Abstract
All strains of Staphylococcus aureus encode a putative copper-sensitive operon repressor (CsoR) and one other CsoR-like protein of unknown function. We show here that NWMN_1991 encodes a bona fide Cu(I)-inducible CsoR of a genetically unlinked copA-copZ copper resistance operon in S. aureus strain Newman. In contrast, an unannotated open reading frame found between NWMN_0027 and NWMN_0026 (denoted NWMN_0026.5) encodes a CsoR-like regulator that represses expression of adjacent genes by binding specifically to a pair of canonical operator sites positioned in the NWMN_0027-0026.5 intergenic region. Inspection of these regulated genes suggests a role in assimilation of inorganic sulfur from thiosulfate and vectorial sulfur transfer, and we designate NWMN_0026.5 as CstR (CsoR-like sulfur transferase repressor). Expression analysis demonstrates that CsoR and CstR control their respective regulons in response to distinct stimuli with no overlap in vivo. Unlike CsoR, CstR does not form a stable complex with Cu(I); operator binding is instead inhibited by oxidation of the intersubunit cysteine pair to a mixture of disulfide and trisulfide linkages by a likely metabolite of thiosulfate assimilation, sulfite. CsoR is unreactive toward sulfite under the same conditions. We conclude that CsoR and CstR are paralogs in S. aureus that function in the same cytoplasm to control distinct physiological processes.
Highlights
M. tuberculosis CsoR6 is a founding member of large family of regulators known collectively to respond to Cu(I), Ni(II), and perhaps other stressors, the structural basis of which is not fully understood [11, 12]
The ⌬csoR strain has elevated copA expression that is nearly independent of copper (Fig. 1B) suggesting that copper-sensitive operon repressor (CsoR) is responsible for controlling the copper stress response in S. aureus
The extended OP1_5GC duplex forms a complex with an affinity within 4-fold of OP1, whereas deletion of one or three GC pairs abolishes specific complex formation (Fig. 4C). These findings reveal that Sau CstR possesses sequence- and/or structure-specific DNA binding properties consistent with other CsoR/RcnR regulators [27]
Summary
CsoR, copper-sensitive operon repressor; MMTS, methylmethanethiosulfonate; EXAFS, extended x-ray absorption fine structure; ESI, electrospray ionization; OP, operator-promoter. Regulation of Copper Sensing and Sulfur Metabolism in S. aureus completely unknown. This wide distribution and involvement in multiple regulatory pathways highlights the importance of understanding the molecular processes governed by this family of proteins. We characterize the regulation of two stress response pathways in S. aureus by paralogs of the CsoR family of DNA-binding proteins. These transcriptional regulators are the copper sensor CsoR and a novel regulator denoted CstR (CsoR-like sulfur transferase regulator), which respond to distinct stressors with no detectable regulatory cross-talk in the cell
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