Bax dimerizes via a symmetric BH3:groove interface during apoptosis
Open accessAbstract
During apoptotic cell death, Bax and Bak change conformation and homo-oligomerize to permeabilize mitochondria. We recently reported that Bak homodimerizes via an interaction between the BH3 domain and hydrophobic surface groove, that this BH3:groove interaction is symmetric, and that symmetric dimers can be linked via the α6-helices to form the high order oligomers thought responsible for pore formation. We now show that Bax also dimerizes via a BH3:groove interaction after apoptotic signaling in cells and in mitochondrial fractions. BH3:groove dimers of Bax were symmetric as dimers but not higher order oligomers could be linked by cysteine residues placed in both the BH3 and groove. The BH3:groove interaction was evident in the majority of mitochondrial Bax after apoptotic signaling, and correlated strongly with cytochrome c release, supporting its central role in Bax function. A second interface between the Bax α6-helices was implicated by cysteine linkage studies, and could link dimers to higher order oligomers. We also found that a population of Bax:Bak heterodimers generated during apoptosis formed via a BH3:groove interaction, further demonstrating that Bax and Bak oligomerize via similar mechanisms. These findings highlight the importance of BH3:groove interactions in apoptosis regulation by the Bcl-2 protein family.
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Activated BAX and BAK form homodimers (also heterodimers in specific settings), resulting in the release of BH3-only proteins and further dimer-by-dimer oligomerization.
“The current view is that activated BAX and BAK form homodimers (also heterodimers in specific settings), resulting in the release of BH3-only proteins and further dimer-by-dimer oligomerization [76–83].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [82]
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Self-citation
- Authors
- Dewson, G., Ma, S., Frederick, P., Hockings, C., Tan, I., Kratina, T., & Kluck, R. M.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- The University of Melbourne (AU)
- Corresponding author
- Kluck, R M
- Venue
- Cell Death & Differentiation
- Published
- 2011-10-21
- Volume
- 19
- Issue
- 4
- Pages
- 661-670
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC3307980
- OpenAlex
- W2002934131
- Cited by
- 189
- References
- 40
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 14 · 2022: 14 · 2021: 10 · 2020: 9 · 2019: 9 · 2018: 14 · 2017: 18 · 2016: 15 · 2015: 16 · 2014: 20 · 2013: 20 · 2012: 8
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian Government
- Stanford Institute for Research in the Social Sciences
- Medical Research Council
- National Health and Medical Research Council (637335)
- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Bax, Bak, mitochondrial membrane permeabilization, apoptosis, Bcl-2 family proteins, cytochrome c release, Bax oligomerization
- MeSH terms
- Animals, Cell Line, Transformed, Humans, Mitochondria, Signal Transduction, Apoptosis, Protein Structure, Secondary, Protein Structure, Tertiary, Mice, Knockout, Cytochromes c, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mice, Protein Multimerization, Hydrophobic and Hydrophilic Interactions
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