1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

PH domain-mediated autoinhibition and oncogenic activation of Akt

  1. Hwan Bae
  2. Thibault Viennet
  3. Eunyoung Park
  4. Nam Chu
  5. Antonieta Salguero
  6. Michael J Eck  Is a corresponding author
  7. Haribabu Arthanari  Is a corresponding author
  8. Philip A Cole  Is a corresponding author
  1. Harvard Medical School, United States
  2. Dana-Farber Cancer Institute, United States
  3. The Ohio State University, United States
  4. Brigham and Women's Hospital, United States
https://doi.org/10.7554/eLife.80148
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  1. Hwan Bae
  2. Thibault Viennet
  3. Eunyoung Park
  4. Nam Chu
  5. Antonieta Salguero
  6. Michael J Eck
  7. Haribabu Arthanari
  8. Philip A Cole
(2022)
PH domain-mediated autoinhibition and oncogenic activation of Akt
eLife 11:e80148.
https://doi.org/10.7554/eLife.80148
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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, Viennet, 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.

Data availability

Diffraction data have been deposited in PDB under the accession code: 7MYXSource data are uploaded as Zip files on the eLife website

Article and author information

Author details

  1. Hwan Bae

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5252-252X

  2. Thibault Viennet

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5349-0179

  3. Eunyoung Park

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5618-1267

  4. Nam Chu

    Department of Cancer Biology and Genetics, The Ohio State University, Columbus, United States
    Competing interests
    No competing interests declared.

  5. Antonieta Salguero

    Department of Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    No competing interests declared.

  6. Michael J Eck

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    eck@crystal.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4247-9403

  7. Haribabu Arthanari

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    For correspondence
    hari_arthanari@hms.harvard.edu
    Competing interests
    No competing interests declared.

  8. Philip A Cole

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    For correspondence
    pacole@bwh.harvard.edu
    Competing interests
    Philip A Cole, Senior editor, eLifePhilip Cole has been a paid consultant for Scorpion Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6873-7824

Funding

National Cancer Institute (R01CA74305)

  • Philip A Cole

National Cancer Institute (R35CA242461)

  • Michael J Eck

National Cancer Institute (K22CA241105)

  • Nam Chu

Claudia Adams Barr Program (Grant)

  • Haribabu Arthanari

National Institutes of Health (EB002026)

  • Haribabu Arthanari

Kwanjeong Education Foundation (Fellowship)

  • Hwan Bae

National Institute of General Medical Sciences (GM124165)

  • Michael J Eck

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Amy H Andreotti, Iowa State University, United States

Version history

  1. Received: May 12, 2022
  2. Preprint posted: May 25, 2022 (view preprint)
  3. Accepted: August 9, 2022
  4. Accepted Manuscript published: August 15, 2022 (version 1)
  5. Version of Record published: August 26, 2022 (version 2)

Copyright

© 2022, Bae et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hwan Bae
  2. Thibault Viennet
  3. Eunyoung Park
  4. Nam Chu
  5. Antonieta Salguero
  6. Michael J Eck
  7. Haribabu Arthanari
  8. Philip A Cole
(2022)
PH domain-mediated autoinhibition and oncogenic activation of Akt
eLife 11:e80148.
https://doi.org/10.7554/eLife.80148

Share this article

https://doi.org/10.7554/eLife.80148

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