Mediation of the antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1 protein
Open accessAbstract
The mitochondrial protein, the voltage-dependent anion channel (VDAC), is implicated in the control of apoptosis, including via its interaction with the pro- and antiapoptotic proteins. We previously demonstrated the direct interaction of Bcl2 with VDAC, leading to reduced channel conductance. VDAC1-based peptides interacted with Bcl2 to prevent its antiapoptotic activity. Here, using a variety of approaches, we show the interaction of the antiapoptotic protein, Bcl-xL, with VDAC1 and reveal that this interaction mediates Bcl-xL protection against apoptosis. C-terminally truncated Bcl-xL(Δ21) interacts with purified VDAC1, as revealed by microscale thermophoresis and as reflected in the reduced channel conductivity of bilayer-reconstituted VDAC1. Overexpression of Bcl-xL prevented staurosporine-induced apoptosis in cells expressing native VDAC1 but not certain VDAC1 mutants. Having identified mutations in VDAC1 that interfere with the Bcl-xL interaction, certain peptides representing VDAC1 sequences, including the N-terminal domain, were designed and generated as recombinant and synthetic peptides. The VDAC1 N-terminal region and two internal sequences were found to bind specifically, and in a concentration- and time-dependent manner, to immobilized Bcl-xL(Δ21), as revealed by surface plasmon resonance. Moreover, expression of the recombinant peptides in cells overexpressing Bcl-xL prevented protection offered by the protein against staurosporine-induced apoptosis. These results point to Bcl-xL acting as antiapoptotic protein, promoting tumor cell survival via binding to VDAC1. These findings suggest that interfering with Bcl-xL binding to the mitochondria by VDAC1-based peptides may serve to induce apoptosis in cancer cells and to potentiate the efficacy of conventional chemotherapeutic agents. Background: Bcl-xL is overexpressed in cancer, contributing to resistance to chemotherapy. Results: Bcl-xL directly interacts with VDAC1 to mediate its antiapoptotic activity, activity that can be prevented by VDAC1-based peptides. Conclusion: Bcl-xL regulates apoptosis through direct interaction with VDAC1. Significance: Interfering with the interaction of Bcl-xL with VDAC1 can lead to apoptosis and potentiate the efficacy of conventional chemotherapeutics.
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The N-terminal domain of VDAC1 interacts with several Bcl-2 family proteins that regulate apoptosis and is involved in gating the channel.
“The N-terminal domain of VDAC1 interacts with several Bcl-2 family proteins that regulate apoptosis and is involved in gating the channel [96,97,98,99,100,101].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [101]
The Results section on N-terminally truncated VDAC1 reports that its N-terminal region interacts with Bcl-xL and that removing it abolishes voltage-dependent conductance, supporting a role in channel gating. The paper also reports interactions between VDAC1 and other Bcl-2 family proteins, but the cited passages do not establish that the N-terminal domain interacts with several of them. No page number is available in our copy. (LLM, conf=0.86)
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- Authors
- Arbel, N., Ben-Hail, D., & Shoshan-Barmatz, V.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- ORCID
- Ben-Hail, Danya
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 287
- Issue
- 27
- Pages
- 23152-23161
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3391160
- OpenAlex
- W1990891202
- Cited by
- 179
- References
- 61
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 13 · 2020: 11 · 2019: 7 · 2018: 17 · 2017: 20 · 2016: 15 · 2015: 14 · 2014: 23 · 2013: 14 · 2012: 5
- FWCI
- 7.19
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- Bcl-xL, VDAC1, voltage-dependent anion channel, apoptosis, anti-apoptotic effects, protein-protein interaction, staurosporine-induced apoptosis, cancer chemotherapy resistance, tumor cell survival
- MeSH terms
- Humans, Mitochondria, Neoplasms, Peptide Fragments, Apoptosis, Protein Structure, Tertiary, Drug Resistance, Neoplasm, Surface Plasmon Resonance, RNA, Small Interfering, Voltage-Dependent Anion Channel 1, bcl-X Protein, Protein Interaction Domains and Motifs, HEK293 Cells
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