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

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

View Accepted Manuscript (DOE)

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

Sponsoring Organization:: 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; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1262023

Alternate ID(s):: OSTI ID: 1252773

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

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
brain-stem
evolution
gene
hearing-loss
marie-tooth-disease
mutations
perrault syndrome
pontocerebellar hypoplasia
spinal-cord involvement
transfer-rna-synthetase

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

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