RT Journal Article
SR Electronic
T1 Structural determinants of persulfide-sensing specificity in a dithiol-based transcriptional regulator
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.22.001966
DO 10.1101/2020.03.22.001966
A1 Daiana A. Capdevila
A1 Brenna J. C. Walsh
A1 Yifan Zhang
A1 Christopher Dietrich
A1 Giovanni Gonzalez-Gutierrez
A1 David P. Giedroc
YR 2020
UL http://biorxiv.org/content/early/2020/03/23/2020.03.22.001966.abstract
AB 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, suggest 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 formation of the tetrasulfide product. These findings lead to the identification of an uncharacterized repressor from the increasingly antibiotic-resistant bacterial pathogen, Acinetobacter baumannii, as a persulfide sensor, illustrating the predictive power of this work and potential applications to bacterial infectious disease.RSSreactive sulfur speciesSqrRsulfide quinone reductase repressorLMWlow molecular weightTMADtetramethylazodicarboxamide