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

Elżbieta Wątor, Piotr Wilk, Artur Biela, Michał Rawski, Krzysztof M. Zak, Wieland Steinchen, Gert Bange, Sebastian Glatt and Przemysław Grudnik ()
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Elżbieta Wątor: 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
Sebastian Glatt: Jagiellonian University
Przemysław Grudnik: Jagiellonian University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37305-2

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