Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acinetobacter baumannii / genetics*
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Acinetobacter baumannii / metabolism
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Amino Acid Sequence
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Bacterial Proteins / chemistry*
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Binding Sites
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Cloning, Molecular
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Crystallography, X-Ray
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Cysteine / chemistry
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Cysteine / metabolism
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Disulfides / chemistry
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Disulfides / metabolism
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Gene Expression Regulation, Bacterial*
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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Glutathione / chemistry
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Glutathione / metabolism
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Kinetics
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Models, Molecular
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Oxidation-Reduction
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Promoter Regions, Genetic
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Quinone Reductases / chemistry*
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Quinone Reductases / genetics
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Quinone Reductases / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Alignment
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Sequence Homology, Amino Acid
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Sulfides / chemistry*
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Sulfides / metabolism
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Sulfur / chemistry
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Sulfur / metabolism
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Thermodynamics
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Transcription, Genetic*
Substances
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Bacterial Proteins
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Disulfides
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Recombinant Proteins
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Sulfides
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persulfides
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Sulfur
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Quinone Reductases
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sulfide quinone reductase
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Glutathione
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Cysteine