A Stapled BID BH3 Helix Directly Binds and Activates BAX
Open accessAbstract
BAX is a multidomain proapoptotic BCL-2 family protein that resides in the cytosol until activated by an incompletely understood trigger mechanism, which facilitates BAX translocation to mitochondria and downstream death events. Whether BAX is activated by direct contact with select BH3-only members of the BCL-2 family is highly debated. Here we detect and quantify a direct binding interaction between BAX and a hydrocarbon-stapled BID BH3 domain, which triggers the functional activation of BAX at nanomolar doses in vitro. Chemical reinforcement of BID BH3 alpha helicity was required to reveal the direct BID BH3-BAX association. We confirm the specificity of this BH3 interaction by characterizing a stapled BAD BH3 peptide that interacts with antiapoptotic BCL-X(L) but does not bind or activate BAX. We further demonstrate that membrane targeting of stapled BID BH3 optimizes its ability to activate BAX, supporting a model in which BID directly engages BAX to trigger mitochondrial apoptosis.
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“However, other intact modes of BAX/BAK activation, including the recently identified p53-based BAX activation pathway ( Chipuk et al., 2004, 2005 ), heat-induced activation (Pagliari et al., 2005), and derepression of direct antiapoptotic inhibition of BAX/BAK by other BH3-only proteins (Chen et al., 2005; Kuwana et a…”
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- Authors
- Walensky, L. D., Pitter, K., Morash, J., Oh, K. J., Barbuto, S., Fisher, J., Smith, E., Verdine, G. L., & Korsmeyer, S. J.
- Affiliations
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Corresponding author
- Walensky, Loren D.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 24
- Issue
- 2
- Pages
- 199-210
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2000011855
- Cited by
- 383
- References
- 52
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 10 · 2020: 18 · 2019: 17 · 2018: 11 · 2017: 18 · 2016: 18 · 2015: 27 · 2014: 20 · 2013: 32 · 2012: 25
- FWCI
- 11.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (K08HL074049)
- National Cancer Institute (P01CA092625, R37CA050239)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- Bax, Bid, BH3-only proteins, Bcl-2 family proteins, hydrocarbon-stapled peptides, protein-protein interaction, Bax activation, mitochondrial apoptosis, Bcl-xL, membrane targeting
- MeSH terms
- Amino Acid Sequence, Cell Membrane, Dose-Response Relationship, Drug, Humans, Liposomes, Molecular Sequence Data, Peptides, Protein Binding, Apoptosis, Sequence Homology, Amino Acid, Jurkat Cells, Protein Transport, bcl-X Protein, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein
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