Structural impacts of two disease-linked ADAR1 mutants: a molecular dynamics study

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
Wen-Chieh Huang, Chia-Hung Hsu, Titus V. Albu, Chia-Ning Yang
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Abstract

Adenosine deaminases acting on RNA (ADARs) are pivotal RNA-editing enzymes responsible for converting adenosine to inosine within double-stranded RNA (dsRNA). Dysregulation of ADAR1 editing activity, often arising from genetic mutations, has been linked to elevated interferon levels and the onset of autoinflammatory diseases. However, understanding the molecular underpinnings of this dysregulation is impeded by the lack of an experimentally determined structure for the ADAR1 deaminase domain. In this computational study, we utilized homology modeling and the AlphaFold2 to construct structural models of the ADAR1 deaminase domain in wild-type and two pathogenic variants, R892H and Y1112F, to decipher the structural impact on the reduced deaminase activity. Our findings illuminate the critical role of structural complementarity between the ADAR1 deaminase domain and dsRNA in enzyme-substrate recognition. That is, the relative position of E1008 and K1120 must be maintained so that they can insert into the minor and major grooves of the substrate dsRNA, respectively, facilitating the flipping-out of adenosine to be accommodated within a cavity surrounding E912. Both amino acid replacements studied, R892H at the orthosteric site and Y1112F at the allosteric site, alter K1120 position and ultimately hinder substrate RNA binding.

Abstract Image

两种与疾病相关的 ADAR1 突变体的结构影响:分子动力学研究。
作用于 RNA 的腺苷脱氨酶(ADARs)是一种关键的 RNA 编辑酶,负责将双链 RNA(dsRNA)中的腺苷转化为肌苷。ADAR1 编辑活性失调通常是由基因突变引起的,与干扰素水平升高和自身炎症性疾病的发病有关。然而,由于缺乏通过实验确定的 ADAR1 脱氨酶结构域结构,人们无法了解这种失调的分子基础。在这项计算研究中,我们利用同源建模和 AlphaFold2 构建了野生型和两种致病变体(R892H 和 Y1112F)中 ADAR1 脱氨酶结构域的结构模型,以破译结构对脱氨酶活性降低的影响。我们的发现阐明了 ADAR1 脱氨酶结构域与 dsRNA 之间的结构互补性在酶底物识别中的关键作用。也就是说,必须保持 E1008 和 K1120 的相对位置,这样它们才能分别插入底物 dsRNA 的小凹槽和大凹槽,促进腺苷的翻转,使其容纳在 E912 周围的空腔中。所研究的这两种氨基酸置换(正表位点上的 R892H 和异表位点上的 Y1112F)都改变了 K1120 的位置,最终阻碍了底物 RNA 的结合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
4.30%
发文量
567
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