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Mathematical model of a short translatable G-quadruplex and an assessment of its relevance to misfolding-induced proteostasis

Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, INDIA

G-quadruplexes can form in protein coding and non-coding segments such as the untranslated regions and introns of the mRNA transcript of several genes. This implies that amino acid forms of the G-quadruplex may have important consequences for protein homeostasis and the diseases caused by their alterations thereof. However, the absence of a suitable model and multitude of predicted physical forms has precluded a comprehensive enumeration and analysis of potential translatable G-quadruplexes. In this manuscript a mathematical model of a short translatable G-quadruplex (TG4) in the protein coding segment of the mRNA of a hypothetical gene is presented. Several novel indices (α, β) are formulated and utilized to categorize and select codons along with the amino acids that they code for. A generic algorithm is then iteratively deployed which computes the entire complement of peptide members that TG4 corresponds to, i.e., PTG4~TG4. The presence, distribution and relevance of this peptidome to protein sequence is investigated by comparing it with disorder promoting short linear motifs. In frame termination codon, co-occurrence, homology and distribution of overlapping/shared amino acids suggests that TG4 (~PTG4) may facilitate misfolding-induced proteostasis. The findings presented rigorously argue for the existence of a unique and potentially clinically relevant peptidome of a short translatable G-quadruplex that could be used as a diagnostic- or prognostic-screen of certain proteopathies.
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Keywords algorithm; codon; G-quadruplex; peptidome; misfolding induced proteopathy; translatable G-quadruplex

Citation: Siddhartha Kundu. Mathematical model of a short translatable G-quadruplex and an assessment of its relevance to misfolding-induced proteostasis. Mathematical Biosciences and Engineering, 2020, 17(3): 2470-2493. doi: 10.3934/mbe.2020135

References

  • 1. E. Y. Lam, D. Beraldi, D. Tannahill, S. Balasubramanian, G-quadruplex structures are stable and detectable in human genomic DNA, Nat. Commun., 4 (2013), 1796.
  • 2. P. Agarwala, S. Pandey, S. Maiti, The tale of RNA G-quadruplex, Org. Biomol. Chem., 13 (2015), 5570-5585.
  • 3. A. Y. Zhang, S. Balasubramanian, The kinetics and folding pathways of intramolecular G-quadruplex nucleic acids, J. Am. Chem. Soc., 134 (2012), 19297-19308.
  • 4. D. Rhodes, H. J. Lipps, G-quadruplexes and their regulatory roles in biology, Nucleic Acids Res., 43 (2015), 8627-8637.
  • 5. S. Millevoi, H. Moine, S. Vagner, G-quadruplexes in RNA biology, Wiley Interdiscip. Rev. RNA, 3 (2012), 495-507.
  • 6. K. Hoogsteen, The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine, Acta Crystallograph., 16 (1963), 907-916.
  • 7. J. Amato, A. Pagano, S. Cosconati, G. Amendola, I. Fotticchia, N. Iaccarino, et al., Discovery of the first dual G-triplex/G-quadruplex stabilizing compound: A new opportunity in the targeting of G-rich DNA structures?, Biochim. Biophys. Acta Gen. Subj., 1861 (2017), 1271-1280.
  • 8. M. Cheng, Y. Cheng, J. Hao, G. Jia, J. Zhou, J. L. Mergny, et al., Loop permutation affects the topology and stability of G-quadruplexes, Nucleic Acids Res., 46 (2018), 9264-9275.
  • 9. S. Pandey, P. Agarwala, S. Maiti, Effect of loops and G-quartets on the stability of RNA G-quadruplexes, J. Phys. Chem. B, 117 (2013), 6896-6905.
  • 10. F. Hao, Y. Ma, Y. Guan, Effects of central loop length and metal ions on the thermal stability of G-quadruplexes, Molecules, 24 (2019).
  • 11. B. A. Tucker, J. S. Hudson, L. Ding, E. Lewis, R. D. Sheardy, E. Kharlampieva, et al., Stability of the Na(+) form of the human telomeric G-quadruplex: Role of adenines in stabilizing G-quadruplex structure, ACS Omega, 3 (2018), 844-855.    
