8A11
Cryo-EM structure of the Human SHMT1-RNA complex
Summary for 8A11
| Entry DOI | 10.2210/pdb8a11/pdb |
| EMDB information | 15065 |
| Descriptor | Serine hydroxymethyltransferase, cytosolic, PYRIDOXAL-5'-PHOSPHATE (2 entities in total) |
| Functional Keywords | riboregulation, metabolism, 1 carbon metablism, moonlighting protein, rna binding protein, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 214480.61 |
| Authors | Spizzichino, S.,Marabelli, C.,Bharadwaj, A.,Jakobi, A.J.,Chaves-Sanjuan, A.,Giardina, G.,Bolognesi, M.,Cutruzzola, F. (deposition date: 2022-05-30, release date: 2023-06-14, Last modification date: 2024-07-24) |
| Primary citation | 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.,Mai, A.,Rotili, D.,Fiorentino, F.,Macone, A.,Giorgi, A.,Tria, G.,Rinaldo, S.,Bolognesi, M.,Giardina, G.,Cutruzzola, F. Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1. Mol.Cell, 2024 Cited by PubMed 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. PubMed: 38996576DOI: 10.1016/j.molcel.2024.06.016 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.52 Å) |
Structure validation
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