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

Ognjenovic, Jana; Wu, Jiang; Matthies, Doreen; Baxa, Ulrich; Subramaniam, Sriram; Ling, Jiqiang; Simonovic, Miljan

doi:10.1093/nar/gkw082

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

Journal Article · Wed Feb 10 00:00:00 EST 2016 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkw082· OSTI ID:1262023

Ognjenovic, Jana ^[1]; Wu, Jiang ^[2]; Matthies, Doreen ^[3]; Baxa, Ulrich ^[3]; Subramaniam, Sriram ^[3]; Ling, Jiqiang ^[2]; Simonovic, Miljan ^[1]

Univ. of Illinois, Chicago, IL (United States)
The Univ. of Texas, Houston, TX (United States)
National Institute of Health, Bethesda, MD (United States)

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

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Research Organization:: Univ. of Texas, Houston, TX (United States)

Sponsoring Organization:: 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

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1262023

Journal Information:: Nucleic Acids Research, Vol. 44, Issue 7; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 12 works

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References (55)

Aminoacyl-tRNA Synthesis Ibba, Michael; Söll, Dieter Annual Review of Biochemistry, Vol. 69, Issue 1 https://doi.org/10.1146/annurev.biochem.69.1.617	journal	June 2000
Mutational isolation of a sieve for editing in a transfer RNA synthetase Schmidt, E.; Schimmel, P. Science, Vol. 264, Issue 5156 https://doi.org/10.1126/science.8146659	journal	April 1994
Human tRNA synthetase catalytic nulls with diverse functions Lo, W. -S.; Gardiner, E.; Xu, Z. Science, Vol. 345, Issue 6194 https://doi.org/10.1126/science.1252943	journal	July 2014
New functions of aminoacyl-tRNA synthetases beyond translation Guo, Min; Yang, Xiang-Lei; Schimmel, Paul Nature Reviews Molecular Cell Biology, Vol. 11, Issue 9 https://doi.org/10.1038/nrm2956	journal	August 2010
Unique domain appended to vertebrate tRNA synthetase is essential for vascular development Xu, Xiaoling; Shi, Yi; Zhang, Hui-Min Nature Communications, Vol. 3, Issue 1 https://doi.org/10.1038/ncomms1686	journal	January 2012
Aminoacyl‐tRNA synthetases in medicine and disease Yao, Peng; Fox, Paul L. EMBO Molecular Medicine, Vol. 5, Issue 3 https://doi.org/10.1002/emmm.201100626	journal	February 2013
The Role of Aminoacyl-tRNA Synthetases in Genetic Diseases Antonellis, Anthony; Green, Eric D. Annual Review of Genomics and Human Genetics, Vol. 9, Issue 1 https://doi.org/10.1146/annurev.genom.9.081307.164204	journal	September 2008
Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V Antonellis, Anthony; Ellsworth, Rachel E.; Sambuughin, Nyamkhishig The American Journal of Human Genetics, Vol. 72, Issue 5 https://doi.org/10.1086/375039	journal	May 2003
Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy Jordanova, Albena; Irobi, Joy; Thomas, Florian P. Nature Genetics, Vol. 38, Issue 2 https://doi.org/10.1038/ng1727	journal	January 2006
A Major Determinant for Binding and Aminoacylation of tRNAAla in Cytoplasmic Alanyl-tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth Disease Latour, Philippe; Thauvin-Robinet, Christel; Baudelet-Méry, Chantal The American Journal of Human Genetics, Vol. 86, Issue 1 https://doi.org/10.1016/j.ajhg.2009.12.005	journal	January 2010
