Calmodulin (CaM) Activates PI3K alpha by Targeting the "Soft" CaM-Binding Motifs in Both the nSH2 and cSH2 Domains of p85 alpha

PI3K alpha is a key lipid kinase in the PI3K/Akt pathway. Its frequent oncogenic mutations make it a primary drug target. Calmodulin (CaM) activates PI3K alpha independently of extracellular signals, indicating a significant role in oncogenic PI3K alpha activation. Here, we reveal the atomic-scale structures of CaM in complexes with the nSH2 and cSH2 domains of the regulatory p8Sa subunit of PI3K alpha, and illustrate how CaM activates PI3K alpha by targeting the "soft 1-5-10" CaM-binding motifs in both nSH2 and cSH2 domains. Experiment observed CaM binding cSH2 first, followed by nSH2 binding hours later. CaM typically prefers binding helical peptides. Here we observe that, unlike in cSH2, the CaM-binding motif in nSH2 populates a mixed beta-sheet/alpha-helix/random coil structure. The population shift from a beta-sheet toward CaM's favored alpha-helical conformation explains why the nSH2 domain needs a longer time for CaM binding in the experiments. The "soft" CaM-binding motifs in both nSH2 and cSH2 domains establish strong CaM-PI3K alpha interactions, collectively facilitating PI3K alpha activation. This work uncovers the structural basis for CaM-driven PI3K alpha activation.

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