Codon influence on protein expression in E. coli correlates with mRNA levels.
Codon influence on protein expression in E. coli correlates with mRNA levels.
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DOI：
10.1038/nature16509
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发表时间：
2016-01-21
期刊：
影响因子：
64.8
通讯作者：
Hunt, John F.
中科院分区：
文献类型：
--
作者：
Boel, Gregory;Letso, Reka;Neely, Helen;Price, W. Nicholson;Wong, Kam-Ho;Su, Min;Luff, Jon D.;Valecha, Mayank;Everett, John K.;Acton, Thomas B.;Xiao, Rong;Montelione, Gaetano T.;Aalberts, Daniel P.;Hunt, John F.
遗传密码的简并性使得单一蛋白质能够由多个同义基因序列编码，在调节蛋白质表达方面具有重要作用，但这种现象的细节存在很大的不确定性。在这里，我们在 6,348 个使用噬菌体 T7 聚合酶在大肠杆菌中合成信使 RNA 的实验中分析了影响蛋白质表达水平的序列特征。 Logistic 回归产生了一种新的密码子影响度量，该度量仅与基因组密码子使用频率相关性较弱，但与整体生理蛋白浓度以及 mRNA 浓度和体内寿命密切相关。总体而言，密码子含量对蛋白质表达的影响比 mRNA 折叠参数更强烈，尽管后者在最初的约 16 个密码子中占主导地位。根据我们的分析重新设计的基因转录效率不变，但在体外翻译效率更高。翻译效率较低的天然序列显示体内 mRNA 水平大大降低。我们的结果表明，密码子含量调节蛋白质延伸和 mRNA 降解之间的动力学竞争，这是生理学的核心特征，也可能是大肠杆菌翻译的调节。
Degeneracy in the genetic code, which enables a single protein to be encoded by a multitude of synonymous gene sequences, has an important role in regulating protein expression, but substantial uncertainty exists concerning the details of this phenomenon. Here we analyze the sequence features influencing protein expression levels in 6,348 experiments using bacteriophage T7 polymerase to synthesize messenger RNA in Escherichia coli. Logistic regression yields a new codon-influence metric that correlates only weakly with genomic codon-usage frequency, but strongly with global physiological protein concentrations and also mRNA concentrations and lifetimes in vivo. Overall, the codon content influences protein expression more strongly than mRNA-folding parameters, although the latter dominate in the initial ~16 codons. Genes redesigned based on our analyses are transcribed with unaltered efficiency but translated with higher efficiency in vitro. The less efficiently translated native sequences show greatly reduced mRNA levels in vivo. Our results suggest that codon content modulates a kinetic competition between protein elongation and mRNA degradation that is a central feature of the physiology and also possibly the regulation of translation in E. coli.
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