9HPS

Human BclxLdeltaLT-VDAC1-N fusion protein complex structure

Summary for 9HPS

• Entry DOI: 10.2210/pdb9hps/pdb
• Descriptor: BclxLdeltaLT, SULFATE ION (3 entities in total)
• Functional Keywords: b-cell lymphoma-extra large, bcl-xl, anti-apoptotic, vdac1, voltage-dependent anion channel protein, complex, fusion, apoptosis
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 47007.66

Authors

Janowski, R.,Niessing, D. (deposition date: 2024-12-16, release date: 2025-09-17, Last modification date: 2025-11-05)

Primary citation

Daniilidis, M.,Gunsel, U.,Broutzakis, G.,Leitl, K.D.,Janowski, R.,Fredriksson, K.,Niessing, D.,Gatsogiannis, C.,Hagn, F.
Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
Nat Commun, 16:9481-9481, 2025

PubMed Abstract: 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.

PubMed: 41145501
DOI: 10.1038/s41467-025-65363-1

Experimental method

X-RAY DIFFRACTION (1.95 Å)