BAX activation is initiated at a novel interaction site

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 () and Loren D. Walensky ()
Additional contact information
Evripidis Gavathiotis: Dana-Farber Cancer Institute, 44 Binney Street, 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
Kenneth Pitter: Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
Gregory H. Bird: Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
Samuel G. Katz: Dana-Farber Cancer Institute, 44 Binney Street, 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

Nature, 2008, vol. 455, issue 7216, 1076-1081

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07396

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