PH domain-mediated autoinhibition and oncogenic activation of Akt
Year: 2022
Type: article
Abstract: 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.
Source: eLife
DOI: 10.7554/elife.80148
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G1295727775, G1434738008, G1696942221, G3152346458, G3611066896, MIT/ Harvard Center for Magnetic Resonance, Pixel Array Detector for Macromolecular Crystallography, G5607048534, G5938681534, G604848185, NMR Fingerprinting: Leveraging optimal control pulse design, tailored isotope labeling, and machine learning to study intractable proteins, G7768958537, G9000020627, G9000051720, G9000051782, G9000350631, NE-CAT: A Resource for Advanced Macromolecular Crystallography
OpenAlex ID: W4291552265