Center for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Institute for Organic Chemistry and Chemical Biology, Frankfurt am Main, Germany.
FEBS Lett. 2022 Jun;596(12):1503-1515. doi: 10.1002/1873-3468.14348. Epub 2022 Apr 15.
The Mycobacterium tuberculosis tyrosine-specific phosphatase MptpA and its cognate kinase PtkA are prospective targets for anti-tuberculosis drugs as they interact with the host defense response within the macrophages. Although both are structurally well-characterized, the functional mechanism regulating their activity remains poorly understood. Here, we investigate the effect of post-translational oxidation in regulating the function of MptpA. Treatment of MptpA with H O /NaHCO , mimicking cellular oxidative stress conditions, leads to oxidation of the catalytic cysteine (C11) and to a conformational rearrangement of the phosphorylation loop (D-loop) by repositioning the conserved tyrosine 128 (Y128) and generating a temporarily inactive preclosed state of the phosphatase. Thus, the catalytic cysteine in the P-loop acts as a redox switch and regulates the phosphatase activity of MptpA.
结核分枝杆菌酪氨酸特异性磷酸酶 MptpA 及其同源激酶 PtkA 与巨噬细胞内的宿主防御反应相互作用，是潜在的抗结核药物靶点。尽管它们的结构都得到了很好的描述，但调节其活性的功能机制仍知之甚少。在这里，我们研究了翻译后氧化对调节 MptpA 功能的影响。用 H O /NaHCO 处理 MptpA，模拟细胞氧化应激条件，导致催化半胱氨酸 (C11) 氧化，并通过重新定位保守的酪氨酸 128 (Y128) 使磷酸化环 (D-环) 发生构象重排，从而产生磷酸酶的暂时非活性预关闭状态。因此，P 环中的催化半胱氨酸充当氧化还原开关，调节 MptpA 的磷酸酶活性。
