Groemping Yvonne, Lapouge Karine, Smerdon Stephen J, Rittinger Katrin
Division of Protein Structure, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Cell. 2003 May 2;113(3):343-55. doi: 10.1016/s0092-8674(03)00314-3.
The multi-subunit NADPH oxidase complex plays a crucial role in host defense against microbial infection through the production of reactive oxygen species. Activation of the NADPH oxidase requires the targeting of a cytoplasmic p40-p47-p67(phox) complex to the membrane bound heterodimeric p22-gp91(phox) flavocytochrome. This interaction is prevented in the resting state due to an auto-inhibited conformation of p47(phox). The X-ray structure of the auto-inhibited form of p47(phox) reveals that tandem SH3 domains function together to maintain the cytoplasmic complex in an inactive form. Further structural and biochemical data show that phosphorylation of p47(phox) activates a molecular switch that relieves the inhibitory intramolecular interaction. This permits p47(phox) to interact with the cytoplasmic tail of p22(phox) and initiate formation of the active, membrane bound enzyme complex.
多亚基NADPH氧化酶复合物通过产生活性氧在宿主抵御微生物感染中起关键作用。NADPH氧化酶的激活需要将细胞质中的p40-p47-p67（phox）复合物靶向到膜结合的异二聚体p22-gp91（phox）黄素细胞色素上。由于p47（phox）的自抑制构象，这种相互作用在静止状态下受到阻碍。p47（phox）自抑制形式的X射线结构表明，串联的SH3结构域共同发挥作用，使细胞质复合物保持无活性形式。进一步的结构和生化数据表明，p47（phox）的磷酸化激活了一个分子开关，解除了抑制性分子内相互作用。这使得p47（phox）能够与p22（phox）的细胞质尾巴相互作用，并启动活性膜结合酶复合物的形成。
