Bax Crystal Structures Reveal How BH3 Domains Activate Bax and Nucleate Its Oligomerization to Induce Apoptosis
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In stressed cells, apoptosis ensues when Bcl-2 family members Bax or Bak oligomerize and permeabilize the mitochondrial outer membrane. Certain BH3-only relatives can directly activate them to mediate this pivotal, poorly understood step. To clarify the conformational changes that induce Bax oligomerization, we determined crystal structures of BaxΔC21 treated with detergents and BH3 peptides. The peptides bound the Bax canonical surface groove but, unlike their complexes with prosurvival relatives, dissociated Bax into two domains. The structures define the sequence signature of activator BH3 domains and reveal how they can activate Bax via its groove by favoring release of its BH3 domain. Furthermore, Bax helices α2-α5 alone adopted a symmetric homodimer structure, supporting the proposal that two Bax molecules insert their BH3 domain into each other's surface groove to nucleate oligomerization. A planar lipophilic surface on this homodimer may engage the membrane. Our results thus define critical Bax transitions toward apoptosis.
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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 [77]
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- Authors
- Czabotar, P. E., Westphal, D., Dewson, G., Ma, S., Hockings, C., Fairlie, W. D., Lee, E. F., Yao, S., Robin, A. Y., Smith, B. J., Huang, D. C. S., Kluck, R. M., Adams, J. M., & Colman, P. M.
- Affiliations
- The University of Melbourne (AU)
- La Trobe University (AU)
- Corresponding author
- Czabotar, Peter E.
- Colman, Peter M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 152
- Issue
- 3
- Pages
- 519-531
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2142713529
- Cited by
- 573
- References
- 70
- Citations by year
- 2026: 29 · 2025: 27 · 2024: 27 · 2023: 37 · 2022: 34 · 2021: 48 · 2020: 42 · 2019: 38 · 2018: 50 · 2017: 53 · 2016: 55 · 2015: 54 · 2014: 44 · 2013: 35
- FWCI
- 28.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leukemia and Lymphoma Society
- Australian Government
- Australian Cancer Research Foundation
- Australian Synchrotron
- Deutsche Forschungsgemeinschaft
- State Government of Victoria
- National Health and Medical Research Council
- Cancer Council Victoria
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Bax, BH3 domain, apoptosis, Bax oligomerization, Bcl-2 family proteins, mitochondrial outer membrane permeabilization, homodimer, surface grooves, conformational change, detergents
- MeSH terms
- Amino Acid Sequence, Animals, Embryo, Mammalian, Liposomes, Liver, Mitochondria, Models, Molecular, Molecular Sequence Data, Protein Conformation, Sequence Alignment, Apoptosis, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Cytochromes c, bcl-2-Associated X Protein, Mice, Hydrophobic and Hydrophilic Interactions
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