BAX activation is initiated at a novel interaction site
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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.
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BID, BIM, PUMA, and NOXA share the ability to physically interact with the mitochondrial pool of BAX and/or BAK to promote conformational changes culminating with dissociation of the core and latch domains of BCL2 effectors.
“BID, BIM, PUMA, and NOXA share the ability to physically (but transiently) interact with the mitochondrial pool of BAX and/or BAK (hence being known as “activators”) to promote a series of conformational changes [59, 64, 67, 71–74] culminating with the dissociation of the core and latch domains of BCL2 effectors [75–77].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [71]
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- Authors
- Gavathiotis, E., Suzuki, M., Davis, M. L., Pitter, K., Bird, G. H., Katz, S. G., Tu, H.-C., Kim, H., Cheng, E. H.-Y., Tjandra, N., & Walensky, L. D.
- Affiliations
- Dana-Farber Cancer Institute (US)
- National Institutes of Health (US)
- Boston Children's Hospital (US)
- Washington University in St. Louis (US)
- Corresponding author
- Tjandra, Nico
- Walensky, Loren D.
- ORCID
- Venue
- Nature
- Published
- 2008-10
- Volume
- 455
- Issue
- 7216
- Pages
- 1076-1081
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2597110
- OpenAlex
- W2012076962
- Cited by
- 700
- References
- 50
- Citations by year
- 2026: 20 · 2025: 23 · 2024: 15 · 2023: 30 · 2022: 31 · 2021: 31 · 2020: 24 · 2019: 37 · 2018: 24 · 2017: 43 · 2016: 45 · 2015: 50 · 2014: 48 · 2013: 57 · 2012: 52
- FWCI
- 23.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R00HL095929, K99HL095929)
- National Cancer Institute (R01CA050239, P01CA092625, 5P01CA92625, R01CA125562, 5R01CA50239)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- Bax, building information modeling, Bax activation, Bcl-2 family proteins, mitochondrial apoptosis, protein-protein interaction sites, Bcl-2, anti-apoptotic proteins
- MeSH terms
- Bcl-2-Like Protein 11, Amino Acid Sequence, Animals, Cell Line, Gene Expression Regulation, Humans, Membrane Proteins, Mutation, Protein Binding, Proto-Oncogene Proteins, Mutagenesis, Site-Directed, Sequence Alignment, Apoptosis, Nuclear Magnetic Resonance, Biomolecular, Apoptosis Regulatory Proteins, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mice
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