Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1.

Autor:	Spizzichino S; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Di Fonzo F; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Marabelli C; Department of Molecular Medicine, University of Pavia, Via Forlanini 3, 27100 Pavia, Italy., Tramonti A; Institute of Molecular Biology and Pathology, National Research Council, P.le A. Moro 5, 00185 Rome, Italy., Chaves-Sanjuan A; Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milano, Italy; Fondazione Romeo e Enrica Invernizzi and NOLIMITS, University of Milan, Via Celoria 26, 20133 Milan, Italy., Parroni A; Institute of Molecular Biology and Pathology, National Research Council, P.le A. Moro 5, 00185 Rome, Italy., Boumis G; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Liberati FR; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Paone A; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy; Department of Biochemical Sciences, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, P.le A. Moro 5, 00185 Rome, Italy., Montemiglio LC; Institute of Molecular Biology and Pathology, National Research Council, P.le A. Moro 5, 00185 Rome, Italy., Ardini M; Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy., Jakobi AJ; Department of Bionanoscience, Kavli Institute of Nanoscience Deft, Delft University of Technology, Van der Maasweg, 92629 HZ Delft, the Netherlands., Bharadwaj A; Department of Bionanoscience, Kavli Institute of Nanoscience Deft, Delft University of Technology, Van der Maasweg, 92629 HZ Delft, the Netherlands., Swuec P; CryoElectron Microscopy Facility, Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy., Tartaglia GG; Centre for Human Technologies (CHT), Istituto Italiano di Tecnologia (IIT), Via Enrico Melen, 83, 16152 Genova, Italy; Department of Biology 'Charles Darwin', Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy., Paiardini A; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Contestabile R; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Mai A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Rotili D; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Fiorentino F; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Macone A; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Giorgi A; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Tria G; CNR Institute of Crystallography - URT Caserta c/o Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche (DiSTABiF), Università degli Studi della Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., Rinaldo S; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy., Bolognesi M; Department of Biosciences, University of Milan, Via Celoria 26, 20133 Milano, Italy; Fondazione Romeo e Enrica Invernizzi and NOLIMITS, University of Milan, Via Celoria 26, 20133 Milan, Italy., Giardina G; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy. Electronic address: giorgio.giardina@uniroma1.it., Cutruzzolà F; Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy; Department of Biochemical Sciences, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: francesca.cutruzzola@uniroma1.it.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Jul 25; Vol. 84 (14), pp. 2682-2697.e6. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1016/j.molcel.2024.06.016
Abstrakt:	RNA can directly control protein activity in a process called riboregulation; only a few mechanisms of riboregulation have been described in detail, none of which have been characterized on structural grounds. Here, we present a comprehensive structural, functional, and phylogenetic analysis of riboregulation of cytosolic serine hydroxymethyltransferase (SHMT1), the enzyme interconverting serine and glycine in one-carbon metabolism. We have determined the cryoelectron microscopy (cryo-EM) structure of human SHMT1 in its free- and RNA-bound states, and we show that the RNA modulator competes with polyglutamylated folates and acts as an allosteric switch, selectively altering the enzyme's reactivity vs. serine. In addition, we identify the tetrameric assembly and a flap structural motif as key structural elements necessary for binding of RNA to eukaryotic SHMT1. The results presented here suggest that riboregulation may have played a role in evolution of eukaryotic SHMT1 and in compartmentalization of one-carbon metabolism. Our findings provide insights for RNA-based therapeutic strategies targeting this cancer-linked metabolic pathway. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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