VDAC1

Voltage-dependent anion-selective channel protein 1 is a is_associated_with::protein that in humans is encoded by the VDAC1 is_associated_with::gene on chromosome 5. This protein is a is_associated_with::voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms, which are involved in the regulation of cell is_associated_with::metabolism, mitochondrial is_associated_with::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 is_associated_with::outer mitochondrial membrane (OMM). Of note, its role in transporting calcium ions allows the protein to regulate the TCA cycle and, by extension, is_associated_with::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 is_associated_with::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 is_associated_with::Bcl-2 proteins, particularly is_associated_with::Bcl-xl, and is_associated_with::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 degeneraation.

Interactions
VDAC1 has been shown to interact with:
 * BCL2-like 1,
 * is_associated_with::Bcl-2-associated X protein,
 * is_associated_with::DYNLT3,
 * is_associated_with::Gelsolin,
 * is_associated_with::PRKCE,
 * is_associated_with::HK1
 * is_associated_with::Parkin
 * is_associated_with::eNOS
 * is_associated_with::Mcl-1
 * is_associated_with::HK