Conformational sampling of membranes by Akt controls its activation and inactivation

Significance Akt is a paradigmatic lipid-activated kinase, which is frequently hyperactivated in human cancer. In the absence of PI(3,4,5)P 3 or PI(3,4)P 2 , Akt is maintained in an inactive conformation by an inhibitory interaction between its membrane-binding PH domain and its kinase domain. Here, we describe the conformational changes associated with its binding to PI(3,4,5)P 3 , leading to disruption of the inhibitory PH−kinase interface, and its consequent activation by protein kinases. Intriguingly, we find that reversal of those conformational changes promotes its inactivation by protein phosphatases. The activation of Akt is thereby restricted to discrete membrane locations, and it is rapidly inactivated upon dissociation. We propose a model in which activation, substrate phosphorylation, and inactivation of Akt are tightly coupled to the membrane.