Article thumbnail

Mistranslation and its control by tRNA synthetases

By Paul Schimmel


Aminoacyl tRNA synthetases are ancient proteins that interpret the genetic material in all life forms. They are thought to have appeared during the transition from the RNA world to the theatre of proteins. During translation, they establish the rules of the genetic code, whereby each amino acid is attached to a tRNA that is cognate to the amino acid. Mistranslation occurs when an amino acid is attached to the wrong tRNA and subsequently is misplaced in a nascent protein. Mistranslation can be toxic to bacteria and mammalian cells, and can lead to heritable mutations. The great challenge for nature appears to be serine-for-alanine mistranslation, where even small amounts of this mistranslation cause severe neuropathologies in the mouse. To minimize serine-for-alanine mistranslation, powerful selective pressures developed to prevent mistranslation through a special editing activity imbedded within alanyl-tRNA synthetases (AlaRSs). However, serine-for-alanine mistranslation is so challenging that a separate, genome-encoded fragment of the editing domain of AlaRS is distributed throughout the Tree of Life to redundantly prevent serine-to-alanine mistranslation. Detailed X-ray structural and functional analysis shed light on why serine-for-alanine mistranslation is a universal problem, and on the selective pressures that engendered the appearance of AlaXps at the base of the Tree of Life

Topics: Articles
Publisher: The Royal Society
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. 6A h e l ,I . ,K o r e n c i c ,D .
  2. (2004). A domain for editing by an archaebacterial tRNA synthetase.
  3. A freestanding proofreading domain is required for protein synthesis quality control in Archaea.
  4. (1988). A simple structural feature is a major determinant of the identity of a transfer RNA.
  5. (2007). An editing-defective aminoacyl-tRNA synthetase is mutagenic in aging bacteria via the SOS response.
  6. (2003). An isolated class II aminoacyl-tRNA synthetase insertion domain is functional in amino acid editing.
  7. (2004). Artificially ambiguous genetic code confers growth yield advantage.
  8. (1999). Atomic determinants for aminoacylation of RNA minihelices and relationship to genetic code.
  9. (1988). Changing the acceptor identity of a transfer RNA by altering nucleotides in a ‘variable pocket’.
  10. (1993). Cognition, mechanism, and evolutionary relationships in aminoacyl-tRNA synthetases.
  11. (2008). CP1-dependent partitioning of pretransfer and posttransfer editing in leucyl-tRNA synthetase.
  12. (1994). Crystal structures at 2.5 A ˚ resolution of seryl-tRNA synthetase complexed with two analogs of seryl adenylate.
  13. (2005). Cys-tRNA(Pro) editing by Haemophilus influenzae YbaK via a novel synthetase.YbaK.tRNA ternary complex.
  14. Distinct domains of tRNA synthetase recognize the same base pair.
  15. Driving change: the evolution of alternative genetic codes.
  16. (1977). Editing mechanisms in protein synthesis. Rejection of valine by the isoleucyl-tRNA synthetase.
  17. (1992). Editing of errors in selection of amino acids for protein synthesis.
  18. (2006). Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.
  19. (2003). Elucidation of tRNA-dependent editing by a class II tRNA synthetase and significance for cell viability.
  20. (1989). Evidence that a major determinant for the identity of a transfer RNA is conserved in evolution.
  21. (2002). Genetic code ambiguity. Cell viability related to the severity of editing defects in mutant tRNA synthetases.
  22. (2006). Global effects of mistranslation from an editing defect in mammalian cells.
  23. (1995). Human alanyl-tRNA synthetase: conservation in evolution of catalytic core and microhelix recognition.
  24. (2005). Molecular basis of alanine discrimination in editing site.
  25. (1994). Mutational isolation of a sieve for editing in a transfer RNA synthetase.
  26. (2002). Mutational separation of two pathways for editing by a class I tRNA synthetase.
  27. (2008). Natural homolog of tRNA synthetase editing domain rescues conditional lethality caused by mistranslation.
  28. (2011). p23 H implicated as cis/trans regulator of AlaXpdirected editing for mammalian cell homeostasis.
  29. (1981). Probing the principles of amino acid selection using the alanyl-tRNA synthetase from Escherichia coli.
  30. (1999). Quality control mechanisms during translation.
  31. (2009). Resampling and editing of mischarged tRNA prior to translation elongation.
  32. (1972). Review. Control of mistranslation
  33. (2007). Structure of the AlaX-M trans-editing enzyme from Pyrococcus horikoshii. Acta Crystallogr.
  34. (2003). Structurespecific tRNA determinants for editing a mischarged amino acid.
  35. (2010). The balance between pre- and post-transfer editing in tRNA synthetases.
  36. (2009). The C-Ala domain brings together editingandaminoacylationfunctionsononetRNA.Science
  37. (2006). The early history of tRNA recognition by aminoacyl-tRNA synthetases.
  38. (1972). Transfer ribonucleic acid synthetase catalyzed deacylation of aminoacyl transfer ribonucleic acid in the absence of adenosine monophosphate and pyrophosphate.
  39. (1976). Transfer RNA: molecular structure, sequence, and properties.
  40. (2001). Two classes of tRNA synthetases suggested by sterically compatible dockings on tRNA acceptor stem.
  41. (2009). Unique protein architecture of alanyl-tRNA synthetase for aminoacylation, editing, and dimerization.
  42. (1995). Wide cross-species aminoacyl-tRNA synthetase replacement in vivo: yeast cytoplasmic alanine enzyme replaced by human polymyositis serum antigen.
  43. (2000). Zinc ion mediated amino acid discrimination by threonyl-tRNA synthetase.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.