PH domain-mediated autoinhibition and oncogenic activation of Akt

Akt is a Ser/Thr protein kinase that plays a central role in metabolism and cancer. Regulation of Akt's activity involves an autoinhibitory intramolecular interaction between its pleckstrin homology (PH) domain and its kinase domain that can be relieved by C-tail phosphorylation. PH domain mutant E17K Akt is a well-established oncogene. Previously, we reported that the conformation of autoinhibited Akt may be shifted by small molecule allosteric inhibitors limiting the mechanistic insights from existing X-ray structures that have relied on such compounds (Chu et al., 2020). Here, we discover unexpectedly that a single mutation R86A Akt exhibits intensified autoinhibitory features with enhanced PH domain-kinase domain affinity. Structural and biochemical analysis uncovers the importance of a key interaction network involving Arg86, Glu17, and Tyr18 that controls Akt conformation and activity. Our studies also shed light on the molecular basis for E17K Akt activation as an oncogenic driver.

Automated summary

Akt is a protein kinase that plays a central role in metabolism and cancer. This study reveals the intensified autoinhibitory features of the R86A Akt mutant, which enhances the PH domain-kinase domain affinity. The key interaction network involving Arg86, Glu17, and Tyr18 is shown to control the conformation and activity of Akt, providing insights into the molecular basis of E17K Akt activation as an oncogenic driver.