TY - JOUR
T1 - Evidence of evolutionary selection for cotranslational folding
AU - Jacobs, William M.
AU - Shakhnovich, Eugene I.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Sanchari Bhattacharyya and Michael Man-hart for many insightful discussions. This work was supported by National Institutes of Health Grants R01GM124044 and F32GM116231.
PY - 2017/10/24
Y1 - 2017/10/24
N2 - Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from cotranslational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for cotranslational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with cotranslational folding intermediates, which may be smaller than a single domain.We show that the intermediates predicted by a native-centric model of cotranslational folding account for the majority of these loci across more than 500 Escherichia coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context.
AB - Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from cotranslational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for cotranslational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with cotranslational folding intermediates, which may be smaller than a single domain.We show that the intermediates predicted by a native-centric model of cotranslational folding account for the majority of these loci across more than 500 Escherichia coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context.
KW - Cotranslational folding
KW - Free-energy landscapes
KW - Protein-folding intermediates
KW - Synonymous codon usage
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U2 - 10.1073/pnas.1705772114
DO - 10.1073/pnas.1705772114
M3 - Article
C2 - 29073068
AN - SCOPUS:85032012844
SN - 0027-8424
VL - 114
SP - 11434
EP - 11439
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 43
ER -