A code within the genetic code: codon usage regulates co-translational protein folding
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A code within the genetic code: codon usage regulates co-translational protein folding Yi Liu
Abstract The genetic code is degenerate, and most amino acids are encoded by two to six synonymous codons. Codon usage bias, the preference for certain synonymous codons, is a universal feature of all genomes examined. Synonymous codon mutations were previously thought to be silent; however, a growing body evidence now shows that codon usage regulates protein structure and gene expression through effects on co-translational protein folding, translation efficiency and accuracy, mRNA stability, and transcription. Codon usage regulates the speed of translation elongation, resulting in non-uniform ribosome decoding rates on mRNAs during translation that is adapted to co-translational protein folding process. Biochemical and genetic evidence demonstrate that codon usage plays an important role in regulating protein folding and function in both prokaryotic and eukaryotic organisms. Certain protein structural types are more sensitive than others to the effects of codon usage on protein folding, and predicted intrinsically disordered domains are more prone to misfolding caused by codon usage changes than other domain types. Bioinformatic analyses revealed that gene codon usage correlates with different protein structures in diverse organisms, indicating the existence of a codon usage code for co-translational protein folding. This review focuses on recent literature on the role and mechanism of codon usage in regulating translation kinetics and co-translational protein folding. Keywords: Codon usage, Translation elongation, Co-translational protein folding, Intrinsically disordered protein
Background Of the 20 standard amino acids, 18 can be encoded by two to six synonymous codons. Preferential use of certain synonymous codons, a phenomenon called codon usage bias, has been found in all genomes evaluated [1–4]. Because synonymous codons encode the same amino acid, they were previously considered to be functionally redundant, and synonymous codon mutations that do not change protein sequences were regarded as silent mutations. However, a large body of evidence now demonstrates that codon usage plays multiple roles regulating gene expression and protein structure through translation-dependent and Correspondence: [email protected] Department of Physiology, ND13.214A, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9040, USA
translation-independent mechanisms [4–8] (Fig. 1a). Synonymous codons are recognized with different efficiencies by cognate tRNAs. In different eukaryotic and prokaryotic organisms, codon usage bias correlates with levels of cognate tRNAs or with tRNA gene copy numbers [1, 9–13]. Codons with strong bias are found to be strongly enriched in highly expressed protein encoding genes, and codon optimization increases endogenous and heterologous gene expression in diverse eukaryotes and prokaryotes [14–23]. Moreover, genome-wide correlations between codon usage bi
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