Structural basis for persulfide-sensing specificity in a transcriptional regulator

CAPDEVILA, DAIANA A; BRENNA J. C. WALSH; ZHANG, YIFAN; CHRISTOPHER DIETRICH; GONZALEZ-GUTIERREZ, GIOVANNI; GIEDROC, DAVID P

NATURE CHEMICAL BIOLOGY

NATURE PUBLISHING GROUP

Año: 2020

1552-4450

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 oxidized sulfur species, e.g., persulfides, to yield a unique 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 lead to the identification of an uncharacterized repressor from the bacterial pathogen, Acinetobacter baumannii, as a persulfide sensor.