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Title: 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 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
 [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:
OSTI Identifier:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Nucleic Acids Research
Additional Journal Information:
Journal Volume: 44; Journal Issue: 7; Journal ID: ISSN 0305-1048
Oxford University Press
Research Org:
Univ. of Texas, Houston, TX (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); 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
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES transfer-rna-synthetase; spinal-cord involvement; marie-tooth-disease; pontocerebellar hypoplasia; brain-stem; perrault syndrome; hearing-loss; mutations; gene; evolution