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Title: Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases

Abstract

Genetic incorporation of noncanonical amino acids (ncAAs) has become a powerful tool to enhance existing functions or introduce new ones into proteins through expanded chemistry. This technology relies on the process of nonsense suppression, which is made possible by directing aminoacyl-tRNA synthetases (aaRSs) to attach an ncAA onto a cognate suppressor tRNA. However, different mechanisms govern aaRS specificity toward its natural amino acid (AA) substrate and hinder the engineering of aaRSs for applications beyond the incorporation of a single l-α-AA. Directed evolution of aaRSs therefore faces two interlinked challenges: the removal of the affinity for cognate AA and improvement of ncAA acylation. Here we review aspects of AA recognition that directly influence the feasibility and success of aaRS engineering toward d- and β-AAs incorporation into proteins in vivo. Emerging directed evolution methods are described and evaluated on the basis of aaRS active site plasticity and its inherent constraints.

Authors:
ORCiD logo; ORCiD logo; ORCiD logo
Publication Date:
Research Org.:
Yale Univ., New Haven, CT (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Chemical Sciences, Geosciences, and Biosciences Division; National Institutes of Health (NIH)
OSTI Identifier:
1529654
Alternate Identifier(s):
OSTI ID: 1610399
Grant/Contract Number:  
FG02-98ER20311; R35GM122560
Resource Type:
Published Article
Journal Name:
International Journal of Molecular Sciences (Online)
Additional Journal Information:
Journal Name: International Journal of Molecular Sciences (Online) Journal Volume: 20 Journal Issue: 9; Journal ID: ISSN 1422-0067
Publisher:
MDPI
Country of Publication:
Switzerland
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Chemistry; aminoacyl-tRNA synthetases; noncanonical amino acids; directed evolution; genetic code expansion; synthetic biology

Citation Formats

Crnković, Ana, Vargas-Rodriguez, Oscar, and Söll, Dieter. Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases. Switzerland: N. p., 2019. Web. doi:10.3390/ijms20092294.
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Crnković, Ana, Vargas-Rodriguez, Oscar, & Söll, Dieter. Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases. Switzerland. https://doi.org/10.3390/ijms20092294
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Crnković, Ana, Vargas-Rodriguez, Oscar, and Söll, Dieter. Thu . "Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases". Switzerland. https://doi.org/10.3390/ijms20092294.
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@article{osti_1529654,
title = {Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases},
author = {Crnković, Ana and Vargas-Rodriguez, Oscar and Söll, Dieter},
abstractNote = {Genetic incorporation of noncanonical amino acids (ncAAs) has become a powerful tool to enhance existing functions or introduce new ones into proteins through expanded chemistry. This technology relies on the process of nonsense suppression, which is made possible by directing aminoacyl-tRNA synthetases (aaRSs) to attach an ncAA onto a cognate suppressor tRNA. However, different mechanisms govern aaRS specificity toward its natural amino acid (AA) substrate and hinder the engineering of aaRSs for applications beyond the incorporation of a single l-α-AA. Directed evolution of aaRSs therefore faces two interlinked challenges: the removal of the affinity for cognate AA and improvement of ncAA acylation. Here we review aspects of AA recognition that directly influence the feasibility and success of aaRS engineering toward d- and β-AAs incorporation into proteins in vivo. Emerging directed evolution methods are described and evaluated on the basis of aaRS active site plasticity and its inherent constraints.},
doi = {10.3390/ijms20092294},
journal = {International Journal of Molecular Sciences (Online)},
number = 9,
volume = 20,
place = {Switzerland},
year = {Thu May 09 00:00:00 EDT 2019},
month = {Thu May 09 00:00:00 EDT 2019}
}
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https://doi.org/10.3390/ijms20092294
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