Multifunctional Proteins: Moonlight Proteins

Yıl 2020, 2020 Özel Sayı, 80 - 88, 26.02.2020

Birşen Bilgici , Sebati Sinan Ürkmez , Yeşim Civil

https://doi.org/10.18663/tjcl.542346

Öz

In recent years, the knowledge that many proteins have
more than one function has begun to take the place of one gene – one protein -
one function idea. Moonlight proteins are a subclass of multi-functional
proteins. The concept of moonlight protein describes the ability of a single
polypeptide chain to carry through multiple biochemical functions. Today more
than 300 moonlight proteins have been identified. However, the data indicate
that there may be more moonlight proteins. Known examples of moonlight proteins
include a variety of protein types including receptors, enzymes, transcription
factors, adhesins, and scaffold proteins. A moonlight protein can activate the
second function in different cell types, at different intracellular locations,
at different oligomeric states, or depending on changes in concentration of a
ligand, substrate, cofactor or a reaction product. However, these mechanisms
are non-specific and the mechanism of transition between functions may use one
of them or their combination. Moonlight proteins have been suggested to be
associated with disease phenotypes such as neurodegenerative diseases and
cancer. Moonlight proteins bring some difficulties to treatment processes by
taking place in pathogenesis of diseases but also offer opportunities as a
potential treatment target and treatment tool. In
this review, we aimed to contribute to our current basic and biochemical
knowledge by discussing the biochemical, physiological and pathological
features of the present moonlight proteins and their relationships with
diseases.

Anahtar Kelimeler

Moonlight proteins, multifunctional proteins, protein function, metabolic coordination, additional novel functions

Çok işlevli Proteinler: Moonlight Proteinler

Öz

Son
yıllarda birçok proteinin birden fazla fonksiyona sahip olduğu bilgisi, bir gen
- bir protein - bir fonksiyon fikrinin yerini almaya başlamıştır. Moonlight
proteinler çok fonksiyonlu proteinlerin bir alt sınıfıdır. Moonlight protein
kavramı, tek bir polipeptid zincirinin çoklu biyokimyasal fonksiyonları yerine
getirmesini tanımlamaktadır. Bugün 300'den fazla moonlight proteini
tanımlanmıştır. Bununla birlikte, veriler daha fazla moonlight proteini olabileceğini
göstermektedir. Moonlight proteinlerin bilinen örnekleri arasında, reseptörler,
enzimler, transkripsiyon faktörleri, adhezinler ve hücre iskeleti de dahil
olmak üzere çeşitli protein türleri bulunmaktadır. Bir moonlight protein,
farklı hücre tiplerinde, farklı hücre içi lokasyonlarda, farklı oligomerik
durumlarda bulunarak veya bir ligandın, substratın, kofaktörün ya da ürünün
konsantrasyonundaki değişikliklere bağlı olarak ikinci fonksiyonunu
aktifleştirebilmektedir. Ancak bu mekanizmalar, özgül değildir ve fonksiyonlar
arasındaki geçişlerde bu yollardan birini ya da bunların bir kombinasyonunu
kullanabilmektedir. Moonlight proteinlerin, nörodejeneratif hastalıklar ve
kanser gibi hastalık fenotipleri ile ilişkili olabileceği öne sürülmektedir. Bunun
yanısıra hastalık patogenezlerinde yer alarak tedavi süreçlerine bir takım
zorluklar getirmekle birlikte potansiyel bir tedavi hedefi ve tedavi aracı
olarak da fırsatlar sunmaktadır.  Biz bu
derlemede, başlıca insanlardaki mevcut moonlight proteinlerin biyokimyasal,
fizyolojik ve patolojik özelliklerini ve hastalıklarla ilişkilerini tartışarak
mevcut temel ve biyokimyasal bilgilerimize katkıda bulunmayı amaçladık.

