Biology:VDAC3
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Voltage-dependent anion-selective channel protein 3 (VDAC3) is a protein that in humans is encoded by the VDAC3 gene on chromosome 8.
[1][2] The protein encoded by this gene is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms.[1][2][3] 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.[4][5] Mutations in VDAC3 have been linked to male infertility, as well as Parkinson’s disease.[6][7]
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.[3] VDACs also contain a mitochondrial targeting sequence for the protein's translocation to the outer mitochondrial membrane.[8] 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.[4]
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 outer mitochondrial membrane. In addition, VDACs form part of the mitochondrial permeability transition pore (MPTP) and, thus, facilitate cytochrome C release, leading to apoptosis.[9] 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.[10] Nonetheless, experiments reveal a lack of pore-forming ability in the VDAC3 isoform, suggesting that it may perform different biological functions.[6][11] Notably, though all VDAC isoforms are ubiquitously expressed, VDAC3 is mostly found in the sperm outer dense fiber (ODF), where it is hypothesized to promote proper assembly and maintenance of sperm flagella.[4][5] 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.[12] For instance, within cells, VDAC3 predominantly localizes to the centrosome and recruits Mps1 to regulate centriole assembly.[4][5] In the case of localization to the mitochondria, VDAC3 interaction with Mps1 instead leads to ciliary disassembly.[5]
Clinical significance
VDAC3 belongs to a group of mitochondrial membrane channels involved in translocation of adenine nucleotides through the outer membrane. These channels may also function as a mitochondrial binding site for hexokinase and glycerol kinase. The VDAC is an important constituent in apoptotic signaling and oxidative stress, most notably as part of the mitochondrial death pathway and cardiac myocyte apoptosis signaling.[13] Programmed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response.[14] It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
In addition, VDAC3 has been implicated in cardioprotection against ischemia-reperfusion injury, such as during ischemic preconditioning of the heart.[15] Although a large burst of reactive oxygen species is known to lead to cell damage, a moderate release of ROS from the mitochondria, which occurs during nonlethal short episodes of ischemia, can play a significant triggering role in the signal transduction pathways of ischemic preconditioning leading to reduction of cell damage. It has even been observed that during this release of reactive oxygen species, VDAC3 plays an important role in the mitochondrial cell death pathway transduction hereby regulating apoptotic signaling and cell death.
As VDAC3 is a regulator of sperm motility, male mice missing VDAC3 result in infertility.[6] 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 reactive oxygen species, the commonly attributed cause of Parkinson’s disease.[7] In addition, it has been found that VDAC3-null mice were born at the expected mendelian ratio. Mutant females were fertile, but males were not due to markedly reduced sperm motility.[16] The majority of epididymal axonemes showed structural defects, most commonly loss of a single microtubule doublet at a conserved position within the axoneme. In testicular sperm, the defect was only rarely observed, suggesting that instability of a normally formed axoneme occurred during sperm maturation. In contrast, tracheal epithelial cilia showed no structural abnormalities, but there was a reduced number of ciliated cells. In skeletal muscle, mitochondria were abnormally shaped, and the activities of respiratory chain complex enzymes were reduced. Citrate synthase activity was unchanged, suggesting an absence of mitochondrial proliferation that commonly occurs in response to respiratory chain defects.
Interactions
VDAC3 has been shown to interact with:
See also
References
- ↑ 1.0 1.1 "Identification of genes expressed in human CD34(+) hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America 95 (14): 8175–80. Jul 1998. doi:10.1073/pnas.95.14.8175. PMID 9653160. Bibcode: 1998PNAS...95.8175M.
- ↑ 2.0 2.1 "Isolation of a novel human voltage-dependent anion channel gene". European Journal of Human Genetics 6 (4): 337–40. Nov 1998. doi:10.1038/sj.ejhg.5200198. PMID 9781040.
- ↑ 3.0 3.1 "Charged residues distribution modulates selectivity of the open state of human isoforms of the voltage dependent anion-selective channel". PLOS ONE 9 (8): e103879. 2014. doi:10.1371/journal.pone.0103879. PMID 25084457. Bibcode: 2014PLoSO...9j3879A.
- ↑ 4.0 4.1 4.2 4.3 4.4 "VDAC3 regulates centriole assembly by targeting Mps1 to centrosomes". Cell Cycle 11 (19): 3666–78. Oct 2012. doi:10.4161/cc.21927. PMID 22935710.
- ↑ 5.0 5.1 5.2 5.3 "VDAC3 and Mps1 negatively regulate ciliogenesis". Cell Cycle 12 (5): 849–58. Mar 2013. doi:10.4161/cc.23824. PMID 23388454.
- ↑ 6.0 6.1 6.2 "Swapping of the N-terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti-aging features to the cell". FEBS Letters 584 (13): 2837–44. Jul 2010. doi:10.1016/j.febslet.2010.04.066. PMID 20434446.
