Structural Model of Active Bax at the Membrane
Open accessAbstract
Bax plays a central role in the mitochondrial pathway of apoptosis. Upon activation, cytosolic Bax monomers oligomerize on the surface of mitochondria and change conformation concertedly to punch holes into the outer membrane. The subsequent release of cytochrome c initiates cell death. However, the structure of membrane-inserted Bax and its mechanism of action remain largely unknown. Here, we propose a 3D model of active Bax at the membrane based on double electron-electron resonance (DEER) spectroscopy in liposomes and isolated mitochondria. We show that active Bax is organized at the membrane as assemblies of dimers. In addition to a stable dimerization domain, each monomer contains a more flexible piercing domain involved in interdimer interactions and pore formation. The most important structural change during Bax activation is the opening of the hairpin formed by helices 5 and 6, which adopts a clamp-like conformation central to the mechanism of mitochondrial permeabilization.
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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 [78]
Oligomerization of BAX and BAK ultimately leads to the assembly of a toroidal lipidic pore that alters mitochondrial permeability and causes profound rearrangements of the mitochondrial ultrastructure.
“Oligomerization ultimately leads to the assembly of a toroidal lipidic pore that alters mitochondrial permeability and causes profound rearrangements of the mitochondrial ultrastructure [78, 84–86].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [78]
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- Authors
- Bleicken, S., Jeschke, G., Stegmueller, C., Salvador-Gallego, R., García-Sáez, A. J., & Bordignon, E.
- Affiliations
- German Cancer Research Center (DE)
- ETH Zurich (CH)
- Corresponding author
- Bordignon, Enrica
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 56
- Issue
- 4
- Pages
- 496-505
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4869853
- OpenAlex
- W1979471022
- Cited by
- 227
- References
- 41
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 13 · 2023: 20 · 2022: 18 · 2021: 18 · 2020: 18 · 2019: 15 · 2018: 15 · 2017: 34 · 2016: 27 · 2015: 22 · 2014: 1
- FWCI
- 11.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, other-oa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (200020, 144441)
- 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 › Protein Structure and Dynamics
- Keywords
- Bax, mitochondrial apoptosis, mitochondrial outer membrane permeabilization, Bax oligomerization, cytochrome c release, mitochondrial membrane structure, DEER spectroscopy, liposomes
- MeSH terms
- Animals, Cell Membrane, Models, Molecular, Protein Structure, Secondary, Protein Structure, Tertiary, Protein Structure, Quaternary, bcl-2-Associated X Protein, Mice, Protein Multimerization
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