Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 321 (5893): 1206-1210

Copyright © 2008 by the American Association for the Advancement of Science

Solution Structure of the Integral Human Membrane Protein VDAC-1 in Detergent Micelles

Sebastian Hiller,1 Robert G. Garces,1* Thomas J. Malia,1*{dagger} Vladislav Y. Orekhov,1,3 Marco Colombini,2 Gerhard Wagner1{ddagger}

Abstract: The voltage-dependent anion channel (VDAC) mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane. VDAC also interacts with antiapoptotic proteins from the Bcl-2 family, and this interaction inhibits release of apoptogenic proteins from the mitochondrion. We present the nuclear magnetic resonance (NMR) solution structure of recombinant human VDAC-1 reconstituted in detergent micelles. It forms a 19-stranded β barrel with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion. In the presence of cholesterol, recombinant VDAC-1 can form voltage-gated channels in phospholipid bilayers similar to those of the native protein. NMR measurements revealed the binding sites of VDAC-1 for the Bcl-2 protein Bcl-xL, for reduced β–nicotinamide adenine dinucleotide, and for cholesterol. Bcl-xL interacts with the VDAC barrel laterally at strands 17 and 18.

1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Biology, University of Maryland, College Park, MD 20742, USA.
3 Swedish NMR Centre, University of Gothenburg, Box 465, 40530 Gothenburg, Sweden.

* These authors contributed equally to this work.

{dagger} Present address: Centocor, Incorporated, Radnor, PA 19087, USA.

