Staphylococcus aureus glucose-induced biofilm accessory protein A (GbaA) is a monothiol-dependent electrophile sensor.

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Staphylococcus aureus glucose-induced biofilm accessory protein A (GbaA) is a monothiol-dependent electrophile sensor.

Biochemistry. 2020 Jul 22;:

Authors: Ray A, Edmonds KA, Palmer LD, Skaar EP, Giedroc DP

Abstract
Staphylococcus aureus is a commensal pathogen that has evolved to protect itself from unfavorable conditions by forming complex community structures termed biofilms. The regulation of the formation of these structures is multifactorial, and in S. aureus involves a number of transcriptional regulators. GbaA (glucose-induced biofilm accessory protein A) is a tetracycline repressor (TetR) family regulator that harbors two conserved Cys residues (C55, C104) and impacts the regulation of formation of poly-N-acetylglucosamine (PNAG)-based biofilms in many methicillin-resistant S. aureus (MRSA) strains. Here, we show that GbaA-regulated transcription of a divergently transcribed operon in a MRSA strain is inducible by potent electrophiles, N-ethylmaleimide and methylglyoxal. Strikingly, induction of transcription in cells requires C55 or C104, but not both. These findings are consistent with in vitro small angle x-ray scattering, chemical modification and DNA operator binding experiments, which reveal that both reduced and intra-protomer (C55-C104) disulfide forms of GbaA have very similar overall structures and each exhibits high affinity for the DNA operator, while DNA binding is strongly inhibited by derivatization of one of the other Cys via mixed disulfide formation with bacillithiol disulfide or monothiol electrophilic addition adducts with NEM. While both Cys are reactive toward electrophiles, C104 in the regulatory domain is the more reactive thiolate. These characteristics enhance the inducer specificity of GbaA, and would preclude sensing of generalized cellular oxidative stress via disulfide bond formation. The implications of the findings on GbaA function in MRSA strains are discussed.

PMID: 32697076 [PubMed - as supplied by publisher]