Multiple binding modes of AKT on PIP$_3$-containing membranes

The PI3K/AKT signaling pathway is triggered by recruitment of AKT to cellular membranes. Although AKT is a multidomain serine/threonine kinase composed of an N-terminal pleckstrin homology (PH) domain and a C-terminal kinase domain, how these domains cooperate to regulate AKT activation on membranes remains unclear at the molecular level. Here, using molecular dynamics simulations of full-length AKT on PIP$_3$-containing lipid bilayers, we identify four distinct membrane-binding modes that differ in the orientations and membrane contacts of the PH and kinase domains. In addition to PIP$_3$ binding to the PH domain, we observe specific PIP$_3$ interactions with basic residues in the kinase domain. In the most stable mode, PIP$_3$ interacts with both the canonical and a secondary binding site in the PH domain, while the kinase domain adopts an orientation in which the activation-loop phosphorylation site is exposed to the solvent. Interestingly, the populations of these binding modes depend on the PIP$_3$ concentration in the membrane, leading to changes in the preferred orientation of AKT. These findings shed light on how lipid recognition by the PH domain and the kinase domain of AKT cooperatively shape its membrane-bound conformations.