Differential Targeting of Prosurvival Bcl-2 Proteins by Their BH3-Only Ligands Allows Complementary Apoptotic Function
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Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1. Strikingly, Noxa bound only Mcl-1 and A1. In accord with their complementary binding, Bad and Noxa cooperated to induce potent killing. The results suggest that apoptosis relies on selective interactions between particular subsets of these proteins and that it should be feasible to discover BH3-mimetic drugs that inactivate specific prosurvival targets.
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Upon induction of apoptosis, BAX retrotranslocation ceases as the mitochondrial pools of BAX and BAK undergo direct or indirect activation by pro-apoptotic BH3-only proteins.
“Upon induction of apoptosis, BAX retrotranslocation ceases as the mitochondrial pools of BAX and BAK undergo direct or indirect activation (see below) by pro-apoptotic BH3-only proteins [48, 56–59].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [57]
Different BH3-only proteins preferentially bind specific anti-apoptotic BCL2 family members (e.g., BID, BIM, and PUMA potently bind all anti-apoptotic BCL2 family members; BAD preferentially interacts with BCL2, BCL-XL, and BCL-W; NOXA preferentially inhibits MCL1; and HRK preferentially inhibits BCL-XL).
“Different BH3-only proteins have been suggested to preferentially bind specific anti-apoptotic BCL2 family members (e.g., BID, BIM, and PUMA potently bind all anti-apoptotic BCL2 family members; BAD preferentially interacts with BCL2, BCL-XL, and BCL-W; NOXA preferentially inhibits MCL1; and HRK preferentially inhibits BCL-XL) [57, 113, 114].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [57]
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- Authors
- Chen, L., Willis, S. N., Wei, A., Smith, B. J., Fletcher, J. I., Hinds, M. G., Colman, P. M., Day, C. L., Adams, J. M., & Huang, D. C. S.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- University of Otago (NZ)
- Corresponding author
- Huang, David C.S.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2005-02
- Volume
- 17
- Issue
- 3
- Pages
- 393-403
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2147318282
- Cited by
- 1,816
- References
- 54
- Citations by year
- 2026: 26 · 2025: 37 · 2024: 32 · 2023: 55 · 2022: 44 · 2021: 63 · 2020: 78 · 2019: 67 · 2018: 52 · 2017: 79 · 2016: 98 · 2015: 86 · 2014: 89 · 2013: 99 · 2012: 111
- FWCI
- 53.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (#CA 80188, R01CA080188)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- apoptosis, Bcl-2 family proteins, BH3-only proteins, building information modeling, PUMA, Bad, Noxa, Mcl-1, A1, Bcl-xL, Bcl-w, BH3 mimetics, protein-protein interaction
- MeSH terms
- Bcl-2-Like Protein 11, Amino Acid Sequence, Animals, Binding, Competitive, Carrier Proteins, Cell Survival, Genetic Complementation Test, Humans, Ligands, Membrane Proteins, Models, Biological, Models, Molecular, Molecular Sequence Data, Neoplasm Proteins, Peptide Fragments, Proteins, Proto-Oncogene Proteins, Recombinant Proteins, Biosensing Techniques, Apoptosis, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Proto-Oncogene Proteins c-bcl-2, Apoptosis Regulatory Proteins, bcl-X Protein, Mice, Myeloid Cell Leukemia Sequence 1 Protein, In Vitro Techniques
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