Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2024-06-25 , DOI: 10.1038/s41594-024-01341-3 Philipp Throll 1 , Luciano G Dolce 1 , Palma Rico-Lastres 2 , Katharina Arnold 2 , Laura Tengo 1 , Shibom Basu 1 , Stefanie Kaiser 3 , Robert Schneider 2 , Eva Kowalinski 1
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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.
中文翻译:
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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
tRNA 反密码子环中 32 位胞嘧啶甲基化为 3-甲基胞嘧啶 (m 3 C) 对于细胞翻译保真度至关重要。 RNA 甲基转移酶的错误调节导致这种修饰可能导致侵袭性癌症和代谢紊乱。在这里,我们报道了与丝氨酰-tRNA合成酶(SerRS)及其共同底物tRNA Ser复合的人m 3 C tRNA甲基转移酶METTL6的冷冻电镜结构。通过复杂的结构,我们鉴定了 METTL6 的 tRNA 结合域。我们证明 SerRS 充当 METTL6 的 tRNA Ser底物选择因子。我们证明 SerRS 增强了 METTL6 的甲基化活性,并且 METTL6 和 SerRS 之间的直接接触对于有效的 tRNA Ser甲基化是必要的。最后,根据 METTL6 与 SerRS 和 tRNA Ser复合物的结构,我们假设 m 3 C RNA 甲基转移酶(包括 METTL2 和 METTL8)具有通用的 tRNA 结合模式,表明这些哺乳动物旁系同源物使用相似的方式来接合各自的tRNA 底物和辅因子。