European Molecular Biology Laboratory, Structural and Computational Biology Unit, Heidelberg, Germany.
Max Planck Research Group at the Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland.
Sci Adv. 2019 Jul 10;5(7):eaaw2326. doi: 10.1126/sciadv.aaw2326. eCollection 2019 Jul.
The highly conserved Elongator complex modifies transfer RNAs (tRNAs) in their wobble base position, thereby regulating protein synthesis and ensuring proteome stability. The precise mechanisms of tRNA recognition and its modification reaction remain elusive. Here, we show cryo-electron microscopy structures of the catalytic subcomplex of Elongator and its tRNA-bound state at resolutions of 3.3 and 4.4 Å. The structures resolve details of the catalytic site, including the substrate tRNA, the iron-sulfur cluster, and a SAM molecule, which are all validated by mutational analyses in vitro and in vivo. tRNA binding induces conformational rearrangements, which precisely position the targeted anticodon base in the active site. Our results provide the molecular basis for substrate recognition of Elongator, essential to understand its cellular function and role in neurodegenerative diseases and cancer.
高度保守的 Elongator 复合物在其摆动碱基位置修饰转移 RNA（tRNA），从而调节蛋白质合成并确保蛋白质组稳定性。tRNA 的识别及其修饰反应的确切机制仍不清楚。在这里，我们展示了 Elongator 催化亚基复合物及其与 tRNA 结合状态的低温电子显微镜结构，分辨率分别为 3.3 和 4.4 Å。这些结构解析了催化位点的细节，包括底物 tRNA、铁硫簇和一个 SAM 分子，这些都通过体外和体内的突变分析得到了验证。tRNA 的结合诱导构象重排，从而将靶向反密码子碱基精确地定位在活性位点中。我们的研究结果为 Elongator 对底物的识别提供了分子基础，这对于理解其在神经退行性疾病和癌症中的细胞功能和作用至关重要。
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