Journal Club: Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding

This paper Pechmann et al discusses the relationship between codons and co-translational regulation of protein folding.  Every amino acid apart from Methionine and Tryptophan has multiple codons and it is well established that codons are translated at varying speeds and thus influence local translational kinetics.

Translation

This codon multiplicity and speed variation may be important for protein folding as several experiments have shown that synonymous substitutions (changing the codon but not the amino acid) alter folding and or function.

codon translation efficeincy depends on tRNA supply and demand

codon translation efficeincy depends on tRNA supply and demand

The new idea presented in this paper is a translational efficiency scale. This is an attempt to calculate the efficiency with which a codon will be translated by considering both the supply of tRNA and the demand for that tRNA. They calculate their new measure nTE for all of the coding sequences in 10 closely related yeast species.

The distribution of the nTE values is unlike that of previous scales as the majority of codons occur in a middle plateau region. The authors suggest that this is due to cost effective proteome maintenance, i.e. for most tRNA supply and demand are closely matched.

They go on to look for the previously observed “ramp” a slow region at the start of coding sequences. They identify a ramp region which is approximately 10 codons long (this is significantly shorter than that seen in other analyses which found a 35-50 codon ramp). This shorter region relates to two other observations, firstly the distance between the peptidyl transferase centre and the constriction site in the ribosome is approximately 10 amino acids long and secondly that experimentally ribosomes are found to pause near the very start of coding sequences.

The codons are now divided into two categories based on their nTE score, optimal codons those with high nTE values that should be translated rapidly and accurately and non-optimal codons. The authors found that codon optimality was conserved between orthologs in their set at rates far higher than those expected by chance (for both optimal and non-optimal codons). When considering those proteins with structural information available, they were also able to observe conservation of positioning of codon types with respect to secondary structures. This evolutionary conservation suggests an evolved function for codon optimality in regulating the rhythm of elongation in order to facilitate co-translational protein folding.

 

Evolutionary conservation of codon optimality reveals hidden signatures of cotranslational folding Nat Struct Mol Biol. 2013 Feb;20(2):237-43 Pechmann S,  Frydman J.

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