Structure-based analysis of VDAC1: N-terminus location, translocation, channel gating and association with anti-apoptotic proteins
Abstract
Structural studies place the VDAC1 (voltage-dependent anion channel 1) N-terminal region within the channel pore. Biochemical and functional studies, however, reveal that the N-terminal domain is cytoplasmically exposed. In the present study, the location and translocation of the VDAC1 N-terminal domain, and its role in voltage-gating and as a target for anti-apoptotic proteins, were addressed. Site-directed mutagenesis and cysteine residue substitution, together with a thiol-specific cross-linker, served to show that the VDAC1 N-terminal region exists in a dynamic equilibrium, located within the pore or exposed outside the β-barrel. Using a single cysteine-residue-bearing VDAC1, we demonstrate that the N-terminal region lies inside the pore. However, the same region can be exposed outside the pore, where it dimerizes with the N-terminal domain of a second VDAC1 molecule. When the N-terminal region α-helix structure was perturbed, intra-molecular cross-linking was abolished and dimerization was enhanced. This mutant also displays reduced voltage-gating and reduced binding to hexokinase, but not to the anti-apoptotic proteins Bcl-2 and Bcl-xL. Replacing glycine residues in the N-terminal domain GRS (glycine-rich sequence) yielded less intra-molecular cross-linked product but more dimerization, suggesting that GRS provides the flexibility needed for N-terminal translocation from the internal pore to the channel face. N-terminal mobility may thus contribute to channel gating and interaction with anti-apoptotic proteins.
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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 [97]
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Self-citation
- Authors
- Geula, S., Ben-Hail, D., & Shoshan-Barmatz, V.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2012-05-29
- Volume
- 444
- Issue
- 3
- Pages
- 475-485
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2315430776
- Cited by
- 105
- References
- 53
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 6 · 2021: 7 · 2020: 8 · 2019: 6 · 2018: 10 · 2017: 7 · 2016: 10 · 2015: 9 · 2014: 8 · 2013: 7 · 2012: 3
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- 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
- Keywords
- VDAC1, N-terminal domain, channel gating, anti-apoptotic proteins, Bcl-2, Bcl-xL, hexokinase, protein dimerization, mitochondrial permeability transition pore, structure-function relationship
- MeSH terms
- Amino Acid Sequence, Animals, Cysteine, Humans, Molecular Sequence Data, Ion Channel Gating, Apoptosis, Protein Transport, Voltage-Dependent Anion Channel 1, Apoptosis Regulatory Proteins, Rats, HEK293 Cells
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