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Structure of the human voltage-dependent anion channel.

ABSTRACT: The voltage-dependent anion channel (VDAC), also known as mitochondrial porin, is the most abundant protein in the mitochondrial outer membrane (MOM). VDAC is the channel known to guide the metabolic flux across the MOM and plays a key role in mitochondrially induced apoptosis. Here, we present the 3D structure of human VDAC1, which was solved conjointly by NMR spectroscopy and x-ray crystallography. Human VDAC1 (hVDAC1) adopts a beta-barrel architecture composed of 19 beta-strands with an alpha-helix located horizontally midway within the pore. Bioinformatic analysis indicates that this channel architecture is common to all VDAC proteins and is adopted by the general import pore TOM40 of mammals, which is also located in the MOM.

SUBMITTER: Bayrhuber M

PROVIDER: S-EPMC2557026 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Structure of the human voltage-dependent anion channel.

Bayrhuber Monika M Meins Thomas T Habeck Michael M Becker Stefan S Giller Karin K Villinger Saskia S Vonrhein Clemens C Griesinger Christian C Zweckstetter Markus M Zeth Kornelius K

Proceedings of the National Academy of Sciences of the United States of America 20081001 40

The voltage-dependent anion channel (VDAC), also known as mitochondrial porin, is the most abundant protein in the mitochondrial outer membrane (MOM). VDAC is the channel known to guide the metabolic flux across the MOM and plays a key role in mitochondrially induced apoptosis. Here, we present the 3D structure of human VDAC1, which was solved conjointly by NMR spectroscopy and x-ray crystallography. Human VDAC1 (hVDAC1) adopts a beta-barrel architecture composed of 19 beta-strands with an alpha ...[more]

PMID: 18832158

Similar Datasets

Structure, gating and interactions of the voltage-dependent anion channel.

Project description:The voltage-dependent anion channel (VDAC) is one of the most highly abundant proteins found in the outer mitochondrial membrane, and was one of the earliest discovered. Here we review progress in understanding VDAC function with a focus on its structure, discussing various models proposed for voltage gating as well as potential drug targets to modulate the channel's function. In addition, we explore the sensitivity of VDAC structure to variations in the membrane environment, comparing DMPC-only, DMPC with cholesterol, and near-native lipid compositions, and use magic-angle spinning NMR spectroscopy to locate cholesterol on the outside of the β-barrel. We find that the VDAC protein structure remains unchanged in different membrane compositions, including conditions with cholesterol.

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Nucleotide interactions of the human voltage-dependent anion channel.

Project description:The voltage-dependent anion channel (VDAC) mediates and gates the flux of metabolites and ions across the outer mitochondrial membrane and is a key player in cellular metabolism and apoptosis. Here we characterized the binding of nucleotides to human VDAC1 (hVDAC1) on a single-residue level using NMR spectroscopy and site-directed mutagenesis. We find that hVDAC1 possesses one major binding region for ATP, UTP, and GTP that partially overlaps with a previously determined NADH binding site. This nucleotide binding region is formed by the N-terminal ?-helix, the linker connecting the helix to the first ?-strand and adjacent barrel residues. hVDAC1 preferentially binds the charged forms of ATP, providing support for a mechanism of metabolite transport in which direct binding to the charged form exerts selectivity while at the same time permeation of the Mg(2+)-complexed ATP form is possible.

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MicroED structure of lipid-embedded mammalian mitochondrial voltage-dependent anion channel.

Project description:A structure of the murine voltage-dependent anion channel (VDAC) was determined by microcrystal electron diffraction (MicroED). Microcrystals of an essential mutant of VDAC grew in a viscous bicelle suspension, making it unsuitable for conventional X-ray crystallography. Thin, plate-like crystals were identified using scanning-electron microscopy (SEM). Crystals were milled into thin lamellae using a focused-ion beam (FIB). MicroED data were collected from three crystal lamellae and merged for completeness. The refined structure revealed unmodeled densities between protein monomers, indicative of lipids that likely mediate contacts between the proteins in the crystal. This body of work demonstrates the effectiveness of milling membrane protein microcrystals grown in viscous media using a focused ion beam for subsequent structure determination by MicroED. This approach is well suited for samples that are intractable by X-ray crystallography. To our knowledge, the presented structure is a previously undescribed mutant of the membrane protein VDAC, crystallized in a lipid bicelle matrix and solved by MicroED.

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Voltage-Dependent Anion Selective Channel Isoforms in Yeast: Expression, Structure, and Functions.

Project description:Mitochondrial porins, also known as voltage-dependent anion selective channels (VDACs), are pore-forming molecules of the outer mitochondrial membranes, involved in the regulation of metabolic flux between cytosol and mitochondria. Playing such an essential role, VDAC proteins are evolutionary conserved and isoforms are present in numerous species. The quest for specific function(s) related to the raise of multiple isoforms is an intriguing theme. The yeast Saccharomyces cerevisiae genome is endowed with two different VDAC genes encoding for two distinct porin isoforms, definitely less characterized in comparison to mammalian counterpart. While yVDAC1 has been extensively studied, the second isoform, yVDAC2, is much less expressed, and has a still misunderstood function. This review will recapitulate the known and poorly known information in the literature, in the light of the growing interest about the features of VDAC isoforms in the cell.