  • 12. A. K. Todd, M. Johnston, S. Neidle, Highly prevalent putative quadruplex sequence motifs in human DNA, Nucleic Acids Res., 33 (2005), 2901-2907.
  • 13. L. Q. Gu, Y. Wang, Biomedical diagnosis perspective of epigenetic detections using alpha-hemolysin nanopore, AIMS Mater. Sci., 2 (2015), 448-472.
  • 14. V. T. Mukundan, A. T. Phan, Bulges in G-quadruplexes: broadening the definition of G-quadruplex-forming sequences, J. Am. Chem. Soc., 135 (2013), 5017-5028.
  • 15. A. Guedin, J. Gros, P. Alberti, J. L. Mergny, How long is too long? Effects of loop size on G-quadruplex stability, Nucleic Acids Res., 38 (2010), 7858-7868.
  • 16. J. M. Garant, M. J. Luce, M. S. Scott, J. P. Perreault, G4RNA: An RNA G-quadruplex database, Database (Oxford), 2015 (2015), bav059.
  • 17. A. Bedrat, L. Lacroix, J. L. Mergny, Re-evaluation of G-quadruplex propensity with G4Hunter, Nucleic Acids Res., 44 (2016), 1746-1759.
  • 18. J. M. Garant, J. P. Perreault, M. S. Scott, Motif independent identification of potential RNA G-quadruplexes by G4RNA screener, Bioinformatics, 33 (2017), 3532-3537.
  • 19. K. Wethmar, A. Barbosa-Silva, M. A. Andrade-Navarro, A. Leutz, uORFdb—a comprehensive literature database on eukaryotic uORF biology, Nucleic Acids Res., 42 (2014), D60-67.
  • 20. J. Ma, C. C. Ward, I. Jungreis, S. A. Slavoff, A. G. Schwaid, J. Neveu, et al., Discovery of human sORF-encoded polypeptides (SEPs) in cell lines and tissue, J. Proteome Res., 13 (2014), 1757-1765.    
  • 21. S. A. Slavoff, A. J. Mitchell, A. G. Schwaid, M. N. Cabili, J. Ma, J. Z. Levin, et al., Peptidomic discovery of short open reading frame-encoded peptides in human cells, Nat. Chem. Biol., 9 (2013), 59-64.
  • 22. M. C. Frith, A. R. Forrest, E. Nourbakhsh, K. C. Pang, C. Kai, J. Kawai, et al., The abundance of short proteins in the mammalian proteome, PLoS Genet., 2 (2006), e52.
  • 23. C. Weldon, J. G. Dacanay, V. Gokhale, P. V. L. Boddupally, I. Behm-Ansmant, G. A. Burley, et al., Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X, Nucleic Acids Res., 46 (2018), 886-896.
  • 24. C. K. Kwok, S. Balasubramanian, Targeted detection of G-quadruplexes in cellular RNAs, Angew. Chem. Int. Ed. Engl., 54 (2015), 6751-6754.
  • 25. G. Mirihana Arachchilage, M. J. Morris, S. Basu, A library screening approach identifies naturally occurring RNA sequences for a G-quadruplex binding ligand, Chem. Commun. (Camb.), 50 (2014), 1250-1252.
  • 26. R. C. Olsthoorn, G-quadruplexes within prion mRNA: The missing link in prion disease?, Nucleic Acids Res., 42 (2014), 9327-9333.
  • 27. T. Endoh, Y. Kawasaki, N. Sugimoto, Stability of RNA quadruplex in open reading frame determines proteolysis of human estrogen receptor alpha, Nucleic Acids Res., 41 (2013), 6222-6231.
  • 28. J. F. Fisette, D. R. Montagna, M. R. Mihailescu, M. S. Wolfe, A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing, J. Neurochem., 121 (2012), 763-773.
  • 29. D. Gomez, A. Guedin, J. L. Mergny, B. Salles, J. F. Riou, M. P. Teulade-Fichou, et al., A G-quadruplex structure within the 5'-UTR of TRF2 mRNA represses translation in human cells, Nucleic Acids Res., 38 (2010), 7187-7198.
  • 30. P. Agarwala, S. Pandey, K. Mapa, S. Maiti, The G-quadruplex augments translation in the 5' untranslated region of transforming growth factor β2, Biochemistry, 52 (2013), 1528-1538.
