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Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition

Author

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  • Bernhard Kuhle

    (The Scripps Research Institute
    University Medical Center Göttingen)

  • Marscha Hirschi

    (The Scripps Research Institute)

  • Lili K. Doerfel

    (The Scripps Research Institute)

  • Gabriel C. Lander

    (The Scripps Research Institute)

  • Paul Schimmel

    (The Scripps Research Institute
    The Scripps Florida Research Institute at the University of Florida)

Abstract

Animal mitochondrial gene expression relies on specific interactions between nuclear-encoded aminoacyl-tRNA synthetases and mitochondria-encoded tRNAs. Their evolution involves an antagonistic interplay between strong mutation pressure on mtRNAs and selection pressure to maintain their essential function. To understand the molecular consequences of this interplay, we analyze the human mitochondrial serylation system, in which one synthetase charges two highly divergent mtRNASer isoacceptors. We present the cryo-EM structure of human mSerRS in complex with mtRNASer(UGA), and perform a structural and functional comparison with the mSerRS-mtRNASer(GCU) complex. We find that despite their common function, mtRNASer(UGA) and mtRNASer(GCU) show no constrain to converge on shared structural or sequence identity motifs for recognition by mSerRS. Instead, mSerRS evolved a bimodal readout mechanism, whereby a single protein surface recognizes degenerate identity features specific to each mtRNASer. Our results show how the mutational erosion of mtRNAs drove a remarkable innovation of intermolecular specificity rules, with multiple evolutionary pathways leading to functionally equivalent outcomes.

Suggested Citation

  • Bernhard Kuhle & Marscha Hirschi & Lili K. Doerfel & Gabriel C. Lander & Paul Schimmel, 2023. "Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40354-2
    DOI: 10.1038/s41467-023-40354-2
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    References listed on IDEAS

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    1. David Nicholson & Marco Salamina & Johan Panek & Karla Helena-Bueno & Charlotte R. Brown & Robert P. Hirt & Neil A. Ranson & Sergey V. Melnikov, 2022. "Adaptation to genome decay in the structure of the smallest eukaryotic ribosome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Bernhard Kuhle & Marscha Hirschi & Lili K. Doerfel & Gabriel C. Lander & Paul Schimmel, 2022. "Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Takeo Suzuki & Yuka Yashiro & Ittoku Kikuchi & Yuma Ishigami & Hironori Saito & Ikuya Matsuzawa & Shunpei Okada & Mari Mito & Shintaro Iwasaki & Ding Ma & Xuewei Zhao & Kana Asano & Huan Lin & Yohei K, 2020. "Complete chemical structures of human mitochondrial tRNAs," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    4. Bernhard Kuhle & Joseph Chihade & Paul Schimmel, 2020. "Relaxed sequence constraints favor mutational freedom in idiosyncratic metazoan mitochondrial tRNAs," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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