Codon influence on protein expression in E. coli correlates with mRNA levels

Grégory Boël, Reka Letso, Helen Neely, W. Nicholson Price, Kam-Ho Wong, Min Su, Jon D. Luff, Mayank Valecha, John K. Everett, Thomas B. Acton, Rong Xiao, Gaetano T. Montelione, Daniel P. Aalberts () and John F. Hunt ()
Additional contact information
Grégory Boël: 702 Fairchild Center, MC2434, Columbia University
Reka Letso: 702 Fairchild Center, MC2434, Columbia University
Helen Neely: 702 Fairchild Center, MC2434, Columbia University
W. Nicholson Price: 702 Fairchild Center, MC2434, Columbia University
Kam-Ho Wong: 702 Fairchild Center, MC2434, Columbia University
Min Su: 702 Fairchild Center, MC2434, Columbia University
Jon D. Luff: 702 Fairchild Center, MC2434, Columbia University
Mayank Valecha: 702 Fairchild Center, MC2434, Columbia University
John K. Everett: Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey
Thomas B. Acton: Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey
Rong Xiao: Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey
Gaetano T. Montelione: Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey
Daniel P. Aalberts: Williams College
John F. Hunt: 702 Fairchild Center, MC2434, Columbia University

Nature, 2016, vol. 529, issue 7586, 358-363

Abstract: Abstract 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 analyse 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.

Date: 2016
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DOI: 10.1038/nature16509

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