- ↑ 7.0 7.1 7.2 "Voltage-dependent anion channels (VDACs) recruit Parkin to defective mitochondria to promote mitochondrial autophagy". The Journal of Biological Chemistry 287 (48): 40652–60. Nov 2012. doi:10.1074/jbc.M112.419721. PMID 23060438.
- ↑ "Voltage-dependent anion-selective channel (VDAC) in the plasma membrane". FEBS Letters 584 (9): 1793–9. May 2010. doi:10.1016/j.febslet.2010.02.049. PMID 20184885.
- ↑ "Entrez Gene: voltage-dependent anion channel 3". https://www.ncbi.nlm.nih.gov/gene/7419.
- ↑ "Identification of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway". Molecular and Cellular Biology 24 (9): 3918–27. May 2004. doi:10.1128/mcb.24.9.3918-3927.2004. PMID 15082785.
- ↑ "Characterization of human VDAC isoforms: a peculiar function for VDAC3?". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 (6–7): 1268–75. 2010. doi:10.1016/j.bbabio.2010.01.031. PMID 20138821.
- ↑ "Voltage-dependent anion-selective channels VDAC2 and VDAC3 are abundant proteins in bovine outer dense fibers, a cytoskeletal component of the sperm flagellum". The Journal of Biological Chemistry 279 (15): 15281–8. Apr 2004. doi:10.1074/jbc.M313433200. PMID 14739283.
- ↑ "Cell death: critical control points". Cell 116 (2): 205–19. Jan 2004. doi:10.1016/S0092-8674(04)00046-7. PMID 14744432.
- ↑ "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics". British Journal of Cancer 26 (4): 239–57. Aug 1972. doi:10.1038/bjc.1972.33. PMID 4561027.
- ↑ "Past and present course of cardioprotection against ischemia-reperfusion injury". Journal of Applied Physiology 103 (6): 2129–36. Dec 2007. doi:10.1152/japplphysiol.00383.2007. PMID 17673563.
- ↑ "Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3". The Journal of Biological Chemistry 276 (42): 39206–12. Oct 2001. doi:10.1074/jbc.M104724200. PMID 11507092.
Further reading
- "A human protein-protein interaction network: a resource for annotating the proteome". Cell 122 (6): 957–68. Sep 2005. doi:10.1016/j.cell.2005.08.029. PMID 16169070. http://edoc.mpg.de/get.epl?fid=21592&did=275687&ver=0.
- "Human spermatozoa contain multiple targets for protein S-nitrosylation: an alternative mechanism of the modulation of sperm function by nitric oxide?". Proteomics 7 (17): 3066–84. Sep 2007. doi:10.1002/pmic.200700254. PMID 17683036.
- "The tissue-specific, alternatively spliced single ATG exon of the type 3 voltage-dependent anion channel gene does not create a truncated protein isoform in vivo". Molecular Genetics and Metabolism 70 (1): 69–74. May 2000. doi:10.1006/mgme.2000.2987. PMID 10833333.
- "Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3". The Journal of Biological Chemistry 276 (42): 39206–12. Oct 2001. doi:10.1074/jbc.M104724200. PMID 11507092.
- "The murine voltage-dependent anion channel gene family. Conserved structure and function". The Journal of Biological Chemistry 272 (30): 18966–73. Jul 1997. doi:10.1074/jbc.272.30.18966. PMID 9228078.
- "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research 10 (10): 1546–60. Oct 2000. doi:10.1101/gr.140200. PMID 11042152.
- "The LIFEdb database in 2006". Nucleic Acids Research 34 (Database issue): D415–8. Jan 2006. doi:10.1093/nar/gkj139. PMID 16381901.
- "DNA cloning using in vitro site-specific recombination". Genome Research 10 (11): 1788–95. Nov 2000. doi:10.1101/gr.143000. PMID 11076863.
- "Voltage-dependent anion-selective channels VDAC2 and VDAC3 are abundant proteins in bovine outer dense fibers, a cytoskeletal component of the sperm flagellum". The Journal of Biological Chemistry 279 (15): 15281–8. Apr 2004. doi:10.1074/jbc.M313433200. PMID 14739283.
- "Revised fine mapping of the human voltage-dependent anion channel loci by radiation hybrid analysis". Mammalian Genome 10 (10): 1041–2. Oct 1999. doi:10.1007/s003359901158. PMID 10501981.
- "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology 23 (1): 94–101. Jan 2005. doi:10.1038/nbt1046. PMID 15592455.
- "From ORFeome to biology: a functional genomics pipeline". Genome Research 14 (10B): 2136–44. Oct 2004. doi:10.1101/gr.2576704. PMID 15489336.
- "A novel isoform of the mitochondrial outer membrane protein VDAC3 via alternative splicing of a 3-base exon. Functional characteristics and subcellular localization". The Journal of Biological Chemistry 273 (46): 30482–6. Nov 1998. doi:10.1074/jbc.273.46.30482. PMID 9804816.
- "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology 3 (1): 89. 2007. doi:10.1038/msb4100134. PMID 17353931.
External links
- VDAC3+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
![]() | Original source: https://en.wikipedia.org/wiki/VDAC3.
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