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<p>Prolyl-tRNA synthetases (ProRSs) exhibit diverse domain architectures and motifs, evolving into prokaryotic (P-type) and eukaryotic/archaeal (E-type) variants. Both types exhibit high specificity for the recognition and aminoacylation of their cognate tRNAs. Interestingly, the parasitic eukaryote <i>Toxoplasma gondii</i> encodes a single E-type ProRS (TgProRS) but utilizes two distinct tRNA<sup>Pro</sup> isoacceptors: a cytosolic E-type (with C72/C73) and an apicoplast P-type (with G72/A73). Our study demonstrates that TgProRS, despite being classified as an E-type enzyme, efficiently charges both tRNA<sup>Pro</sup> isoacceptors and functionally compensates for yeast cytoplasmic and mitochondrial ProRS activities. Notably, while C72/C73 are dispensable for cytosolic tRNA<sup>Pro</sup> charging, G72/A73 are crucial for apicoplast tRNA<sup>Pro</sup> aminoacylation. Furthermore, Mutations in the motif 2 loop selectively affect E- or P-type tRNA<sup>Pro</sup> recognition. While TgProRS exhibits similar susceptibility to azetidine (a proline mimic) when charging both tRNA<sup>Pro</sup> types, cytosolic tRNA<sup>Pro</sup> charging is five times more sensitive to inhibition by halofuginone (a Pro-A76 mimic) compared to apicoplast tRNA<sup>Pro</sup> charging. These findings underscore TgProRS’s dual functionality, showcasing its remarkable evolutionary adaptability and providing valuable insights for developing more selective therapeutic agents.</p>

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Dual-mode recognition of tRNAPro isoacceptors by Toxoplasma gondii Prolyl-tRNA synthetase

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月28日

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  • Indira Rizqita Ivanesthi,
  • Emi Latifah,
  • Shih-Yang Liu,
  • Yi-Kuan Tseng,
  • Hung-Chuan Pan,
  • Chien-Chia Wang

摘要

Prolyl-tRNA synthetases (ProRSs) exhibit diverse domain architectures and motifs, evolving into prokaryotic (P-type) and eukaryotic/archaeal (E-type) variants. Both types exhibit high specificity for the recognition and aminoacylation of their cognate tRNAs. Interestingly, the parasitic eukaryote Toxoplasma gondii encodes a single E-type ProRS (TgProRS) but utilizes two distinct tRNAPro isoacceptors: a cytosolic E-type (with C72/C73) and an apicoplast P-type (with G72/A73). Our study demonstrates that TgProRS, despite being classified as an E-type enzyme, efficiently charges both tRNAPro isoacceptors and functionally compensates for yeast cytoplasmic and mitochondrial ProRS activities. Notably, while C72/C73 are dispensable for cytosolic tRNAPro charging, G72/A73 are crucial for apicoplast tRNAPro aminoacylation. Furthermore, Mutations in the motif 2 loop selectively affect E- or P-type tRNAPro recognition. While TgProRS exhibits similar susceptibility to azetidine (a proline mimic) when charging both tRNAPro types, cytosolic tRNAPro charging is five times more sensitive to inhibition by halofuginone (a Pro-A76 mimic) compared to apicoplast tRNAPro charging. These findings underscore TgProRS’s dual functionality, showcasing its remarkable evolutionary adaptability and providing valuable insights for developing more selective therapeutic agents.