BH3-Triggered Structural Reorganization Drives the Activation of Proapoptotic BAX
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BAX is a proapoptotic BCL-2 family member that lies dormant in the cytosol until converted into a killer protein in response to cellular stress. Having recently identified the elusive trigger site for direct BAX activation, we now delineate by NMR and biochemical methods the essential allosteric conformational changes that transform ligand-triggered BAX into a fully activated monomer capable of propagating its own activation. Upon BAX engagement by a triggering BH3 helix, the unstructured loop between α helices 1 and 2 is displaced, the carboxy-terminal helix 9 is mobilized for membrane translocation, and the exposed BAX BH3 domain propagates the death signal through an autoactivating interaction with the trigger site of inactive BAX monomers. Our structure-activity analysis of this seminal apoptotic process reveals pharmacologic opportunities to modulate cell death by interceding at key steps of the BAX activation pathway.
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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 [72]
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Self-citation
- Authors
- Gavathiotis, E., Reyna, D. E., Davis, M. L., Bird, G. H., & Walensky, L. D.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Walensky, Loren D.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 40
- Issue
- 3
- Pages
- 481-492
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3050027
- OpenAlex
- W2081490942
- Cited by
- 310
- References
- 66
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 13 · 2023: 19 · 2022: 16 · 2021: 18 · 2020: 12 · 2019: 17 · 2018: 17 · 2017: 20 · 2016: 32 · 2015: 25 · 2014: 20 · 2013: 37 · 2012: 19
- FWCI
- 9.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- American Society of Hematology
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R00HL095929, K99HL095929)
- National Cancer Institute (R01CA050239)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- Bax, Bcl-2 family proteins, apoptosis, BH3 domain, allosteric conformational change, Bax activation, self-activation, membrane translocation, BCL-2 inhibitor, structure-activity analysis
- MeSH terms
- Amino Acid Sequence, Binding Sites, Humans, Ligands, Mitochondria, Models, Biological, Models, Molecular, Molecular Sequence Data, Protein Binding, Structure-Activity Relationship, Apoptosis, Protein Structure, Secondary, Protein Transport, bcl-2-Associated X Protein, Hydrophobic and Hydrophilic Interactions
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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