Structure of autoinhibited Akt1 reveals mechanism of PIP<sub>3</sub>-mediated activation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34385319.
- Also identified by DOI 10.1073/pnas.2101496118 and PMC identifier 8379990.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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)P<sub>3</sub>] and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P<sub>2</sub>] 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)P<sub>3</sub>- or PI(3,4)P<sub>2</sub>-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.
Medical subject headings
- Phosphatidylinositol Phosphates
- Proto-Oncogene Proteins c-akt
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase