title: GroEL dependency affects codon usage--support for a critical role of misfolding in gene evolution.
abstract: It has recently been suggested that the use of optimal codons limits mistranslation-induced protein misfolding, yet evidence for this remains largely circumstantial. In contrast, molecular chaperones have long been recognized to play crucial roles in misfolding prevention and remedy. We propose that putative error limitation in cis can be elucidated by examining the interaction between codon usage and chaperoning processes. Using Escherichia coli as a model system, we find that codon optimality covaries with dependency on the chaperonin GroEL. Sporadic but not obligate substrates of GroEL exhibit higher average codon adaptation and are conspicuously enriched for optimal codons at structurally sensitive sites. Further, codon optimality of sporadic clients is more conserved in the E. coli clone Shigella dysenteriae. We suggest that highly expressed genes cannot routinely use GroEL for error control so that codon usage has evolved to provide complementary error limitation. These findings provide independent evidence for a role of misfolding in shaping gene evolution and highlight the need to co-characterize adaptations in cis and trans to unravel the workings of integrated molecular systems.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, UK. T.Warnecke@bath.ac.uk
authors.forename: Tobias
authors.initials: T
authors.lastname: Warnecke
authors.forename: Laurence D
authors.initials: LD
authors.lastname: Hurst
mesh_terms: D018834:Chaperonin 60 / Q000235:genetics* / Q000378:metabolism; D003062:Codon; D019295:Computational Biology; D030541:Databases, Genetic; D048168:Escherichia coli K12 / Q000235:genetics* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D015964:Gene Expression Regulation, Bacterial; D009154:Mutation; D011487:Protein Conformation; D017510:Protein Folding; D012333:RNA, Messenger / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D012762:Shigella dysenteriae / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018834:Chaperonin 60; D003062:Codon; D029968:Escherichia coli Proteins; D012333:RNA, Messenger