8A11

Cryo-EM structure of the Human SHMT1-RNA complex

8A11 の概要

• エントリーDOI: 10.2210/pdb8a11/pdb
• EMDBエントリー: 15065
• 分子名称: Serine hydroxymethyltransferase, cytosolic, PYRIDOXAL-5'-PHOSPHATE (2 entities in total)
• 機能のキーワード: riboregulation, metabolism, 1 carbon metablism, moonlighting protein, rna binding protein, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 214480.61

構造登録者

Spizzichino, S.,Marabelli, C.,Bharadwaj, A.,Jakobi, A.J.,Chaves-Sanjuan, A.,Giardina, G.,Bolognesi, M.,Cutruzzola, F. (登録日: 2022-05-30, 公開日: 2023-06-14, 最終更新日: 2024-07-24)

主引用文献

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

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: 38996576
DOI: 10.1016/j.molcel.2024.06.016

実験手法

ELECTRON MICROSCOPY (3.52 Å)