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New functions of aminoacyl-tRNA synthetases beyond translation

Nature Reviews Molecular Cell Biology volume 11, pages 668–674 (2010)Cite this article

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Abstract

Over the course of evolution, eukaryotic aminoacyl-tRNA synthetases (aaRSs) progressively incorporated domains and motifs that have no essential connection to aminoacylation reactions. Their accretive addition to virtually all aaRSs correlates with the progressive evolution and complexity of eukaryotes. Based on recent experimental findings focused on a few of these additions and analysis of the aaRS proteome, we propose that they are markers for aaRS-associated functions beyond translation.

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Figure 1: Domain additions to specific higher eukaryote aminoacyl-tRNA synthetases.
Figure 2: Temporal elaboration of new domains for all aaRSs and the increasing complexity of organisms.
Figure 3: Sequence extensions of human ribosomal proteins, eukaryotic markers, amino acid-binding proteins and aaRSs.

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References

  1. Carter, C. W. Jr. Cognition, mechanism, and evolutionary relationships in aminoacyl-tRNA synthetases. Annu. Rev. Biochem. 62, 715–748 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Woese, C. R., Olsen, G. J., Ibba, M. & Söll, D. Aminoacyl-tRNA synthetases, the genetic code, and the evolutionary process. Microbiol. Mol. Biol. Rev. 64, 202–236 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rodin, S. N. & Ohno, S. Two types of aminoacyl-tRNA synthetases could be originally encoded by complementary strands of the same nucleic acid. Orig. Life Evol. Biosph. 25, 565–589 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Pham, Y. et al. A minimal TrpRS catalytic domain supports sense/antisense ancestry of class I and II aminoacyl-tRNA synthetases. Mol. Cell 25, 851–862 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Ribas de Pouplana, L. & Schimmel, P. Two classes of tRNA synthetases suggested by sterically compatible dockings on tRNA acceptor stem. Cell 104, 191–193 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Terada, T. et al. Functional convergence of two lysyl-tRNA synthetases with unrelated topologies. Nature Struct. Biol. 9, 257–262 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Ling, J., Reynolds, N. & Ibba, M. Aminoacyl-tRNA synthesis and translational quality control. Annu. Rev. Microbiol. 63, 61–78 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Guo, M. et al. The C-Ala domain brings together editing and aminoacylation functions on one tRNA. Science 325, 744–747 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guo, M., Schimmel, P. & Yang, X. L. Functional expansion of human tRNA synthetases achieved by structural inventions. FEBS Lett. 584, 434–442 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rho, S. B. et al. Genetic dissection of protein–protein interactions in multi-tRNA synthetase complex. Proc. Natl Acad. Sci. USA 96, 4488–4493 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kao, J. et al. Characterization of a novel tumor-derived cytokine. Endothelial-monocyte activating polypeptide II. J. Biol. Chem. 269, 25106–25119 (1994).

    CAS  PubMed  Google Scholar 

  12. Ko, Y. G., Park, H. & Kim, S. Novel regulatory interactions and activities of mammalian tRNA synthetases. Proteomics 2, 1304–1310 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Kim, M. J. et al. Downregulation of FUSE-binding protein and c-Myc by tRNA synthetase cofactor p38 is required for lung cell differentiation. Nature Genet. 34, 330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Park, B. J. et al. The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell 120, 209–221 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Zhu, X. et al. MSC p43 required for axonal development in motor neurons. Proc. Natl Acad. Sci. USA 106, 15944–15949 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wakasugi, K. & Schimmel, P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science 284, 147–151 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Wakasugi, K. & Schimmel, P. Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase. J. Biol. Chem. 274, 23155–23159 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Kapoor, M., Otero, F. J., Slike, B. M., Ewalt, K. L. & Yang, X. L. Mutational separation of aminoacylation and cytokine activities of human tyrosyl-tRNA synthetase. Chem. Biol. 16, 531–539 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wakasugi, K. et al. Induction of angiogenesis by a fragment of human tyrosyl-tRNA synthetase. J. Biol. Chem. 277, 20124–20126 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Strieter, R. M. et al. CXC chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer. Ann. NY Acad. Sci. 1028, 351–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Tandle, A. T. et al. Endothelial monocyte activating polypeptide-II modulates endothelial cell responses by degrading hypoxia-inducible factor-1α through interaction with PSMA7, a component of the proteasome. Exp. Cell Res. 315, 1850–1859 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Yang, X. L., Skene, R. J., McRee, D. E. & Schimmel, P. Crystal structure of a human aminoacyl-tRNA synthetase cytokine. Proc. Natl Acad. Sci. USA 99, 15369–15374 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang, X. L. et al. Gain-of-function mutational activation of human tRNA synthetase procytokine. Chem. Biol. 14, 1323–1333 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fleckner, J., Rasmussen, H. H. & Justesen, J. Human interferon γ potently induces the synthesis of a 55-kDa protein (γ2) highly homologous to rabbit peptide chain release factor and bovine tryptophanyl-tRNA synthetase. Proc. Natl Acad. Sci. USA 88, 11520–11524 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wakasugi, K. et al. A human aminoacyl-tRNA synthetase as a regulator of angiogenesis. Proc. Natl Acad. Sci. USA 99, 173–177 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kise, Y. et al. A short peptide insertion crucial for angiostatic activity of human tryptophanyl-tRNA synthetase. Nature Struct. Mol. Biol. 11, 149–156 (2004).

