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Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders

Author

Listed:
  • Elżbieta Wątor

    (Jagiellonian University
    Jagiellonian University)

  • Piotr Wilk

    (Jagiellonian University)

  • Artur Biela

    (Jagiellonian University)

  • Michał Rawski

    (Jagiellonian University)

  • Krzysztof M. Zak

    (Jagiellonian University)

  • Wieland Steinchen

    (Philipps-University Marburg, Center for Synthetic Microbiology (SYNMIKRO) & Faculty of Chemistry)

  • Gert Bange

    (Philipps-University Marburg, Center for Synthetic Microbiology (SYNMIKRO) & Faculty of Chemistry
    Molecular Physiology of Microbes)

  • Sebastian Glatt

    (Jagiellonian University)

  • Przemysław Grudnik

    (Jagiellonian University)

Abstract

Hypusination is a unique post-translational modification of the eukaryotic translation factor 5A (eIF5A) that is essential for overcoming ribosome stalling at polyproline sequence stretches. The initial step of hypusination, the formation of deoxyhypusine, is catalyzed by deoxyhypusine synthase (DHS), however, the molecular details of the DHS-mediated reaction remained elusive. Recently, patient-derived variants of DHS and eIF5A have been linked to rare neurodevelopmental disorders. Here, we present the cryo-EM structure of the human eIF5A-DHS complex at 2.8 Å resolution and a crystal structure of DHS trapped in the key reaction transition state. Furthermore, we show that disease-associated DHS variants influence the complex formation and hypusination efficiency. Hence, our work dissects the molecular details of the deoxyhypusine synthesis reaction and reveals how clinically-relevant mutations affect this crucial cellular process.

Suggested Citation

  • Elżbieta Wątor & Piotr Wilk & Artur Biela & Michał Rawski & Krzysztof M. Zak & Wieland Steinchen & Gert Bange & Sebastian Glatt & Przemysław Grudnik, 2023. "Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37305-2
    DOI: 10.1038/s41467-023-37305-2
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    References listed on IDEAS

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    1. Metin Aksu & Sergei Trakhanov & Dirk Görlich, 2016. "Structure of the exportin Xpo4 in complex with RanGTP and the hypusine-containing translation factor eIF5A," Nature Communications, Nature, vol. 7(1), pages 1-10, September.
    2. Víctor Faundes & Martin D. Jennings & Siobhan Crilly & Sarah Legraie & Sarah E. Withers & Sara Cuvertino & Sally J. Davies & Andrew G. L. Douglas & Andrew E. Fry & Victoria Harrison & Jeanne Amiel & D, 2021. "Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
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