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.

中文翻译：

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GroEL 依赖性影响密码子的使用——支持错误折叠在基因进化中的关键作用。

最近有人建议使用最佳密码子限制错误翻译诱导的蛋白质错误折叠，但这方面的证据仍然主要是间接的。相比之下，分子伴侣早已被认为在错误折叠的预防和补救中发挥着至关重要的作用。我们建议可以通过检查密码子使用和伴侣过程之间的相互作用来阐明顺式中假定的错误限制。使用大肠杆菌作为模型系统，我们发现密码子最优性随伴侣蛋白 GroEL 的依赖性而变化。GroEL 的零星但非专性底物表现出更高的平均密码子适应性，并且在结构敏感位点明显富集了最佳密码子。此外，散在客户的密码子优化在大肠杆菌克隆痢疾志贺氏菌中更为保守。我们建议高度表达的基因不能常规使用 GroEL 进行错误控制，因此密码子的使用已经演变为提供互补的错误限制。这些发现为错误折叠在塑造基因进化中的作用提供了独立的证据，并强调需要共同表征顺式和反式的适应以解开集成分子系统的工作原理。