Małopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland.
Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland.
Nat Commun. 2023 Mar 27;14(1):1698. doi: 10.1038/s41467-023-37305-2.
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.
Hypusination 是真核翻译因子 5A (eIF5A) 的一种独特的翻译后修饰，对于克服多脯氨酸序列延伸处的核糖体停滞至关重要。Hypusination 的初始步骤是 deoxyhypusine 的形成，由 deoxyhypusine synthase (DHS) 催化，然而，DHS 介导的反应的分子细节仍然难以捉摸。最近，患者来源的 DHS 和 eIF5A 的变体与罕见的神经发育障碍有关。在这里，我们展示了 2.8 Å 分辨率的人 eIF5A-DHS 复合物的 cryo-EM 结构和 DHS 被捕获在关键反应过渡态的晶体结构。此外，我们表明，与疾病相关的 DHS 变体影响复合物的形成和 Hypusination 效率。因此，我们的工作剖析了 deoxyhypusine 合成反应的分子细节，并揭示了临床相关突变如何影响这一关键的细胞过程。
