The mechanism of PI3Kα activation at the atomic level.

ABSTRACT: PI3K lipid kinases phosphorylate PIP₂ to PIP₃ in the PI3K/Akt/mTOR pathway to regulate cellular processes. They are frequently mutated in cancer. Here we determine the PI3Kα activation mechanism at the atomic level. Unlike protein kinases where the substrate abuts the ATP, crystal structures indicate that in PI3Kα, the distance between the γ phosphate of the ATP and the PIP₂ lipid substrate is over 6 Å, much too far for the phosphoryl transfer, raising the question of how catalysis is executed. PI3Kα has two subunits, the catalytic p110α and the regulatory p85α. Our simulations show that release of the autoinhibition exerted by the nSH2 domain of the p85α triggers significant conformational change in p110α, leading to the exposure of the kinase domain for m

SUBMITTER: Zhang M 

PROVIDER: S-EPMC6430085 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature