Translational quality control by trans-editing domains

通过转编辑域控制翻译质量

基本信息

批准号：
10822416
负责人：
Karin M Musier-Forsyth
金额：
$ 15.65万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-17 至 2026-04-30
项目状态：
未结题

项目摘要

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.

概括氨酰基-tRNA 合成酶 (ARS) 建立了遗传密码的规则，其中每个氨基酸连接至同源 tRNA。此过程中的错误会导致误译，从而可能对细胞有毒。大约一半的 ARS 拥有校对（或编辑）功能水解错误带电的 aa-tRNA 的功能和非蛋白质氨基酸的证据对忠诚度构成最大威胁的问题正在开始显现。 Musier-Forsyth 实验室的早期工作重点关注我们发现的 II 类脯氨酰-tRNA 合成酶 (ProRS) 编辑。这导致了对细菌 ProRS 转移后编辑域 (INS) 和证明INS域名。我们随后发现单域 INS 同源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，关于这些假定的反式生理功能的许多悬而未决的问题编辑蛋白质仍然存在。本 MIRA 申请中描述的研究的总体目标是为了揭示一个不断增长的反式编辑蛋白家族的特定功能，称为反式编辑蛋白 INS 超家族。这个多样化但普遍保存的家族现在拥有了坚实而可靠的积累体外结构功能知识库，有力支持了保持翻译保真度。我们对这些更广泛的生理作用的了解蛋白质，尤其是真核生物中的蛋白质，仍处于起步阶段，刚刚开始揭示更广泛的作用比之前预期的要多。这项工作将解决这一重大差距。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aminoacylation-defective bi-allelic mutations in human EPRS1 associated with psychomotor developmental delay, epilepsy, and deafness.

人类 EPRS1 中氨酰化缺陷的双等位基因突变与精神运动性发育迟缓、癫痫和耳聋相关。

DOI：
发表时间：
2023-03
期刊：
影响因子：
3.5
作者：
Jin, Danni;Wek, Sheree A;Cordova, Ricardo A;Wek, Ronald C;Lacombe, Didier;Michaud, Vincent;Musier
通讯作者：
Musier

Structural basis of tRNAPro acceptor stem recognition by a bacterial trans-editing domain.

细菌反式编辑域识别 tRNAPro 受体茎的结构基础。

DOI：
发表时间：
2023-05-08
期刊：
影响因子：
14.9
作者：
Ma, Xiao;Bakhtina, Marina;Shulgina, Irina;Cantara, William A;Kuzmishin Nagy, Alexandra B;Goto, Yuki;Suga, Hiroaki;Foster, Mark P;Musier
通讯作者：
Musier

Disease-associated mutations in a bifunctional aminoacyl-tRNA synthetase gene elicit the integrated stress response.

双功能氨酰基-tRNA 合成酶基因中与疾病相关的突变会引发综合应激反应。