BAX Activation is Initiated at a Novel Interaction Site

By E. Gavathiotis, Motoshi Suzuki, Marguerite L. Davis, K. Pitter, Gregory H Bird, Samuel G Katz, Ho-Chou Tu, Hyungjin Kim, E. Cheng, N. Tjandra and 1 more. Nature, 2008

703 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c592724cf4b9a62be0376cec03e4ce001434db2a

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In Molecular Biology

1. Douglas R. Green
2. Guido Kroemer
3. L. Galluzzi
4. Simone Fulda
5. J. Chipuk
6. F. Llambi
7. S. Tait
8. A. Letai

Citations in the corpus

• Mitochondria and cell death: outer membrane permeabilization and beyond (2010, background): “Structural analysis of BAX in complex with a chemically stapled BCL-2-interacting mediator of cell death ( BIM ; also known as BCL2L11) BH3 domain peptide termed BIM SAHB (stablized α-helices of BCL-2 domains) revealed a somewhat unexpected interaction sit”
• Bax, Bak and beyond — mitochondrial performance in apoptosis (2018, background): “Two binding sites have been reported for Bax: i) the ‘rear’ activation site (helices α1- α6) on the opposite side of the hydrophobic groove, which has been identified by NMR studies using full-length Bax and a stapled Bim-BH3 peptide [21, 22], ii) and the canonical hydrophobic groove, which has been”
• Role of Bcl-2 family proteins and caspases in the regulation of apoptosis (2011, background): “Gavathiotis and colleagues have demonstrated that stabilized alpha-helix of Bcl-2 domains (SAHBs) directly initiates Bax-mediated mitochondrial apoptosis [61].”
• GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death (2016, neutral): “Whereas GSDMD is activated by proteolytic cleavage, Bax is activated by interactions within the Bcl-2 family of proteins (Gavathiotis et al , 2008; Czabotar et al , 2013).”
• BCL-2 family proteins: changing partners in the dance towards death (2017, background): “Ku B, Liang C, Jung JU, Oh BH. Evidence that inhibition of BAX activation by BCL-2 involves its tight and preferential interaction with the BH3 domain of BAX.”
• The BCL-2 Family Reunion (2010, methodology): “The BAX$BIM SAHB complex was nevertheless unstable, precluding structural determination by conventional NMR.”
• Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies (2016, background): “The pro-apoptotic BH3-only proteins act upstream of this event binding with high affinity to anti-apoptotic Bcl-2 family members thereby allowing Bax/Bak to elicit MOMP and activation of the caspase cascade [36,37].”