Translation rate is genetically encoded and influences protein folding
The degeneracy of the genetic code allows most amino acids to be encoded by multiple codons. The distribution of these so-called synonymous codons among protein coding sequences is not random and multiple theories have arisen to explain the biological significance of such non-uniform codon selection. Many ideas revolve around the notion that certain codons allow for faster or more efficient translation, whereas the presence of others result in slower translation rates. The presence of these different types of codons along a message is postulated in turn to confer variable rates of emergence of the nascent polypeptide from the ribosome, which may influence its capacity to fold towards the native state, among other properties. Previous studies have reported conflicting results with regards to whether certain kinds of codons correlate or not with particular structural or folding properties of the encoded protein. We believe this has arisen, in part, because different criteria have been traditionally used for predicting whether a codon will be translated quickly or slowly in a given organism, including its frequency of occurrence among highly expressed genes and the concentration of tRNA species capable of decoding it, which do not always correlate. We have developed a metric to predict organism-specific polypeptide elongation rates of any mRNA based on whether each codon is decoded by tRNAs capable of Watson-Crick, non-Watson-Crick or both types of interactions. We demonstrate by pulse-chase analyses in living E. coli cells that sequence engineering based on these concepts predictably modulates translation rates due to changes in polypeptide elongation and show that such alterations significantly impact the folding of proteins of eukaryotic origin. We also demonstrate that sequence harmonization based on expression-host tRNA content designed to mimic ribosome movement of the original organism can significantly increase the folding of the encoded polypeptide. Additionally, we show that the rate at which a polypeptide emerges from the ribosome can affect co-translational chaperone binding, which may explain some of the observed changes in folding efficiencies. We have also begun to identify certain folding regions that may be more sensitive than others to translation speed modulation. This body of work could provide insight into how synonymous nucleotide substitutions result in altered protein function and disease.
protein folding, silent mutations, translation rates, molecular chaperones
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The University of Texas Medical Branch at Galveston