  • 31. A. Arora, B. Suess, An RNA G-quadruplex in the 3' UTR of the proto-oncogene PIM1 represses translation, RNA Biol., 8 (2011), 802-805.
  • 32. M. J. Morris, S. Basu, An unusually stable G-quadruplex within the 5'-UTR of the MT3 matrix metalloproteinase mRNA represses translation in eukaryotic cells, Biochemistry, 48 (2009), 5313-5319.
  • 33. S. Kumari, A. Bugaut, J. L. Huppert, S. Balasubramanian, An RNA G-quadruplex in the 5' UTR of the NRAS proto-oncogene modulates translation, Nat. Chem. Biol., 3 (2007), 218-221.
  • 34. R. van der Lee, M. Buljan, B. Lang, R. J. Weatheritt, G. W. Daughdrill, A. K. Dunker, et al., Classification of intrinsically disordered regions and proteins, Chem. Rev., 114 (2014), 6589-6631.
  • 35. N. E. Davey, G. Trave, T. J. Gibson, How viruses hijack cell regulation, Trends Biochem. Sci., 36 (2011), 159-169.
  • 36. M. Jucker, L. C. Walker, Self-propagation of pathogenic protein aggregates in neurodegenerative diseases, Nature, 501 (2013), 45-51.
  • 37. M. Goedert, M. G. Spillantini, K. Del Tredici, H. Braak, 100 years of Lewy pathology, Nat. Rev. Neurol., 9 (2013), 13-24.
  • 38. D. Piovesan, F. Tabaro, I. Micetic, M. Necci, F. Quaglia, C. J. Oldfield, et al., DisProt 7.0: A major update of the database of disordered proteins, Nucleic Acids Res., 45 (2017), D219-D227.
  • 39. S. Hutchinson, A. Furger, D. Halliday, D. P. Judge, A. Jefferson, H. C. Dietz, et al., Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: A potential modifier of phenotype?, Hum. Mol. Genet., 12 (2003), 2269-2276.
  • 40. Y. F. Chang, J. S. Imam, M. F. Wilkinson, The nonsense-mediated decay RNA surveillance pathway, Annu. Rev. Biochem., 76 (2007), 51-74.
  • 41. M. M. Klein, A. G. Gittis, H. P. Su, M. O. Makobongo, J. M. Moore, S. Singh, et al., The cysteine-rich interdomain region from the highly variable plasmodium falciparum erythrocyte membrane protein-1 exhibits a conserved structure, PLoS Pathog., 4 (2008), e1000147.
  • 42. J. A. Corcoran, R. Syvitski, D. Top, R. M. Epand, R. F. Epand, D. Jakeman, et al., Myristoylation, a protruding loop, and structural plasticity are essential features of a nonenveloped virus fusion peptide motif, J. Biol. Chem., 279 (2004), 51386-51394.
  • 43. K. A. Morrow, C. D. Ochoa, R. Balczon, C. Zhou, L. Cauthen, M. Alexeyev, et al., Pseudomonas aeruginosa exoenzymes U and Y induce a transmissible endothelial proteinopathy, Am. J. Physiol. Lung Cell Mol. Physiol., 310 (2016), L337-353.
  • 44. A. L. Woerman, S. A. Kazmi, S. Patel, A. Aoyagi, A. Oehler, K. Widjaja, D. A. Mordes, et al., Familial Parkinson's point mutation abolishes multiple system atrophy prion replication, Proc. Natl. Acad. Sci. U S A, 115 (2018), 409-414.
  • 45. J. D. Beaudoin, J. P. Perreault, Exploring mRNA 3'-UTR G-quadruplexes: evidence of roles in both alternative polyadenylation and mRNA shortening, Nucleic Acids Res., 41 (2013), 5898-5911.
  • 46. J. D. Beaudoin, R. Jodoin, J. P. Perreault, New scoring system to identify RNA G-quadruplex folding, Nucleic Acids Res., 42 (2014), 1209-1223.
  • 47. R. Shahid, A. Bugaut, S. Balasubramanian, The BCL-2 5' untranslated region contains an RNA G-quadruplex-forming motif that modulates protein expression, Biochemistry, 49 (2010), 8300-8306.
