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-Structure paper
タイトル | Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1. |
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ジャーナル・号・ページ | Mol Cell, Vol. 84, Issue 14, Page 2682-22697.e6, Year 2024 |
掲載日 | 2024年7月25日 |
著者 | Sharon Spizzichino / Federica Di Fonzo / Chiara Marabelli / Angela Tramonti / Antonio Chaves-Sanjuan / Alessia Parroni / Giovanna Boumis / Francesca Romana Liberati / Alessio Paone / Linda Celeste Montemiglio / Matteo Ardini / Arjen J Jakobi / Alok Bharadwaj / Paolo Swuec / Gian Gaetano Tartaglia / Alessandro Paiardini / Roberto Contestabile / Antonello Mai / Dante Rotili / Francesco Fiorentino / Alberto Macone / Alessandra Giorgi / Giancarlo Tria / Serena Rinaldo / Martino Bolognesi / Giorgio Giardina / Francesca Cutruzzolà / |
PubMed 要旨 | 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 ...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. |
リンク | Mol Cell / PubMed:38996576 |
手法 | EM (単粒子) |
解像度 | 3.29 - 3.52 Å |
構造データ | EMDB-15065, PDB-8a11: EMDB-18973, PDB-8r7h: |
化合物 | ChemComp-PLP: |
由来 |
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キーワード | TRANSFERASE / Riboregulation / Metabolism / 1 carbon metablism / Moonlighting protein / RNA BINDING PROTEIN / Serine / Glycine Metabolism |