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.
Division of Protein Structure, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Yvonne
Y
Groemping
Karine
K
Lapouge
Stephen J
SJ
Smerdon
Katrin
K
Rittinger
D000595:Amino Acid Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D046911:Macromolecular Substances; D026901:Membrane Transport Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009252:NADPH Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D018909:src Homology Domains
D046911:Macromolecular Substances; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1; D009252:NADPH Dehydrogenase