m3C RNA 甲基转移酶 METTL6 与 SerRS 丝氨酰-tRNA 合成酶复合物识别 tRNA 的结构基础

IF 12.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Philipp Throll, Luciano G. Dolce, Palma Rico-Lastres, Katharina Arnold, Laura Tengo, Shibom Basu, Stefanie Kaiser, Robert Schneider, Eva Kowalinski
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引用次数: 0

摘要

将 tRNA 反密码子环中的胞嘧啶 32 甲基化为 3-甲基胞嘧啶(m3C)对细胞翻译的可靠性至关重要。设置这种修饰的 RNA 甲基转移酶的失调可导致侵袭性癌症和代谢紊乱。在这里,我们报告了人类 m3C tRNA 甲基转移酶 METTL6 与丝氨酰-tRNA 合成酶(SerRS)和它们的共同底物 tRNASer 复合物的冷冻电镜结构。 通过该复合物结构,我们确定了 METTL6 的 tRNA 结合域。我们发现 SerRS 是 METTL6 的 tRNASer 底物选择因子。我们证明 SerRS 增强了 METTL6 的甲基化活性,而且 METTL6 和 SerRS 之间的直接接触是高效 tRNASer 甲基化的必要条件。最后,根据 METTL6 与 SerRS 和 tRNASer 复合物的结构,我们推测包括 METTL2 和 METTL8 在内的 m3C RNA 甲基转移酶有一种通用的 tRNA 结合模式,这表明这些哺乳动物旁系亲属使用类似的方式与各自的 tRNA 底物和辅助因子结合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase

Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase

Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase
Methylation of cytosine 32 in the anticodon loop of tRNAs to 3-methylcytosine (m3C) is crucial for cellular translation fidelity. Misregulation of the RNA methyltransferases setting this modification can cause aggressive cancers and metabolic disturbances. Here, we report the cryo-electron microscopy structure of the human m3C tRNA methyltransferase METTL6 in complex with seryl-tRNA synthetase (SerRS) and their common substrate tRNASer. Through the complex structure, we identify the tRNA-binding domain of METTL6. We show that SerRS acts as the tRNASer substrate selection factor for METTL6. We demonstrate that SerRS augments the methylation activity of METTL6 and that direct contacts between METTL6 and SerRS are necessary for efficient tRNASer methylation. Finally, on the basis of the structure of METTL6 in complex with SerRS and tRNASer, we postulate a universal tRNA-binding mode for m3C RNA methyltransferases, including METTL2 and METTL8, suggesting that these mammalian paralogs use similar ways to engage their respective tRNA substrates and cofactors. The authors use cryo-electron microscopy and biochemistry to reveal how 3-methylcytosine (m3C) methyltransferases bind tRNA. They also find that the human m3C methyltransferase METTL6 forms a tRNA-dependent complex with seryl-tRNA synthetase to methylate target tRNAs efficiently.
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来源期刊
Nature Structural & Molecular Biology
Nature Structural & Molecular Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOPHYSICS
CiteScore
22.00
自引率
1.80%
发文量
160
审稿时长
3-8 weeks
期刊介绍: Nature Structural & Molecular Biology is a comprehensive platform that combines structural and molecular research. Our journal focuses on exploring the functional and mechanistic aspects of biological processes, emphasizing how molecular components collaborate to achieve a particular function. While structural data can shed light on these insights, our publication does not require them as a prerequisite.
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