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Title: Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis

Abstract

Glycyl-tRNA synthetase (GlyRS) is the enzyme that covalently links glycine to cognate tRNA for translation. It is of great interest because of its nonconserved quaternary structures, unique species-specific aminoacylation properties, and noncanonical functions in neurological diseases, but none of these is fully understood. We report two crystal structures of human GlyRS variants, in the free form and in complex with tRNA Gly respectively, and reveal new aspects of the glycylation mechanism. We discover that insertion 3 differs considerably in conformation in catalysis and that it acts like a "switch" and fully opens to allow tRNA to bind in a cross-subunit fashion. The flexibility of the protein is supported by molecular dynamics simulation, as well as enzymatic activity assays. The biophysical and biochemical studies suggest that human GlyRS may utilize its flexibility for both the traditional function (regulate tRNA binding) and alternative functions (roles in diseases).

Authors:
 [1];  [2];  [1];  [1];  [3];  [3];  [4];  [4];  [1];  [1];  [1];  [1]
+ Show Author Affiliations
  1. Sun Yat-Sen Univ., Guangzhou, (China)
  2. Chinese Academy of Sciences (CAS), Guangzhou (China)
  3. Univ. of Science and Technology of China, Hefei (China)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1379154
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 291; Journal Issue: 11; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Deng, Xiangyu, Qin, Xiangjing, Chen, Lei, Jia, Qian, Zhang, Yonghui, Zhang, Zhiyong, Lei, Dongsheng, Ren, Gang, Zhou, Zhihong, Wang, Zhong, Li, Qing, and Xie, Wei. Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis. United States: N. p., 2016. Web. doi:10.1074/jbc.M115.679126.
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Deng, Xiangyu, Qin, Xiangjing, Chen, Lei, Jia, Qian, Zhang, Yonghui, Zhang, Zhiyong, Lei, Dongsheng, Ren, Gang, Zhou, Zhihong, Wang, Zhong, Li, Qing, & Xie, Wei. Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis. United States. https://doi.org/10.1074/jbc.M115.679126
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Deng, Xiangyu, Qin, Xiangjing, Chen, Lei, Jia, Qian, Zhang, Yonghui, Zhang, Zhiyong, Lei, Dongsheng, Ren, Gang, Zhou, Zhihong, Wang, Zhong, Li, Qing, and Xie, Wei. Thu . "Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis". United States. https://doi.org/10.1074/jbc.M115.679126. https://www.osti.gov/servlets/purl/1379154.
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@article{osti_1379154,
title = {Large Conformational Changes of Insertion 3 in Human Glycyl-tRNA Synthetase (hGlyRS) during Catalysis},
author = {Deng, Xiangyu and Qin, Xiangjing and Chen, Lei and Jia, Qian and Zhang, Yonghui and Zhang, Zhiyong and Lei, Dongsheng and Ren, Gang and Zhou, Zhihong and Wang, Zhong and Li, Qing and Xie, Wei},
abstractNote = {Glycyl-tRNA synthetase (GlyRS) is the enzyme that covalently links glycine to cognate tRNA for translation. It is of great interest because of its nonconserved quaternary structures, unique species-specific aminoacylation properties, and noncanonical functions in neurological diseases, but none of these is fully understood. We report two crystal structures of human GlyRS variants, in the free form and in complex with tRNA Gly respectively, and reveal new aspects of the glycylation mechanism. We discover that insertion 3 differs considerably in conformation in catalysis and that it acts like a "switch" and fully opens to allow tRNA to bind in a cross-subunit fashion. The flexibility of the protein is supported by molecular dynamics simulation, as well as enzymatic activity assays. The biophysical and biochemical studies suggest that human GlyRS may utilize its flexibility for both the traditional function (regulate tRNA binding) and alternative functions (roles in diseases).},
doi = {10.1074/jbc.M115.679126},
journal = {Journal of Biological Chemistry},
number = 11,
volume = 291,
place = {United States},
year = {Thu Jan 21 00:00:00 EST 2016},
month = {Thu Jan 21 00:00:00 EST 2016}
}
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https://doi.org/10.1074/jbc.M115.679126
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