A metal ion mediated functional dichotomy encodes plasticity during translation quality control

Jotin Gogoi, Komal Ishwar Pawar, Koushick Sivakumar, Akshay Bhatnagar, Katta Suma, Kezia J. Ann, Sambhavi Pottabathini, Shobha P. Kruparani and Rajan Sankaranarayanan ()
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Jotin Gogoi: CSIR-Centre for Cellular and Molecular Biology
Komal Ishwar Pawar: CSIR-Centre for Cellular and Molecular Biology
Koushick Sivakumar: CSIR-Centre for Cellular and Molecular Biology
Akshay Bhatnagar: CSIR-Centre for Cellular and Molecular Biology
Katta Suma: CSIR-Centre for Cellular and Molecular Biology
Kezia J. Ann: CSIR-Centre for Cellular and Molecular Biology
Sambhavi Pottabathini: CSIR-Centre for Cellular and Molecular Biology
Shobha P. Kruparani: CSIR-Centre for Cellular and Molecular Biology
Rajan Sankaranarayanan: CSIR-Centre for Cellular and Molecular Biology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Proofreading during translation of the genetic code is a key process for not only translation quality control but also for its modulation under stress conditions to provide fitness advantage. A major class of proofreading modules represented by editing domains of alanyl-tRNA synthetase (AlaRS-Ed) and threonyl-tRNA synthetase (ThrRS-Ed) features a common fold and an invariant Zn2+ binding motif across life forms. Here, we reveal the structural basis and functional consequence along with the necessity for their operational dichotomy, i.e., the metal ion is ubiquitous in one and inhibitor for the other. The universally conserved Zn2+ in AlaRS-Ed protects its proofreading activity from reactive oxygen species (ROS) to maintain high fidelity Ala-codons translation, necessary for cell survival. On the other hand, mistranslation of Thr-codons is well tolerated by the cells, thereby allowing for a ROS-based modulation of ThrRS-Ed’s activity. A single residue rooted over ~3.5 billion years of evolution has been shown to be primarily responsible for the functional divergence. The study presents a remarkable example of how protein quality control is integrated with redox signalling through leveraging the tunability of metal binding sites from the time of last universal common ancestor (LUCA).

Date: 2025
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DOI: 10.1038/s41467-025-58787-2

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