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Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel
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Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel
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Journal Article
Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel
2025
Overview
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.
TGF-β is a latent complex (L-TGF-β). Latency is conferred by a homodimeric prodomain with a previously undefined domain architecture. Here we define the architecture of the prodomain as domain-swapped providing structural insights into the mechanism of activation of L-TGF-β.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 101/58
/ 101/6
/ 82/16
/ 82/29
/ 82/83
/ 96/2
/ Animals
/ Anions
/ bcl-2 Homologous Antagonist-Killer Protein - metabolism
/ Binding
/ Grooves
/ Humanities and Social Sciences
/ Humans
/ Latency
/ Lipids
/ Mitochondrial Membranes - metabolism
/ NMR
/ Proteins
/ Proto-Oncogene Proteins c-bcl-2 - metabolism
/ Science
/ Transforming growth factor-b
/ Voltage
/ Voltage-Dependent Anion Channel 1 - chemistry
/ Voltage-Dependent Anion Channel 1 - genetics
/ Voltage-Dependent Anion Channel 1 - metabolism
/ Voltage-Dependent Anion Channel 1 - ultrastructure
