Genetic Mechanisms Coordinating Protein Synthesis and Folding

Abstract

Since the process of translation is directional, nascent proteins emerge from the ribosome as incomplete chains that are susceptible to misfolding. Ribosome movement along an mRNA is influenced by tRNA availability and the physical‐chemical properties of the anticodon‐codon interaction. Experiments from our laboratory suggest that polypeptide elongation rates and local folding events of the nascent protein are intimately coupled. Our current goal is to understand how genetically encoded information regulates protein synthesis rates and folding pathways. Differences in tRNA availability and protein folding efficiencies between bacteria and eukaryotes are being exploited to study these relationships. In order to accelerate or decelerate translation speed, sequences are engineered that encode identical proteins but contain variations along wobble positions of synonymous codons. We find that harmonization of translation rates based on tRNA availability of the organism of origin of the polypeptide with that of the production host leads to robust enhancement of folding efficiencies. These studies provide insight into how the genetic code, although nearly universal in its amino acid encoding properties, is utilized differently between bacteria and eukaryotes to regulate local protein folding events.This work was supported by The Welch Foundation and The Pew Charitable Trusts.