Systematic Detection of Amino Acid Substitutions in Proteomes Reveals Mechanistic Basis of Ribosome Errors and Selection for Translation Fidelity

Ernest Mordret, Orna Dahan, Omer Asraf, Roni Rak, Avia Yehonadav, Georgina D. Barnabas, Jürgen Cox, T. Geiger*, Ariel B. Lindner, Yitzhak Pilpel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The translation machinery and the genes it decodes co-evolved to achieve production throughput and accuracy. Nonetheless, translation errors are frequent, and they affect physiology and protein evolution. Mapping translation errors in proteomes and understanding their causes is hindered by lack of a proteome-wide experimental methodology. We present the first methodology for systematic detection and quantification of errors in entire proteomes. Following proteome mass spectrometry, we identify, in E. coli and yeast, peptides whose mass indicates specific amino acid substitutions. Most substitutions result from codon-anticodon mispairing. Errors occur at sites that evolve rapidly and that minimally affect energetic stability, indicating selection for high translation fidelity. Ribosome density data show that errors occur at sites where ribosome velocity is higher, demonstrating a trade-off between speed and accuracy. Treating bacteria with an aminoglycoside antibiotic or deprivation of specific amino acids resulted in particular patterns of errors. These results reveal a mechanistic and evolutionary basis for translation fidelity. Errors in translation are common, occurring almost once per protein. Mordret et al. have developed a methodology to detect and quantify translation errors and applied it to bacteria and yeast. Errors appear to be programmed, reduced in highly expressed proteins and conserved protein sites. Codon identity and ribosome speed participate in governing a protein translation fidelity code.

Original languageEnglish
Pages (from-to)427-441.e5
JournalMolecular Cell
Volume75
Issue number3
DOIs
StatePublished - 8 Aug 2019

Keywords

  • anticodon
  • codon
  • fidelity
  • mass spectrometry
  • misloading
  • mispairing
  • ribosome errors
  • tRNA
  • translation

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