西亚试剂：BAX activation is initiated at a novel interaction site

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.

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 -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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