Figure 7.

A “Three-Brake” Regulatory Model for Inhibition of p110β Basal Activity

Model of the “three-brake” inhibition of p110β activity by the nSH2, iSH2, and cSH2 domains of p85. All three domains make inhibitory interactions with the catalytic subunit. The nSH2 and cSH2 are in contact with the “regulatory square” formed by the three C-terminal helices of p110β (Kα10–Kα12). This “regulatory square” encloses the catalytic and activation loop and could mediate the SH2 inhibitory effects. RTK phosphopeptide binding to SH2 domains relieves the inhibition. The main contact between nSH2 and catalytic subunit overlaps perfectly with pY-binding site on nSH2, but not on cSH2. Therefore, relief from cSH2 inhibition requires an extended pYXXM motif.