Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine.

Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine. Research Abstract Details 

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Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine. Abstract Text:

Xiang-Lei Yang,Mili Kapoor,Francella J Otero,Bonnie M Slike,Hiro Tsuruta,Ricardo Frausto,Alison Bates,Karla L Ewalt,David A Cheresh,Paul Schimmel,Xiang-Lei Yang,Mili Kapoor,Francella J Otero,Bonnie M Slike,Hiro Tsuruta,Ricardo Frausto,Alison Bates,Karla L Ewalt,David A Cheresh,Paul Schimmel,

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.

Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine. Publishing Authors By Initials

XL Yang,M Kapoor,FJ Otero,BM Slike,H Tsuruta,R Frausto,A Bates,KL Ewalt,DA Cheresh,P Schimmel,XL Yang,M Kapoor,FJ Otero,BM Slike,H Tsuruta,R Frausto,A Bates,KL Ewalt,DA Cheresh,P Schimmel,

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Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Chemistry & biology

VOLUME: 14

Page Numbers: 1323-33

Journal Abbreviation: Chem. Biol.

ISSN: 1074-5521

DAY: 21

MONTH: Dec

YEAR: 2007

Gain-of-Function Mutational Activation of Human tRNA Synthetase Procytokine. Information

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LANGUAGE: eng

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AFFILIATION: Departments of Molecular Biology and Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Country: England

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MEDLINETA: Chem Biol

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