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广东快乐十分分析最准:Oxidation of phenylalanyl-tRNA synthetase positively regulates translational quality control
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Regulation of translational quality control during adverse growth conditions is critical to maintain cellular homeostasis. Translational quality control is maintained by proofreading by the aminoacyl-tRNA synthetases (aaRS), which ensure that cognate aminoacyl-tRNAs are provided to the ribosome for protein synthesis. Our findings now show that under oxidative stress a global conformational change in the phenylalanyl-tRNA synthetase positively regulates quality control by increasing the rate of proofreading. These results demonstrate that the translational machinery is able to rapidly and positively respond to environmental challenges to maintain the accuracy of protein synthesis.
Accurate translation of the genetic code is maintained in part by aminoacyl-tRNA synthetases (aaRS) proofreading mechanisms that ensure correct attachment of a cognate amino acid to a transfer RNA (tRNA). During environmental stress, such as oxidative stress, demands on aaRS proofreading are altered by changes in the availability of cytoplasmic amino acids. For example, oxidative stress increases levels of cytotoxic tyrosine isomers, noncognate amino acids normally excluded from translation by the proofreading activity of phenylalanyl-tRNA synthetase (PheRS). Here we show that oxidation of PheRS induces a conformational change, generating a partially unstructured protein. This conformational change does not affect Phe or Tyr activation or the aminoacylation activity of PheRS. However, in vitro and ex vivo analyses reveal that proofreading activity to hydrolyze Tyr-tRNAPhe is increased during oxidative stress, while the cognate Phe-tRNAPhe aminoacylation activity is unchanged. In HPX?, Escherichia coli that lack reactive oxygen-scavenging enzymes and accumulate intracellular H2O2, we found that PheRS proofreading is increased by 11%, thereby providing potential protection against hazardous cytoplasmic m-Tyr accumulation. These findings show that in response to oxidative stress, PheRS proofreading is positively regulated without negative effects on the enzyme’s housekeeping activity in translation. Our findings also illustrate that while the loss of quality control and mistranslation may be beneficial under some conditions, increased proofreading provides a mechanism for the cell to appropriately respond to environmental changes during oxidative stress.
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Author contributions: R.E.S. and M.I. designed research; R.E.S. and A.M.K. performed research; R.E.S., A.M.K., and M.I. analyzed data; and R.E.S. and M.I. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1901634116/-/DCSupplemental.
Published under the PNAS license.