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Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1

Journal Article (2024)
Author(s)

Chiara Marabelli (Università di Pavia)

Angela Tramonti (IMAMOTER - C.N.R.)

Antonio Chaves-Sanjuan (University of Milan)

Matteo Ardini (University of L'Aquila)

Arjen J. Jakobi (Kavli institute of nanoscience Delft, TU Delft - Applied Sciences)

Alok Bharadwaj (Kavli institute of nanoscience Delft, TU Delft - Applied Sciences)

Paolo Swuec (Human Technopole)

Gian Gaetano Tartaglia (Sapienza University of Rome, Istituto Italiano di Tecnologia)

Giancarlo Tria (Università degli Studi della Campania Luigi Vanvitelli)

Giorgio Giardina (Sapienza University of Rome)

Francesca Cutruzzolà (Sapienza University of Rome)

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Research Group
BN/Arjen Jakobi Lab
DOI related publication
https://doi.org/10.1016/j.molcel.2024.06.016 Final published version
More Info
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Publication Year
2024
Language
English
Research Group
BN/Arjen Jakobi Lab
Issue number
14
Volume number
84
Pages (from-to)
2682-2697
Downloads counter
305
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Abstract

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.