Mistranslation of the genetic code

Abstract

During mRNA decoding at the ribosome, deviations from stringent codon identity, or "mistranslation," are generally deleterious and infrequent. Observations of organisms that decode some codons ambiguously, and the discovery of a compensatory increase in mistranslation frequency to combat environmental stress have changed the way we view "errors" in decoding. Modern tools for the study of the frequency and phenotypic effects of mistranslation can provide quantitative and sensitive measurements of decoding errors that were previously inaccessible. Mistranslation with non-protein amino acids, in particular, is an enticing prospect for new drug therapies and the study of molecular evolution.

Keywords: Amino acid; Mistranslation; Protein synthesis; Quality control; Translation; tRNA.

Figure 1. Aminoacyl-tRNA synthesis and quality control mechanisms

aa-tRNA synthesis is a two-step process, with checkpoints at each step to ensure proper product formation. An aminoacyl-adenylate formed by the activation of a noncognate amino acid may be hydrolyzed by pre-transfer editing mechanisms in the active site of the aaRS. Misactivated amino acids that escape pre-transfer editing may be acylated to tRNA, forming aa-tRNA. If an aaRS bears a post-transfer editing domain, mispaired aa-tRNA may be hydrolyzed, releasing the amino acid and tRNA.

Figure 2. Non-protein amino acids as a threat to quality control in aminoacyl-tRNA synthesis

NPAs that pose a threat to translational fidelity bear similar physiochemical and structural features compared to cognate amino acids. E. coli PheRS post-transfer editing activity prevents release of tRNA^Phe charged with the NPA m-Tyr, which differs from cognate Phe by a single oxygen atom [11]. E. coli LeuRS post-transfer editing activity prevents release of tRNA^Leu charged with norvaline, which differs from cognate Leu by a methylene group [56, 58].

Figure 3. Mistranslation and the statistical proteome

Represented here are various copies of a single protein arising from translation in low- or high-frequency mistranslation systems. Amino acids inserted at appropriate codons are shown as blue. Inappropriately inserted amino acids are represented as green and red. Typical mistranslation is infrequent, resulting in protein populations with minor variability. In organisms that naturally mistranslate more frequently [7, 10], or in conditions that promote less stringent quality control [12, 23, 25, 26], protein populations become more diverse in their primary sequences. Proteins arising from “statistical proteomes” have various folding and binding properties, resulting in phenotypic diversity in the host organism. Expanded to include all proteins in a cell, the effects of mistranslation can be drastic at the molecular and cellular levels.