Fig. 6. Molecular mechanism of activation of WT PIK3CA, and how oncogenic mutations mimic this process.

Summary of molecular mechanisms of PI3K inhibition by the ABD and regulatory subunit, how activation occurs for wild-type p110α-p85 (A), and how oncogenic mutations can alter this process (B–D). A Proposed mechanism of activation of wild-type p110α-p85α. Activation is initiated by nSH2 disengagement through binding pYXXM motifs (pY), followed by ABD-p85 disengagement, followed by membrane binding (which can be promoted through binding to membrane localised Ras). B Activation of p110α-p85α by oncogenic mutants that promote the nSH2 disengagement step of PI3K activation (nSH2-helical hot spot-mutants, E542K, E545K). See Supplementary Fig. 7 for complete list of mutants. C Activation of p110α-p85α by oncogenic mutants that promote the ABD-p85 disengagement step of PI3K activation (ABD, ABD-RBD linker, C2-iSH2 mutants). See Supplementary Fig. 7 for complete list of mutants. D Different molecular mechanisms driving activation of C-terminal mutations in p110α. The regulatory motif is coloured green, with the C-terminus coloured red, and the activation loop in black (inactive) or red (orange). The C-terminus when in its closed conformation has the membrane binding WIF motif oriented away from the membrane surface. Membrane binding requires the reorientation of this tail, with the membrane itself likely involved in this conformational change. Mutations that disrupt this interface (H1047R, G1049R) are in an open conformation, leading to greatly increased membrane binding. In the N1068fs mutant there is no change in conformation in solution, but the added KLKR motif dramatically increases membrane recruitment.