C-terminal evolutionary remodelling of isoleucyl-tRNA synthetases is a prokaryote-specific strategy for tuning aminoacylation rate
Abstract
Aminoacyl-tRNA synthetases are the guardians of translational fidelity. Their complex function is mirrored by an elaborate structure, which includes multiple nested domains. While the evolutionary pressures that promoted the emergence of some domains, such as the editing domain, are clear, the pressures acting on other domains, particularly those at the C-terminus, are not. Here, we combine kinetic analysis, X-ray crystallography, and bioinformatics to unveil the history and evolutionary forces that have shaped isoleucyl-tRNA synthetase (IleRS) domain structure. We find that the traditional classification of IleRSs based on the C-terminal tRNA-recognition domains is incomplete, as it fails to capture features of the synthetic domain. Guided by a crystal structure of the Priestia megaterium IleRS2:tRNA Ile complex, we removed key interactions between IleRS2 and its cognate tRNA and characterised their impact on enzyme activity. We found that D-loop interactions with the IleRS2 C-terminal domains are non-essential in prokaryotes, and their loss can even increase catalytic turnover. Further, we show that the zinc-binding domain of IleRS1 recognises the anticodon less stringently than the canonical C-terminal domain of IleRS2. Our data suggest that C-terminal evolutionary remodelling of IleRSs is an ongoing process with a historical precedent and is consistent with selection for faster aminoacylation rate.
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BibTeX
@article{modrusan2026cterminal,
title = {{C-terminal evolutionary remodelling of isoleucyl-tRNA synthetases is a prokaryote-specific strategy for tuning aminoacylation rate}},
author = {Petra Modrusan and Alojzije Brkic and Andre Lecona Buttelli and Marc Leibundgut and Igor Zivkovic and Nenad Ban and Liam M. Longo and Ita Gruic-Sovulj},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78241-1},
url = {https://www.nature.com/articles/s41467-026-78241-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - C-terminal evolutionary remodelling of isoleucyl-tRNA synthetases is a prokaryote-specific strategy for tuning aminoacylation rate
AU - Petra Modrusan
AU - Alojzije Brkic
AU - Andre Lecona Buttelli
AU - Marc Leibundgut
AU - Igor Zivkovic
AU - Nenad Ban
AU - Liam M. Longo
AU - Ita Gruic-Sovulj
PY - 2026
DA - 2026/10/12
JO - Nature Communications
DO - 10.1038/s41467-026-78241-1
UR - https://www.nature.com/articles/s41467-026-78241-1
AB - Aminoacyl-tRNA synthetases are the guardians of translational fidelity. Their complex function is mirrored by an elaborate structure, which includes multiple nested domains. While the evolutionary pressures that promoted the emergence of some domains, such as the editing domain, are clear, the pressures acting on other domains, particularly those at the C-terminus, are not. Here, we combine kinetic analysis, X-ray crystallography, and bioinformatics to unveil the history and evolutionary forces that have shaped isoleucyl-tRNA synthetase (IleRS) domain structure. We find that the traditional classification of IleRSs based on the C-terminal tRNA-recognition domains is incomplete, as it fails to capture features of the synthetic domain. Guided by a crystal structure of the Priestia megaterium IleRS2:tRNA Ile complex, we removed key interactions between IleRS2 and its cognate tRNA and characterised their impact on enzyme activity. We found that D-loop interactions with the IleRS2 C-terminal domains are non-essential in prokaryotes, and their loss can even increase catalytic turnover. Further, we show that the zinc-binding domain of IleRS1 recognises the anticodon less stringently than the canonical C-terminal domain of IleRS2. Our data suggest that C-terminal evolutionary remodelling of IleRSs is an ongoing process with a historical precedent and is consistent with selection for faster aminoacylation rate.
SN - 2041-1723
ER -