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

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Ognjenović J, Wu J, Matthies D, Baxa U, Subramaniam S, Ling J, Simonović M
OpenAccess logo Nucleic Acids Res 44 3420-31 (2016)
Related entries: 4ye6, 4ye8

Cited: 10 times
EuropePMC logo PMID: 26869582

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. 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.

Articles - 4ye9 mentioned but not cited (1)

  1. The crystal structure of human GlnRS provides basis for the development of neurological disorders. Ognjenović J, Wu J, Matthies D, Baxa U, Subramaniam S, Ling J, Simonović M. Nucleic Acids Res 44 3420-3431 (2016)


Reviews citing this publication (1)

  1. Human aminoacyl-tRNA synthetases in diseases of the nervous system. Ognjenović J, Simonović M. RNA Biol 15 623-634 (2018)

Articles citing this publication (8)

  1. Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence. Hall H, Medina P, Cooper DA, Escobedo SE, Rounds J, Brennan KJ, Vincent C, Miura P, Doerge R, Weake VM. BMC Genomics 18 894 (2017)
  2. 3-Dimensional architecture of the human multi-tRNA synthetase complex. Khan K, Baleanu-Gogonea C, Willard B, Gogonea V, Fox PL. Nucleic Acids Res 48 8740-8754 (2020)
  3. Influence of Disease-Causing Mutations on Protein Structural Networks. Prabantu VM, Naveenkumar N, Srinivasan N. Front Mol Biosci 7 620554 (2020)
  4. Structural basis for early-onset neurological disorders caused by mutations in human selenocysteine synthase. Puppala AK, French RL, Matthies D, Baxa U, Subramaniam S, Simonović M. Sci Rep 6 32563 (2016)
  5. Peculiarities of aminoacyl-tRNA synthetases from trypanosomatids. Parrot C, Moulinier L, Bernard F, Hashem Y, Dupuy D, Sissler M. J Biol Chem 297 100913 (2021)
  6. An optimized protocol for in vitro and in cellulo structural determination of the multi-tRNA synthetase complex by cross-linking mass spectrometry. Khan K, Baleanu-Gogonea C, Willard B, Gogonea V, Fox PL. STAR Protoc 3 101201 (2022)
  7. Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy. Johannesen KM, Mitter D, Janowski R, Janowski R, Roth C, Toulouse J, Poulat AL, Ville DM, Chatron N, Brilstra E, Geleijns K, Born AP, McLean S, Nugent K, Baynam G, Poulton C, Dreyer L, Gration D, Schulz S, Dieckmann A, Helbig KL, Merkenschlager A, Jamra R, Finck A, Gardella E, Hjalgrim H, Mirzaa G, Brancati F, Bierhals T, Denecke J, Hempel M, Lemke JR, Rubboli G, Muschke P, Guerrini R, Vetro A, Niessing D, Lesca G, Møller RS. Neurol Genet 5 e373 (2019)
  8. Glutaminyl-tRNA Synthetase from Pseudomonas aeruginosa: Characterization, structure, and development as a screening platform. Escamilla Y, Hughes CA, Abendroth J, Dranow DM, Balboa S, Dean FB, Bullard JM. Protein Sci 29 905-918 (2020)


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