Unlocking the serine mischarging paradox and inhibiting lactyltransferase activity of AlaRS by a single-point mutation

生物 转移RNA 氨基酸 点突变 突变体 突变 丝氨酸 生物化学 翻译(生物学) 校对 遗传学 计算生物学 核糖核酸 聚合酶 基因 信使核糖核酸
作者
Wooyoung Park,Se‐Young Son,Joon‐Yeop Yi,Seungwoo Cha,Hankyeol Moon,Minyoung Kim,Sangho Ji,Wookyung Yu,Changmin Sung,Sun‐Shin Cha,Ji‐Sook Hahn
出处
期刊:Nucleic Acids Research [Oxford University Press]
卷期号:53 (11)
标识
DOI:10.1093/nar/gkaf462
摘要

Aminoacyl-tRNA synthetases are critical for accurate genetic translation, attaching amino acids to their corresponding transfer RNA 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 misactivating larger Ser by AlaRS was considered inevitable due to its inherent design, sharing an essential acidic residue to accommodate the activated adenylated intermediates from both cognate and non-cognate amino acids. Here we show a groundbreaking discovery where a single-point mutation, L219M, in AlaRS from Methylomonas sp. DH-1, effectively eliminates Ser misactivation. Structural analysis of the pre-activation state unveiled 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 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 showed that AlaRSL219M also eliminates the enzyme's inherent lactyltransferase activity, suggesting that the lactate tolerance observed might result from preventing excessive protein lactylation under lactate stress. This opens possibilities for developing high-fidelity and lactylation-deficient AlaRS mutants across various organisms, facilitating studies on their potential benefits in different physiological scenarios.
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