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

Wator, Elzbieta; Wilk, Piotr; Biela, Artur; Rawski, Michal; Zak, Krzysztof M; Steinchen, Wieland; Bange, Gert; Glatt, Sebastian; Grudnik, Przemyslaw

doi:10.1038/s41467-023-37305-2

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

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Bange, Gert
Max Planck Fellow Molecular Physiology of Microbes, Max Planck Institute for Terrestrial Microbiology, Max Planck Society;
Philipps-Universität Marburg, Center for Synthetic Microbiology;
Philipps-Universität Marburg, Department Chemistry;

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https://doi.org/10.1038/s41467-023-37305-2
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Citation

Wator, E., Wilk, P., Biela, A., Rawski, M., Zak, K. M., Steinchen, W., et al. (2023). Cryo-EM structure of human eIF5A-DHS complex reveals the molecular basis of hypusination-associated neurodegenerative disorders. Nature Communications, 14: 1698. doi:10.1038/s41467-023-37305-2.

Cite as: https://hdl.handle.net/21.11116/0000-000C-E0BD-2

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 2.8A 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.