Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation

Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2101496118. doi: 10.1073/pnas.2101496118.

Abstract

The protein kinase Akt is one of the primary effectors of growth factor signaling in the cell. Akt responds specifically to the lipid second messengers phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] via its PH domain, leading to phosphorylation of its activation loop and the hydrophobic motif of its kinase domain, which are critical for activity. We have now determined the crystal structure of Akt1, revealing an autoinhibitory interface between the PH and kinase domains that is often mutated in cancer and overgrowth disorders. This interface persists even after stoichiometric phosphorylation, thereby restricting maximum Akt activity to PI(3,4,5)P3- or PI(3,4)P2-containing membranes. Our work helps to resolve the roles of lipids and phosphorylation in the activation of Akt and has wide implications for the spatiotemporal control of Akt and potentially lipid-activated kinase signaling in general.

Keywords: Akt; PIP3; kinase; lipid; signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Humans
  • Insecta
  • Lipid Metabolism
  • Phosphatidylinositol Phosphates / genetics
  • Phosphatidylinositol Phosphates / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Domains
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase / metabolism*
  • Sf9 Cells

Substances

  • PDK1 protein, human
  • Phosphatidylinositol Phosphates
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • phosphatidylinositol 3,4,5-triphosphate
  • phosphatidylinositol 3,4-diphosphate
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt