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- Title
BAX activation is initiated at a novel interaction site.
- Authors
Gavathiotis, Evripidis; Suzuki, Motoshi; Davis, Marguerite L; Pitter, Kenneth; Bird, Gregory H; Katz, Samuel G; Tu, Ho-Chou; Kim, Hyungjin; Cheng, Emily H-Y; Tjandra, Nico; Walensky, Loren D
- 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 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.
- Publication
Nature, 2008, Vol 455, Issue 7216, p1076
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature07396