Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis
Open accessAbstract
Significance: Voltage-dependent anion channel 2 (VDAC2), like other VDAC proteins, transports solutes across the outer mitochondrial membrane, but it is the only isoform that supports mitochondrial import of cell death-executing proteins, Bak/Bax. To address the underlying mechanism, we created chimeras of VDAC2 and VDAC1 and tested their competency to rescue Bak insertion and apoptosis in VDAC2-deficient cells. Our gain-of-function studies revealed that the middle domain (123–179 aa) is required for rescue. Loss-of-function studies identified two critical residues (T168, D170). Finally, applying these clues to recently solved structures we identified a discrete site on the cytoplasmic side of VDAC2's pore that likely supports Bak insertion and apoptosis.
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BAK constitutively resides at the OMM, where it inserts within the lipid bilayer via its hydrophobic C-terminal α9 helix upon interaction with VDAC2.
“In contrast, BAK constitutively resides at the OMM, where it inserts within the lipid bilayer via its hydrophobic C-terminal α9 helix upon interaction with voltage dependent anion channel 2 (VDAC2) [51–54].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [53]
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- Authors
- Naghdi, S., Várnai, P., & Hajnóczky, G.
- Affiliations
- Thomas Jefferson University (US)
- Semmelweis University (HU)
- Corresponding author
- Hajnóczky, György
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-09-28
- Volume
- 112
- Issue
- 41
- Pages
- E5590-9
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4611654
- OpenAlex
- W2165792071
- Cited by
- 96
- References
- 51
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 10 · 2023: 7 · 2022: 3 · 2021: 13 · 2020: 5 · 2019: 9 · 2018: 9 · 2017: 7 · 2016: 11 · 2015: 1
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Medicine Forum (submittedVersion)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Funders
- HHS | NIH | National Institute of General Medical Sciences (GM59419)
- Országos Tudományos Kutatási Alapprogramok (K105006)
- 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
- VDAC2, voltage-dependent anion channel, truncated Bid, mitochondrial outer membrane, VDAC1, chimeric constructs
- MeSH terms
- Animals, Cells, Cultured, Fibroblasts, Humans, Mitochondria, Apoptosis, Protein Structure, Tertiary, Mice, Knockout, Amino Acid Motifs, Protein Transport, Voltage-Dependent Anion Channel 2, bcl-2 Homologous Antagonist-Killer Protein, BH3 Interacting Domain Death Agonist Protein, Mice
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