MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou, China; School of Pharmacy, Jiangxi Science &Technology Normal University, Nanchang, China.
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-sen University, Guangzhou, China.
J Biol Chem. 2022 Mar;298(3):101587. doi: 10.1016/j.jbc.2022.101587. Epub 2022 Jan 13.
Catabolite control protein A (CcpA) of the human pathogen Staphylococcus aureus is an essential DNA regulator for carbon catabolite repression and virulence, which facilitates bacterial survival and adaptation to a changing environment. Here, we report that copper (II) signaling mediates the DNA-binding capability of CcpA in vitro and in vivo. Copper (II) catalyzes the oxidation of two cysteine residues (Cys216 and Cys242) in CcpA to form intermolecular disulfide bonds between two CcpA dimers, which results in the formation and dissociation of a CcpA tetramer of CcpA from its cognate DNA promoter. We further demonstrate that the two cysteine residues on CcpA are important for S. aureus to resist host innate immunity, indicating that S. aureus CcpA senses the redox-active copper (II) ions as a natural signal to cope with environmental stress. Together, these findings reveal a novel regulatory mechanism for CcpA activity through copper (II)-mediated oxidation.
金黄色葡萄球菌（Staphylococcus aureus）病原体的分解代谢物控制蛋白 A（Catabolite control protein A，CcpA）是一种对碳分解代谢物抑制和毒力至关重要的 DNA 调节剂，有助于细菌的生存和适应不断变化的环境。在这里，我们报告铜（II）信号介导了 CcpA 在体外和体内的 DNA 结合能力。铜（II）催化 CcpA 中两个半胱氨酸残基（Cys216 和 Cys242）的氧化，在两个 CcpA 二聚体之间形成分子间二硫键，导致 CcpA 四聚体与其同源 DNA 启动子的形成和解离。我们进一步证明 CcpA 上的两个半胱氨酸残基对于金黄色葡萄球菌抵抗宿主固有免疫至关重要，表明金黄色葡萄球菌 CcpA 将具有氧化还原活性的铜（II）离子作为一种天然信号来应对环境压力。总之，这些发现揭示了通过铜（II）介导的氧化来调节 CcpA 活性的新机制。
