4.8 Article

Structural basis for persulfide-sensing specificity in a transcriptional regulator

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NATURE CHEMICAL BIOLOGY
卷 17, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41589-020-00671-9

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资金

  1. National Institutes of Health [R35 GM118157]
  2. Pew Foundation Latin American Fellows
  3. Williams foundation
  4. NIH [T32 GM109825, T32 GM131994]
  5. Indiana University Department of Chemistry

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Structural and kinetic analyses of the transcriptional repressor protein SqrR reveal its persulfide selectivity mechanism, shedding light on the coordinated regulation function of cysteine thiol-based transcriptional regulators in cellular redox homeostasis.
Structural and kinetic analyses of the transcriptional repressor SqrR in multiple states indicate that its persulfide selectivity is determined by structural frustration in the disulfide form, favoring formation of the tetrasulfide-bridged product. Cysteine thiol-based transcriptional regulators orchestrate the coordinated regulation of redox homeostasis and other cellular processes by 'sensing' or detecting a specific redox-active molecule, which in turn activates the transcription of a specific detoxification pathway. The extent to which these sensors are truly specific in cells for a singular class of reactive small-molecule stressors, for example, reactive oxygen or sulfur species, is largely unknown. Here, we report structural and mechanistic insights into the thiol-based transcriptional repressor SqrR, which reacts exclusively with oxidized sulfur species such as persulfides, to yield a tetrasulfide bridge that inhibits DNA operator-promoter binding. Evaluation of crystallographic structures of SqrR in various derivatized states, coupled with the results of a mass spectrometry-based kinetic profiling strategy, suggest that persulfide selectivity is determined by structural frustration of the disulfide form. These findings led to the identification of an uncharacterized repressor from the bacterial pathogen Acinetobacter baumannii as a persulfide sensor.

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