Magnesium ions mitigate metastable states in the regulatory landscape of mRNA elements.

IF 4.2 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RNA Pub Date : 2024-07-16 DOI:10.1261/rna.079767.123
Erdong Ding, Susmit Narayan Chaudhury, Jigneshkumar Dahyabhai Prajapati, José N Onuchic, Karissa Y Sanbonmatsu
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Abstract

Residing in the 5' untranslated region of the mRNA, the 2'-deoxyguanosine (2'-dG) riboswitch mRNA element adopts an alternative structure upon binding of the 2'-dG molecule, which terminates transcription. RNA conformations are generally strongly affected by positively charged metal ions (especially Mg2+). We have quantitatively explored the combined effect of ligand (2'-dG) and Mg2+ binding on the energy landscape of the aptamer domain of the 2'-dG riboswitch with both explicit solvent all-atom molecular dynamics simulations (99 μsec aggregate sampling for the study) and selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) experiments. We show that both ligand and Mg2+ are required for the stabilization of the aptamer domain; however, the two factors act with different modalities. The addition of Mg2+ remodels the energy landscape and reduces its frustration by the formation of additional contacts. In contrast, the binding of 2'-dG eliminates the metastable states by nucleating a compact core for the aptamer domain. Mg2+ ions and ligand binding are required to stabilize the least stable helix, P1 (which needs to unfold to activate the transcription platform), and the riboswitch core formed by the backbone of the P2 and P3 helices. Mg2+ and ligand also facilitate a more compact structure in the three-way junction region.

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镁离子缓解 mRNA 成分调控格局中的易变状态
2'-deoxyguanosine (2'-dG) 核糖开关 mRNA 元件位于 mRNA 的 5'非翻译区,与 2'-dG 分子结合后会采用另一种结构,从而终止转录。一般来说,RNA 的构象会受到带正电的金属离子(尤其是 Mg2+)的强烈影响。我们通过显式溶剂全原子分子动力学模拟和 SHAPE 生化探测实验,定量探讨了配体(2'-dG)和 Mg2+ 结合对 2'-dG 核糖开关的适配体结构域的能量景观的综合影响。我们的研究表明,配体和 Mg2+ 都是稳定适配体结构域所必需的;但是,这两个因素以不同的方式发挥作用。Mg2+ 的加入重塑了能量图谱,并通过形成额外的接触减少了能量图谱的挫折感,而 2'-dG 的结合则通过为aptamer 结构域建立一个紧凑的核心消除了瞬变状态。特别是,需要 Mg2+ 离子和配体的结合来稳定最不稳定的螺旋 P1(需要展开才能激活转录平台),以及由 P2 和 P3 螺旋骨架形成的核糖开关核心。它们还有助于在三向连接区域形成更紧凑的结构。
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来源期刊
RNA
RNA 生物-生化与分子生物学
CiteScore
8.30
自引率
2.20%
发文量
101
审稿时长
2.6 months
期刊介绍: RNA is a monthly journal which provides rapid publication of significant original research in all areas of RNA structure and function in eukaryotic, prokaryotic, and viral systems. It covers a broad range of subjects in RNA research, including: structural analysis by biochemical or biophysical means; mRNA structure, function and biogenesis; alternative processing: cis-acting elements and trans-acting factors; ribosome structure and function; translational control; RNA catalysis; tRNA structure, function, biogenesis and identity; RNA editing; rRNA structure, function and biogenesis; RNA transport and localization; regulatory RNAs; large and small RNP structure, function and biogenesis; viral RNA metabolism; RNA stability and turnover; in vitro evolution; and RNA chemistry.
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