Voltage-dependent anion-selective channel protein 2 (VDAC2)
The protein contains 294 amino acids for an estimated molecular weight of 31567 Da.
Forms a channel through the mitochondrial outer membrane that allows diffusion of small hydrophilic molecules (By similarity). The channel adopts an open conformation at low or zero membrane potential and a closed conformation at potentials above 30-40 mV (By similarity). The open state has a weak anion selectivity whereas the closed state is cation-selective (By similarity). Binds various lipids, including the sphingolipid ceramide, the phospholipid phosphatidylcholine, and the sterol cholesterol (PubMed:31015432). Binding of ceramide promotes the mitochondrial outer membrane permeabilization (MOMP) apoptotic pathway (PubMed:31015432). (updated: Feb. 10, 2021)
Protein identification was indicated in the following studies:
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| empty |
Biological Process
Anion transport
Binding of sperm to zona pellucida
Mitochondrial outer membrane permeabilization
Negative regulation of intrinsic apoptotic signaling pathway
Negative regulation of protein polymerization
The reference OMIM entry for this protein is 193245
Voltage-dependent anion channel 2; vdac2
CLONING
The voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane, a small abundant protein found in all eukaryotic kingdoms, forms a voltage-gated pore when incorporated into planar lipid bilayers. VDAC is also the site of binding of the metabolic enzymes hexokinase and glycerol kinase to the mitochondrion in what may be a significant metabolic regulatory interaction. Blachly-Dyson et al. (1993) identified and characterized 2 human cDNAs encoding VDAC homologs. To confirm VDAC function, each human protein was expressed in yeast lacking the endogenous VDAC gene. Human proteins isolated from yeast mitochondria formed channels with the characteristics expected of VDAC when incorporated into planar lipid bilayers. In addition, expression of the human proteins in such strains complemented phenotypic defects associated with elimination of the endogenous yeast VDAC gene. Mitochondria expressing VDAC1 (604492) were capable of specifically binding hexokinase, whereas mitochondria expressing VDAC2 only bound hexokinase at background levels. Each human cDNA was expressed in essentially all human cell lines and tissues examined. Huizing et al. (1998) studied the human tissue distribution of mitochondrial transmembrane metabolite carriers by Northern and Western blot analyses. VDAC2 appeared to be expressed only in the heart.GENE FUNCTION
Cheng et al. (2003) found that in viable cells, BAK (600516) complexed with the mitochondrial outer membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1 exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate 'BH3-only' molecules such as tBID (601997), BIM (603827), or BAD (603167), which displace VDAC2 from BAK, enabling homooligomerization of BAK and apoptosis. Thus, Cheng et al. (2003) concluded that VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway. Yogoda et al. (2007) described the mechanism of action of the selective antitumor agent erastin, involving the RAS-RAF-MEK signaling pathway functioning in cell proliferation, differentiation, and survival. Erastin exhibits greater lethality in human tumor cells harboring mutations in the oncogenes HRAS (190020), KRAS (190070), or BRAF (164757). Using affinity purification and mass spectrometry, Yogoda et al. (2007) discovered that erastin acts through mitochondrial voltage-dependent anion channels (VDACs), a novel target for anticancer drugs. Yogoda et al. (2007) showed that erastin treatment of cells harboring oncogenic RAS causes the appearance of oxidative species and subsequent death through an oxidative, nonapoptotic mechanism. RNA interference-mediated knockdown of VDAC2 or VDAC3 (610029) caused resistance to erastin, implicating these 2 VDAC isoforms in the mechanism of action of erastin. Moreover, using purified mitochondria expressing a single VDAC isoform, Yogoda et al. (2007) found that erastin alters the permeability of the outer mitochondrial membrane. Finally, using a radiolabeled analog and a filter-binding assay, Yogoda et al. (2007) showed that erastin binds directly to VDAC2. Y ... More on the omim web site
Feb. 16, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.
July 1, 2020: Protein entry updated
Automatic update: OMIM entry 193245 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).