Anahtar Kelimeler

Moonlight proteinler, çok işlevli proteinler, protein fonksiyonu, metabolik düzenlenme

Kaynakça

• 1. Ezkurdia I, Juan D, Rodriguez J et al. Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes. Hum Mol Genet 2014; 23: 5866–78.
• 2. O'Leary NA, Wright MW, Brister JR et al. Reference sequence (RefSeq) database at NCBI: current status, taxonomic expansion, and functional annotation. Nucleic Acids Res 2016; 44:733-34.
• 3. Omenn GS, Lane L, Lundberg EK et al. Metrics for the human proteome project 2016: progress on identifying and characterizing the human proteome, including post-translational modifications. J Proteome Res 2016; 15: 3951–60.
• 4. Jeffery CJ. Moonlighting proteins—an update. Mol BioSyst 2009; 5: 345–50.
• 5. Jeffery CJ. Moonlighting proteins. Trends Biochem Sci 1999; 24: 8–11.
• 6. Piatigorsky J and Wistow GJ. Enzyme/crystallins: gene sharing as an evolutionary strategy. Cell 1989; 57: 197–99.
• 7. Wistow G and Piatigorsky J. Recruitment of enzymes as lens structural proteins. Science 1987; 236: 1554–56.
• 8. Cvekl A and Zheng D. Gene sharing and evolution. Hum Genomics 2009; 4: 66-67.
• 9. Jeffery CJ. Multifunctional proteins: examples of gene sharing. Ann Med 2003; 35: 28–35.
• 10. Copley SD. Moonlighting is mainstream: Paradigm adjustment required. Bioessays 2012; 34: 578–88.
• 11. Copley SD. Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr Opin Chem Biol 2003; 7: 265–72.
• 12. Stutts MJ, Canessa CM, Olsen JC et al. CFTR as a cAMP-dependent regulator of sodium channels. Science 1995; 269: 847–50.
• 13. Chen JW, Dodia C, Feinstein SI, Jain MK, Fisher AB. 1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. J Biol Chem 2000; 275: 28421-27.
• 14. Vu TK, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-68.
• 15. Al Jord A, Shihavuddin A, Servignat d'Aout R et al. Calibrated mitotic oscillator drives motile ciliogenesis. Science 2017; 358: 803-06.
• 16. Suzukia CK, Rep M, van Dijl JB, Suda K, Grivell LA, Schatz G. ATP-dependent proteases that also chaperone protein biogenesis. Trends Biochem Sci 1997; 22: 118-23.
• 17. Russo J, Jalkanen AL, Heck AM, Schmidt CM, Wilusz J, Wilusz CJ. Sequences encoding C2H2 zinc fingers inhibit polyadenylation and mRNA export in human cells. Sci Rep 2018; 8: 16995.
• 18. Gancedo C and Flores CL. Moonlighting proteins in yeasts. Microbiol Mol Biol Rev 2008; 72: 197–210.
• 19. Huberts DH and van der Klei IJ. Moonlighting proteins: an intriguing mode of multitasking. Biochim Biophys Acta 2010; 1803: 520–25.
• 20. Amblee V and Jeffery CJ. Physical Features of Intracellular Proteins that Moonlight on the Cell Surface. PLoS ONE 2015; 10: e0130575.
• 21. Chen C, Zabad S, Liu H, Wang W, Jeffery C. MoonProt 2.0: an expansion and update of the moonlighting proteins database. Nucleic Acids Res 2018; 46: 640-44.
• 22. Jeffery CJ. Moonlighting proteins: complications and implications for proteomics research. Drug Discov Today: Targets 2004; 3: 71–78.
• 23. Lu Z and Hunter T. Metabolic Kinases Moonlighting as Protein Kinases. Trends Biochem Sci 2018; 43: 301-310.
• 24. Kim JW and Dang CV. Multifaceted roles of glycolytic enzymes. Trends Biochem Sci 2005; 30: 142–50.
• 25. Tompa P, Szász C, Buday L. Structural disorder throws new light on moonlighting. Trends Biochem Sci 2005; 30: 484–89.