Compound Heterozygosity for Loss-of-Function Lysyl-tRNA Synthetase Mutations in a Patient with Peripheral Neuropathy McLaughlin, Heather M.; Sakaguchi, Reiko; Liu, Cuiping The American Journal of Human Genetics, Vol. 87, Issue 4 https://doi.org/10.1016/j.ajhg.2010.09.008	journal	October 2010
Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases Puffenberger, Erik G.; Jinks, Robert N.; Sougnez, Carrie PLoS ONE, Vol. 7, Issue 1 https://doi.org/10.1371/journal.pone.0028936	journal	January 2012
Mutation of the Mitochondrial Tyrosyl-tRNA Synthetase Gene, YARS2, Causes Myopathy, Lactic Acidosis, and Sideroblastic Anemia—MLASA Syndrome Riley, Lisa G.; Cooper, Sandra; Hickey, Peter The American Journal of Human Genetics, Vol. 87, Issue 1 https://doi.org/10.1016/j.ajhg.2010.06.001	journal	July 2010
Mutations in the Mitochondrial Methionyl-tRNA Synthetase Cause a Neurodegenerative Phenotype in Flies and a Recessive Ataxia (ARSAL) in Humans Bayat, Vafa; Thiffault, Isabelle; Jaiswal, Manish PLoS Biology, Vol. 10, Issue 3 https://doi.org/10.1371/journal.pbio.1001288	journal	March 2012
Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation Scheper, Gert C.; van der Klok, Thom; van Andel, Rob J. Nature Genetics, Vol. 39, Issue 4 https://doi.org/10.1038/ng2013	journal	March 2007
Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations Steenweg, Marjan E.; Ghezzi, Daniele; Haack, Tobias Brain, Vol. 135, Issue 5 https://doi.org/10.1093/brain/aws070	journal	April 2012
Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome Pierce, S. B.; Chisholm, K. M.; Lynch, E. D. Proceedings of the National Academy of Sciences, Vol. 108, Issue 16 https://doi.org/10.1073/pnas.1103471108	journal	April 2011
Mutations in LARS2, Encoding Mitochondrial Leucyl-tRNA Synthetase, Lead to Premature Ovarian Failure and Hearing Loss in Perrault Syndrome Pierce, Sarah B.; Gersak, Ksenija; Michaelson-Cohen, Rachel The American Journal of Human Genetics, Vol. 92, Issue 4 https://doi.org/10.1016/j.ajhg.2013.03.007	journal	April 2013
Deleterious Mutation in the Mitochondrial Arginyl–Transfer RNA Synthetase Gene Is Associated with Pontocerebellar Hypoplasia Edvardson, Simon; Shaag, Avraham; Kolesnikova, Olga The American Journal of Human Genetics, Vol. 81, Issue 4 https://doi.org/10.1086/521227	journal	October 2007
Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2 Glamuzina, Emma; Brown, Ruth; Hogarth, Kieran Journal of Inherited Metabolic Disease, Vol. 35, Issue 3 https://doi.org/10.1007/s10545-011-9413-6	journal	November 2011
Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy Elo, Jenni M.; Yadavalli, Srujana S.; Euro, Liliya Human Molecular Genetics, Vol. 21, Issue 20 https://doi.org/10.1093/hmg/dds294	journal	July 2012
Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity Taft, Ryan J.; Vanderver, Adeline; Leventer, Richard J. The American Journal of Human Genetics, Vol. 92, Issue 5 https://doi.org/10.1016/j.ajhg.2013.04.006	journal	May 2013
Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders Novarino, G.; Fenstermaker, A. G.; Zaki, M. S. Science, Vol. 343, Issue 6170 https://doi.org/10.1126/science.1247363	journal	January 2014
Congenital Visual Impairment and Progressive Microcephaly Due to Lysyl–Transfer Ribonucleic Acid (RNA) Synthetase ( KARS ) Mutations : The Expanding Phenotype of Aminoacyl–Transfer RNA Synthetase Mutations in Human Disease McMillan, Hugh J.; Humphreys, Peter; Smith, Amanda Journal of Child Neurology, Vol. 30, Issue 8 https://doi.org/10.1177/0883073814553272	journal	October 2014
