Till stress do us ataRT: a novel toxin-antitoxin system targeting translation initiation.
Till stress do us ataRT: a novel toxin-antitoxin system targeting translation initiation.
复制标题
直到压力降临 ataRT：一种针对翻译起始的新型毒素-抗毒素系统。
DOI：
10.1038/cdd.2017.66
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发表时间：
2017
影响因子：
12.4
通讯作者：
Pizzinga M
中科院分区：
文献类型：
--
作者：
Pizzinga M
蛋白质合成是一个高度调控的三阶段过程，包括起始、延伸和终止。简而言之，在起始过程中，信使 RNA (mRNA) 与小核糖体亚基上的 mRNA 通道结合，起始密码子位于 P-（肽基）解码位点内。带电荷的起始转移RNA (tRNA)，在原核生物中通常是(甲酰基)甲硫氨酰-tRNAi (met-tRNAfMet)，在真核生物中是tRNAiMet，被招募到起始密码子。重要的是，通过解码 mRNA 的第一个三联体，起始 tRNA 确定阅读框。大核糖体亚基与核糖体 P 位点的起始 tRNA 结合形成核糖体复合物，为延伸阶段做好准备，在此阶段信息被解码。在延伸过程中，具有与 mRNA 密码子互补的反密码子的氨酰基-tRNA 被招募到核糖体 A 位点。通过将连接到 P 位点中的 tRNA 的氨基酸/肽转移到相邻 A 位点中的氨酰基-tRNA 来形成肽键，并且新形成的肽基-tRNA 随后与 mRNA 一起从 A 位点转移到 P 位点。这些过程由核糖体和延伸因子促进。当终止密码子进入 A 位点时，终止因子与核糖体结合并促进肽基-tRNA 的水解。 1 mRNA 翻译过程通过改变其成分的生物利用度和/或功能受到高度调控。 1 虽然 tRNA 以前被认为在蛋白质合成的整体调节中具有相当“被动”的作用，但最近的数据表明，通过它们的修饰和生物利用度，它们对生命所有领域中 mRNA 翻译的整体调节做出了重大贡献。事后看来，这或许并不令人意外，因为 tRNA 通过提供 mRNA 和氨基酸之间的联系，在蛋白质合成中发挥着核心作用。氨基酸通过氨酰化作用附着在 tRNA 上，氨酰化作用由氨酰基 RNA 合成酶催化。氨酰化和解码过程的高精度部分是通过 tRNA 的转录后修饰实现的，其中描述了 100 多种不同的转录后修饰。 2 在解码目标位置 34（摆动核苷酸）和位置 37（与反密码子 3' 相邻的核苷酸）过程中保持准确性所需的许多修改。 3 一些修饰，例如导致 37 位 N1-甲基鸟苷 (m1G37) 的甲基化，在生命的所有三个结构域中都是保守的。 4 有趣的是，虽然大多数 tRNA 修饰是组成型的，但有些修饰取决于细胞状态，并受到生长或应激的影响。例如，tRNA 修饰酶葡萄糖抑制分裂蛋白 (GidA) 与 GTPase MnmE 一起催化在反密码子摆动尿苷的第 5 位上添加羧甲基氨基甲基，5 对于细胞应激后变形链球菌的存活非常重要。 6 在真核细胞中，tRNAiMet 的结合受到高度调控并依赖于细胞状态。因此，通过调节 tRNAiMet 的可用性，可以实现对起始的总体控制，从而实现对 mRNA 翻译的总体控制。 1 一般来说，这是通过真核起始因子 2 (eIF2) 的 α 亚基磷酸化而发生的，从而抑制 Met-tRNAi 与核糖体的结合（参见参考文献 7、8 的评论）。在原核生物中，通过调节 tRNAfMet 生物利用度来控制起始的描述较少。然而，众所周知，除了 RNA 部分的改变类型之外……
Protein synthesis is a highly regulated, three-stage process, comprised of initiation, elongation and termination. In brief, during initiation, the messenger RNA (mRNA) binds to the mRNA channel on the small ribosomal subunit and the startcodon is positioned within the P-(peptidyl) decoding site. A charged initiator transfer RNA (tRNA), which in prokaryotes is normally (formyl) methionyl-tRNAi (met-tRNAfMet) and in eukaryotes is tRNAiMet, is recruited to the start-codon. Importantly, by decoding the first triplet of the mRNA, the initiator tRNA determines the reading frame. The large ribosomal subunit joins to form a ribosomal complex with the initiator tRNA in the P-site of the ribosome, which is primed for the elongation stage, where the message is decoded. During the elongation process, an aminoacyl-tRNA that has an anticodon complementary to the mRNA codon is recruited to the ribosomal A-site. A peptide bond is formed by transfer of the amino acid/peptide attached to the tRNA in the P-site to the aminoacyl-tRNA in the adjacent A-site, and the newly formed peptidyl-tRNA is subsequently translocated from the A-site to the P-site, in conjunction with the mRNA. These processes are promoted by both the ribosome and elongation factors. When a termination codon enters the A-site, termination factors bind to the ribosome and promote the hydrolysis of the peptidyl-tRNA. 1 The process of mRNA translation is highly regulated via altering the bioavailability and/or function of its components. 1 Although tRNAs were previously considered to have a fairly “passive” role in the overall regulation of protein synthesis, the recent data suggest that, through their modification and bioavailability, they make a major contribution to the global regulation of mRNA translation in all domains of life. With hindsight, this is perhaps unsurprising, since tRNAs play a central role in protein synthesis by providing the link between mRNAs and amino acids. Amino acids are attached to tRNAs through aminoacylation, which is catalysed by aminoacyltRNA synthetases. The high level of precision with which the processes of aminoacylation and decoding occur is, in part, achieved through post-transcriptional modification of tRNAs, with over 100 different post-transcriptional modifications described. 2 Many of the modifications required to maintain accuracy during decoding target position 34, the wobble nucleotide, and position 37, the nucleotide 3'-adjacent to the anticodon. 3 Some modifications, such as methylation resulting in N1-methylguanosine at position 37 (m1G37), are conserved amongst all three domains of life. 4 Interestingly, while the majority of tRNA modifications are constitutive, some are dependent on cell state and are influenced by growth or exposure to stress. For example, the tRNA modification enzyme glucose-inhibited division protein (GidA), which catalyses the addition of a carboxymethylaminomethyl group to position 5 of the anticodon wobble uridine in conjunction with the GTPase MnmE, 5 is important for the survival of Streptococcus mutans following cell stress. 6 In eukaryotic cells, the binding of tRNAiMet is highly regulated and dependent upon cell state. Accordingly, by modulating tRNAiMet availability, overall control of initiation, and therefore, of mRNA translation, can be achieved. 1 In general, this occurs through phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2), which results in an inhibition of Met-tRNAi binding to ribosomes (see refs 7, 8 for reviews). In prokaryotes, control of initiation through regulation of tRNAfMet bioavailability has been less well described. However, it is known that in addition to the types of alterations of RNA moiety of …