VDAC3

Voltage-dependent anion-selective channel protein 3 (VDAC3) is a is_associated_with::protein that in humans is encoded by the VDAC3 is_associated_with::gene on chromosome 8. The is_associated_with::protein encoded by this gene is a is_associated_with::voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms. Nonetheless, VDAC3 demonstrates limited pore-forming ability and, instead, interacts with other proteins to perform its biological functions, including sperm flagella assembly and centriole assembly. Mutations in VDAC3 have been linked to male infertility, as well as is_associated_with::Parkinson’s disease.

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. The sequence of the VDAC3 isoform contains an abundance of cysteines, which allow for the formation of disulfide bridges and, ultimately, affect the flexibility of the β-barrel. VDAC3 still yet possesses multiple isoforms, including a full-length form and shorter form termed VDAC3b. This shorter form is predominantly expressed over the full-length form at cell centrosomes.

Function
VDAC3 belongs to the mitochondrial porin family and is expected to share similar biological functions to the other VDAC isoforms. VDACs are involved in cell metabolism by transporting ATP and other small metabolites across the is_associated_with::outer mitochondrial membrane. 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. Nonetheless, experiments reveal a lack of pore-forming ability in the VDAC3 isoform, suggesting that it may perform different biological functions. Notably, though all VDAC isoforms are ubiquitously expressed, VDAC3 is majorly found in the sperm outer dense fiber (ODF), where it is hypothesized to promote proper assembly and maintenance of sperm flagella. Because the ODF membranes are not likely to support pore formation, VDAC3 may interact with protein partners to carry out other functions in the ODF. For instance, within cells, VDAC3 predominantly localizes to the centrosome and recruits is_associated_with::Mps1 to regulate centriole assembly. In the case of localization to the mitochondria, VDAC3 interaction with Mps1 instead leads to ciliary disassembly.

Clinical Significance
As VDAC3 is a regulator of sperm motility, male mice missing VDAC3 result in infertility. Mutations in VDAC3 are also associated with Parkinson’s disease, as VDAC3 has been observed to target Parkin to defective mitochondria to eliminate them by mitophagy. Failure to eliminate these mitochondria result in the accumulation of is_associated_with::reactive oxygen species, the commonly attributed cause of Parkinson’s disease.

Interactions
VDAC3 has been shown to interact with:
 * is_associated_with::Mps1
 * is_associated_with::Parkin