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Evolutionary Gain of Alanine Mischarging to Noncognate tRNAs with a G4:U69 Base Pair

Author:
Sun, Litao, Gomes, Ana Cristina, He, Weiwei, Zhou, Huihao, Wang, Xiaoyun, Pan, David W., Schimmel, Paul, Pan, Tao, Yang, Xiang-Lei
Source:
Journal of the American Chemical Society 2016 v.138 no.39 pp. 12948-12955
ISSN:
1520-5126
Subject:
Escherichia coli, alanine, aminoacyl tRNA ligases, bacteria, crystal structure, eukaryotic cells, gain-of-function mutation, humans, proteins, transfer RNA, translation (genetics)
Abstract:
Fidelity of translation, which is predominately dictated by the accuracy of aminoacyl-tRNA synthetases in pairing amino acids with correct tRNAs, is of central importance in biology. Yet, deliberate modifications of translational fidelity can be beneficial. Here we found human and not E. coli AlaRS has an intrinsic capacity for mispairing alanine onto nonalanyl-tRNAs including tRNACʸˢ. Consistently, a cysteine-to-alanine substitution was found in a reporter protein expressed in human cells. All human AlaRS-mischarged tRNAs have a G4:U69 base pair in the acceptor stem. The base pair is required for the mischarging. By solving the crystal structure of human AlaRS and comparing it to that of E. coli AlaRS, we identified a key sequence divergence between eukaryotes and bacteria that influences mischarging. Thus, the expanded tRNA specificity of AlaRS appears to be an evolutionary gain-of-function to provide posttranscriptional alanine substitutions in eukaryotic proteins for potential regulations.
Agid:
5560533