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

Jana Ognjenović, Jiang Wu, Doreen Matthies, Ulrich Baxa, Sriram Subramaniam, Jiqiang Ling, Miljan Simonović

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)3420-3431
Number of pages12
JournalNucleic Acids Research
Volume44
Issue number7
DOIs
StatePublished - Feb 10 2016
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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