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<p>The radical SAM enzyme Elp3 and eukaryotic Elongator complex catalyze formation of a key intermediate transfer RNA (tRNA) modification, 5-carboxymethyluridine (cm<sup>5</sup>U), in the anticodons of tRNAs across all domains of life. cm<sup>5</sup>U-derived modifications are important for fine tuning codon-anticodon interactions and efficient protein translation, and defects in this modification are linked to development of neurodegenerative disease in humans. Here we reconstitute tRNA modification activity with a model Elp3 enzyme and combine structural analyses, enzymology, and isotope incorporation experiments to show Elp3 harbors a conserved molecular tunnel that shuttles free acetate molecules from the acetyl-CoA binding domain to the radical SAM active site over 20 Å away, where acetate undergoes radical-mediated reaction and addition to tRNA U34. Our model explains how Elp3 bridges a large distance between active sites to catalyze tRNA carboxymethylation and illustrates a unique mechanism for intermediate transport in radical SAM enzymes.</p>

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Elp3 uses a conserved molecular tunnel to transport acetate between distant active sites and catalyze tRNA wobble base modification

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Evan P. Geissler,
  • Youmna Moawad,
  • Paige N. Roehling,
  • Cassidy Driscoll,
  • Katherine Martin,
  • Papa Nii Asare-Okai,
  • Jeffrey S. Mugridge

摘要

The radical SAM enzyme Elp3 and eukaryotic Elongator complex catalyze formation of a key intermediate transfer RNA (tRNA) modification, 5-carboxymethyluridine (cm5U), in the anticodons of tRNAs across all domains of life. cm5U-derived modifications are important for fine tuning codon-anticodon interactions and efficient protein translation, and defects in this modification are linked to development of neurodegenerative disease in humans. Here we reconstitute tRNA modification activity with a model Elp3 enzyme and combine structural analyses, enzymology, and isotope incorporation experiments to show Elp3 harbors a conserved molecular tunnel that shuttles free acetate molecules from the acetyl-CoA binding domain to the radical SAM active site over 20 Å away, where acetate undergoes radical-mediated reaction and addition to tRNA U34. Our model explains how Elp3 bridges a large distance between active sites to catalyze tRNA carboxymethylation and illustrates a unique mechanism for intermediate transport in radical SAM enzymes.