• 26. Hernández S, Amela I, Cedano J et al. Do moonlighting proteins belong to the intrinsic disordered proteins class? J J Proteomics Bioinform 2012; 5: 262–64.
• 27. Jeffery CJ. Molecular mechanisms for multitasking: recent crystal structures of moonlighting proteins. Curr Opin Struct Biol 2004; 14: 663–68.
• 28. Jeffery CJ. An introduction to protein moonlighting. Biochem Soc Trans 2014; 42: 1679–83.
• 29. Chaput M, Claes V, Portetelle D et al. The neurotrophic factor neuroleukin is 90% homologous with phosphohexose isomerase. Nature 1988; 332: 454–55.
• 30. Gurney ME, Apatoff BR, Spear GT et al. Neuroleukin: a lymphokine product of lectin stimulated T cells. Science 1986; 234(4776): 574–81.
• 31. Gurney ME, Heinrich SP, Lee MR, Yin H. Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons. Science 1986; 234: 566–74.
• 32. Watanabe, H. Takehana K, Date M, Shinozaki T, Raz A. Tumor Cell Autocrine Motility Factor Is the Neuroleukin/Phosphohexose Isomerase Polypeptide. Cancer Res 1996; 56: 2960–63.
• 33. Xu W, Seiter K, Feldman E, Ahmed T, Chiao JW. The differentiation and maturation mediator for human myeloid leukemia cells shares homology with neuroleukin or phosphoglucose isomerase. Blood 1996; 87: 4502–06.
• 34. Jobin PG, Butler GS, Overall CM. New intracellular activities of matrix metalloproteinases shine in the moonlight. Biochim Biophys Acta Mol Cell Res 2017; 1864: 2043-55.
• 35. Furukawa T, Yoshimura A, Sumizawa T et al. Angiogenic Factor. Nature 1992; 356: 668.
• 36. Jeffery CJ. Mass spectrometry and the search for moonlighting protein. Mass Spectrom Rev 2005; 24: 772–82.
• 37. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor. Cell 1998; 92: 735–45.
• 38. Meyer-Siegler K, Mauro DJ, Seal G, Wurzer J, deRiel JK, Sirover MA. A human nuclear uracil DNA glycosylase is the 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase. Proc Natl Acad Sci USA 1991; 88: 8460–64.
• 39. Kato H, Fukuda T, Parkison C, McPhie P, Cheng SY. Cytosolic thyroid hormone binding protein is a monomer of pyruvate kinase. Proc Natl Acad Sci USA 1989; 86: 7861-65.
• 40. Kennedy MC, Mende-Mueller L, Blondin GA, Beinert H. Purification and characterization of cytosolic aconitase from beef liver and its relationship to the iron-responsive element binding protein. Proc Natl Acad Sci U S A 1992; 89: 11730–34.
• 41. Ehinger S, Schubert WD, Bergmann S, Hammerschmidt S, Heinz DW. Plasmin(ogen)-binding alphaenolase from Streptococcus pneumoniae: crystal structure and evaluation of plasmin(ogen)-binding sites. J Mol Biol 2004; 343: 997–1005.
• 42. Zhou H, Zhang L, Vartuli RL, Ford HL, Zhao R. The Eya phosphatase: Its unique role in cancer. Int J Biochem Cell Biol 2018; 96: 165-70.
• 43. Basilion JP, Rouault TA, Massinople CM, Klausner RD, Burgess WH. The iron-responsive element-binding protein: localization of the RNA-binding site to the aconitase active-site cleft. Proc Natl Acad Sci USA 1994; 91: 574–78.
• 44. Jeffery CJ. Protein species and moonlighting proteins: Very small changes in a protein's covalent structure can change its biochemical function. J Proteomics 2016; 134: 19-24.
• 45. Jeffery CJ. Moonlighting proteins: complications and implications for proteomics research. Drug Discov Today: Targets 2004; 3: 71–78.