    Article  CAS  Google Scholar 

  27. Dorrell, M. I., Aguilar, E., Scheppke, L., Barnett, F. H. & Friedlander, M. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc. Natl Acad. Sci. USA 104, 967–972 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tzima, E. et al. VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. J. Biol. Chem. 280, 2405–2408 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Zhou, Q. et al. Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality. Nature Struct. Mol. Biol. 17, 57–61 (2010).

    Article  CAS  Google Scholar 

  30. Yang, X. L. et al. Crystal structures that suggest late development of genetic code components for differentiating aromatic side chains. Proc. Natl Acad. Sci. USA 100, 15376–15380 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cerini, C., Semeriva, M. & Gratecos, D. Evolution of the aminoacyl-tRNA synthetase family and the organization of the Drosophila glutamyl-prolyl-tRNA synthetase gene. Intron/exon structure of the gene, control of expression of the two mRNAs, selective advantage of the multienzyme complex. Eur. J. Biochem. 244, 176–185 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Cerini, C. et al. A component of the multisynthetase complex is a multifunctional aminoacyl-tRNA synthetase. EMBO J. 10, 4267–4277 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mukhopadhyay, R., Jia, J., Arif, A., Ray, P. S. & Fox, P. L. The GAIT system: a gatekeeper of inflammatory gene expression. Trends. Biochem. Sci. 34, 324–331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jia, J., Arif, A., Ray, P. S. & Fox, P. L. WHEP domains direct noncanonical function of glutamyl-prolyl tRNA synthetase in translational control of gene expression. Mol. Cell 29, 679–690 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ray, P. S. et al. A stress-responsive RNA switch regulates VEGFA expression. Nature 457, 915–919 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Kleiman, L. & Cen, S. The tRNALys packaging complex in HIV-1. Int. J. Biochem. Cell Biol. 36, 1776–1786 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Park, S. G. et al. Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response. Proc. Natl Acad. Sci. USA 102, 6356–6361 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yannay-Cohen, N. et al. LysRS serves as a key signaling molecule in the immune response by regulating gene expression. Mol. Cell 34, 603–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Amsterdam, A. et al. Identification of 315 genes essential for early zebrafish development. Proc. Natl Acad. Sci. USA 101, 12792–12797 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fukui, H., Hanaoka, R. & Kawahara, A. Noncanonical activity of seryl-tRNA synthetase is involved in vascular development. Circ. Res. 104, 1253–1259 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Herzog, W., Muller, K., Huisken, J. & Stainier, D. Y. Genetic evidence for a noncanonical function of seryl-tRNA synthetase in vascular development. Circ. Res. 104, 1260–1266 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nilsen, T. W. & Graveley, B. R. Expansion of the eukaryotic proteome by alternative splicing. Nature 463, 457–463 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Koonin, E. V. Orthologs, paralogs, and evolutionary genomics. Annu. Rev. Genet. 39, 309–338 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Hu, S. et al. Profiling the human protein–DNA interactome reveals ERK2 as a transcriptional repressor of interferon signaling. Cell 139, 610–622 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Radisky, D. C., Stallings-Mann, M., Hirai, Y. & Bissell, M. J. Single proteins might have dual but related functions in intracellular and extracellular microenvironments. Nature Rev. Mol. Cell Biol. 10, 228–234 (2009).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  47. Jeffery, C. J. Moonlighting proteins. Trends Biochem. Sci. 24, 8–11 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Jeffery, C. J. Moonlighting proteins: old proteins learning new tricks. Trends Genet. 19, 415–417 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Jeffery, C. J. Moonlighting proteins — an update. Mol. Biosyst. 5, 345–350 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Bashton, M. & Chothia, C. The generation of new protein functions by the combination of domains. Structure 15, 85–99 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Warner, J. R. & McIntosh, K. B. How common are extraribosomal functions of ribosomal proteins? Mol. Cell 34, 3–11 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Blumenthal, T. & Carmichael, G. G. RNA replication: function and structure of Qβ-replicase. Annu. Rev. Biochem. 48, 525–548 (1979).

