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Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E3940-E3949. doi: 10.1073/pnas.1716109115. Epub 2018 Apr 9.

Conformational sampling of membranes by Akt controls its activation and inactivation.

Author information

1
Department of Structural and Computational Biology, Max F. Perutz Laboratories, 1030 Vienna, Austria.
2
Center for Medical Biochemistry, Medical University of Vienna, 1030 Vienna, Austria.
3
Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada V8W 2Y2.
4
Department of Structural and Computational Biology, Max F. Perutz Laboratories, 1030 Vienna, Austria; thomas.leonard@meduniwien.ac.at.

Abstract

The protein kinase Akt controls myriad signaling processes in cells, ranging from growth and proliferation to differentiation and metabolism. Akt is activated by a combination of binding to the lipid second messenger PI(3,4,5)P3 and its subsequent phosphorylation by phosphoinositide-dependent kinase 1 and mechanistic target of rapamycin complex 2. The relative contributions of these mechanisms to Akt activity and signaling have hitherto not been understood. Here, we show that phosphorylation and activation by membrane binding are mutually interdependent. Moreover, the converse is also true: Akt is more rapidly dephosphorylated in the absence of PIP3, an autoinhibitory process driven by the interaction of its PH and kinase domains. We present biophysical evidence for the conformational changes in Akt that accompany its activation on membranes, show that Akt is robustly autoinhibited in the absence of PIP3 irrespective of its phosphorylation, and map the autoinhibitory PH-kinase interface. Finally, we present a model for the activation and inactivation of Akt by an ordered series of membrane binding, phosphorylation, dissociation, and dephosphorylation events.

KEYWORDS:

Akt; HDX-MS; SAXS; allostery; kinase

PMID:
29632185
PMCID:
PMC5924885
DOI:
10.1073/pnas.1716109115
[Indexed for MEDLINE]
Free PMC Article

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