Crystal structure of archaeal IF5A-DHS complex reveals insights into the hypusination mechanism.

Autor:	D'Agostino M; Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy; Architecture et Réactivité de l'ARN, CNRS UPR 9002, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France., Simonetti A; Architecture et Réactivité de l'ARN, CNRS UPR 9002, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France., Motta S; Department of Earth and Environmental Sciences, University of Milano Bicocca, Piazza della Scienza 1, 20126 Milan, Italy., Wolff P; Architecture et Réactivité de l'ARN, CNRS UPR 9002, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France., Romagnoli A; Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy; New York-Marche Structural Biology Center (Ny-Masbic), Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy., Piccinini A; Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy., Spinozzi F; Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy., Di Marino D; Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy; New York-Marche Structural Biology Center (Ny-Masbic), Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy; Neuronal Death and Neuroprotection Unit, Department of Neuroscience, Mario Negri Institute for Pharmacological Research-IRCCS, Via Mario Negri 2, 20156 Milano, Italy. Electronic address: d.dimarino@univpm.it., La Teana A; Department of Life and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy; New York-Marche Structural Biology Center (Ny-Masbic), Polytechnic University of Marche, Via Brecce Bianche, 60131 Ancona, Italy. Electronic address: a.lateana@univpm.it., Ennifar E; Architecture et Réactivité de l'ARN, CNRS UPR 9002, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France. Electronic address: e.ennifar@unistra.fr.
Jazyk:	angličtina
Zdroj:	Structure (London, England : 1993) [Structure] 2024 Jul 11; Vol. 32 (7), pp. 878-888.e4. Date of Electronic Publication: 2024 Apr 05.
DOI:	10.1016/j.str.2024.03.008
Abstrakt:	The translation factor IF5A is highly conserved in Eukarya and Archaea and undergoes a unique post-translational hypusine modification by the deoxyhypusine synthase (DHS) enzyme. DHS transfers the butylamine moiety from spermidine to IF5A using NAD as a cofactor, forming a deoxyhypusine intermediate. IF5A is a key player in protein synthesis, preventing ribosome stalling in proline-rich sequences during translation elongation and facilitating translation elongation and termination. Additionally, human eIF5A participates in various essential cellular processes and contributes to cancer metastasis, with inhibiting hypusination showing anti-proliferative effects. The hypusination pathway of IF5A is therefore an attractive new therapeutic target. We elucidated the 2.0 Å X-ray crystal structure of the archaeal DHS-IF5A complex, revealing hetero-octameric architecture and providing a detailed view of the complex active site including the hypusination loop. This structure, along with biophysical data and molecular dynamics simulations, provides new insights into the catalytic mechanism of the hypusination reaction. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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