GSE133370
Pairs of amino acids at the P- and A-sites of the ribosome predictably and causally modulate translation-elongation rates
Variation in translation-elongation kinetics along a transcript's coding sequence plays an important role in the maintenance of cellular protein homeostasis by regulating co-translational protein folding, localization, and maturation. Translation-elongation speed is influenced by molecular factors within mRNA and protein sequences. For example, when proline is present in the ribosome's P- or A-site translation slows down, but the effect of other pairs of amino acids, in the context of all 400 possible pairs, has not been characterized. Here, we study Saccharomyces cerevisiae using a combination of mutational experiments, bioinformatics, and evolutionary analyses, and show that many different pairs of amino acids and their associated tRNA molecules predictably and causally encode translation rate information when these pairs are present in the A- and P-sites of the ribosome independent of other factors known to influence translation speed, including mRNA structure, wobble base pairing, tripeptide motifs, positively charged upstream nascent chain residues, and cognate tRNA concentration. The fast-translating pairs of amino acids that we identify are enriched seven-fold relative to the slow-translating pairs across Saccharomyces cerevisiae's proteome, while the slow-translating pairs are enriched downstream of domain boundaries. Thus, the chemical identity of amino acid pairs contributes to variability in translation rates, elongation kinetics are causally encoded in the primary structure of proteins, and signatures of evolutionary selection indicate their potential role in co-translational processes. Overall design: Ribosome profiling of mutant strains with mutations spread across 5 genes in S288C yeast cells