VDAC1

Voltage-dependent anion-selective channel protein 1 is a protein that in humans is encoded by the VDAC1 gene on chromosome 5. This protein is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms, which are involved in the regulation of cell metabolism, mitochondrial apoptosis, and spermatogenesis. In particular, VDAC1 is the major calcium ion transport channel and is implicated in cancer and Parkinson’s Disease (PD).

Structure

The three VDAC isoforms in human are highly conserved, particularly with respect to their 3D structure. VDACs form a wide β-barrel structure, inside of which the N-terminal resides to partially close the pore. For VDAC1, this barrel-like channel is composed of 19 amphipathic β-strands, and the end of the N-terminal contains α-helix segments. The N-terminal is proposed to as a gate to the pore via swinging motions facilitated by a short glycine-containing motif. Additionally, the N-terminal serves as a docking site for HK1 binding.

Function

VDAC1 belongs to the mitochondrial porin family and is expected to share similar biological functions to the other VDAC isoforms. Of the three isoforms, VDAC1 is the main calcium ion transport channel and the most abundantly transcribed. VDACs are involved in cell metabolism by transporting ATP and other small metabolites across the outer mitochondrial membrane (OMM). Of note, its role in transporting calcium ions allows the protein to regulate the TCA cycle and, by extension, reactive oxygen species (ROS) production. In yeast cells, ROS accumulates in response to oxidative stress, which results in impaired mitochondrial function and a “petite” phenotype. However, petite yeast cells exhibit a longer lifespan than wildtype cells and indicate a protective function by VDAC1 in similar circumstances, such as aging. In addition, VDACs form part of the mitochondrial permeability transition pore (MPTP) and, thus, facilitate cytochrome C release, leading to apoptosis. VDACs have also been observed to interact with pro- or antiapoptotic proteins, such as Bcl-2 family proteins and kinases, and so may contribute to apoptosis independently from the MPTP.

Clinical Significance

VDAC1 has been implicated in cancer through its interactions with antiapoptotic Bcl-2 proteins, particularly Bcl-xl, and Mcl-1, which are overexpressed during cancer. These two Bcl-2 proteins interact with VDAC1 to regulate calcium ion transport across the OMM and, ultimately, ROS production. While high levels of ROS induce cell death, non-lethal levels interfere with signal transduction pathways that can then promote cell proliferation, migration, and invasion in cancer cells. Moreover, VDAC1 overexpression has been associated with increased apoptotic response and anti-cancer drugs and treatment efficacy, further supporting VDAC1 as a therapeutic target for cancer treatment.

VDAC1 function in calcium ion transport also involves the protein in neurodegenerative diseases. In PD, VDAC1 increases calcium ion levels within the mitochondria, resulting in increased mitochondrial permeability, disrupted mitochondrial membrane potential, elevated ROS production, cell death, and neuronal degeneration.

Interactions

VDAC1 has been shown to interact with:

• BCL2-like 1,
• Bcl-2-associated X protein,
• DYNLT3,
• Gelsolin,
• PRKCE,
• HK1
• Parkin
• eNOS
• Mcl-1
• HK

See also

• Voltage-dependent anion channel

External links

• VDAC1 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)