THE RIBOREGULATION MECHANISM OF HUMAN SERINE HYDROXYMETHYLTRANSFERASE IS ROOTED IN AN ALLOSTERIC SWITCH

Spizzichino, S.; Di Fonzo, F.; Marabelli, C.; Tramonti, A.; Chaves-Sanjuan, A.; Parroni, A.; Boumis, G.; Liberati, F. R.; Paone, A.; Montemiglio, L. C.; Ardini, M.; Jakobi, A. J.; Bharadwaj, A.; Swuec, P.; Tartaglia, G. G.; Paiardini, A.; Contestabile, R.; Rinaldo, S.; Bolognesi, M.; Giardina, G.; Cutruzzola, F.

doi:10.1101/2023.03.17.532973

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bioRxiv · 10.1101/2023.03.17.532973

THE RIBOREGULATION MECHANISM OF HUMAN SERINE HYDROXYMETHYLTRANSFERASE IS ROOTED IN AN ALLOSTERIC SWITCH

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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 these being 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 show that the RNA modulator competes with polyglutamylated folates and acts as an allosteric switch, selectively altering the enzymes 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 the evolution of eukaryotic SHMT1 and the compartmentalization of one-carbon metabolism. The findings also provide insights for RNA-based therapeutic strategies targeting this cancer-linked metabolic pathway.

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Spizzichino, S., Di Fonzo, F., Marabelli, C., Tramonti, A., Chaves-Sanjuan, A., Parroni, A., Boumis, G., Liberati, F. R., Paone, A., Montemiglio, L. C., Ardini, M., Jakobi, A. J., Bharadwaj, A., Swuec, P., Tartaglia, G. G., Paiardini, A., Contestabile, R., Rinaldo, S., Bolognesi, M., Giardina, G., Cutruzzola, F.. 2023-03-17. THE RIBOREGULATION MECHANISM OF HUMAN SERINE HYDROXYMETHYLTRANSFERASE IS ROOTED IN AN ALLOSTERIC SWITCH. https://doi.org/10.1101/2023.03.17.532973

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