RNA can directly control protein activity in a process called riboregulation; only a few mechanisms of riboregulation have been described in detail, none of these being characterised 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 cryo-electron 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.
STRUCTURE-BASED MECHANISM OF RIBOREGULATION OF THE METABOLIC ENZYME SHMT1 / Spizzichino, Sharon; DI FONZO, Federica; Marabelli, Chiara; Tramonti, Angela; Chaves-Sanjuan, Antonio; Parroni, Alessia; Boumis, Giovanna; Liberati, FRANCESCA ROMANA; Paone, Alessio; Montemiglio, LINDA CELESTE; Ardini, Matteo; Jakobi, Arjen J.; Bharadwaj, Alok; Swuec, Paolo; Tartaglia, GIAN GAETANO; Paiardini, Alessandro; Contestabile, Roberto; Mai, Antonello; Rotili, Dante; Fiorentino, Francesco; Macone, Alberto; Giorgi, Alessandra; Tria, Giancarlo; Rinaldo, Serena; Bolognesi, Martino; Giardina, Giorgio; Cutruzzola, Francesca. - In: MOLECULAR CELL. - ISSN 1097-2765. - (2024).
STRUCTURE-BASED MECHANISM OF RIBOREGULATION OF THE METABOLIC ENZYME SHMT1
Sharon SpizzichinoCo-primo
;Federica Di FonzoCo-primo
;Angela Tramonti;Alessia Parroni;Giovanna Boumis;Francesca Romana Liberati;Alessio Paone;Linda Celeste Montemiglio;Matteo Ardini;Gian Gaetano Tartaglia;Alessandro Paiardini;Roberto Contestabile;Antonello Mai;Dante Rotili;Francesco Fiorentino;Alberto Macone;Alessandra Giorgi;Giancarlo Tria;Serena Rinaldo;Giorgio Giardina
Penultimo
;Francesca Cutruzzola
Ultimo
2024
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 these being characterised 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 cryo-electron 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