• 46. Sirover MA. On the functional diversity of glyceraldehyde-3-phosphate dehydrogenase: biochemical mechanisms and regulatory control. Biochim Biophys Acta 2011; 1810: 741–51.
• 47. Jeffery CJ. Proteins with Neomorphic Moonlighting Functions in Disease. IUBMB Life 2011; 63: 489-94.
• 48. Orosz F, Oláh J, Ovádi J. Triosephosphate isomerase deficiency: facts and doubts. IUBMB Life. 2006; 58: 703-15.
• 49. Mazzola JL, Sirover MA. Alteration of intracellular structure and function of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype of neurodegenerative disorders? Neurotoxicology 2002; 23: 603-09.
• 50. Chuang DM, Hough C, Senatorov VV. Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annu Rev Pharmacol Toxicol 2005; 45: 269-90.
• 51. Liz MA, Mar FM, Franquinho F, Sousa MM. Aboard transthyretin: from transport to cleavage. IUBMB Life 2010; 62: 429-35.
• 52. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des 2008; 14: 3219-30.
• 53. Babady NE, Pang YP, Elpeleg O, Isaya G. Cryptic proteolytic activity of dihydrolipoamide dehydrogenase. Proc Natl Acad Sci U S A 2007; 104: 6158-63.
• 54. Molavi G, Samadi N, Hosseingholi EZ. The roles of moonlight ribosomal proteins in the development of human cancers. J Cell Physiol 2019; 234: 8327-41.
• 55. Whitesell L and Lindquist SL. HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005; 5: 761-72.
• 56. Min KW, Lee SH, Baek SJ. Moonlighting proteins in cancer. Cancer Lett 2016; 370: 108–16.
• 57. Song X, Wang X, Zhuo W, et al. The regulatory mechanism of extracellular Hsp90{alpha} on matrix metalloproteinase-2 processing and tumor angiogenesis. J Biol Chem 2010; 285: 40039-49.
• 58. Hance MW, Dole K, Gopal U et al. Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J Biol Chem 2012; 287: 37732-44.
• 59. Díaz-Ramos A, Roig-Borrellas A, García-Melero A, López-Alemany R. α-Enolase, a multifunctional protein: its role on pathophysiological situations. J Biomed Biotechnol 2012; 2012: 156795.
• 60. Hara MR, Thomas B, Cascio MB et al. Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc Natl Acad Sci USA 2006; 103: 3887-89.
• 61. Daddacha W, Koyen AE, Bastien AJ, Head PE, Dhere VR, Nabeta GN. SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination. Cell Rep 2017; 20: 1921-35.
• 62. Broadley SA, Vanags D, Williams B et al. Results of a phase IIa clinical trial of an anti-inflammatory molecule, chaperonin 10, in multiple sclerosis. Mult Scler 2009; 15: 329-36.
• 63. Vanags D, Williams B, Johnson B et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomised trial. Lancet 2006; 368: 855-63.
• 64. Williams B, Vanags D, Hall S et al. Efficacy and safety of chaperonin 10 in patients with moderate to severe plaque psoriasis: evidence of utility beyond a single indication. Arch Dermatol 2008; 144: 683-85.
• 65. Yang J, Chen Z, Liu N, Chen Y. Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells. Redox Biol 2018; 19: 158-65.
• 66. Hernández S, Ferragut G, Amela I et al. MultitaskProtDB: a database of multitasking proteins. Nucleic Acids Res 2014; 42: 517-20.
• 67. Chapple CE, Robisson B, Spinelli L, Guien C, Becker E, Brun C. Extreme multifunctional proteins identified from a human protein interaction network. Nat Commun 2015; 6: 7412.
• 68. Prieto C and Javier De Las Rivas J. APID: Agile Protein Interaction Data Analyzer. Nucleic Acids Res 2006; 34: 298–302.