The C-Ala domain brings together editing and aminoacylation functions on one tRNA.
The C-Ala domain brings together editing and aminoacylation functions on one tRNA.
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DOI：
10.1126/science.1174343
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发表时间：
2009-08-07
期刊：
影响因子：
--
通讯作者：
Schimmel P
中科院分区：
文献类型：
--
作者：
Guo M;Chong YE;Beebe K;Shapiro R;Yang XL;Schimmel P
蛋白质合成包括氨基酸与其相匹配的tRNA分子的精确连接。丙氨酸的丝氨酸或甘氨酸的误译是通过独立但协同的氨酰化和丙氨酰-tRNA合成酶（AlaRSs）的编辑结构域的功能来防止的。在这里，我们表明，C-Ala结构域在AlaRS功能中起着关键作用。在AlaRS和许多同源的独立编辑蛋白中，C-Ala结构域普遍与编辑结构域相连。晶体结构和功能分析表明，C-Ala形成一个古老的单链核酸结合基序，促进氨酰化和编辑结构域与tRNAAla的合作结合。此外，C-Ala可能在AlaRSs的进化中发挥了重要作用，通过将氨酰化与编辑偶联以防止误译。在蛋白质合成的第一步反应中建立了遗传密码的算法。在该反应中，氨酰-tRNA合成酶（AARS）催化氨基酸与其同源转移RNA（tRNA）的连接，所述tRNA携带遗传密码的三联体反密码子。当tRNA被错误的氨基酸酰化时，如果错酰化的tRNA从合成酶中释放出来，被延伸因子捕获，并在核糖体中用于肽合成，就会发生错误翻译。为了防止误译，一些AARS具有单独的编辑活性，其从tRNA水解错酰化的氨基酸。由于有编辑缺陷的tRNA合成酶对细菌和哺乳动物细胞有毒，并且与动物疾病有因果关系，因此强大的选择压力在整个进化过程中保留了这些编辑活动。
Protein synthesis involves the accurate attachment of amino acids to their matching tRNA molecules. Mistranslating the amino acids serine or glycine for alanine is prevented by the function of independent but collaborative aminoacylation and editing domains of alanyl-tRNA synthetases (AlaRSs). Here we show that the C-Ala domain plays a key role in AlaRS function. The C-Ala domain is universally tethered to the editing domain both in AlaRS and in many homologous free-standing, editing proteins. Crystal structure and functional analyses showed that C-Ala forms an ancient single-stranded nucleic acid binding motif that promotes cooperative binding of both aminoacylation and editing domains to tRNAAla. In addition, C-Ala may have played an essential role in the evolution of AlaRSs by coupling aminoacylation to editing to prevent mistranslation. The algorithm of the genetic code is established in the first reaction of protein synthesis. In this reaction, aminoacyl-tRNA synthetases (AARSs) catalyze the attachment of amino acids to their cognate transfer RNAs (tRNAs) that bear the triplet anticodons of the genetic code. When a tRNA is acylated with the wrong amino acid, mistranslation occurs if the misacylated tRNA is released from the synthetase, captured by elongation factor, and used at the ribosome for peptide synthesis. To prevent mistranslation, some AARSs have separate editing activities that hydrolyze the misacylated amino acid from the tRNA. Because an editing-defective tRNA synthetase is toxic to bacterial and mammalian cells, and is causally linked to disease in animals, strong selective pressure retains these editing activities throughout evolution.