IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v455y2008i7216d10.1038_nature07396.html
   My bibliography  Save this article

BAX activation is initiated at a novel interaction site

Author

Listed:
  • Evripidis Gavathiotis

    (Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Motoshi Suzuki

    (Laboratory of Molecular Biophysics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA)

  • Marguerite L. Davis

    (Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Kenneth Pitter

    (Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Gregory H. Bird

    (Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Samuel G. Katz

    (Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Ho-Chou Tu

    (Washington University School of Medicine, Saint Louis, Missouri 63110, USA)

  • Hyungjin Kim

    (Washington University School of Medicine, Saint Louis, Missouri 63110, USA)

  • Emily H.-Y. Cheng

    (Washington University School of Medicine, Saint Louis, Missouri 63110, USA)

  • Nico Tjandra

    (Laboratory of Molecular Biophysics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA)

  • Loren D. Walensky

    (Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
    Children’s Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
    Harvard Medical School, Boston, Massachusetts 02115, USA)

Abstract

BAX is a pro-apoptotic protein of the BCL-2 family that is stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Anti-apoptotic proteins such as BCL-2 counteract BAX-mediated cell death. Although an interaction site that confers survival functionality has been defined for anti-apoptotic proteins, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown. We previously developed stabilized α-helix of BCL-2 domains (SAHBs) that directly initiate BAX-mediated mitochondrial apoptosis. Here we demonstrate by NMR analysis that BIM SAHB binds BAX at an interaction site that is distinct from the canonical binding groove characterized for anti-apoptotic proteins. The specificity of the human BIM-SAHB–BAX interaction is highlighted by point mutagenesis that disrupts functional activity, confirming that BAX activation is initiated at this novel structural location. Thus, we have now defined a BAX interaction site for direct activation, establishing a new target for therapeutic modulation of apoptosis.

Suggested Citation

  • Evripidis Gavathiotis & Motoshi Suzuki & Marguerite L. Davis & Kenneth Pitter & Gregory H. Bird & Samuel G. Katz & Ho-Chou Tu & Hyungjin Kim & Emily H.-Y. Cheng & Nico Tjandra & Loren D. Walensky, 2008. "BAX activation is initiated at a novel interaction site," Nature, Nature, vol. 455(7216), pages 1076-1081, October.
    • Handle: RePEc:nat:nature:v:455:y:2008:i:7216:d:10.1038_nature07396
    DOI: 10.1038/nature07396
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature07396
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature07396?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Andrea Lopez & Denis E. Reyna & Nadege Gitego & Felix Kopp & Hua Zhou & Miguel A. Miranda-Roman & Lars Ulrik Nordstrøm & Swathi-Rao Narayanagari & Ping Chi & Eduardo Vilar & Aristotelis Tsirigos & Evr, 2022. "Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Nadege Gitego & Bogos Agianian & Oi Wei Mak & Vasantha Kumar MV & Emily H. Cheng & Evripidis Gavathiotis, 2023. "Chemical modulation of cytosolic BAX homodimer potentiates BAX activation and apoptosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Crina-Maria Ionescu & Radka Svobodová Vařeková & Jochen H M Prehn & Heinrich J Huber & Jaroslav Koča, 2012. "Charge Profile Analysis Reveals That Activation of Pro-apoptotic Regulators Bax and Bak Relies on Charge Transfer Mediated Allosteric Regulation," PLOS Computational Biology, Public Library of Science, vol. 8(6), pages 1-11, June.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:455:y:2008:i:7216:d:10.1038_nature07396. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.