Essential nontranslational functions of tRNA synthetases Guo, Min; Schimmel, Paul Nature Chemical Biology, Vol. 9, Issue 3 https://doi.org/10.1038/nchembio.1158	journal	February 2013
Transfer RNA and human disease Abbott, Jamie A.; Francklyn, Christopher S.; Robey-Bond, Susan M. Frontiers in Genetics, Vol. 5 https://doi.org/10.3389/fgene.2014.00158	journal	June 2014
Mutations in QARS, Encoding Glutaminyl-tRNA Synthetase, Cause Progressive Microcephaly, Cerebral-Cerebellar Atrophy, and Intractable Seizures Zhang, Xiaochang; Ling, Jiqiang; Barcia, Giulia The American Journal of Human Genetics, Vol. 94, Issue 4 https://doi.org/10.1016/j.ajhg.2014.03.003	journal	April 2014
Structure of E. coli glutaminyl-tRNA synthetase complexed with tRNA(Gln) and ATP at 2.8 A resolution Rould, M.; Perona, J.; Soll, D. Science, Vol. 246, Issue 4934 https://doi.org/10.1126/science.2479982	journal	December 1989
Genetic dissection of protein-protein interactions in multi-tRNA synthetase complex Rho, S. B.; Kim, M. J.; Lee, J. S. Proceedings of the National Academy of Sciences, Vol. 96, Issue 8 https://doi.org/10.1073/pnas.96.8.4488	journal	April 1999
Structural conservation of an ancient tRNA sensor in eukaryotic glutaminyl-tRNA synthetase Grant, Thomas D.; Snell, Edward H.; Luft, Joseph R. Nucleic Acids Research, Vol. 40, Issue 8 https://doi.org/10.1093/nar/gkr1223	journal	December 2011
The Structure of Yeast Glutaminyl-tRNA Synthetase and Modeling of Its Interaction with tRNA Grant, Thomas D.; Luft, Joseph R.; Wolfley, Jennifer R. Journal of Molecular Biology, Vol. 425, Issue 14 https://doi.org/10.1016/j.jmb.2013.03.043	journal	July 2013
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
A short history of SHELX Sheldrick, George M. Acta Crystallographica Section A Foundations of Crystallography, Vol. 64, Issue 1, p. 112-122 https://doi.org/10.1107/S0108767307043930	journal	December 2007
Histogram matching as a new density modification technique for phase refinement and extension of protein molecules Zhang, K. Y. J.; Main, P. Acta Crystallographica Section A Foundations of Crystallography, Vol. 46, Issue 1 https://doi.org/10.1107/S0108767389009311	journal	January 1990
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Protein structure alignment by incremental combinatorial extension (CE) of the optimal path Shindyalov, I. N.; Bourne, P. E. Protein Engineering Design and Selection, Vol. 11, Issue 9 https://doi.org/10.1093/protein/11.9.739	journal	September 1998
Two enzymes bound to one transfer RNA assume alternative conformations for consecutive reactions Ito, Takuhiro; Yokoyama, Shigeyuki Nature, Vol. 467, Issue 7315 https://doi.org/10.1038/nature09411	journal	September 2010
Systematic humanization of yeast genes reveals conserved functions and genetic modularity Kachroo, A. H.; Laurent, J. M.; Yellman, C. M. Science, Vol. 348, Issue 6237 https://doi.org/10.1126/science.aaa0769	journal	May 2015
Evolution of the Glx-tRNA synthetase family: the glutaminyl enzyme as a case of horizontal gene transfer. Lamour, V.; Quevillon, S.; Diriong, S. Proceedings of the National Academy of Sciences, Vol. 91, Issue 18 https://doi.org/10.1073/pnas.91.18.8670	journal	August 1994
Aminoacyl-tRNA Synthetases, the Genetic Code, and the Evolutionary Process Woese, C. R.; Olsen, G. J.; Ibba, M. Microbiology and Molecular Biology Reviews, Vol. 64, Issue 1 https://doi.org/10.1128/MMBR.64.1.202-236.2000	journal	March 2000
