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Title: The crystal structure of human GlnRS provides basis for the development of neurological disorders

Abstract

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. As a result, 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. Keywords

Authors:
 [1];  [2];  [3];  [3];  [3];  [2];  [1]
  1. Univ. of Illinois, Chicago, IL (United States)
  2. The Univ. of Texas, Houston, TX (United States)
  3. National Institute of Health, Bethesda, MD (United States)
Publication Date:
Research Org.:
Univ. of Texas, Houston, TX (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor; NCI; National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH); The University of Texas, Health Science Center at Houston
OSTI Identifier:
1262023
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 44; Journal Issue: 7; Journal ID: ISSN 0305-1048
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; transfer-rna-synthetase; spinal-cord involvement; marie-tooth-disease; pontocerebellar hypoplasia; brain-stem; perrault syndrome; hearing-loss; mutations; gene; evolution

Citation Formats

Ognjenovic, Jana, Wu, Jiang, Matthies, Doreen, Baxa, Ulrich, Subramaniam, Sriram, Ling, Jiqiang, and Simonovic, Miljan. The crystal structure of human GlnRS provides basis for the development of neurological disorders. United States: N. p., 2016. Web. doi:10.1093/nar/gkw082.
Ognjenovic, Jana, Wu, Jiang, Matthies, Doreen, Baxa, Ulrich, Subramaniam, Sriram, Ling, Jiqiang, & Simonovic, Miljan. The crystal structure of human GlnRS provides basis for the development of neurological disorders. United States. https://doi.org/10.1093/nar/gkw082
Ognjenovic, Jana, Wu, Jiang, Matthies, Doreen, Baxa, Ulrich, Subramaniam, Sriram, Ling, Jiqiang, and Simonovic, Miljan. 2016. "The crystal structure of human GlnRS provides basis for the development of neurological disorders". United States. https://doi.org/10.1093/nar/gkw082. https://www.osti.gov/servlets/purl/1262023.
@article{osti_1262023,
title = {The crystal structure of human GlnRS provides basis for the development of neurological disorders},
author = {Ognjenovic, Jana and Wu, Jiang and Matthies, Doreen and Baxa, Ulrich and Subramaniam, Sriram and Ling, Jiqiang and Simonovic, Miljan},
abstractNote = {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. As a result, 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. Keywords},
doi = {10.1093/nar/gkw082},
url = {https://www.osti.gov/biblio/1262023}, journal = {Nucleic Acids Research},
issn = {0305-1048},
number = 7,
volume = 44,
place = {United States},
year = {Wed Feb 10 00:00:00 EST 2016},
month = {Wed Feb 10 00:00:00 EST 2016}
}

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Cited by: 12 works
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Works referenced in this record:

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A Major Determinant for Binding and Aminoacylation of tRNAAla in Cytoplasmic Alanyl-tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth Disease
journal, January 2010


Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome
journal, July 2010


Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome
journal, April 2013


Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity
journal, May 2013


The Structure of Yeast Glutaminyl-tRNA Synthetase and Modeling of Its Interaction with tRNA
journal, July 2013


Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy
journal, December 2014


Two enzymes bound to one transfer RNA assume alternative conformations for consecutive reactions
journal, September 2010


Essential nontranslational functions of tRNA synthetases
journal, February 2013


Unique domain appended to vertebrate tRNA synthetase is essential for vascular development
journal, January 2012


Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy
journal, January 2006


Cellular strategies for controlling protein aggregation
journal, October 2010


Converging concepts of protein folding in vitro and in vivo
journal, June 2009


Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome
journal, April 2011


Genetic dissection of protein-protein interactions in multi-tRNA synthetase complex
journal, April 1999


Catalytic Peptide of Human Glutaminyl-tRNA Synthetase Is Essential for Its Assembly to the Aminoacyl-tRNA Synthetase Complex
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journal, November 2000


Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V
journal, May 2003

  • Antonellis, Anthony; Ellsworth, Rachel E.; Sambuughin, Nyamkhishig
  • The American Journal of Human Genetics, Vol. 72, Issue 5
  • https://doi.org/10.1086/375039

Deleterious Mutation in the Mitochondrial Arginyl–Transfer RNA Synthetase Gene Is Associated with Pontocerebellar Hypoplasia
journal, October 2007


Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy
journal, July 2012


Structure of an archaeal non-discriminating glutamyl-tRNA synthetase: a missing link in the evolution of Gln-tRNAGln formation
journal, July 2010


Structural conservation of an ancient tRNA sensor in eukaryotic glutaminyl-tRNA synthetase
journal, December 2011


Protein structure alignment by incremental combinatorial extension (CE) of the optimal path
journal, September 1998


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Human tRNA synthetase catalytic nulls with diverse functions
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Mutational isolation of a sieve for editing in a transfer RNA synthetase
journal, April 1994


Aminoacyl-tRNA Synthesis
journal, June 2000


The Role of Aminoacyl-tRNA Synthetases in Genetic Diseases
journal, September 2008


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text, January 2010


Works referencing / citing this record:

Glutaminyl‐tRNA Synthetase from Pseudomonas aeruginosa : Characterization, structure, and development as a screening platform
journal, December 2019


Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase
journal, August 2016