Jan 22, 2014

Structural determinants of persulfide-sensing specificity in a dithiol-based transcriptional regulator

BioRxiv : the Preprint Server for Biology
Siqi TianDavid P Giedroc

Abstract

Cysteine thiol-based transcriptional regulators orchestrate 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, e.g., reactive oxygen or sulfur species, is largely unknown. Here we report novel structural and mechanistic insights into a thiol-based transcriptional repressor SqrR, that reacts exclusively with organic and inorganic oxidized sulfur species, e.g., persulfides, to yield a unique tetrasulfide bridge that allosterically inhibits DNA operator-promoter binding. Evaluation of five crystallographic structures of SqrR in various derivatized states, coupled with the results of a mass spectrometry-based kinetic profiling strategy, suggests that persulfide selectivity is determined by structural frustration of the disulfide form. This energetic roadblock effectively decreases the reactivity toward major oxidants to kinetically favor the formation of the tetrasulfide product. These findings lead to the identification of an uncharacterized repressor fro...Continue Reading

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Mentioned in this Paper

RNA, Untranslated
Three-dimensional
Primer Extension
Macromolecular Alteration
Hydroxyl group
Oligonucleotide Primers
Ribosomes
Nucleotides
Structure
Base Pairing

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