  Google Scholar 

  142. Gogl G, Tugaeva KV, Eberling P, Kostmann C, Trave G, Sluchanko NN (2021) Hierarchized phosphotarget binding by the seven human 14–3-3 isoforms. Nat Commun 12(1):1677. https://doi.org/10.1038/s41467-021-21908-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Sluchanko NN (1854) Uversky VN (2015) Hidden disorder propensity of the N-terminal segment of universal adapter protein 14–3-3 is manifested in its monomeric form: novel insights into protein dimerization and multifunctionality. Biochim Biophys Acta 5:492–504. https://doi.org/10.1016/j.bbapap.2015.02.017

    Article  CAS  Google Scholar 

  144. Mani M, Chen C, Amblee V, Liu H, Mathur T, Zwicke G, Zabad S, Patel B, Thakkar J, Jeffery CJ (2015) MoonProt: a database for proteins that are known to moonlight. Nucleic Acids Res 43(Database issue):D277-282. https://doi.org/10.1093/nar/gku954

    Article  CAS  PubMed  Google Scholar 

  145. Chen C, Zabad S, Liu H, Wang W, Jeffery C (2018) MoonProt 2.0: an expansion and update of the moonlighting proteins database. Nucleic Acids Res 46(D1):D640–D644. https://doi.org/10.1093/nar/gkx1043

    Article  CAS  PubMed  Google Scholar 

  146. Chen C, Liu H, Zabad S, Rivera N, Rowin E, Hassan M, Gomez De Jesus SM, Llinas Santos PS, Kravchenko K, Mikhova M, Ketterer S, Shen A, Shen S, Navas E, Horan B, Raudsepp J, Jeffery C (2021) MoonProt 3.0: an update of the moonlighting proteins database. Nucleic Acids Res 49(D1):D368–D372. https://doi.org/10.1093/nar/gkaa1101

    Article  CAS  PubMed  Google Scholar 

  147. Hernandez S, Ferragut G, Amela I, Perez-Pons J, Pinol J, Mozo-Villarias A, Cedano J, Querol E (2014) MultitaskProtDB: a database of multitasking proteins. Nucleic Acids Res 42(Database issue):D517-520. https://doi.org/10.1093/nar/gkt1153

    Article  CAS  PubMed  Google Scholar 

  148. Franco-Serrano L, Hernandez S, Calvo A, Severi MA, Ferragut G, Perez-Pons J, Pinol J, Pich O, Mozo-Villarias A, Amela I, Querol E, Cedano J (2018) MultitaskProtDB-II: an update of a database of multitasking/moonlighting proteins. Nucleic Acids Res 46(D1):D645–D648. https://doi.org/10.1093/nar/gkx1066

    Article  CAS  PubMed  Google Scholar 

  149. Franco-Serrano L, Huerta M, Hernandez S, Cedano J, Perez-Pons J, Pinol J, Mozo-Villarias A, Amela I, Querol E (2018) Multifunctional proteins: involvement in human diseases and targets of current drugs. Protein J 37(5):444–453. https://doi.org/10.1007/s10930-018-9790-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Franco-Serrano L, Sanchez-Redondo D, Najar-Garcia A, Hernandez S, Amela I, Perez-Pons JA, Pinol J, Mozo-Villarias A, Cedano J, Querol E (2021) Pathogen moonlighting proteins: from ancestral key metabolic enzymes to virulence factors. Microorganisms. https://doi.org/10.3390/microorganisms9061300

    Article  PubMed  PubMed Central  Google Scholar 

  151. Bielli P, Calabrese L (2002) Structure to function relationships in ceruloplasmin: a “moonlighting” protein. Cell Mol Life Sci 59(9):1413–1427. https://doi.org/10.1007/s00018-002-8519-2

    Article  CAS  PubMed  Google Scholar 

  152. Hotmberg CG, LaureLt CB (1948) Investigations in serum copper. II. Isolation of the copper-containing protein and a description of some of its properties. Acta Chem Scand 2:550

    Article  Google Scholar 

  153. Texel SJ, Xu X, Harris ZL (2008) Ceruloplasmin in neurodegenerative diseases. Biochem Soc Trans 36(Pt 6):1277–1281. https://doi.org/10.1042/BST0361277

