Translational quality control by trans-editing domains

摘要 氨基酰-tRNA合成酶(ARs)建立了遗传密码的规则，由此每个 氨基酸与同源tRNA相连。这一过程中的错误会导致误译，即 可能会对细胞产生毒性。大约一半的ARS拥有校对(或编辑)功能 对错误荷电的AA-tRNA的作用和非蛋白质类氨基酸的证据 对保真度构成最大威胁的情况开始出现。Musier-Forsyth实验室的早期工作 专注于我们发现的第二类脯氨酰-tRNA合成酶(ProRS)编辑。这导致了一种 细菌ProRS转移后编辑结构域(INS)的机制理解 证明了INS域。我们随后发现，单域INS 同系物在细菌中广泛存在，近年来，我们在这一领域的重点已经转向 几乎完全是为了了解这些INS样结构域在tRNA编辑中的功能。 然而，许多关于这些假定的反式作用的生理功能的悬而未决的问题。 编辑蛋白质仍然存在。此Mira应用程序中描述的研究的总体目标 是揭示一个不断增长的反式编辑蛋白家族的特定功能，该家族被称为 INS超级家族。这个多样化但普遍受到保护的家庭现在有一个坚实的 积累体外结构-功能知识库，这有力地支持了 保持翻译的保真度。我们对这些更广泛的生理作用的了解 蛋白质，特别是真核生物中的蛋白质，仍处于初级阶段，刚刚开始揭示更广泛的作用。 比之前预期的要好。这一重大差距将在这项工作中得到解决。

Summary Aminoacyl-tRNA synthetases (ARSs) establish the rules of the genetic code, whereby each amino acid is attached to a cognate tRNA. Errors in this process lead to mistranslation, which can be toxic to cells. Approximately half of the ARSs possess a proofreading (or editing) function to hydrolyze mischarged aa-tRNAs and evidence that non-proteinaceous amino acids pose the greatest threat to fidelity is beginning to emerge. Early work in the Musier-Forsyth lab focused on our discovery of Class II prolyl-tRNA synthetase (ProRS) editing. This led to a mechanistic understanding of the bacterial ProRS posttransfer editing domain (INS) and the demonstration that the INS domain. We subsequently discovered that single-domain INS homologs are widespread in Bacteria and in recent years, our focus in this area has turned almost entirely to understanding the function of these INS-like domains in tRNA editing. However, many open questions regarding the physiological function of these putative trans- editing proteins remain. The overarching goal of the research described in this MIRA application is to uncover the specific functions of a growing family of trans-editing proteins known as the INS superfamily. This diverse yet universally conserved family now has a solid and accumulating in vitro structure-function knowledge base, which strongly supports a role in maintaining translational fidelity. Our knowledge of the broader physiological roles of these proteins, especially in eukaryotes, is still in its infancy and is just beginning to reveal wider roles than previously anticipated. This major gap will be addressed in this work.