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研究揭示METTL1-WDR4介导tRNA甲基化的结构和机制
2023-01-07 15:01
来源：小柯机器人

美国德克萨斯大学Yunsun Nam小组揭示METTL1-WDR4介导tRNA甲基化的结构和机制。相关论文于2023年1月4日在线发表在《自然》杂志上。

研究人员表示，RNA的特异性、调节性修饰对基因的正常表达很重要。tRNA富含各种化学修饰，影响其稳定性和功能。tRNA第46位的7-甲基鸟苷（m7G）是一种保守的修饰，它可以调节稳态tRNA水平，从而影响细胞的生长。METTL1-WDR4复合物在人类中产生m7G46，METTL1-WDR4的失调与脑畸形和多种癌症有关。
 
研究人员报道了METTL1和WDR4如何合作识别RNA底物并催化甲基化。METTL1-WDR4的晶体结构和METTL1-WDR4-tRNA的冷冻电镜结构显示，复合蛋白表面通过形状互补性识别tRNA弯头。METTL1-WDR4-tRNA与S-腺苷蛋氨酸或S-腺苷高半胱氨酸的冷冻电镜结构以及METTL1晶体结构通过揭示多种状态下的活性部位，为催化机制提供了更多的见解。METTL1的N端将辅助因子的结合与tRNA、催化环和WDR4 C端的构象变化联系起来，作为激活m7G甲基化的开关。因此，这个结构模型解释了METTL1 N末端的翻译后修饰如何能调节甲基化。总之，这个工作阐明了METTL1 m7G修饰的核心和调节机制，为理解其对生物学和疾病的贡献提供了框架。
 
附：英文原文

Title: Structures and mechanisms of tRNA methylation by METTL1–WDR4

Author: Ruiz-Arroyo, Victor M., Raj, Rishi, Babu, Kesavan, Onolbaatar, Otgonbileg, Roberts, Paul H., Nam, Yunsun

Issue&Volume: 2023-01-04

Abstract: Specific, regulated modification of RNAs is important for proper gene expression1,2. tRNAs are rich with various chemical modifications that affect their stability and function3,4. 7-Methylguanosine (m7G) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth5,6. The METTL1–WDR4 complex generates m7G46 in humans, and dysregulation of METTL1–WDR4 has been linked to brain malformation and multiple cancers7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22. Here we show how METTL1 and WDR4 cooperate to recognize RNA substrates and catalyse methylation. A crystal structure of METTL1–WDR4 and cryo-electron microscopy structures of METTL1–WDR4–tRNA show that the composite protein surface recognizes the tRNA elbow through shape complementarity. The cryo-electron microscopy structures of METTL1–WDR4–tRNA with S-adenosylmethionine or S-adenosylhomocysteine along with METTL1 crystal structures provide additional insights into the catalytic mechanism by revealing the active site in multiple states. The METTL1 N terminus couples cofactor binding with conformational changes in the tRNA, the catalytic loop and the WDR4 C terminus, acting as the switch to activate m7G methylation. Thus, our structural models explain how post-translational modifications of the METTL1 N terminus can regulate methylation. Together, our work elucidates the core and regulatory mechanisms underlying m7G modification by METTL1, providing the framework to understand its contribution to biology and disease.

DOI: 10.1038/s41586-022-05565-5

Source: https://www.nature.com/articles/s41586-022-05565-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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