    Article  CAS  PubMed  Google Scholar 

  154. Doyle A, Rusli F, Bhathal P (2015) Aceruloplasminaemia: a rare but important cause of iron overload. BMJ Case Rep. https://doi.org/10.1136/bcr-2014-207541

    Article  PubMed  PubMed Central  Google Scholar 

  155. Ryden LG, Hunt LT (1993) Evolution of protein complexity: the blue copper-containing oxidases and related proteins. J Mol Evol 36(1):41–66. https://doi.org/10.1007/BF02407305

    Article  CAS  PubMed  Google Scholar 

  156. Ortel TL, Takahashi N, Putnam FW (1984) Structural model of human ceruloplasmin based on internal triplication, hydrophilic/hydrophobic character, and secondary structure of domains. Proc Natl Acad Sci USA 81(15):4761–4765. https://doi.org/10.1073/pnas.81.15.4761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hellman NE, Gitlin JD (2002) Ceruloplasmin metabolism and function. Annu Rev Nutr 22:439–458. https://doi.org/10.1146/annurev.nutr.22.012502.114457

    Article  CAS  PubMed  Google Scholar 

  158. Piatigorsky J (1989) Lens crystallins and their genes: diversity and tissue-specific expression. FASEB J 3(8):1933–1940. https://doi.org/10.1096/fasebj.3.8.2656357

    Article  CAS  PubMed  Google Scholar 

  159. Piatigorsky J (2003) Crystallin genes: specialization by changes in gene regulation may precede gene duplication. J Struct Funct Genomics 3(1–4):131–137

    Article  CAS  PubMed  Google Scholar 

  160. Piatigorsky J (1998) Gene sharing in lens and cornea: facts and implications. Prog Retin Eye Res 17(2):145–174. https://doi.org/10.1016/s1350-9462(97)00004-9

    Article  CAS  PubMed  Google Scholar 

  161. Piatigorsky J (1998) Multifunctional lens crystallins and corneal enzymes. More than meets the eye. Ann N Y Acad Sci 842:7–15. https://doi.org/10.1111/j.1749-6632.1998.tb09626.x

    Article  CAS  PubMed  Google Scholar 

  162. Tomarev SI, Piatigorsky J (1996) Lens crystallins of invertebrates–diversity and recruitment from detoxification enzymes and novel proteins. Eur J Biochem 235(3):449–465. https://doi.org/10.1111/j.1432-1033.1996.00449.x

    Article  CAS  PubMed  Google Scholar 

  163. Piatigorsky J, Kantorow M, Gopal-Srivastava R, Tomarev SI (1994) Recruitment of enzymes and stress proteins as lens crystallins. EXS 71:241–250. https://doi.org/10.1007/978-3-0348-7330-7_24

    Article  CAS  PubMed  Google Scholar 

  164. Piatigorsky J (1993) Puzzle of crystallin diversity in eye lenses. Dev Dyn 196(4):267–272. https://doi.org/10.1002/aja.1001960408

    Article  CAS  PubMed  Google Scholar 

  165. Piatigorsky J (1992) Lens crystallins. Innovation associated with changes in gene regulation. J Biol Chem 267(7):4277–4280

    Article  CAS  PubMed  Google Scholar 

  166. Piatigorsky J (1990) Molecular biology: recent studies on enzyme/crystallins and alpha-crystallin gene expression. Exp Eye Res 50(6):725–728. https://doi.org/10.1016/0014-4835(90)90121-a

    Article  CAS  PubMed  Google Scholar 

  167. Wistow G, Kim H (1991) Lens protein expression in mammals: taxon-specificity and the recruitment of crystallins. J Mol Evol 32(3):262–269. https://doi.org/10.1007/BF02342749

    Article  CAS  PubMed  Google Scholar 

  168. Cvekl A, Eliscovich C (2021) Crystallin gene expression: insights from studies of transcriptional bursting. Exp Eye Res 207:108564. https://doi.org/10.1016/j.exer.2021.108564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Roskamp KW, Montelongo DM, Anorma CD, Bandak DN, Chua JA, Malecha KT, Martin RW (2017) Multiple aggregation pathways in human gammaS-crystallin and its aggregation-prone G18V variant. Invest Ophthalmol Vis Sci 58(4):2397–2405. https://doi.org/10.1167/iovs.16-20621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Bucala R (1996) MIF re-discovered: pituitary hormone and glucocorticoid-induced regulator of cytokine production. Cytokine Growth Factor Rev 7(1):19–24. https://doi.org/10.1016/1359-6101(96)00008-1

