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PH Domain-Mediated Autoinhibition and Oncogenic Activation of Akt
Open accessPreprint — published as 10.7554/elife.80148 · Paper page
Abstract
Previously, we reported that the conformation of autoinhibited Akt, a Ser/Thr protein kinase that plays a central role in metabolism and cancer, may be shifted by small molecule allosteric inhibitors limiting the mechanistic insights from existing X-ray structures that have relied on such compounds (Chu, Viennet, et al, 2020). Here we discover unexpectedly that a single mutation, R86A, in Akt’s PH domain 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.
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Metadata
- Authors
- Bae, H., Viennet, T., Park, E., Chu, N., Salguero, A. L., Eck, M. J., Arthanari, H., & Cole, P. A.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Eck, Michael J.
- Arthanari, Haribabu
- Cole, Philip A.
- ORCID
- Venue
- eLife
- Publisher
- openRxiv
- Published
- 2022-05-25
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9417420
- OpenAlex
- W4291552265
- Cited by
- 31
- References
- 63
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 8 · 2023: 7
- FWCI
- 2.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Kwanjeong Educational Foundation
- National Institutes of Health (1s10od021527-01, DE-AC02–06CH11357, EB-002026, GM124165, CA74305)
- National Cancer Institute (R01-CA74305, DE-AC02-06CH11357, R50CA221830, CA 74305, K22CA241105, R29CA074305, R35CA242461, R01CA074305)
- National Institute of General Medical Sciences (R01GM136859, P30GM124165)
- National Institute of Biomedical Imaging and Bioengineering (P41EB002026)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Akt, pleckstrin homology domain, autoinhibition, allosteric regulation, kinase domain
- MeSH terms
- Pleckstrin Homology Domains, Oncogenes, Phosphorylation, Signal Transduction, Proto-Oncogene Proteins c-akt
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