Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation

Significance Akt is an essential protein kinase that controls cell growth, survival, and metabolism. Akt is activated by the lipid second messengers PIP 3 and PI(3,4)P 2 and by phosphorylation. However, the relative contributions of lipid binding and phosphorylation to Akt activity in the cell are controversial. Here, we have determined the structure of autoinhibited Akt1, which reveals how the lipid-binding PH domain maintains the kinase domain in an inactive conformation in the absence of PIP 3 . Despite stoichiometric phosphorylation, Akt adopts an autoinhibited conformation with low basal activity in the absence of PIP 3 . Our work reveals the mechanistic basis of Akt hyperactivation in cancer and overgrowth diseases and unambiguously establishes that Akt depends on lipids for activity in the cell.