    Article  CAS  PubMed  Google Scholar 

  171. Kapurniotu A, Gokce O, Bernhagen J (2019) The multitasking potential of alarmins and atypical chemokines. Front Med (Lausanne) 6:3. https://doi.org/10.3389/fmed.2019.00003

    Article  PubMed  Google Scholar 

  172. Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H (1996) The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction. Mol Med 2(1):143–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Rosengren E, Aman P, Thelin S, Hansson C, Ahlfors S, Bjork P, Jacobsson L, Rorsman H (1997) The macrophage migration inhibitory factor MIF is a phenylpyruvate tautomerase. FEBS Lett 417(1):85–88. https://doi.org/10.1016/s0014-5793(97)01261-1

    Article  CAS  PubMed  Google Scholar 

  174. Kleemann R, Kapurniotu A, Mischke R, Held J, Bernhagen J (1999) Characterization of catalytic centre mutants of macrophage migration inhibitory factor (MIF) and comparison to Cys81Ser MIF. Eur J Biochem 261(3):753–766. https://doi.org/10.1046/j.1432-1327.1999.00327.x

    Article  CAS  PubMed  Google Scholar 

  175. Kleemann R, Kapurniotu A, Frank RW, Gessner A, Mischke R, Flieger O, Juttner S, Brunner H, Bernhagen J (1998) Disulfide analysis reveals a role for macrophage migration inhibitory factor (MIF) as thiol-protein oxidoreductase. J Mol Biol 280(1):85–102. https://doi.org/10.1006/jmbi.1998.1864

    Article  CAS  PubMed  Google Scholar 

  176. Swope MD, Lolis E (1999) Macrophage migration inhibitory factor: cytokine, hormone, or enzyme? Rev Physiol Biochem Pharmacol 139:1–32. https://doi.org/10.1007/BFb0033647

    Article  CAS  PubMed  Google Scholar 

  177. Yang D, Han Z, Oppenheim JJ (2017) Alarmins and immunity. Immunol Rev 280(1):41–56. https://doi.org/10.1111/imr.12577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Stolzenberg E, Berry D, Yang D, Lee EY, Kroemer A, Kaufman S, Wong GCL, Oppenheim JJ, Sen S, Fishbein T, Bax A, Harris B, Barbut D, Zasloff MA (2017) A role for neuronal alpha-synuclein in gastrointestinal immunity. J Innate Immun 9(5):456–463. https://doi.org/10.1159/000477990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Uversky VN (2017) Looking at the recent advances in understanding alpha-synuclein and its aggregation through the proteoform prism. F1000Res 6:525. https://doi.org/10.12688/f1000research.10536.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Uversky VN (2011) Flexible nets of malleable guardians: intrinsically disordered chaperones in neurodegenerative diseases. Chem Rev 111(2):1134–1166. https://doi.org/10.1021/cr100186d

    Article  CAS  PubMed  Google Scholar 

  181. Webster JM, Darling AL, Uversky VN, Blair LJ (2019) Small heat shock proteins, big impact on protein aggregation in neurodegenerative disease. Front Pharmacol 10:1047. https://doi.org/10.3389/fphar.2019.01047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Marzullo L, Turco MC, Uversky VN (2022) What’s in the BAGs? Intrinsic disorder angle of the multifunctionality of the members of a family of chaperone regulators. J Cell Biochem 123(1):22–42. https://doi.org/10.1002/jcb.30123

    Article  CAS  PubMed  Google Scholar 

  183. Permyakov SE, Ismailov RG, Xue B, Denesyuk AI, Uversky VN, Permyakov EA (2011) Intrinsic disorder in S100 proteins. Mol Biosyst 7(7):2164–2180. https://doi.org/10.1039/c0mb00305k

    Article  CAS  PubMed  Google Scholar 

  184. Weisz J, Uversky VN (2020) Zooming into the dark side of human annexin-S100 complexes: dynamic alliance of flexible partners. Int J Mol Sci. https://doi.org/10.3390/ijms21165879

    Article  PubMed  PubMed Central  Google Scholar 

  185. Smith LM, Kelleher NL, Consortium for Top Down P (2013) Proteoform: a single term describing protein complexity. Nat Methods 10(3):186–187. https://doi.org/10.1038/nmeth.2369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. DeForte S, Uversky VN (2016) Order, disorder, and everything in between. Molecules. https://doi.org/10.3390/molecules21081090

    Article  PubMed  PubMed Central  Google Scholar 

  187. Uversky VN (2016) Dancing protein clouds: the strange biology and chaotic physics of intrinsically disordered proteins. J Biol Chem 291(13):6681–6688. https://doi.org/10.1074/jbc.R115.685859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Fonin AV, Darling AL, Kuznetsova IM, Turoverov KK, Uversky VN (2019) Multi-functionality of proteins involved in GPCR and G protein signaling: making sense of structure-function continuum with intrinsic disorder-based proteoforms. Cell Mol Life Sci 76(22):4461–4492. https://doi.org/10.1007/s00018-019-03276-1

    Article  CAS  PubMed  Google Scholar 

  189. Uversky VN (2019) Protein intrinsic disorder and structure-function continuum. Prog Mol Biol Transl Sci 166:1–17. https://doi.org/10.1016/bs.pmbts.2019.05.003

    Article  CAS  PubMed  Google Scholar 

  190. Kagi JH, Valee BL (1960) Metallothionein: a cadmium- and zinc-containing protein from equine renal cortex. J Biol Chem 235:3460–3465

    Article  CAS  PubMed  Google Scholar 

  191. Abdin AY, Jacob C, Kastner L (2021) The enigmatic metallothioneins: a case of upward-looking research. Int J Mol Sci. https://doi.org/10.3390/ijms22115984

    Article  PubMed  PubMed Central  Google Scholar 

  192. Vasak M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16(7):1067–1078. https://doi.org/10.1007/s00775-011-0799-2

    Article  CAS  PubMed  Google Scholar 

  193. Krezel A, Maret W (2017) The functions of metamorphic metallothioneins in zinc and copper metabolism. Int J Mol Sci. https://doi.org/10.3390/ijms18061237

    Article  PubMed  PubMed Central  Google Scholar 

  194. Seren N, Glaberman S, Carretero MA, Chiari Y (2014) Molecular evolution and functional divergence of the metallothionein gene family in vertebrates. J Mol Evol 78(3–4):217–233. https://doi.org/10.1007/s00239-014-9612-5

    Article  CAS  PubMed  Google Scholar 

  195. Si M, Lang J (2018) The roles of metallothioneins in carcinogenesis. J Hematol Oncol 11(1):107. https://doi.org/10.1186/s13045-018-0645-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Cherian MG, Jayasurya A, Bay BH (2003) Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res 533(1–2):201–209. https://doi.org/10.1016/j.mrfmmm.2003.07.013

    Article  CAS  PubMed  Google Scholar 

  197. Kim JE, Lindahl PA (2023) CUP1 metallothionein from healthy Saccharomyces cerevisiae colocalizes to the cytosol and mitochondrial intermembrane space. Biochemistry 62(1):62–74. https://doi.org/10.1021/acs.biochem.2c00481

    Article  CAS  PubMed  Google Scholar 

  198. Coyle P, Philcox JC, Carey LC, Rofe AM (2002) Metallothionein: the multipurpose protein. Cell Mol Life Sci 59(4):627–647. https://doi.org/10.1007/s00018-002-8454-2

    Article  CAS  PubMed  Google Scholar 

  199. Kim JW, Dang CV (2005) Multifaceted roles of glycolytic enzymes. Trends Biochem Sci 30(3):142–150. https://doi.org/10.1016/j.tibs.2005.01.005

    Article  CAS  PubMed  Google Scholar 

  200. Bian X, Jiang H, Meng Y, Li YP, Fang J, Lu Z (2022) Regulation of gene expression by glycolytic and gluconeogenic enzymes. Trends Cell Biol 32(9):786–799. https://doi.org/10.1016/j.tcb.2022.02.003

