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The crystal structure of human GlnRS provides basis for the development of neurological disorders
Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mut...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838373/ https://www.ncbi.nlm.nih.gov/pubmed/26869582 http://dx.doi.org/10.1093/nar/gkw082 |
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author | Ognjenović, Jana Wu, Jiang Matthies, Doreen Baxa, Ulrich Subramaniam, Sriram Ling, Jiqiang Simonović, Miljan |
author_facet | Ognjenović, Jana Wu, Jiang Matthies, Doreen Baxa, Ulrich Subramaniam, Sriram Ling, Jiqiang Simonović, Miljan |
author_sort | Ognjenović, Jana |
collection | PubMed |
description | Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggest that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. This report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. |
format | Online Article Text |
id | pubmed-4838373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-48383732016-04-21 The crystal structure of human GlnRS provides basis for the development of neurological disorders Ognjenović, Jana Wu, Jiang Matthies, Doreen Baxa, Ulrich Subramaniam, Sriram Ling, Jiqiang Simonović, Miljan Nucleic Acids Res Structural Biology Cytosolic glutaminyl-tRNA synthetase (GlnRS) is the singular enzyme responsible for translation of glutamine codons. Compound heterozygous mutations in GlnRS cause severe brain disorders by a poorly understood mechanism. Herein, we present crystal structures of the wild type and two pathological mutants of human GlnRS, which reveal, for the first time, the domain organization of the intact enzyme and the structure of the functionally important N-terminal domain (NTD). Pathological mutations mapping in the NTD alter the domain structure, and decrease catalytic activity and stability of GlnRS, whereas missense mutations in the catalytic domain induce misfolding of the enzyme. Our results suggest that the reduced catalytic efficiency and a propensity of GlnRS mutants to misfold trigger the disease development. This report broadens the spectrum of brain pathologies elicited by protein misfolding and provides a paradigm for understanding the role of mutations in aminoacyl-tRNA synthetases in neurological diseases. Oxford University Press 2016-04-20 2016-02-10 /pmc/articles/PMC4838373/ /pubmed/26869582 http://dx.doi.org/10.1093/nar/gkw082 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Structural Biology Ognjenović, Jana Wu, Jiang Matthies, Doreen Baxa, Ulrich Subramaniam, Sriram Ling, Jiqiang Simonović, Miljan The crystal structure of human GlnRS provides basis for the development of neurological disorders |
title | The crystal structure of human GlnRS provides basis for the development of neurological disorders |
title_full | The crystal structure of human GlnRS provides basis for the development of neurological disorders |
title_fullStr | The crystal structure of human GlnRS provides basis for the development of neurological disorders |
title_full_unstemmed | The crystal structure of human GlnRS provides basis for the development of neurological disorders |
title_short | The crystal structure of human GlnRS provides basis for the development of neurological disorders |
title_sort | crystal structure of human glnrs provides basis for the development of neurological disorders |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838373/ https://www.ncbi.nlm.nih.gov/pubmed/26869582 http://dx.doi.org/10.1093/nar/gkw082 |
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