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Structural basis for shape-selective recognition and aminoacylation of a D-armless human mitochondrial tRNA

Author

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  • Bernhard Kuhle

    (The Scripps Research Institute)

  • 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

Human mitochondrial gene expression relies on the specific recognition and aminoacylation of mitochondrial tRNAs (mtRNAs) by nuclear-encoded mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs). Despite their essential role in cellular energy homeostasis, strong mutation pressure and genetic drift have led to an unparalleled sequence erosion of animal mtRNAs. The structural and functional consequences of this erosion are not understood. Here, we present cryo-EM structures of the human mitochondrial seryl-tRNA synthetase (mSerRS) in complex with mtRNASer(GCU). These structures reveal a unique mechanism of substrate recognition and aminoacylation. The mtRNASer(GCU) is highly degenerated, having lost the entire D-arm, tertiary core, and stable L-shaped fold that define canonical tRNAs. Instead, mtRNASer(GCU) evolved unique structural innovations, including a radically altered T-arm topology that serves as critical identity determinant in an unusual shape-selective readout mechanism by mSerRS. Our results provide a molecular framework to understand the principles of mito-nuclear co-evolution and specialized mechanisms of tRNA recognition in mammalian mitochondrial gene expression.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32544-1
    DOI: 10.1038/s41467-022-32544-1
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    References listed on IDEAS

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    1. 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.
    2. 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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    1. 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.

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