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A substrate binding model for the KEOPS tRNA modifying complex

Author

Listed:
  • Jonah Beenstock

    (Mount Sinai Hospital)

  • Samara Mishelle Ona

    (Mount Sinai Hospital
    University of Toronto)

  • Jennifer Porat

    (York University)

  • Stephen Orlicky

    (Mount Sinai Hospital)

  • Leo C. K. Wan

    (Mount Sinai Hospital
    University of Toronto)

  • Derek F. Ceccarelli

    (Mount Sinai Hospital)

  • Pierre Maisonneuve

    (Mount Sinai Hospital)

  • Rachel K. Szilard

    (Mount Sinai Hospital)

  • Zhe Yin

    (Mount Sinai Hospital
    University of Toronto)

  • Dheva Setiaputra

    (Mount Sinai Hospital)

  • Daniel Y. L. Mao

    (Mount Sinai Hospital)

  • Morgan Khan

    (University of Calgary)

  • Shaunak Raval

    (University of Calgary)

  • David C. Schriemer

    (University of Calgary
    University of Calgary)

  • Mark A. Bayfield

    (York University)

  • Daniel Durocher

    (Mount Sinai Hospital
    University of Toronto)

  • Frank Sicheri

    (Mount Sinai Hospital
    University of Toronto
    University of Toronto)

Abstract

The KEOPS complex, which is conserved across archaea and eukaryotes, is composed of four core subunits; Pcc1, Kae1, Bud32 and Cgi121. KEOPS is crucial for the fitness of all organisms examined. In humans, pathogenic mutations in KEOPS genes lead to Galloway–Mowat syndrome, an autosomal-recessive disease causing childhood lethality. Kae1 catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine, but the precise roles of all other KEOPS subunits remain an enigma. Here we show using structure-guided studies that Cgi121 recruits tRNA to KEOPS by binding to its 3’ CCA tail. A composite model of KEOPS bound to tRNA reveals that all KEOPS subunits form an extended tRNA-binding surface that we have validated in vitro and in vivo to mediate the interaction with the tRNA substrate and its modification. These findings provide a framework for understanding the inner workings of KEOPS and delineate why all KEOPS subunits are essential.

Suggested Citation

  • Jonah Beenstock & Samara Mishelle Ona & Jennifer Porat & Stephen Orlicky & Leo C. K. Wan & Derek F. Ceccarelli & Pierre Maisonneuve & Rachel K. Szilard & Zhe Yin & Dheva Setiaputra & Daniel Y. L. Mao , 2020. "A substrate binding model for the KEOPS tRNA modifying complex," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19990-5
    DOI: 10.1038/s41467-020-19990-5
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    Cited by:

    1. Marie-Claire Daugeron & Sophia Missoury & Violette Cunha & Noureddine Lazar & Bruno Collinet & Herman Tilbeurgh & Tamara Basta, 2023. "A paralog of Pcc1 is the fifth core subunit of the KEOPS tRNA-modifying complex in Archaea," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Aline Umuhire Juru & Rodolfo Ghirlando & Jinwei Zhang, 2024. "Structural basis of tRNA recognition by the widespread OB fold," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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