Article

Nature 455, 1076-1081 (23 October 2008) | doi:10.1038/nature07396; Received 11 April 2008; Accepted 1 September 2008

BAX activation is initiated at a novel interaction site

Evripidis Gavathiotis1,2,3,6, Motoshi Suzuki4,6, Marguerite L. Davis1,2,3, Kenneth Pitter1,2,3, Gregory H. Bird1,2,3, Samuel G. Katz1,2,3, Ho-Chou Tu5, Hyungjin Kim5, Emily H.-Y. Cheng5, Nico Tjandra4 & Loren D. Walensky1,2,3

  1. Department of Pediatric Oncology and the Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
  2. Division of Hematology/Oncology, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA
  3. Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
  4. Laboratory of Molecular Biophysics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
  5. Departments of Internal Medicine and Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA
  6. These authors contributed equally to this work.

Correspondence to: Nico Tjandra4Loren D. Walensky1,2,3 Correspondence and requests for materials should be addressed to N.T. (Email: tjandran@nhlbi.nih.gov) or L.D.W. (Email: loren_walensky@dfci.harvard.edu).

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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 alpha-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.

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