title: The crystal structure of human GlnRS provides basis for the development of neurological disorders.
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.
authors: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors: Jana
authors: J
authors: Ognjenović
authors: Department of Microbiology and Molecular Genetics, The University of Texas, Health Science Center at Houston, Houston, TX 77030, USA.
authors: Jiang
authors: J
authors: Wu
authors: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Doreen
authors: D
authors: Matthies
authors: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Ulrich
authors: U
authors: Baxa
authors: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Sriram
authors: S
authors: Subramaniam
authors: Department of Microbiology and Molecular Genetics, The University of Texas, Health Science Center at Houston, Houston, TX 77030, USA Jiqiang.ling@uth.tmc.edu.
authors: Jiqiang
authors: J
authors: Ling
authors: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA msimon5@uic.edu.
authors: Miljan
authors: M
authors: Simonović
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics*; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D000604:Amino Acyl-tRNA Synthetases; C020659:glutaminyl-tRNA synthetase