基于结构的代谢酶 SHMT1 核糖调节机制。
Structure-based mechanism of riboregulation of the metabolic enzyme SHMT1.
发表日期：2024 Jul 09
作者：
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
来源：
MOLECULAR CELL
摘要：
RNA 可以在称为核糖调节的过程中直接控制蛋白质活性；仅详细描述了少数核糖调节机制，但没有一个在结构基础上进行表征。在这里，我们对胞浆丝氨酸羟甲基转移酶（SHMT1）的核糖调节进行了全面的结构、功能和系统发育分析，SHMT1是一碳代谢中丝氨酸和甘氨酸相互转化的酶。我们已经确定了人 SHMT1 在游离状态和 RNA 结合状态下的冷冻电子显微镜 (cryo-EM) 结构，并且我们表明 RNA 调节剂与聚谷氨酰化叶酸竞争并充当变构开关，选择性地改变酶的反应性与酶的反应性。丝氨酸。此外，我们还确定了四聚体组装和瓣结构基序是 RNA 与真核 SHMT1 结合所必需的关键结构元件。这里提出的结果表明，核糖调节可能在真核 SHMT1 的进化和一碳代谢的区室化中发挥了作用。我们的研究结果为针对这种癌症相关代谢途径的基于 RNA 的治疗策略提供了见解。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.