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BAX activation is initiated at a novel interaction site

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  • 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
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    Cited by:

    1. 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.
    2. 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.
    3. 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.

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