Voltage-dependent anion channel

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Eukaryotic porin
TCDB
1.B.8
OPM superfamily189
OPM protein3emn
CDDcd07306
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Voltage-dependent anion channels, or mitochondrial porins, are a class of

outer mitochondrial membrane.[1][2] There is debate as to whether or not this channel is expressed in the cell surface membrane.[3][4][5]

This major protein of the outer

hydrophilic molecules.[6][7][8][9] The channel adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30–40 mV. VDAC facilitates the exchange of ions and molecules between mitochondria and cytosol and is regulated by the interactions with other proteins and small molecules.[10]

Structure

This protein contains about 280 amino acids and forms a beta barrel which spans the mitochondrial outer membrane.[11][12]

Since its discovery in 1976, extensive function and structure analysis of VDAC proteins has been conducted. A prominent feature of the pore emerged: when reconstituted into planar lipid bilayers, there is a voltage-dependent switch between an anion-selective high-conductance state with high metabolite flux and a cation-selective low-conductance state with limited passage of metabolites.

More than 30 years after its initial discovery, in 2008, three independent structural projects of VDAC-1 were completed. The first was solved by multi-dimensional NMR spectroscopy. The second applied a hybrid approach using crystallographic data. The third was for mouse VDAC-1 crystals determined by X-ray crystallographic techniques. The three projects of the 3D structures of VDAC-1 revealed many structural features. First, VDAC-1 represents a new structural class of outer membrane β-barrel proteins with an odd number of strands. Another aspect is that the negatively charged side chain of residue E73 is oriented towards the hydrophobic membrane environment. The 19-stranded 3D structure obtained under different experimental sources by three different laboratories fits the EM and AFM data from native membrane sources and represents a biologically relevant state of VDAC-1.[10]

Mechanism

At membrane potentials exceeding 30 mV (positive or negative), VDAC assumes a closed state, and transitions to its open state once the

metabolites fall.[13] The precise mechanism for coupling voltage changes to conformational changes within the protein has not yet been worked out, but studies by Thomas et al. suggest that when the protein transitions to the closed form, voltage changes lead to the removal of a large section of the protein from the channel and decrease effective pore radius.[14] Several lysine residues, as well as Glu-152, have been implicated as especially important sensor residues within the protein.[15]

Biological function

The voltage-dependent ion channel plays a key role in regulating metabolic and energetic flux across the outer mitochondrial membrane. It is involved in the transport of

malate, and other metabolites, and thus communicates extensively with enzymes from metabolic pathways.[13] The ATP-dependent cytosolic enzymes hexokinase, glucokinase, and glycerol kinase, as well as the mitochondrial enzyme creatine kinase, have all been found to bind to VDAC. This binding puts them in close proximity to ATP released from the mitochondria. In particular, the binding of hexokinase is presumed to play a key role in coupling glycolysis to oxidative phosphorylation.[14] Additionally, VDAC is an important regulator of Ca2+ transport in and out of the mitochondria. Because Ca2+ is a cofactor for metabolic enzymes such as pyruvate dehydrogenase and isocitrate dehydrogenase, energetic production and homeostasis are both affected by VDAC's permeability to Ca2+.[16]

Disease relevance

VDAC has also been shown to play a role in

Bax interacts directly with VDAC to increase pore size and promote cytochrome c release, while anti-apoptotic Bcl-xL produces the exact opposite effect.[20] In fact, it has been shown that antibodies that inhibit VDAC also interfere with Bax-mediated cytochrome c release in both isolated mitochondria and whole cells.[21]
This key role in apoptosis suggests VDAC as a potential target for chemotherapeutic drugs.

Examples

Yeast contains two members of this family (genes POR1 and POR2); vertebrates have at least three members (genes VDAC1, VDAC2 and VDAC3).[11]

Humans, like most higher eukaryotes, encode three different VDACs; VDAC1, VDAC2, and VDAC3. Together with TOMM40 and TOMM40L they represent a family of evolutionarily related β-barrels.[22]

Plants have the largest number of VDACs. Arabidopsis encode four different VDACs but this number can be larger in other species.[23]

References

  1. PMID 17524423
    .
  2. S2CID 38314888
    .
  3. PMID 21986486
    .
  4. S2CID 3391282
    .
  5. PMID 21637820
    .
  6. PMID 8031826
    .
  7. PMID 1384178
    .
  8. S2CID 2199583
    .
  9. S2CID 10219032
    .
  10. ^
    PMID 20708406
    .
  11. ^
    PMID 8812436
    .
  12. PMID 20450883
    .
  13. ^
    S2CID 38314888
    .
  14. ^
    PMID 8744209
    .
  15. PMID 7685903
    .
  16. S2CID 33628015
    .
  17. PMID 16307870
    .
  18. PMID 12022949
    .
  19. PMID 15456403
    .
  20. S2CID 4423304
    .
  21. PMID 11266442
    .
  22. PMID 22178864
    .
  23. PMID 22155681
    .

External links
This article incorporates text from the public domain Pfam and InterPro: IPR001925
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