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The SrrAB two-component system regulates Staphylococcus aureus pathogenicity through redox sensitive cysteines

AuthorsTiwari, Nitija; López-Redondo, Marisa ; Miguel-Romero, Laura ; Kulhankova, Katarina; Cahill, Michael P.; Tran, Phuong M.; Kinney, Kyle J.; Kilgore, Samuel H.; Al-Tameemi, Hassan; Herfst, Christine A.; Tuffs, Stephen W.; Kirby, John R.; Boyd, Jeffery M.; McCormick, John K.; Salgado-Pabón, Wilmara; Marina, Alberto ; Schlievert, Patrick M.; Fuentes, Ernesto J.
KeywordsSrrAB two-component system
Staphylococcus aureus
Cysteine disulfide bond
Sensor histidine kinase
Issue Date30-Apr-2020
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences of the USA 117(20):10989-10999 (2020)
AbstractStaphylococcus aureus infections can lead to diseases that range from localized skin abscess to life-threatening toxic shock syndrome. The SrrAB two-component system (TCS) is a global regulator of S. aureus virulence and critical for survival under environmental conditions such as hypoxic, oxidative, and nitrosative stress found at sites of infection. Despite the critical role of SrrAB in S. aureus pathogenicity, the mechanism by which the SrrAB TCS senses and responds to these environmental signals remains unknown. Bioinformatics analysis showed that the SrrB histidine kinase contains several domains, including an extracellular Cache domain and a cytoplasmic HAMP-PAS-DHp-CA region. Here, we show that the PAS domain regulates both kinase and phosphatase enzyme activity of SrrB and present the structure of the DHp-CA catalytic core. Importantly, this structure shows a unique intramolecular cysteine disulfide bond in the ATP-binding domain that significantly affects autophosphorylation kinetics. In vitro data show that the redox state of the disulfide bond affects S. aureus biofilm formation and toxic shock syndrome toxin-1 production. Moreover, with the use of the rabbit infective endocarditis model, we demonstrate that the disulfide bond is a critical regulatory element of SrrB function during S. aureus infection. Our data support a model whereby the disulfide bond and PAS domain of SrrB sense and respond to the cellular redox environment to regulate S. aureus survival and pathogenesis.
Description11 pag, 6 figs. Coordinates for the model of SrrB DHp-CA region solved by X-ray crystallography have been deposited in the Protein Data Bank, https://www.rcsb.org/ (ID code 6PAJ). This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1921307117/-/DCSupplemental.
Publisher version (URL)http://dx.doi.org/10.1073/pnas.1921307117
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