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Distinct pre-initiation steps in human mitochondrial translation

Author

Listed:
  • Anas Khawaja

    (Division of Molecular Metabolism, Karolinska Institutet, Biomedicum
    Karolinska Institutet)

  • Yuzuru Itoh

    (Division of Molecular Metabolism, Karolinska Institutet, Biomedicum
    Stockholm University)

  • Cristina Remes

    (Max-Planck-Institute for Biology of Ageing)

  • Henrik Spåhr

    (Division of Molecular Metabolism, Karolinska Institutet, Biomedicum
    Karolinska Institutet
    Max-Planck-Institute for Biology of Ageing)

  • Olessya Yukhnovets

    (RWTH Aachen, I. Physikalisches Institut (IA)
    Institute of Complex Systems ICS-5)

  • Henning Höfig

    (RWTH Aachen, I. Physikalisches Institut (IA)
    Institute of Complex Systems ICS-5)

  • Alexey Amunts

    (Division of Molecular Metabolism, Karolinska Institutet, Biomedicum
    Stockholm University)

  • Joanna Rorbach

    (Division of Molecular Metabolism, Karolinska Institutet, Biomedicum
    Karolinska Institutet)

Abstract

Translation initiation in human mitochondria relies upon specialized mitoribosomes and initiation factors, mtIF2 and mtIF3, which have diverged from their bacterial counterparts. Here we report two distinct mitochondrial pre-initiation assembly steps involving those factors. Single-particle cryo-EM revealed that in the first step, interactions between mitochondria-specific protein mS37 and mtIF3 keep the small mitoribosomal subunit in a conformation favorable for a subsequent accommodation of mtIF2 in the second step. Combination with fluorescence cross-correlation spectroscopy analyses suggests that mtIF3 promotes complex assembly without mRNA or initiator tRNA binding, where exclusion is achieved by the N-terminal and C-terminal domains of mtIF3. Finally, the association of large mitoribosomal subunit is required for initiator tRNA and leaderless mRNA recruitment to form a stable initiation complex. These data reveal fundamental aspects of mammalian protein synthesis that are specific to mitochondria.

Suggested Citation

  • Anas Khawaja & Yuzuru Itoh & Cristina Remes & Henrik Spåhr & Olessya Yukhnovets & Henning Höfig & Alexey Amunts & Joanna Rorbach, 2020. "Distinct pre-initiation steps in human mitochondrial translation," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16503-2
    DOI: 10.1038/s41467-020-16503-2
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    Cited by:

    1. Miriam Cipullo & Genís Valentín Gesé & Shreekara Gopalakrishna & Annika Krueger & Vivian Lobo & Maria A. Pirozhkova & James Marks & Petra Páleníková & Dmitrii Shiriaev & Yong Liu & Jelena Misic & Yu C, 2024. "GTPBP8 plays a role in mitoribosome formation in human mitochondria," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Annika Krüger & Cristina Remes & Dmitrii Igorevich Shiriaev & Yong Liu & Henrik Spåhr & Rolf Wibom & Ilian Atanassov & Minh Duc Nguyen & Barry S. Cooperman & Joanna Rorbach, 2023. "Human mitochondria require mtRF1 for translation termination at non-canonical stop codons," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Vivek Singh & Yuzuru Itoh & Samuel Del’Olio & Asem Hassan & Andreas Naschberger & Rasmus Kock Flygaard & Yuko Nobe & Keiichi Izumikawa & Shintaro Aibara & Juni Andréll & Paul C. Whitford & Antoni Barr, 2024. "Mitoribosome structure with cofactors and modifications reveals mechanism of ligand binding and interactions with L1 stalk," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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