    Article  CAS  PubMed  Google Scholar 

  201. Commichau FM, Rothe FM, Herzberg C, Wagner E, Hellwig D, Lehnik-Habrink M, Hammer E, Volker U, Stulke J (2009) Novel activities of glycolytic enzymes in Bacillus subtilis: interactions with essential proteins involved in mRNA processing. Mol Cell Proteomics 8(6):1350–1360. https://doi.org/10.1074/mcp.M800546-MCP200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Meyerhof O (1935) Über die wirkungsweise der hexokinase. Naturwissenschaften 23(50):850–851

    Article  CAS  Google Scholar 

  203. von Euler H, Adler E (1935) Über die Komponenten der Dehydrasesysteme. VI. Dehydrierung von Hexosen unter Mitwirkung von Adenosintriphosphorsäure.

  204. Trayser KA, Colowick SP (1961) Properties of crystalline hexokinase from yeast. IV. Multiple forms of the enzyme. Arch Biochem Biophys 94:177–181. https://doi.org/10.1016/0003-9861(61)90026-1

    Article  CAS  PubMed  Google Scholar 

  205. Brown J, Miller DM, Holloway MT, Leve GD (1967) Hexokinase isoenzymes in liver and adipose tissue of man and dog. Science 155(3759):205–207. https://doi.org/10.1126/science.155.3759.205

    Article  CAS  PubMed  Google Scholar 

  206. Gonzalez C, Ureta T, Sanchez R, Niemeyer H (1964) Multiple molecular forms of ATP:hexose 6-phosphotransferase from rat liver. Biochem Biophys Res Commun 16(4):347–352. https://doi.org/10.1016/0006-291x(64)90038-5

    Article  CAS  PubMed  Google Scholar 

  207. Jang JC, Leon P, Zhou L, Sheen J (1997) Hexokinase as a sugar sensor in higher plants. Plant Cell 9(1):5–19. https://doi.org/10.1105/tpc.9.1.5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Kamata K, Mitsuya M, Nishimura T, Eiki J, Nagata Y (2004) Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure 12(3):429–438. https://doi.org/10.1016/j.str.2004.02.005

    Article  CAS  PubMed  Google Scholar 

  209. Feng J, Zhao S, Chen X, Wang W, Dong W, Chen J, Shen JR, Liu L, Kuang T (2015) Biochemical and structural study of Arabidopsis hexokinase 1. Acta Crystallogr D Biol Crystallogr 71(Pt 2):367–375. https://doi.org/10.1107/S1399004714026091

    Article  CAS  PubMed  Google Scholar 

  210. Rodriguez-Saavedra C, Morgado-Martinez LE, Burgos-Palacios A, King-Diaz B, Lopez-Coria M, Sanchez-Nieto S (2021) Moonlighting proteins: the case of the hexokinases. Front Mol Biosci 8:701975. https://doi.org/10.3389/fmolb.2021.701975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Didiasova M, Schaefer L, Wygrecka M (2019) When place matters: shuttling of enolase-1 across cellular compartments. Front Cell Dev Biol 7:61. https://doi.org/10.3389/fcell.2019.00061

    Article  PubMed  PubMed Central  Google Scholar 

  212. Tarze A, Deniaud A, Le Bras M, Maillier E, Molle D, Larochette N, Zamzami N, Jan G, Kroemer G, Brenner C (2007) GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization. Oncogene 26(18):2606–2620. https://doi.org/10.1038/sj.onc.1210074

    Article  CAS  PubMed  Google Scholar 

  213. Boradia VM, Raje M, Raje CI (2014) Protein moonlighting in iron metabolism: glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Biochem Soc Trans 42(6):1796–1801. https://doi.org/10.1042/BST20140220

    Article  CAS  PubMed  Google Scholar 

  214. Kosova AA, Khodyreva SN, Lavrik OI (2017) Role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in DNA repair. Biochemistry (Mosc) 82(6):643–654. https://doi.org/10.1134/S0006297917060013

    Article  CAS  PubMed  Google Scholar 

  215. Sweeny EA, Singh AB, Chakravarti R, Martinez-Guzman O, Saini A, Haque MM, Garee G, Dans PD, Hannibal L, Reddi AR, Stuehr DJ (2018) Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. J Biol Chem 293(37):14557–14568. https://doi.org/10.1074/jbc.RA118.004169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Malhotra H, Kumar M, Chauhan AS, Dhiman A, Chaudhary S, Patidar A, Jaiswal P, Sharma K, Sheokand N, Raje CI, Raje M (2019) Moonlighting protein glyceraldehyde-3-phosphate dehydrogenase: a cellular rapid-response molecule for maintenance of iron homeostasis in hypoxia. Cell Physiol Biochem 52(3):517–531. https://doi.org/10.33594/000000037