Structure of an archaeal non-discriminating glutamyl-tRNA synthetase: a missing link in the evolution of Gln-tRNAGln formation Nureki, Osamu; O’Donoghue, Patrick; Watanabe, Nobuhisa Nucleic Acids Research, Vol. 38, Issue 20 https://doi.org/10.1093/nar/gkq605	journal	July 2010
From one amino acid to another: tRNA-dependent amino acid biosynthesis Sheppard, K.; Yuan, J.; Hohn, M. J. Nucleic Acids Research, Vol. 36, Issue 6 https://doi.org/10.1093/nar/gkn015	journal	February 2008
Rational design of an evolutionary precursor of glutaminyl-tRNA synthetase O'Donoghue, P.; Sheppard, K.; Nureki, O. Proceedings of the National Academy of Sciences, Vol. 108, Issue 51 https://doi.org/10.1073/pnas.1117294108	journal	December 2011
Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy Kodera, Hirofumi; Osaka, Hitoshi; Iai, Mizue Journal of Human Genetics, Vol. 60, Issue 2 https://doi.org/10.1038/jhg.2014.103	journal	December 2014
Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities Salvarinova, Ramona; Ye, Cynthia X.; Rossi, Andrea neurogenetics, Vol. 16, Issue 2 https://doi.org/10.1007/s10048-014-0432-y	journal	November 2014
tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia Budde, Birgit S.; Namavar, Yasmin; Barth, Peter G. Nature Genetics, Vol. 40, Issue 9 https://doi.org/10.1038/ng.204	journal	August 2008
Impairment of the tRNA-splicing endonuclease subunit 54 (tsen54) gene causes neurological abnormalities and larval death in zebrafish models of pontocerebellar hypoplasia Kasher, Paul R.; Namavar, Yasmin; van Tijn, Paula Human Molecular Genetics, Vol. 20, Issue 8 https://doi.org/10.1093/hmg/ddr034	journal	January 2011
Cellular strategies for controlling protein aggregation Tyedmers, Jens; Mogk, Axel; Bukau, Bernd Nature Reviews Molecular Cell Biology, Vol. 11, Issue 11 https://doi.org/10.1038/nrm2993	journal	October 2010
Converging concepts of protein folding in vitro and in vivo Hartl, F. Ulrich; Hayer-Hartl, Manajit Nature Structural & Molecular Biology, Vol. 16, Issue 6 https://doi.org/10.1038/nsmb.1591	journal	June 2009
Gene Descent, Duplication, and Horizontal Transfer in the Evolution of Glutamyl- and Glutaminyl-tRNA Synthetases Brown, James R.; Doolittle, W. Ford Journal of Molecular Evolution, Vol. 49, Issue 4 https://doi.org/10.1007/pl00006571	journal	October 1999
Catalytic Peptide of Human Glutaminyl-tRNA Synthetase Is Essential for Its Assembly to the Aminoacyl-tRNA Synthetase Complex Kim, Taeho; Park, Sang Gyu; Kim, Jee Eun Journal of Biological Chemistry, Vol. 275, Issue 28 https://doi.org/10.1074/jbc.m002404200	journal	May 2000
Glutamine-dependent Antiapoptotic Interaction of Human Glutaminyl-tRNA Synthetase with Apoptosis Signal-regulating Kinase 1 Ko, Young-Gyu; Kim, Eun-Kyoung; Kim, Taeho Journal of Biological Chemistry, Vol. 276, Issue 8 https://doi.org/10.1074/jbc.m006189200	journal	November 2000
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/s0907444904019158	journal	November 2004
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/s0907444910045749	journal	March 2011
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010

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59 BASIC BIOLOGICAL SCIENCES
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spinal-cord involvement
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hearing-loss
mutations
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Title: The crystal structure of human GlnRS provides basis for the development of neurological disorders

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