Stepwise Activation of BAX and BAK by tBID, BIM, and PUMA Initiates Mitochondrial Apoptosis
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While activation of BAX/BAK by BH3-only molecules (BH3s) is essential for mitochondrial apoptosis, the underlying mechanisms remain unsettled. Here we demonstrate that BAX undergoes stepwise structural reorganization leading to mitochondrial targeting and homo-oligomerization. The alpha1 helix of BAX keeps the alpha9 helix engaged in the dimerization pocket, rendering BAX as a monomer in cytosol. The activator BH3s, tBID/BIM/PUMA, attack and expose the alpha1 helix of BAX, resulting in secondary disengagement of the alpha9 helix and thereby mitochondrial insertion. Activator BH3s remain associated with the N-terminally exposed BAX through the BH1 domain to drive homo-oligomerization. BAK, an integral mitochondrial membrane protein, has bypassed the first activation step, explaining why its killing kinetics are faster than those of BAX. Furthermore, death signals initiated at ER induce BIM and PUMA to activate mitochondrial apoptosis. Accordingly, deficiency of Bim/Puma impedes ER stress-induced BAX/BAK activation and apoptosis. Our study provides mechanistic insights regarding the spatiotemporal execution of BAX/BAK-governed cell death.
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BID, BIM, PUMA, and NOXA share the ability to physically interact with the mitochondrial pool of BAX and/or BAK to promote conformational changes culminating with dissociation of the core and latch domains of BCL2 effectors.
“BID, BIM, PUMA, and NOXA share the ability to physically (but transiently) interact with the mitochondrial pool of BAX and/or BAK (hence being known as “activators”) to promote a series of conformational changes [59, 64, 67, 71–74] culminating with the dissociation of the core and latch domains of BCL2 effectors [75–77].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [73]
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Tan, C. T., Zhou, Q.-L., Su, Y.-C., Fu, N. Y., Chang, H.-C., Tao, R. N., Sukumaran, S. K., Baksh, S., Tan, Y.-J., Sabapathy, K., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.05.068 · Cited by 35 · see citing works
Proapoptotic role of nuclear clusterin in brain
Kim, N., & Choi, W. S. (2011) · Anatomy & Cell Biology · doi:10.5115/acb.2011.44.3.169 · Cited by 29 · see citing works
- Authors
- Kim, H., Tu, H.-C., Ren, D., Takeuchi, O., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., & Cheng, E. H.-Y.
- Affiliations
- Washington University in St. Louis (US)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Cheng, Emily H.-Y.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 36
- Issue
- 3
- Pages
- 487-499
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3163439
- OpenAlex
- W1995773170
- Cited by
- 600
- References
- 52
- Citations by year
- 2026: 17 · 2025: 15 · 2024: 25 · 2023: 39 · 2022: 22 · 2021: 29 · 2020: 28 · 2019: 35 · 2018: 36 · 2017: 29 · 2016: 33 · 2015: 50 · 2014: 39 · 2013: 60 · 2012: 50
- FWCI
- 19.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (K01CA098320, K01CA98320, P 30CA 21765, R01CA125562, P30CA021765)
- National Institute of General Medical Sciences (R01GM083159)
- 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 apoptosis, BH3-only proteins, tBid, building information modeling, PUMA, Bax oligomerization, mitochondrial targeting, endoplasmic reticulum stress, ER stress-induced apoptosis
- MeSH terms
- Bcl-2-Like Protein 11, Animals, Cells, Cultured, Etoposide, Fibroblasts, Membrane Proteins, Microscopy, Fluorescence, Mitochondria, Models, Biological, Mutation, Protein Binding, Proto-Oncogene Proteins, Tunicamycin, Immunoblotting, Apoptosis, Mice, Knockout, Thapsigargin, Staurosporine, Tumor Suppressor Proteins, Immunoprecipitation, Green Fluorescent Proteins, bcl-2 Homologous Antagonist-Killer Protein, Apoptosis Regulatory Proteins, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mice, Protein Multimerization
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