  • 48. S. Saxena, D. Miyoshi, N. Sugimoto, Sole and stable RNA duplexes of G-rich sequences located in the 5'-untranslated region of protooncogenes, Biochemistry, 49 (2010), 7190-7201.
  • 49. J. D. Beaudoin, J. P. Perreault, 5'-UTR G-quadruplex structures acting as translational repressors, Nucleic Acids Res., 38 (2010), 7022-7036.
  • 50. R. Jodoin, L. Bauer, J. M. Garant, A. Mahdi Laaref, F. Phaneuf, J. P. Perreault, The folding of 5'-UTR human G-quadruplexes possessing a long central loop, RNA, 20 (2014), 1129-1141.
  • 51. D. Bhattacharyya, P. Diamond, S. Basu, An Independently folding RNA G-quadruplex domain directly recruits the 40S ribosomal subunit, Biochemistry, 54 (2015), 1879-1885.
  • 52. A. Cammas, A. Dubrac, B. Morel, A. Lamaa, C. Touriol, M. P. Teulade-Fichou, et al., Stabilization of the G-quadruplex at the VEGF IRES represses cap-independent translation, RNA Biol., 12 (2015), 320-329.
  • 53. M. J. Morris, Y. Negishi, C. Pazsint, J. D. Schonhoft, S. Basu, An RNA G-quadruplex is essential for cap-independent translation initiation in human VEGF IRES, J. Am. Chem. Soc., 132 (2010), 17831-17839.
  • 54. J. Christiansen, M. Kofod, F. C. Nielsen, A guanosine quadruplex and two stable hairpins flank a major cleavage site in insulin-like growth factor II mRNA, Nucleic Acids Res., 22 (1994), 5709-5716.
  • 55. S. Lammich, F. Kamp, J. Wagner, B. Nuscher, S. Zilow, A. K. Ludwig, et al., Translational repression of the disintegrin and metalloprotease ADAM10 by a stable G-quadruplex secondary structure in its 5'-untranslated region, J. Biol. Chem., 286 (2011), 45063-45072.
  • 56. P. Agarwala, S. Pandey, S. Maiti, Role of G-quadruplex located at 5' end of mRNAs, Biochim. Biophys. Acta, 1840 (2014), 3503-3510.
  • 57. M. Subramanian, F. Rage, R. Tabet, E. Flatter, J. L. Mandel, H. Moine, G-quadruplex RNA structure as a signal for neurite mRNA targeting, EMBO Rep., 12 (2011), 697-704.
  • 58. A. von Hacht, O. Seifert, M. Menger, T. Schutze, A. Arora, Z. Konthur, et al., Identification and characterization of RNA guanine-quadruplex binding proteins, Nucleic Acids Res., 42 (2014), 6630-6644.
  • 59. S. Balaratnam, S. Basu, Divalent cation-aided identification of physico-chemical properties of metal ions that stabilize RNA G-quadruplexes, Biopolymers, 103 (2015), 376-386.
  • 60. S. Stefanovic, G. J. Bassell, M. R. Mihailescu, G quadruplex RNA structures in PSD-95 mRNA: potential regulators of miR-125a seed binding site accessibility, RNA, 21 (2015), 48-60.
  • 61. J. C. Grigg, N. Shumayrikh, D. Sen, G-quadruplex structures formed by expanded hexanucleotide repeat RNA and DNA from the neurodegenerative disease-linked C9orf72 gene efficiently sequester and activate heme, PLoS One, 9 (2014), e106449.
  • 62. P. Fratta, S. Mizielinska, A. J. Nicoll, M. Zloh, E. M. Fisher, G. Parkinson, et al., C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes, Sci. Rep., 2 (2012), 1016.
  • 63. H. Y. Weng, H. L. Huang, P. P. Zhao, H. Zhou, L. H. Qu, Translational repression of cyclin D3 by a stable G-quadruplex in its 5' UTR: implications for cell cycle regulation, RNA Biol., 9 (2012), 1099-1109.
  • 64. H. H. Woo, T. Baker, C. Laszlo, S. K. Chambers, Nucleolin mediates microRNA-directed CSF-1 mRNA deadenylation but increases translation of CSF-1 mRNA, Mol. Cell Proteomics, 12 (2013), 1661-1677.
