Structural basis for S-adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1
Structural basis for S-adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1
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DOI：
10.1093/nar/gkt547
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发表时间：
2013-09-01
影响因子：
14.9
通讯作者：
Garcia-Diaz, Miguel
中科院分区：
文献类型：
--
作者：
Guja, Kip E.;Venkataraman, Krithika;Garcia-Diaz, Miguel
bar（TFB）蛋白下的真核转录因子（B）与KsgA/Dim 1核糖体RNA（rRNA）甲基转移酶同源。哺乳动物TFB 1，线粒体（TFB 1 M）因子是线粒体基因表达所必需的必需蛋白。TFB 1 M介导小核糖体亚基中的rRNA修饰，因此发挥类似于KsgA/Dim 1蛋白的作用。这种修饰与线粒体功能障碍有关，导致母系遗传性耳聋、氨基糖苷类敏感性和糖尿病。在这里，我们提出了哺乳动物TFB 1因子的第一个结构特征。我们已经解决了两个X射线晶体结构的TFB 1 M与（2.1埃）和没有（2.0埃）其辅因子S-腺苷-L-蛋氨酸。这些结构揭示了TFB 1 M与其他KsgA/Dim 1甲基转移酶共享保守的甲基转移酶核心，并揭示了S-腺苷-L-甲硫氨酸结合和甲基转移酶活性的结构基础。连同诱变研究，这些数据表明底物结合的模型，并提供深入了解甲基转移的机制，澄清了这个因素在线粒体功能的一个重要过程中的作用。
Eukaryotic transcription factor (B) under bar (TFB) proteins are homologous to KsgA/Dim1 ribosomal RNA (rRNA) methyltransferases. The mammalian TFB1, mitochondrial (TFB1M) factor is an essential protein necessary for mitochondrial gene expression. TFB1M mediates an rRNA modification in the small ribosomal subunit and thus plays a role analogous to KsgA/Dim1 proteins. This modification has been linked to mitochondrial dysfunctions leading to maternally inherited deafness, aminoglycoside sensitivity and diabetes. Here, we present the first structural characterization of the mammalian TFB1 factor. We have solved two X-ray crystallographic structures of TFB1M with (2.1 angstrom) and without (2.0 angstrom) its cofactor S-adenosyl-L-methionine. These structures reveal that TFB1M shares a conserved methyltransferase core with other KsgA/Dim1 methyltransferases and shed light on the structural basis of S-adenosyl-L-methionine binding and methyltransferase activity. Together with mutagenesis studies, these data suggest a model for substrate binding and provide insight into the mechanism of methyl transfer, clarifying the role of this factor in an essential process for mitochondrial function.