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Functional model of metabolite gating by human voltage-dependent anion channel 2.

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Functional dynamics in the voltage-dependent anion channel.

Project description:The voltage-dependent anion channel (VDAC), located in the outer mitochondrial membrane, acts as a gatekeeper for the entry and exit of mitochondrial metabolites. Here we reveal functional dynamics of isoform one of VDAC (VDAC1) by a combination of solution NMR spectroscopy, Gaussian network model analysis, and molecular dynamics simulation. Micro- to millisecond dynamics are significantly increased for the N-terminal six β-strands of VDAC1 in micellar solution, in agreement with increased B-factors observed in the same region in the bicellar crystal structure of VDAC1. Molecular dynamics simulations reveal that a charge on the membrane-facing glutamic acid 73 (E73) accounts for the elevation of N-terminal protein dynamics as well as a thinning of the nearby membrane. Mutation or chemical modification of E73 strongly reduces the micro- to millisecond dynamics in solution. Because E73 is necessary for hexokinase-I-induced VDAC channel closure and inhibition of apoptosis, our results imply that micro- to millisecond dynamics in the N-terminal part of the barrel are essential for VDAC interaction and gating.

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Loss of voltage dependent anion channel 1 affects mitochondrial bioenergetics in rat dopamine cells

Project description:Voltage dependent anion channel 1 (VDAC1) is a multi-functional protein that regulates mitochondrial membrane potential, calcium regulation, and apoptosis. VDAC1 also interacts with a number of signaling pathways important for energy homeostasis and proteins involved in neurodegenerative diseases such as alpha-synuclein. To identify novel signaling pathways dependent upon VDAC1 protein in dopamine cells, we used CRISPR-Cas9 gene editing in rat immortalized dopaminergic N27 cells. Western blot confirmed that VDAC1 protein levels were reduced ~90%. Mitochondrial bioenergetics was assessed to determine if there was functional loss of mitochondrial function without VDAC1. Loss of VDAC1 resulted in lower ATP-linked and maximum respiration, and spare respiratory capacity. Transcriptomics was conducted in these cells to identify the pathways perturbed by loss of VDAC. This study sheds novel insight into the different regulatory roles mediated by VDAC1 in dopamine cells.

2019-07-31 | GSE118737 | GEO

Structure of voltage-dependent anion channel-tethered bilayer lipid membranes determined using neutron reflectivity.

Project description:Neutron reflectivity (NR) has emerged as a powerful technique to study the structure and behavior of membrane proteins at planar lipid interfaces. Integral membrane proteins (IMPs) remain a significant challenge for NR owing to the difficulty of forming complete bilayers with sufficient protein density for scattering techniques. One strategy to achieve high protein density on a solid substrate is the capture of detergent-stabilized, affinity-tagged IMPs on a nitrilotriacetic acid (NTA)-functionalized self-assembled monolayer (SAM), followed by reconstitution into the lipids of interest. Such protein-tethered bilayer lipid membranes (ptBLMs) have the notable advantage of a uniform IMP orientation on the substrate. Here, NR is used to provide a structural characterization of the ptBLM process from formation of the SAM to capture of the detergent-stabilized IMP and lipid reconstitution. The mitochondrial outer-membrane voltage-dependent anion channel (VDAC), which controls the exchange of bioenergetic metabolites between mitochondria and the cytosol, was used as a model β-barrel IMP. Molecular dynamics simulations were used for comparison with the experimental results and to inform the parameters of the physical models describing the NR data. The detailed structure of the SAM is shown to depend on the density of the NTA chelating groups. The relative content of detergent and protein in surface-immobilized, detergent-stabilized VDAC is measured, while the reconstituted lipid bilayer is shown to be complete to within a few percent, using the known atomic structure of VDAC. Finally, excess lipid above the reconstituted bilayer, which is of consequence for more indirect structural and functional studies, is shown to be present.

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Molecular Plasticity of the Human Voltage-Dependent Anion Channel Embedded Into a Membrane.

Project description:The voltage-dependent anion channel (VDAC) regulates the flux of metabolites and ions across the outer mitochondrial membrane. Regulation of ion flow involves conformational transitions in VDAC, but the nature of these changes has not been resolved to date. By combining single-molecule force spectroscopy with nuclear magnetic resonance spectroscopy we show that the β barrel of human VDAC embedded into a membrane is highly flexible. Its mechanical flexibility exceeds by up to one order of magnitude that determined for β strands of other membrane proteins and is largest in the N-terminal part of the β barrel. Interaction with Ca(2+), a key regulator of metabolism and apoptosis, considerably decreases the barrel's conformational variability and kinetic free energy in the membrane. The combined data suggest that physiological VDAC function depends on the molecular plasticity of its channel.

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The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease.

Project description:The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson's disease (PD), Friedreich's ataxia (FA), lupus, and cancer. To fully address the molecular role of VDAC in disease pathology, major questions must be answered on the structural conformers of VDAC. For example, further information is needed on the structure of the closed state, how binding partners or membrane potential could lead to the open/closed states, the function and mobility of the N-terminal α-helical domain of VDAC, and the physiological role of VDAC oligomers. This review covers our current understanding of the various states of VDAC, VDAC interaction partners, and the roles they play in mitochondrial regulation pertaining to human diseases.

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