Figure 1. Akt domain architecture, two distinct activation mechanisms mediated by C-tail phosphorylations, and the current model for drug-induced autoinhibited form.

(A) Schematic representation of Akt domains with phosphorylation sites of interest highlighted as red balls. (B) Cartoon model depicted for two distinct Akt activation mechanisms induced by phospho-Ser473 and dual phospho-Ser477/Thr479 (Chu et al., 2018). Without C-tail phosphorylations, Akt remains in an inactive autoinhibited state where the PH and kinase domains interact intramolecularly. The mTORC2-mediated Ser473 phosphorylation activates Akt by inducing an interaction between the C-tail and the PH-kinase domain linker, dislodging the PH domain from the kinase domain. Alternatively, the dual Cdk2/cyclinA-mediated pSer477/pThr479 is presumed to activate Akt by interaction with the activation loop and PH domain. Note that, although C-terminal phosphorylation is shown preceding activation loop Thr308 phosphorylation by PDK1, it is uncertain in normal cell signaling whether C-terminal phosphorylation or Thr308 phosphorylation comes first in Akt activation or if it is in random order. (C) Crystal structure of Akt (aa 1–443) bound to allosteric inhibitor compound VIII (left, PDB: 3O96, [Wu et al., 2010]) and cartoon model illustrating the current model of the allosteric drug-induced autoinhibited form of Akt with the non-phosphorylated C-tail.