小柯机器人

美国波士顿儿童医院Richard I. Gregory团队近期取得重要工作进展，他们研究发现了METTL1-WDR4调节m⁷G tRNA修饰的结构基础。相关研究成果2023年1月4日在线发表于《自然》杂志上。

据介绍，RNA的化学修饰在许多生物过程中起着关键作用。N⁷-甲基鸟苷（m⁷G）是大部分tRNA完整性和稳定性所必需的。甲基转移酶1-WD重复序列蛋白4（METTL1-WDR4）复合物是修饰某些特定tRNA可变环中G46的甲基转移酶，其失调驱动多种癌症类型的肿瘤发生。WDR4突变导致包括小头畸形在内的人类发育表型。METTL1-WDR4如何修饰tRNA底物并进行调控，目前仍不清楚。

研究人员通过对人METTL1-WDR4的结构、生化和细胞研究表明，WDR4作为METTL1和tRNA T臂的支架。在tRNA结合后，METTL1的αC区转变为螺旋，与α6螺旋一起固定tRNA可变环的两端。研究人员发现，METTL1预测的无序N-末端区域是催化口袋的一部分，对甲基转移酶活性至关重要。

此外，研究人员发现METTL1 N末端区域的S27磷酸化通过局部破坏催化中心来抑制甲基转移酶活性。

总之，这一结果提供了对tRNA底物识别和磷酸化介导的METTL1-WDR4调控的分子理解，并揭示了METTL1的假定无序N-末端区域作为甲基转移酶活性的纽带。

附：英文原文

Title: Structural basis of regulated m7G tRNA modification by METTL1–WDR4

Author: Li, Jiazhi, Wang, Longfei, Hahn, Quentin, Nowak, Radosaw P., Viennet, Thibault, Orellana, Esteban A., Roy Burman, Shourya S., Yue, Hong, Hunkeler, Moritz, Fontana, Pietro, Wu, Hao, Arthanari, Haribabu, Fischer, Eric S., Gregory, Richard I.

Issue&Volume: 2023-01-04

Abstract: Chemical modifications of RNA have key roles in many biological processes1,2,3. N7-methylguanosine (m7G) is required for integrity and stability of a large subset of tRNAs4,5,6,7. The methyltransferase 1–WD repeat-containing protein 4 (METTL1–WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types8,9,10,11,12,13,14. Mutations in WDR4 cause human developmental phenotypes including microcephaly15,16,17. How METTL1–WDR4 modifies tRNA substrates and is regulated remains elusive18. Here we show,  through structural, biochemical and cellular studies of human METTL1–WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the αC region of METTL1 transforms into a helix, which together with the α6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1–WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity.

DOI: 10.1038/s41586-022-05566-4

Source: https://www.nature.com/articles/s41586-022-05566-4

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
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