2. Academic Validation
  3. The crystal structure of human GlnRS provides basis for the development of neurological disorders

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

  • Nucleic Acids Res. 2016 Apr 20;44(7):3420-31. doi: 10.1093/nar/gkw082.
Jana Ognjenović 1,  Jiang Wu 2,  Doreen Matthies 3,  Ulrich Baxa 3,  Sriram Subramaniam 3,  Jiqiang Ling 4,  Miljan Simonović 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • 2 Department of Microbiology and Molecular Genetics, The University of Texas, Health Science Center at Houston, Houston, TX 77030, USA.
  • 3 Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 4 Department of Microbiology and Molecular Genetics, The University of Texas, Health Science Center at Houston, Houston, TX 77030, USA Jiqiang.ling@uth.tmc.edu.
  • 5 Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA msimon5@uic.edu.
PMID: 26869582 DOI: 10.1093/nar/gkw082
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.

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