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

RNA-binding protein RNA-protein interactions cancer cryo-EM metabolic enzyme one-carbon metabolism riboregulation translational control

Journal

Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571

Informations de publication

Date de publication:
09 Jul 2024
Historique:
received: 05 04 2023
revised: 26 01 2024
accepted: 18 06 2024
medline: 13 7 2024
pubmed: 13 7 2024
entrez: 12 7 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.molcel.2024.06.016 PMID: 38996576
pubmed: 38996576
pii: S1097-2765(24)00523-9
doi: 10.1016/j.molcel.2024.06.016
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Sharon Spizzichino (S)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Federica Di Fonzo (F)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Chiara Marabelli (C)

Department of Molecular Medicine, University of Pavia, Via Forlanini 3, 27100 Pavia, Italy.

Angela Tramonti (A)

Institute of Molecular Biology and Pathology, National Research Council, P.le A. Moro 5, 00185 Rome, Italy.

Antonio 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.

Alessia Parroni (A)

Institute of Molecular Biology and Pathology, National Research Council, P.le A. Moro 5, 00185 Rome, Italy.

Giovanna Boumis (G)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Francesca Romana Liberati (FR)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Alessio 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.

Linda Celeste Montemiglio (LC)

Institute of Molecular Biology and Pathology, National Research Council, P.le A. Moro 5, 00185 Rome, Italy.

Matteo Ardini (M)

Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.

Arjen J Jakobi (AJ)

Department of Bionanoscience, Kavli Institute of Nanoscience Deft, Delft University of Technology, Van der Maasweg, 92629 HZ Delft, the Netherlands.

Alok Bharadwaj (A)

Department of Bionanoscience, Kavli Institute of Nanoscience Deft, Delft University of Technology, Van der Maasweg, 92629 HZ Delft, the Netherlands.

Paolo Swuec (P)

CryoElectron Microscopy Facility, Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy.

Gian Gaetano 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.

Alessandro Paiardini (A)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Roberto Contestabile (R)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Antonello Mai (A)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Dante Rotili (D)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Francesco Fiorentino (F)

Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Alberto Macone (A)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Alessandra Giorgi (A)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Giancarlo 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.

Serena Rinaldo (S)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.

Martino 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.

Giorgio Giardina (G)

Department of Biochemical Sciences, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy. Electronic address: giorgio.giardina@uniroma1.it.

Francesca 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.

Classifications MeSH