Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosine to inosine in duplex RNA, a modification that exhibits a multitude of effects on RNA structure and function. Recent studies have identified ADAR1 as a potential cancer therapeutic target. ADARs are also important in the development of directed RNA editing therapeutics. A comprehensive understanding of the molecular mechanism of the ADAR reaction will advance efforts to develop ADAR inhibitors and new tools for directed RNA editing. Here we report the X-ray crystal structure of a fragment of human ADAR2 comprising its deaminase domain and double stranded RNA binding domain 2 (dsRBD2) bound to an RNA duplex as an asymmetric homodimer. We identified a highly conserved ADAR dimerization interface and validated the importance of these sequence elements on dimer formation via gel mobility shift assays and size exclusion chromatography. We also show that mutation in the dimerization interface inhibits editing in an RNA substrate-dependent manner for both ADAR1 and ADAR2.

中文翻译：

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作用于 RNA 的腺苷脱氨酶的不对称二聚化促进底物识别。

作用于 RNA 的腺苷脱氨酶 (ADAR) 是将双链 RNA 中的腺苷转化为肌苷的酶，这种修饰对 RNA 的结构和功能具有多种影响。最近的研究已将 ADAR1 确定为潜在的癌症治疗靶点。ADAR 在定向 RNA 编辑疗法的开发中也很重要。对 ADAR 反应分子机制的全面了解将推动开发 ADAR 抑制剂和用于定向 RNA 编辑的新工具的努力。在这里，我们报告了人类 ADAR2 片段的 X 射线晶体结构，该片段包含其脱氨酶域和双链 RNA 结合域 2 (dsRBD2)，作为不对称同源二聚体与 RNA 双链体结合。我们确定了一个高度保守的 ADAR 二聚化界面，并通过凝胶迁移率变化分析和尺寸排阻色谱验证了这些序列元素对二聚体形成的重要性。我们还表明，二聚化界面中的突变抑制 ADAR1 和 ADAR2 以 RNA 底物依赖性方式进行编辑。