    Article  CAS  PubMed  Google Scholar 

  53. Wool, I. G. Extraribosomal functions of ribosomal proteins. Trends Biochem. Sci. 21, 164–165 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Sampath, P. et al. Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation. Cell 119, 195–208 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Mukhopadhyay, R. et al. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol. Cell 32, 371–382 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tekle, Y. I., Grant, J. R., Kovner, A. M., Townsend, J. P. & Katz, L. A. Identification of new molecular markers for assembling the eukaryotic tree of life. Mol. Phylogenet. Evol. 55, 1177–1182 (2010).

    Article  CAS  PubMed  Google Scholar 

  57. Kaminska, M., Shalak, V. & Mirande, M. The appended C-domain of human methionyl-tRNA synthetase has a tRNA-sequestering function. Biochemistry 40, 14309–14316 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Kyriacou, S. V. & Deutscher, M. P. An important role for the multienzyme aminoacyl-tRNA synthetase complex in mammalian translation and cell growth. Mol. Cell 29, 419–427 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ko, Y. G. et al. Glutamine-dependent antiapoptotic interaction of human glutaminyl-tRNA synthetase with apoptosis signal-regulating kinase 1. J. Biol. Chem. 276, 6030–6036 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Antonellis, A. et al. Glycyl tRNA synthetase mutations in Charcot–Marie–Tooth disease type 2D and distal spinal muscular atrophy type V. Am. J. Hum. Genet. 72, 1293–1299 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Park, S. G., Schimmel, P. & Kim, S. Aminoacyl tRNA synthetases and their connections to disease. Proc. Natl Acad. Sci. USA 105, 11043–11049 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Antonellis, A. & Green, E. D. The role of aminoacyl-tRNA synthetases in genetic diseases. Annu. Rev. Genomics Hum. Genet. 9, 87–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Seburn, K. L., Nangle, L. A., Cox, G. A., Schimmel, P. & Burgess, R. W. An active dominant mutation of glycyl-tRNA synthetase causes neuropathy in a Charcot–Marie–Tooth 2D mouse model. Neuron 51, 715–726 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Nangle, L. A., Zhang, W., Xie, W., Yang, X. L. & Schimmel, P. Charcot–Marie–Tooth disease-associated mutant tRNA synthetases linked to altered dimer interface and neurite distribution defect. Proc. Natl Acad. Sci. USA 104, 11239–11244 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Storkebaum, E. et al. Dominant mutations in the tyrosyl-tRNA synthetase gene recapitulate in Drosophila features of human Charcot–Marie–Tooth neuropathy. Proc. Natl Acad. Sci. USA 106, 11782–11787 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants GM 15539, GM 23562 and U54RR025204 from the National Institutes of Health, grant CA92577 from the National Cancer Institute and a fellowship from the National Foundation for Cancer Research.

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  1. Xiang-Lei Yang and Paul Schimmel are at The Skaggs Institute for Chemical Biology and Department of Molecular Biology, Min Guo, The Scripps Research Institute, La Jolla, California 92037, USA.,

    Min Guo, Xiang-Lei Yang & Paul Schimmel

  2. Min Guo is also at The Department of Cancer Biology, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.,

    Min Guo

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Guo, M., Yang, XL. & Schimmel, P. New functions of aminoacyl-tRNA synthetases beyond translation. Nat Rev Mol Cell Biol 11, 668–674 (2010). https://doi.org/10.1038/nrm2956

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