{ddagger} To whom correspondence should be addressed. E-mail: gerhard_wagner{at}

Mitochondrial Channels: Ion Fluxes and More.
I. Szabo and M. Zoratti (2014)
Physiol Rev 94, 519-608
   Abstract »    Full Text »    PDF »
Modulation of Human Mitochondrial Voltage-dependent Anion Channel 2 (hVDAC-2) Structural Stability by Cysteine-assisted Barrel-lipid Interactions.
S. R. Maurya and R. Mahalakshmi (2013)
J. Biol. Chem. 288, 25584-25592
   Abstract »    Full Text »    PDF »
Tissue plasminogen activator regulates Purkinje neuron development and survival.
J. Li, L. Yu, X. Gu, Y. Ma, R. Pasqualini, W. Arap, E. Y. Snyder, and R. L. Sidman (2013)
PNAS 110, E2410-E2419
   Abstract »    Full Text »    PDF »
Voltage-dependent Anion Channels Modulate Mitochondrial Metabolism in Cancer Cells: REGULATION BY FREE TUBULIN AND ERASTIN.
E. N. Maldonado, K. L. Sheldon, D. N. DeHart, J. Patnaik, Y. Manevich, D. M. Townsend, S. M. Bezrukov, T. K. Rostovtseva, and J. J. Lemasters (2013)
J. Biol. Chem. 288, 11920-11929
   Abstract »    Full Text »    PDF »
Ultrastructural Pathology and Interorganelle Cross Talk in Hepatotoxicity.
N. F. Cheville (2013)
Toxicol Pathol 41, 210-226
   Abstract »    Full Text »    PDF »
Role of Detergents in Conformational Exchange of a G Protein-coupled Receptor.
K. Y. Chung, T. H. Kim, A. Manglik, R. Alvares, B. K. Kobilka, and R. S. Prosser (2012)
J. Biol. Chem. 287, 36305-36311
   Abstract »    Full Text »    PDF »
Warburg Revisited: Regulation of Mitochondrial Metabolism by Voltage-Dependent Anion Channels in Cancer Cells.
E. N. Maldonado and J. J. Lemasters (2012)
J. Pharmacol. Exp. Ther. 342, 637-641
   Abstract »    Full Text »    PDF »
Determination of solution structures of proteins up to 40 kDa using CS-Rosetta with sparse NMR data from deuterated samples.
O. F. Lange, P. Rossi, N. G. Sgourakis, Y. Song, H.-W. Lee, J. M. Aramini, A. Ertekin, R. Xiao, T. B. Acton, G. T. Montelione, et al. (2012)
PNAS 109, 10873-10878
   Abstract »    Full Text »    PDF »
Mediation of the Antiapoptotic Activity of Bcl-xL Protein upon Interaction with VDAC1 Protein.
N. Arbel, D. Ben-Hail, and V. Shoshan-Barmatz (2012)
J. Biol. Chem. 287, 23152-23161
   Abstract »    Full Text »    PDF »
Affixing N-terminal {alpha}-Helix to the Wall of the Voltage-dependent Anion Channel Does Not Prevent Its Voltage Gating.
O. Teijido, R. Ujwal, C.-O. Hillerdal, L. Kullman, T. K. Rostovtseva, and J. Abramson (2012)
J. Biol. Chem. 287, 11437-11445
   Abstract »    Full Text »    PDF »
Structure-based Analysis of VDAC1 Protein: DEFINING OLIGOMER CONTACT SITES.
S. Geula, H. Naveed, J. Liang, and V. Shoshan-Barmatz (2012)
J. Biol. Chem. 287, 2179-2190
   Abstract »    Full Text »    PDF »
Phylogenetic Analysis of Mitochondrial Outer Membrane {beta}-Barrel Channels.
M. Wojtkowska, M. Jakalski, J. R. Pienkowska, O. Stobienia, A. Karachitos, T. M. Przytycka, J. Weiner 3rd, H. Kmita, and W. Makalowski (2012)
Genome Biol Evol 4, 110-125
   Abstract »    Full Text »    PDF »
Early steps in steroidogenesis: intracellular cholesterol trafficking: Thematic Review Series: Genetics of Human Lipid Diseases.
W. L. Miller and H. S. Bose (2011)
J. Lipid Res. 52, 2111-2135
   Abstract »    Full Text »    PDF »
Structural Basis for the Interaction of Lipopolysaccharide with Outer Membrane Protein H (OprH) from Pseudomonas aeruginosa.
T. C. Edrington, E. Kintz, J. B. Goldberg, and L. K. Tamm (2011)
J. Biol. Chem. 286, 39211-39223
   Abstract »    Full Text »    PDF »
Benzoquinone ansamycin 17AAG binds to mitochondrial voltage-dependent anion channel and inhibits cell invasion.
Q. Xie, R. Wondergem, Y. Shen, G. Cavey, J. Ke, R. Thompson, R. Bradley, J. Daugherty-Holtrop, Y. Xu, E. Chen, et al. (2011)
PNAS 108, 4105-4110
   Abstract »    Full Text »    PDF »
Functional dynamics in the voltage-dependent anion channel.
S. Villinger, R. Briones, K. Giller, U. Zachariae, A. Lange, B. L. de Groot, C. Griesinger, S. Becker, and M. Zweckstetter (2010)
PNAS 107, 22546-22551
   Abstract »    Full Text »    PDF »
Oligomerization of the Mitochondrial Protein Voltage-Dependent Anion Channel Is Coupled to the Induction of Apoptosis.
N. Keinan, D. Tyomkin, and V. Shoshan-Barmatz (2010)
Mol. Cell. Biol. 30, 5698-5709
   Abstract »    Full Text »    PDF »
Inhibition of Bak Activation by VDAC2 Is Dependent on the Bak Transmembrane Anchor.
M. Lazarou, D. Stojanovski, A. E. Frazier, A. Kotevski, G. Dewson, W. J. Craigen, R. M. Kluck, D. L. Vaux, and M. T. Ryan (2010)
J. Biol. Chem. 285, 36876-36883
   Abstract »    Full Text »    PDF »
R. C. Allsopp, U. Lalo, and R. J. Evans (2010)
J. Biol. Chem. 285, 32770-32777
   Abstract »    Full Text »    PDF »
Assembly of outer-membrane proteins in bacteria and mitochondria.
J. Tommassen (2010)
Microbiology 156, 2587-2596
   Abstract »    Full Text »    PDF »
The Mitochondrial Porin, VDAC, Has Retained the Ability to Be Assembled in the Bacterial Outer Membrane.
D. M. Walther, M. P. Bos, D. Rapaport, and J. Tommassen (2010)
Mol. Biol. Evol. 27, 887-895
   Abstract »    Full Text »    PDF »
Voltage-dependent Anion Channel 1-based Peptides Interact with Bcl-2 to Prevent Antiapoptotic Activity.
N. Arbel and V. Shoshan-Barmatz (2010)
J. Biol. Chem. 285, 6053-6062
   Abstract »    Full Text »    PDF »
Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein.
A. Szigeti, E. Hocsak, E. Rapolti, B. Racz, A. Boronkai, E. Pozsgai, B. Debreceni, Z. Bognar, S. Bellyei, B. Sumegi, et al. (2010)
J. Biol. Chem. 285, 2140-2151
   Abstract »    Full Text »    PDF »
HHomp--prediction and classification of outer membrane proteins.
M. Remmert, D. Linke, A. N. Lupas, and J. Soding (2009)
Nucleic Acids Res. 37, W446-W451
   Abstract »    Full Text »    PDF »
Solution Nuclear Magnetic Resonance Structure of Membrane-Integral Diacylglycerol Kinase.
W. D. Van Horn, H.-J. Kim, C. D. Ellis, A. Hadziselimovic, E. S. Sulistijo, M. D. Karra, C. Tian, F. D. Sonnichsen, and C. R. Sanders (2009)
Science 324, 1726-1729
   Abstract »    Full Text »    PDF »
Structure and topology of monomeric phospholamban in lipid membranes determined by a hybrid solution and solid-state NMR approach.
N. J. Traaseth, L. Shi, R. Verardi, D. G. Mullen, G. Barany, and G. Veglia (2009)
PNAS 106, 10165-10170
   Abstract »    Full Text »    PDF »
The VDAC1 N-terminus is essential both for apoptosis and the protective effect of anti-apoptotic proteins.
S. Abu-Hamad, N. Arbel, D. Calo, L. Arzoine, A. Israelson, N. Keinan, R. Ben-Romano, O. Friedman, and V. Shoshan-Barmatz (2009)
J. Cell Sci. 122, 1906-1916
   Abstract »    Full Text »    PDF »
Voltage-dependent Anion Channel 1-based Peptides Interact with Hexokinase to Prevent Its Anti-apoptotic Activity.
L. Arzoine, N. Zilberberg, R. Ben-Romano, and V. Shoshan-Barmatz (2009)
J. Biol. Chem. 284, 3946-3955
   Abstract »    Full Text »    PDF »
Opening and closing the metabolite gate.
S. Tornroth-Horsefield and R. Neutze (2008)
PNAS 105, 19565-19566
   Full Text »    PDF »
Physiology 23, 310-312
   Full Text »    PDF »
The crystal structure of mouse VDAC1 at 2.3 A resolution reveals mechanistic insights into metabolite gating.
R. Ujwal, D. Cascio, J.-P. Colletier, S. Faham, J. Zhang, L. Toro, P. Ping, and J. Abramson (2008)
PNAS 105, 17742-17747
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882