The voltage-dependent anion channel (VDAC) mediates trafficking of small molecules and ions across the eukaryotic outer mitochondrial membrane. There are three isoforms that have distinct reported interactions with small molecules and proteins. These include pro- and anti-apoptotic members of the Bcl-2 family, and the different isoforms of VDAC have been implied to play roles in apoptosis, such as formation or inhibition of the mitochondrial exit channel. Recently, we obtained NMR assignments and determined the solution structure of human VDAC-1 in detergent micelles (Hiller et al., 2008). VDAC has been known for thirty years and numerous reports of interactions and functional aspects have been reported. With the recent NMR characterization of VDAC-1 we are now in a position to validate these reports and elucidate the function of the channel. The goal of the proposed research is to study the structure, interactions and function of VDAC isoforms. We will pursue the following specific aims: 1. Compare structure and interactions of VDAC-1 in LDAO micelles and phospholipids nanodiscs to assess differences between micelle and bilayer environments. 2. Determine the structure of VDAC-2, which contains an N-terminal extension and has reported functions distinct from VDAC-1. 3. Determine the membrane/micelle-bound structures of Bcl-2 type proteins and study VDAC complexes. 4. Characterize complexes of VDAC with the porin PorB from pathogenic bacteria.

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We will study the solution structure of the human voltage-dependent anion channel (VDAC) in the membrane mimicking phospholipids nanodiscs and compare it with our recent structure obtained in LDAO micelles. We will also determine the structure of the VDAC-2 isoform, which has been shown to stabilize an inactive form of the Bak protein and may play a crucial role in controlling the onset of apoptosis. We also will investigate interactions of VDAC with Bcl-2-type proteins, bacterial pathogens and small molecules.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Chin, Jean
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Harvard University
Schools of Medicine
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Hagn, Franz; Wagner, Gerhard (2015) Structure refinement and membrane positioning of selectively labeled OmpX in phospholipid nanodiscs. J Biomol NMR 61:249-60
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Coote, Paul; Leigh, Kendra E; Yu, Tsyr-Yan et al. (2014) A new broadband homonuclear mixing pulse for NMR with low applied power. J Chem Phys 141:024201
Hagn, Franz; Etzkorn, Manuel; Raschle, Thomas et al. (2013) Optimized phospholipid bilayer nanodiscs facilitate high-resolution structure determination of membrane proteins. J Am Chem Soc 135:1919-25
Coote, Paul; Arthanari, Haribabu; Yu, Tsyr-Yan et al. (2013) Pulse design for broadband correlation NMR spectroscopy by multi-rotating frames. J Biomol NMR 55:291-302
Eddy, Matthew T; Ong, Ta-Chung; Clark, Lindsay et al. (2012) Lipid dynamics and protein-lipid interactions in 2D crystals formed with the ?-barrel integral membrane protein VDAC1. J Am Chem Soc 134:6375-87
Hiller, Sebastian; Abramson, Jeff; Mannella, Carmen et al. (2010) The 3D structures of VDAC represent a native conformation. Trends Biochem Sci 35:514-21
Raschle, Thomas; Hiller, Sebastian; Etzkorn, Manuel et al. (2010) Nonmicellar systems for solution NMR spectroscopy of membrane proteins. Curr Opin Struct Biol 20:471-9
Hiller, Sebastian; Malia, Thomas J; Garces, Robert G et al. (2010) Backbone and ILV side chain methyl group assignments of the integral human membrane protein VDAC-1. Biomol NMR Assign 4:29-32
Raschle, Thomas; Hiller, Sebastian; Yu, Tsyr-Yan et al. (2009) Structural and functional characterization of the integral membrane protein VDAC-1 in lipid bilayer nanodiscs. J Am Chem Soc 131:17777-9

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