    Article  CAS  PubMed  Google Scholar 

  217. Ahmad I, Singh R, Pal S, Prajapati S, Sachan N, Laiq Y, Husain H (2023) Exploring the role of glycolytic enzymes PFKFB3 and GAPDH in the modulation of Abeta and neurodegeneration and their potential of therapeutic targets in Alzheimer’s disease. Appl Biochem Biotechnol. https://doi.org/10.1007/s12010-023-04340-0

    Article  PubMed  PubMed Central  Google Scholar 

  218. Tossounian MA, Zhang B, Gout I (2020) The writers, readers, and erasers in redox regulation of GAPDH. Antioxidants (Basel). https://doi.org/10.3390/antiox9121288

    Article  PubMed  Google Scholar 

  219. Sirover MA (2021) The role of posttranslational modification in moonlighting glyceraldehyde-3-phosphate dehydrogenase structure and function. Amino Acids 53(4):507–515. https://doi.org/10.1007/s00726-021-02959-z

    Article  CAS  PubMed  Google Scholar 

  220. Dai Y, Fleischhacker AS, Liu L, Fayad S, Gunawan AL, Stuehr DJ, Ragsdale SW (2022) Heme delivery to heme oxygenase-2 involves glyceraldehyde-3-phosphate dehydrogenase. Biol Chem 403(11–12):1043–1053. https://doi.org/10.1515/hsz-2022-0230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Stuehr DJ, Dai Y, Biswas P, Sweeny EA, Ghosh A (2022) New roles for GAPDH, Hsp90, and NO in regulating heme allocation and hemeprotein function in mammals. Biol Chem 403(11–12):1005–1015. https://doi.org/10.1515/hsz-2022-0197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Naletova I, Schmalhausen E, Kharitonov A, Katrukha A, Saso L, Caprioli A, Muronetz V (2008) Non-native glyceraldehyde-3-phosphate dehydrogenase can be an intrinsic component of amyloid structures. Biochim Biophys Acta 1784(12):2052–2058. https://doi.org/10.1016/j.bbapap.2008.07.013

    Article  CAS  PubMed  Google Scholar 

  223. Butterfield DA, Hardas SS, Lange ML (2010) Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer’s disease: many pathways to neurodegeneration. J Alzheimers Dis 20(2):369–393. https://doi.org/10.3233/JAD-2010-1375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. El Kadmiri N, Slassi I, El Moutawakil B, Nadifi S, Tadevosyan A, Hachem A, Soukri A (2014) Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer’s disease. Pathol Biol (Paris) 62(6):333–336. https://doi.org/10.1016/j.patbio.2014.08.002

    Article  PubMed  Google Scholar 

  225. Li M, Zhang CS, Zong Y, Feng JW, Ma T, Hu M, Lin Z, Li X, Xie C, Wu Y, Jiang D, Li Y, Zhang C, Tian X, Wang W, Yang Y, Chen J, Cui J, Wu YQ, Chen X, Liu QF, Wu J, Lin SY, Ye Z, Liu Y, Piao HL, Yu L, Zhou Z, Xie XS, Hardie DG, Lin SC (2019) Transient receptor potential V channels are essential for glucose sensing by aldolase and AMPK. Cell Metab 30(3):508-524 e512. https://doi.org/10.1016/j.cmet.2019.05.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Huangyang P, Li F, Lee P, Nissim I, Weljie AM, Mancuso A, Li B, Keith B, Yoon SS, Simon MC (2020) Fructose-1,6-bisphosphatase 2 inhibits sarcoma progression by restraining mitochondrial biogenesis. Cell Metab 31(1):174-188 e177. https://doi.org/10.1016/j.cmet.2019.10.012

    Article  CAS  PubMed  Google Scholar 

  227. Xu D, Wang Z, Xia Y, Shao F, Xia W, Wei Y, Li X, Qian X, Lee JH, Du L, Zheng Y, Lv G, Leu JS, Wang H, Xing D, Liang T, Hung MC, Lu Z (2020) The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 580(7804):530–535. https://doi.org/10.1038/s41586-020-2183-2

