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Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine
- Source :
-
Chemistry & Biology . Dec2007, Vol. 14 Issue 12, p1323-1333. 11p. - Publication Year :
- 2007
-
Abstract
- Summary: 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. [Copyright &y& Elsevier]
- Subjects :
- *TRANSFER RNA
*LIGASES
*CELLULAR immunity
*X-ray scattering
Subjects
Details
- Language :
- English
- ISSN :
- 10745521
- Volume :
- 14
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- Chemistry & Biology
- Publication Type :
- Academic Journal
- Accession number :
- 27946761
- Full Text :
- https://doi.org/10.1016/j.chembiol.2007.10.016