Quality control by the ribosome following peptide bond formation

The overall fidelity of protein synthesis has been thought to rely on the combined accuracy of two basic processes: the aminoacylation of transfer RNAs with their cognate amino acid by the aminoacyl- tRNA synthetases, and the selection of cognate aminoacyl- tRNAs by the ribosome in cooperation with the GTPase elongation factor EF- Tu. These two processes, which together ensure the specific acceptance of a correctly charged cognate tRNA into the aminoacyl ( A) site, operate before peptide bond formation. Here we report the identification of an additional mechanism that contributes to high fidelity protein synthesis after peptidyl transfer, using a well- defined in vitro bacterial translation system. In this retrospective quality control step, the incorporation of an amino acid from a non- cognate tRNA into the growing polypeptide chain leads to a general loss of specificity in the A site of the ribosome, and thus to a propagation of errors that results in abortive termination of protein synthesis.