    Article  CAS  PubMed  Google Scholar 

  228. Henderson B, Fares MA, Martin AC (2016) Protein moonlighting in biology and medicine. Wiley, New York

    Book  Google Scholar 

  229. Gupta MN, Pandey S, Ehtesham NZ, Hasnain SE (2019) Medical implications of protein moonlighting. Indian J Med Res 149(3):322–325. https://doi.org/10.4103/ijmr.IJMR_2192_18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Henderson B, Martin A (2013) Bacterial moonlighting proteins and bacterial virulence. Curr Top Microbiol Immunol 358:155–213. https://doi.org/10.1007/82_2011_188

    Article  CAS  PubMed  Google Scholar 

  231. Satala D, Satala G, Zawrotniak M, Kozik A (2021) Candida albicans and Candida glabrata triosephosphate isomerase—a moonlighting protein that can be exposed on the candidal cell surface and bind to human extracellular matrix proteins. BMC Microbiol 21(1):199. https://doi.org/10.1186/s12866-021-02235-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Satala D, Satala G, Karkowska-Kuleta J, Bukowski M, Kluza A, Rapala-Kozik M, Kozik A (2020) Structural Insights into the Interactions of Candidal Enolase with Human Vitronectin, Fibronectin and Plasminogen. Int J Mol Sci. https://doi.org/10.3390/ijms21217843

    Article  PubMed  PubMed Central  Google Scholar 

  233. Henderson B, Lund PA, Coates AR (2010) Multiple moonlighting functions of mycobacterial molecular chaperones. Tuberculosis (Edinb) 90(2):119–124. https://doi.org/10.1016/j.tube.2010.01.004

    Article  CAS  PubMed  Google Scholar 

  234. Workman P, Clarke P (2012) PI3 kinase in cancer: from biology to clinic. Am Soc Clin Oncol Educ Book. https://doi.org/10.14694/EdBook_AM.2012.32.e93

    Article  PubMed  Google Scholar 

  235. Davé V, Uversky VN (2023) Roles of intrinsically disordered regions in phosphoinositide 3-kinase biocatalysis. Structure and intrinsic disorder in enzymology. Elsevier, Amsterdam, pp 225–240

    Chapter  Google Scholar 

  236. Madsen RR, Vanhaesebroeck B, Semple RK (2018) Cancer-associated PIK3CA mutations in overgrowth disorders. Trends Mol Med 24(10):856–870. https://doi.org/10.1016/j.molmed.2018.08.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Lindhurst MJ, Parker VE, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Tziotzios C, Dixon AK, Helliwell T, O’Rahilly S, Savage DB, Wakelam MJ, Barroso I, Biesecker LG, Semple RK (2012) Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet 44(8):928–933. https://doi.org/10.1038/ng.2332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Marshall JDS, Whitecross DE, Mellor P, Anderson DH (2019) Impact of p85alpha alterations in cancer. Biomolecules. https://doi.org/10.3390/biom9010029

    Article  PubMed  PubMed Central  Google Scholar 

  239. Noorolyai S, Shajari N, Baghbani E, Sadreddini S, Baradaran B (2019) The relation between PI3K/AKT signalling pathway and cancer. Gene 698:120–128. https://doi.org/10.1016/j.gene.2019.02.076

    Article  CAS  PubMed  Google Scholar 

  240. Lucas CL, Tangye SG (2020) Editorial: human disorders of PI3K biology. Front Immunol 11:617464. https://doi.org/10.3389/fimmu.2020.617464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Collingridge PW, Brown RW, Ginger ML (2010) Moonlighting enzymes in parasitic protozoa. Parasitology 137(9):1467–1475. https://doi.org/10.1017/S0031182010000259

    Article  CAS  PubMed  Google Scholar 

  242. Balmer EA, Faso C (2021) The road less traveled? Unconventional protein secretion at parasite-host interfaces. Front Cell Dev Biol 9:662711. https://doi.org/10.3389/fcell.2021.662711

