Molecular Basis of Phosphorylation-Induced Activation of the NADPH Oxidase

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.