Assembly of the Bak Apoptotic Pore
Open accessAbstract
Bak and Bax are the essential effectors of the intrinsic pathway of apoptosis. Following an apoptotic stimulus, both undergo significant changes in conformation that facilitates their self-association to form pores in the mitochondrial outer membrane. However, the molecular structures of Bak and Bax oligomeric pores remain elusive. To characterize how Bak forms pores during apoptosis, we investigated its oligomerization under native conditions using blue native PAGE. We report that, in a healthy cell, inactive Bak is either monomeric or in a large complex involving VDAC2. Following an apoptotic stimulus, activated Bak forms BH3:groove homodimers that represent the basic stable oligomeric unit. These dimers multimerize to higher-order oligomers via a labile interface independent of both the BH3 domain and groove. Linkage of the α6:α6 interface is sufficient to stabilize higher-order Bak oligomers on native PAGE, suggesting an important role in the Bak oligomeric pore. Mutagenesis of the α6 helix disrupted apoptotic function because a chimera of Bak with the α6 derived from Bcl-2 could be activated by truncated Bid (tBid) and could form BH3:groove homodimers but could not form high molecular weight oligomers or mediate cell death. An α6 peptide could block Bak function but did so upstream of dimerization, potentially implicating α6 as a site for activation by BH3-only proteins. Our examination of native Bak oligomers indicates that the Bak apoptotic pore forms by the multimerization of BH3:groove homodimers and reveals that Bak α6 is not only important for Bak oligomerization and function but may also be involved in how Bak is activated by BH3-only proteins. Background: Bak and Bax form pores that damage mitochondria during apoptosis. Results: Under native conditions, the basic oligomeric unit of Bak is a BH3:groove homodimer that requires the α6 helix to multimerize and mediate cell death. Conclusion: Bak forms pores via two independent requisite interfaces. Significance: Characterizing Bak pores will facilitate inhibition of damaging apoptosis, e.g. in ischemic stroke.
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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 [81]
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- Authors
- Ma, S., Hockings, C., Anwari, K., Kratina, T., Fennell, S., Lazarou, M., Ryan, M. T., Kluck, R. M., & Dewson, G.
- Affiliations
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- National Institutes of Health (US)
- La Trobe University (AU)
- Corresponding author
- Dewson, Grant
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 288
- Issue
- 36
- Pages
- 26027-26038
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3764807
- OpenAlex
- W2136058929
- Cited by
- 71
- References
- 54
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 5 · 2017: 13 · 2016: 10 · 2015: 11 · 2014: 12 · 2013: 4
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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 › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- Bak, Bax, mitochondrial apoptosis, VDAC2, BH3-only proteins, truncated Bid, Bcl-2, mitochondrial outer membrane permeabilization, blue native PAGE
- MeSH terms
- Animals, Cells, Cultured, Apoptosis, Protein Structure, Secondary, Protein Structure, Tertiary, Mice, Knockout, Protein Structure, Quaternary, Voltage-Dependent Anion Channel 2, bcl-2 Homologous Antagonist-Killer Protein, BH3 Interacting Domain Death Agonist Protein, Mice, Protein Multimerization
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