Evidence that tRNA synthetase-directed proton transfer stops mistranslation.

Evidence that tRNA synthetase-directed proton transfer stops mistranslation. Research Abstract Details 

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Evidence that tRNA synthetase-directed proton transfer stops mistranslation. Abstract Text:

William F Waas,Paul Schimmel,William F Waas,Paul Schimmel,

To prevent mistranslation, aminoacyl-tRNA synthetases (AARSs) discriminate against noncognate amino acids and cellular metabolites. Defects in specificity produce statistical proteins which, in mammalian cells, lead to activation of the unfolded protein response and cell death. Because of inherent limitations in amino acid discrimination by a single active site, AARSs evolved a separate domain to clear mischarged amino acids. Although the structure of a widely distributed editing domain for ThrRS and AlaRS is known, the mechanism of amino acid clearance remains elusive. This domain has two motifs that together have four conserved residues in the pocket used to clear serine from mischarged tRNAs. Here, using ThrRS as an example, rapid single-turnover kinetics, mutagenesis, and solvent isotope analysis show that a strictly conserved histidine (between ThrRS and AlaRS) extracts a proton in the chemical step of the editing reaction. Three other conserved residues, and two additional residues in the editing pocket, are not directly implicated in the chemical step. These results are relevant to the previously reported mutagenesis of the homologous editing pocket of alanyl-tRNA synthetase, where even a mild defect in editing causes neurodegeneration in the mouse. Thus, a single proton-transfer event needed to prevent mistranslation can have profound implications for disease.

Evidence that tRNA synthetase-directed proton transfer stops mistranslation. Publishing Authors By Initials

WF Waas,P Schimmel,WF Waas,P Schimmel,

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Evidence that tRNA synthetase-directed proton transfer stops mistranslation. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Biochemistry

VOLUME: 46

Page Numbers: 12062-70

Journal Abbreviation: Biochemistry

ISSN: 0006-2960

DAY: 9

MONTH: 10

YEAR: 2007

Evidence that tRNA synthetase-directed proton transfer stops mistranslation. Information

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LANGUAGE: eng

NlmUniqueID: 370623

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Grant and Affiliation Information for Evidence that tRNA synthetase-directed proton transfer stops mistranslation.

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

Country: United States

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MEDLINETA: Biochemistry

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