Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine
| Autor: | Bonnie M. Slike, Mili Kapoor, Xiang-Lei Yang, David A. Cheresh, Francella J. Otero, Paul Schimmel, Ricardo F. Frausto, Alison Bates, Karla L. Ewalt, Hiro Tsuruta |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Protein Conformation Amino Acid Motifs Clinical Biochemistry Chick Embryo Biochemistry chemistry.chemical_compound Mice Protein structure X-Ray Diffraction Cell Movement Tyrosine-tRNA Ligase Drug Discovery Tyrosine Genetics General Medicine Phenotype Chemotaxis Leukocyte Tyrosine—tRNA ligase Transfer RNA Cytokines Molecular Medicine PROTEINS Mice Nude Neovascularization Physiologic Aminoacylation Biology Models Biological Article Amino Acyl-tRNA Synthetases Evolution Molecular Scattering Small Angle Animals Humans Gene Molecular Biology Cell Proliferation Pharmacology Aminoacyl tRNA synthetase Endothelial Cells Peptide Fragments Protein Structure Tertiary CHEMBIO chemistry Amino Acid Substitution Mutation Leukocytes Mononuclear Cattle Nervous System Diseases Peptide Hydrolases |
| Zdroj: | Chemistry & Biology. 14(12):1323-1333 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2007.10.016 |
| Popis: | SummaryDisease-causing mutations occur in genes for aminoacyl tRNA synthetases. That some mutations are dominant suggests a gain of function. Native tRNA synthetases, such as tyrosyl-tRNA synthetase (TyrRS) and tryptophanyl-tRNA synthetase, catalyze aminoacylation and are also procytokines that are activated by natural fragmentation. In principle, however, gain-of-function phenotypes could arise from mutational activation of synthetase procytokines. From crystal structure analysis, we hypothesized that a steric block of a critical Glu-Leu-Arg (ELR) motif in full-length TyrRS suppresses the cytokine activity of a natural fragment. To test this hypothesis, we attempted to uncover ELR in the procytokine by mutating a conserved tyrosine (Y341) that tethers ELR. Site-specific proteolytic cleavage and small-angle X-ray scattering established subtle opening of the structure by the mutation. Strikingly, four different assays demonstrated mutational activation of cytokine functions. The results prove the possibilities for constitutive gain-of-function mutations in tRNA synthetases. |
| Databáze: | OpenAIRE |
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