Figure 3. Activation of NOX2 is driven by p47^phox S-379 phosphorylation leading to the interaction between regulatory and membrane components.

In the resting state, NOX2 oxidase is disassociated into its subunits and cofactors, while NOX2 and p22^phox are in the membrane, p47^phox–p67^phox – p40^phox are in an associated, yet dephosphorylated, state in a soluble trimeric complex, in which the p67^phox and p40^phox PB1 domains bind and a SH3 domain at the C-terminus of p67^phox binds to the PRR of p47^phox. At this time, the SH3 super-groove and PX domain of p47^phox are masked by the polybasic auto-inhibitory region (AIR) which restricts p47^phox to its folded and inactive state. Upon activation by diverse stimuli, protein kinase C (PKC) gets activated and phosphorylates p47^phox on critical serines, this in turn disrupts the hydrogen bonds linking the C-terminal AIR and the tandem SH3 domains and exposes the supergroove pocket. This allows for the secondary phosphorylation of serine residues (S379) (see insert) permitting translocation and binding of p47^phox to p22^phox’s PRR domain. p47^phox and p40^phox acting through hallmark binding domains outlined in Figure 2 function to engage p67^phox and Rac1 and scaffold the entire complex in place for NOX2 activation.