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A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects | |
2016-03-18 | |
发表期刊 | JOURNAL OF BIOLOGICAL CHEMISTRY (IF:4.0[JCR-2023],4.4[5-Year]) |
ISSN | 1083351X |
卷号 | 291期号:12页码:6507-6520 |
发表状态 | 已发表 |
DOI | 10.1074/jbc.M115.700849 |
摘要 | Mitochondria require all translational components, including aminoacyl-tRNA synthetases (aaRSs), to complete organelle protein synthesis. Some aaRS mutations cause mitochondrial disorders, including human mitochondrial threonyl-tRNA synthetase (hmtThrRS) (encoded by TARS2), the P282L mutation of which causes mitochondrial encephalomyopathies. However, its catalytic and structural consequences remain unclear. Herein, we cloned TARS2 and purified the wild-type and P282L mutant hmtThrRS. hmtThrRS misactivates non-cognate Ser and uses post-transfer editing to clear erroneously synthesized products. In vitro and in vivo analyses revealed that the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities and a change in the protein structure and/or stability, which might cause reduced catalytic efficiency. We also identified a splicing variant of TARS2 mRNA lacking exons 8 and 9, the protein product of which is targeted into mitochondria. In HEK293T cells, the variant does not dimerize and cannot complement the ThrRS knock-out strain in yeast, suggesting that the truncated protein is inactive and might have a non-canonical function, as observed for other aaRS fragments. The present study describes the aminoacylation and editing properties of hmtThrRS, clarifies the molecular consequences of the P282L mutation, and shows that the yeast ThrRS-deletion model is suitable to test pathology-associated point mutations or alternative splicing variants of mammalian aaRS mRNAs. |
关键词 | alternative splicing aminoacyl-tRNA synthetase enzyme kinetics mitochondria mitochondrial disease threonyl-tRNA synthetase |
收录类别 | SCI ; EI |
语种 | 英语 |
资助项目 | Committee of Science and Technology in Shanghai[12JC1409700] ; Committee of Science and Technology in Shanghai[15ZR1446500] |
WOS研究方向 | Biochemistry & Molecular Biology |
WOS类目 | Biochemistry & Molecular Biology |
WOS记录号 | WOS:000372894200037 |
出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
EI入藏号 | 20161902345054 |
EI主题词 | Amino acids ; Biosynthesis ; Cloning ; Mammals ; Proteins ; Yeast |
EI分类号 | Bioengineering and Biology:461 ; Organic Compounds:804.1 ; Food Products:822.3 |
WOS关键词 | EDITING ACTIVITY ; QUALITY-CONTROL ; PROTEIN ; DOMAIN ; CODON ; MISTRANSLATION ; TRANSLATION ; MECHANISM ; ERRORS |
原始文献类型 | Article |
引用统计 | 正在获取...
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文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1892 |
专题 | 生命科学与技术学院 生命科学与技术学院_特聘教授组_王恩多组 生命科学与技术学院_博士生 |
通讯作者 | Zhou, Xiao-Long; Wang, En-Duo |
作者单位 | 1.Univ Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol,Inst Biochem & Cell Biol, Chinese Acad Sci,Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, 319 Yue Yang Rd, Shanghai 200031, Peoples R China 3.Univ Strasbourg, Inst Biol Mol & Cellulaire, CNRS, Architecture & React ARN,UPR9002, 15 Rue Rene Descartes, F-67084 Strasbourg, France |
第一作者单位 | 生命科学与技术学院 |
通讯作者单位 | 生命科学与技术学院 |
推荐引用方式 GB/T 7714 | Wang, Yong,Zhou, Xiao-Long,Ruan, Zhi-Rong,et al. A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2016,291(12):6507-6520. |
APA | Wang, Yong,Zhou, Xiao-Long,Ruan, Zhi-Rong,Liu, Ru-Juan,Eriani, Gilbert,&Wang, En-Duo.(2016).A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects.JOURNAL OF BIOLOGICAL CHEMISTRY,291(12),6507-6520. |
MLA | Wang, Yong,et al."A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects".JOURNAL OF BIOLOGICAL CHEMISTRY 291.12(2016):6507-6520. |
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