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Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
Nat. Commun. 16:9481 (2025)
The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to apoptosis induced by various stimuli. However, the mechanistic and structural basis of apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Bcl-2 Family Proteins; Phospholipid-bilayer Nanodiscs; Cytochrome-c; Membrane-proteins; Vdac; Release; Conformation; Bcl-x(l); Binding; Bax
ISSN (print) / ISBN
2041-1723
e-ISSN
2041-1723
Journal
Nature Communications
Quellenangaben
Volume: 16,
Issue: 1,
Article Number: 9481
Publisher
Nature Publishing Group
Publishing Place
London
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
Grants
Helmholtz Association
Deutsche Forschungsgemeinschaft (German Research Foundation)
Deutsche Forschungsgemeinschaft (German Research Foundation)