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Accuracy of genetic code translation and its orthogonal corruption by aminoglycosides and Mg2+ ions

Jingji Zhang1, Michael Y Pavlov1, Måns Ehrenberg1

  • 1Department of Cell and Molecular Biology, Uppsala University, Husargatan 3, Box 596, Uppsala 75124, Sweden.

Nucleic Acids Research
|December 22, 2017
PubMed

Insights

Aminoglycosides and magnesium ions reduce translation accuracy through distinct mechanisms. Aminoglycosides alter rRNA base interactions, while magnesium slows elongation factor dissociation, impacting protein synthesis fidelity.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • Accurate protein synthesis relies on precise codon selection by aminoacyl-tRNA.
  • Elongation factor Tu (EF-Tu) facilitates ternary complex (aminoacyl-tRNA, EF-Tu, GTP) binding to ribosomes.
  • Aminoglycosides and magnesium ions are known modulators of ribosomal function.

Purpose of the Study:

  • To investigate the distinct effects of aminoglycosides and Mg2+ concentration on the accuracy of initial codon selection.
  • To elucidate the molecular mechanisms by which these factors influence translational fidelity.
  • To re-evaluate existing biochemical data and structural insights in light of new findings.

Main Methods:

  • Biochemical assays measuring ternary complex binding and dissociation kinetics.
  • Analysis of 16S rRNA 'monitoring base' interactions.
  • Thermodynamic modeling to estimate intrinsic ribosomal selectivity.

Main Results:

  • Aminoglycosides decrease accuracy by stabilizing an 'activated' state of rRNA monitoring bases (A1492, A1493, G530) via specific factors.
  • Increased Mg2+ concentration reduces accuracy by slowing EF-Tu dissociation from the ribosome, independent of codon identity.
  • These distinct mechanisms suggest aminoglycosides reduce expressed accuracy without altering intrinsic ribosomal selectivity.

Conclusions:

  • Aminoglycosides and Mg2+ employ separate pathways to impair translational accuracy.
  • The ribosome possesses an 'intrinsic selectivity' that aminoglycosides do not change but reduce its expression.
  • Induced fit mechanisms may enhance codon reading accuracy and speed while maintaining intrinsic selectivity.

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