  • 65. H. Dhayan, A. R. Baydoun, A. Kukol, G-quadruplex formation of FXYD1 pre-mRNA indicates the possibility of regulating expression of its protein product, Arch. Biochem. Biophys., 560 (2014), 52-58.
  • 66. S. G. Rouleau, J. D. Beaudoin, M. Bisaillon, J. P. Perreault, Small antisense oligonucleotides against G-quadruplexes: specific mRNA translational switches, Nucleic Acids Res., 43 (2015), 595-606.
  • 67. J. Kralovicova, A. Lages, A. Patel, A. Dhir, E. Buratti, M. Searle, et al., Optimal antisense target reducing INS intron 1 retention is adjacent to a parallel G quadruplex, Nucleic Acids Res., 42 (2014), 8161-8173.
  • 68. M. Faudale, S. Cogoi, L. E. Xodo, Photoactivated cationic alkyl-substituted porphyrin binding to g4-RNA in the 5'-UTR of KRAS oncogene represses translation, Chem. Commun. (Camb.), 48 (2012), 874-876.
  • 69. M. M. Ribeiro, G. S. Teixeira, L. Martins, M. R. Marques, A. P. de Souza, S. R. Line, G-quadruplex formation enhances splicing efficiency of PAX9 intron 1, Hum. Genet., 134 (2015), 37-44.
  • 70. E. P. Booy, R. Howard, O. Marushchak, E. O. Ariyo, M. Meier, S. K. Novakowski, et al., The RNA helicase RHAU (DHX36) suppresses expression of the transcription factor PITX1, Nucleic Acids Res., 42 (2014), 3346-3361.
  • 71. Y. Zhang, C. M. Gaetano, K. R. Williams, G. J. Bassell, M. R. Mihailescu, FMRP interacts with G-quadruplex structures in the 3'-UTR of its dendritic target Shank1 mRNA, RNA Biol., 11 (2014), 1364-1374.
  • 72. H. Martadinata, A. T. Phan, Formation of a stacked dimeric G-quadruplex containing bulges by the 5'-terminal region of human telomerase RNA (hTERC), Biochemistry, 53 (2014), 1595-1600.
  • 73. K. Hirashima, H. Seimiya, Telomeric repeat-containing RNA/G-quadruplex-forming sequences cause genome-wide alteration of gene expression in human cancer cells in vivo, Nucleic Acids Res., 43 (2015), 2022-2032.
  • 74. Y. Katsuda, S. Sato, L. Asano, Y. Morimura, T. Furuta, H. Sugiyama, et al., A Small Molecule That Represses Translation of G-Quadruplex-Containing mRNA, J. Am. Chem. Soc., 138 (2016), 9037-9040.
  • 75. C. K. Kwok, A. B. Sahakyan, S. Balasubramanian, Structural Analysis using SHALiPE to Reveal RNA G-Quadruplex Formation in Human Precursor MicroRNA, Angew. Chem. Int. Ed. Engl., 55 (2016), 8958-8961.
  • 76. P. Agarwala, S. Kumar, S. Pandey, S. Maiti, Human telomeric RNA G-quadruplex response to point mutation in the G-quartets, J. Phys. Chem. B, 119 (2015), 4617-4627.
  • 77. V. Marcel, P. L. Tran, C. Sagne, G. Martel-Planche, L. Vaslin, M. P. Teulade-Fichou, et al., G-quadruplex structures in TP53 intron 3: role in alternative splicing and in production of p53 mRNA isoforms, Carcinogenesis, 32 (2011), 271-278.
  • 78. A. Decorsiere, A. Cayrel, S. Vagner, S. Millevoi, Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3'-end processing and function during DNA damage, Genes Dev., 25 (2011), 220-225.
  • 79. W. Huang, P. J. Smaldino, Q. Zhang, L. D. Miller, P. Cao, K. Stadelman, et al., Yin Yang 1 contains G-quadruplex structures in its promoter and 5'-UTR and its expression is modulated by G4 resolvase 1, Nucleic Acids Res., 40 (2012), 1033-1049.
  • 80. A. Arora, M. Dutkiewicz, V. Scaria, M. Hariharan, S. Maiti, J. Kurreck, Inhibition of translation in living eukaryotic cells by an RNA G-quadruplex motif, RNA, 14 (2008), 1290-1296.

 

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