BAX activation is initiated at a novel interaction site

Article

关键词: MITOCHONDRIAL-MEMBRANE PERMEABILIZATION;    STABILIZED ALPHA-HELICES;    BCL-X-L;    BH3-ONLY PROTEINS;    CELL-DEATH;    INTRACELLULAR-LOCALIZATION;    PROAPOPTOTIC ACTIVITY;    BH3 DOMAINS;    APOPTOSIS;    FAMILY;   

DOI  :  10.1038/nature07396

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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