Structural insights into dimethylation of 12S rRNA by TFB1M: indispensable role in translation of mitochondrial genes and mitochondrial function
Structural insights into dimethylation of 12S rRNA by TFB1M: indispensable role in translation of mitochondrial genes and mitochondrial function
复制标题
TFB1M 对 12S rRNA 二甲基化的结构见解：在线粒体基因翻译和线粒体功能中不可或缺的作用。
DOI：
10.1093/nar/gkz505
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发表时间：
2019-08-22
影响因子：
14.9
通讯作者：
Shi, Yunyu
中科院分区：
文献类型：
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作者：
Liu, Xiaodan;Shen, Shengqi;Shi, Yunyu
线粒体是氧化磷酸化系统 (OXPHOS) 维持细胞能量供应的重要分子机制。线粒体转录因子 B1 (TFB1M) 是一种二甲基转移酶，通过催化 12S rRNA 螺旋 45 (h45) 中两个相邻腺嘌呤的二甲基化来维持线粒体稳态。这种 m(2)(6)A 修饰对于人类线粒体核糖体的组装和成熟是必不可少的。然而，TFB1M 催化机制和 TFB1M 在线粒体稳态中的精确功能尚不清楚。在这里，我们报道了人（hs）TFB1M-h45-S-腺苷甲硫氨酸的三元复合物和二元复合物hsTFB1M-h45的晶体结构。这些结构揭示了 hsTFB1M 与其 rRNA 底物以及参与 m(2)(6)A 修饰的初始酶状态相互作用的独特模式。 hsTFB1M蛋白水平的抑制或失活hsTFB1M突变体的过度表达导致ATP产生减少和线粒体OXPHOS成分表达减少，而不影响相应基因的转录及其在线粒体中的定位。因此，hsTFB1M 通过 h45 中的 m(2)(6)A 修饰调节线粒体基因的翻译，而不是其转录。
Mitochondria are essential molecular machinery for the maintenance of cellular energy supply by the oxidative phosphorylation system (OXPHOS). Mitochondrial transcription factor B1 (TFB1M) is a dimethyltransferase that maintains mitochondrial homeostasis by catalyzing dimethylation of two adjacent adenines located in helix45 (h45) of 12S rRNA. This m(2)(6)A modification is indispensable for the assembly and maturation of human mitochondrial ribosomes. However, both the mechanism of TFB1M catalysis and the precise function of TFB1M in mitochondrial homeostasis are unknown. Here we report the crystal structures of a ternary complex of human (hs) TFB1M-h45-S-adenosyl-methionine and a binary complex hsTFB1M-h45. The structures revealed a distinct mode of hsTFB1M interaction with its rRNA substrate and with the initial enzymatic state involved in m(2)(6)A modification. The suppression of hsTFB1M protein level or the overexpression of inactive hsTFB1M mutants resulted in decreased ATP production and reduced expression of components of the mitochondrial OXPHOS without affecting transcription of the corresponding genes and their localization to the mitochondria. Therefore, hsTFB1M regulated the translation of mitochondrial genes rather than their transcription via m(2)(6)A modification in h45.