    Article  PubMed  PubMed Central  Google Scholar 

  243. Sriram G, Martinez JA, McCabe ER, Liao JC, Dipple KM (2005) Single-gene disorders: what role could moonlighting enzymes play? Am J Hum Genet 76(6):911–924. https://doi.org/10.1086/430799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21(3):297–308. https://doi.org/10.1016/j.ccr.2012.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Reina-Campos M, Moscat J, Diaz-Meco M (2017) Metabolism shapes the tumor microenvironment. Curr Opin Cell Biol 48:47–53. https://doi.org/10.1016/j.ceb.2017.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Lv L, Lei Q (2021) Proteins moonlighting in tumor metabolism and epigenetics. Front Med 15(3):383–403. https://doi.org/10.1007/s11684-020-0818-1

    Article  PubMed  Google Scholar 

  247. Adamo A, Frusteri C, Pallotta MT, Pirali T, Sartoris S, Ugel S (2020) Moonlighting proteins are important players in cancer immunology. Front Immunol 11:613069. https://doi.org/10.3389/fimmu.2020.613069

    Article  CAS  PubMed  Google Scholar 

  248. Boukouris AE, Zervopoulos SD, Michelakis ED (2016) Metabolic enzymes moonlighting in the nucleus: metabolic regulation of gene transcription. Trends Biochem Sci 41(8):712–730. https://doi.org/10.1016/j.tibs.2016.05.013

    Article  CAS  PubMed  Google Scholar 

  249. Pan C, Li B, Simon MC (2021) Moonlighting functions of metabolic enzymes and metabolites in cancer. Mol Cell 81(18):3760–3774. https://doi.org/10.1016/j.molcel.2021.08.031

    Article  CAS  PubMed  Google Scholar 

  250. Yadav P, Singh R, Sur S, Bansal S, Chaudhry U, Tandon V (2023) Moonlighting proteins: beacon of hope in era of drug resistance in bacteria. Crit Rev Microbiol 49(1):57–81. https://doi.org/10.1080/1040841X.2022.2036695

    Article  CAS  PubMed  Google Scholar 

  251. Copley SD (2015) An evolutionary biochemist’s perspective on promiscuity. Trends Biochem Sci 40(2):72–78. https://doi.org/10.1016/j.tibs.2014.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Gupta MN, Uversky VN (2023) Pre-molten, wet, and dry molten globules en route to the functional state of proteins. Int J Mol Sci 24(3):2424. https://doi.org/10.3390/ijms24032424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Zidek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596(7873):583–589. https://doi.org/10.1038/s41586-021-03819-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Dayhoff GW 2nd, Uversky VN (2022) Rapid prediction and analysis of protein intrinsic disorder. Protein Sci 31(12):e4496. https://doi.org/10.1002/pro.4496

    Article  CAS  PubMed  Google Scholar 

  255. Meszaros B, Erdos G, Dosztanyi Z (2018) IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res 46(W1):W329–W337. https://doi.org/10.1093/nar/gky384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Obradovic Z, Peng K, Vucetic S, Radivojac P, Dunker AK (2005) Exploiting heterogeneous sequence properties improves prediction of protein disorder. Proteins 61(Suppl 7):176–182. https://doi.org/10.1002/prot.20735

    Article  CAS  PubMed  Google Scholar 

  257. Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinform 7:208. https://doi.org/10.1186/1471-2105-7-208

    Article  CAS  Google Scholar 

  258. Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK, Obradovic Z (2005) Optimizing long intrinsic disorder predictors with protein evolutionary information. J Bioinform Comput Biol 3(1):35–60. https://doi.org/10.1142/s0219720005000886

    Article  CAS  PubMed  Google Scholar 

  259. Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins 42(1):38–48. https://doi.org/10.1002/1097-0134(20010101)42:1%3c38::aid-prot50%3e3.0.co;2-3

    Article  CAS  PubMed  Google Scholar 

  260. Xue B, Dunbrack RL, Williams RW, Dunker AK (1804) Uversky VN (2010) PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 4:996–1010. https://doi.org/10.1016/j.bbapap.2010.01.011

    Article  CAS  Google Scholar 

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Gupta, M.N., Uversky, V.N. Moonlighting enzymes: when cellular context defines specificity. Cell. Mol. Life Sci. 80, 130 (2023). https://doi.org/10.1007/s00018-023-04781-0

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