Ewha Researchers Discover Key Mutation That Strengthens Protein Synthesis Accuracy
Professor Sun-Shin Cha and his research team from the Department of Chemistry & Nanoscience have been successfully enhanced the accuracy of protein synthesis with a single-point mutation, while simultaneously suppressing the enzyme’s epigenetic function of lactylation. The study was jointly conducted by Professor Cha (corresponding author) and Se-Young Son (first author, integrated master’s and doctoral program) at Ewha Womans University, in collaboration with Professor Ji-Sook Hahn (corresponding author) and Wooyoung Park (first author, integrated master’s and doctoral program) at Seoul National University. The findings were published in the prestigious international journal Nucleic Acids Research (Impact Factor: 13.1; Biochemistry & Molecular Biology category, top 3.9%).
Aminoacyl-tRNA synthetases are essential for accurate genetic translation, as they attach amino acids to their corresponding transfer RNA (tRNA) molecules. Alanyl-tRNA synthetase (AlaRS) often misactivates Ser or Gly instead of Ala, which is detrimental unless corrected by its editing functions. The paradox of AlaRS misactivating the larger amino acid Ser was long considered inevitable, due to its inherent design that relies on an essential acidic residue to accommodate adenylated intermediates from both cognate and non-cognate amino acids.
Here, we report a groundbreaking discovery that a single-point mutation, L219M, in AlaRS from Methylomonas sp. DH-1 effectively eliminates Ser misactivation. Structural analysis of the pre-activation state revealed that the flexibility of Val204 is the key to preventing Ser binding in AlaRSL219M. This research elucidates the amino acid discrimination mechanism in AlaRS, independent of its editing domain.
Remarkably, the AlaRSL219M mutation was initially identified as a causal mutation enhancing lactate tolerance in a strain developed through adaptive laboratory evolution. We further demonstrated that AlaRSL219M eliminates the enzyme’s inherent lactyltransferase activity, suggesting that the observed lactate tolerance may result from preventing excessive protein lactylation under lactate stress. This discovery opens new possibilities for developing high-fidelity, lactylation-deficient AlaRS mutant across diverse organisms, enabling further studies on their potential benefits under different physiological conditions.
View Published Paper: https://academic.oup.com/nar/article/53/11/gkaf462/8158037?login=true