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Gain-of-function mutational activation of human tRNA synthetase procytokine

Academic Article
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Overview

authors

  • Yang, Xiang-Lei
  • Kapoor, M.
  • Otero, F. J.
  • Slike, B. M.
  • Tsuruta, H.
  • Frausto, R.
  • Bates, A.
  • Ewalt, K. L.
  • Cheresh, D. A.
  • Schimmel, Paul

publication date

  • 2007

journal

  • Chemistry & Biology  Journal

abstract

  • Disease-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.

subject areas

  • Amino Acid Motifs
  • Amino Acid Substitution
  • Animals
  • Cattle
  • Cell Movement
  • Cell Proliferation
  • Chemotaxis, Leukocyte
  • Chick Embryo
  • Cytokines
  • Endothelial Cells
  • Humans
  • Leukocytes, Mononuclear
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Mutation
  • Neovascularization, Physiologic
  • Peptide Fragments
  • Peptide Hydrolases
  • Protein Conformation
  • Protein Structure, Tertiary
  • Scattering, Small Angle
  • Tyrosine-tRNA Ligase
  • X-Ray Diffraction
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Identity

PubMed Central ID

  • PMC2693404

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2007.10.016

PubMed ID

  • 18096501
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Additional Document Info

start page

  • 1323

end page

  • 1333

volume

  • 14

issue

  • 12

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