Source: http://tcdb.org/tcfamilybrowse.php?tc=1.B.8
Timestamp: 2019-04-24 11:50:14+00:00

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Porins of the MPP family are found in eukaryotic organelles. The organelles include mitochondria of many eukaryotes as well as chloroplasts and plastids of plants. The best characterized members of the MPP family are the voltage-dependent anion-selective channel (VDAC) porins in the mitochondrial outer membrane. These porins have an estimated channel diameter of 2.5-3 nm. Topological models have been proposed in which VDAC consists of an N-terminal, globular α-helix and (1) 12 or 13 β-strands, (2) 16 β-strands or (3) 19 β-strands (now favored; see below) (Casadio et al., 2002). VDAC also appears to be present in plasma membranes (De Pinto et al., 2010). Prostacyclin receptor-mediated ATP release from ethrocytes requires VDAC (Sridharan et al., 2011). Phylogenetic analyses of eukaryotic VDAC proteins from diverse organisms have been reported (Wojtkowska et al. 2012). Over-oxidation of cysteines and succinylation of cysteines in VDACs has been noticed (Saletti et al. 2018).
A murine VDAC, VDAC-1, exhibits more than one topological type due to the use of alternative first exons. Thus, two different porins, differing only with respect to their N-termini, have been identified. One porin isoform (plasmalemmal VDAC-1) has a hydrophobic leader peptide that targets the protein through the golgi apparatus to the plasma membrane; the other isoform (mitochondrial VDAC-1) is translocated to the outer mitochondrial membrane because it lacks the N-terminal hydrophobic leader. The former is believed to account for the plasma membrane Maxi (large conductance) Cl- channel (Bahamonde et al., 2003).
VDACs play a role in forming the mitochondrial permeability transition pore (PTP) which is important for Ca2+ homeostasis and programmed cell death. PTP is triggered by Ca2+ influx into mitochondria, and VDAC is permeable to Ca2+. It is also regulated by various compounds such as glutamate, NADH and nucleotides. VDAC has two nucleotide binding sites (Yehezkel et al., 2006). In VDAC1 the two cysteine residues seem not to be required for apoptosis or VDAC1 oligomerization (Aram et al., 2010). Ions interact intimately with the inner walls of the channel and are selected by their 3-dimensional structure, not merely by their size and charge (Colombini 2016). The N-terminus acts not as a gate on a stable barrel, but rather stabilizes the barrel, preventing its shift into a partially collapsed, low-conductance, closed state (Shuvo et al. 2016).
Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons. Misfolded mutant SOD1 binds directly to VDAC1. Direct binding of mutant SOD1 to VDAC1 inhibits conductance of channels when reconstituted in a lipid bilayer (Israelson et al., 2010).
VDAC-protein interactions for each mammalian isoform (VDAC1, 2 and 3) showed that VDAC1 is mainly involved in the maintenance of cellular homeostasis and in pro-apoptotic processes, whereas VDAC2 displays an anti-apoptotic role, while VDAC3 may contribute to mitochondrial protein quality control and act as a marker of oxidative status (Caterino et al. 2017). In pathological conditions, namely neurodegenerative and cardiovascular diseases, both VDAC1 and VDAC2 establish abnormal interactions aimed to counteract the mitochondrial dysfunction which contributes to end-organ damage.
Persistent opening of PTP creates a bioenergetic crisis with collapse of the membrane potential, ATP depletion, Ca2+ deregulation, and release of proteins such as cytochrome c into the cytoplasm. These events promote cell death. The PTP traverses the inner and outer membranes and involves the ATP/ADP exchanger in the inner membrane and VDAC in the other membrane (Cesura et al., 2003). Another postulate suggests that a calcium-triggered conformational change of the mitochondrial phosphate carrier (PiC), facilitated by cyclophilin-D (CyP-D), induces pore opening. This is enhanced by an association of the PiC with the 'c' conformation of the ANT. Agents that modulate pore opening may act on either or both the PiC and the ANT (Leung and Halestrap, 2008).
The selective anti-tumour agent erastin causes the appearance of oxidative species and subsequent death through an oxidative, non-apoptotic mechanism. RNA-interference-mediated knockdown of VDAC2 or VDAC3 caused resistance to erastin. Using purified mitochondria expressing a single VDAC isoform, erastin alters the permeability of the outer mitochondrial membrane by binding directly to VDAC2. Thus, ligands to VDAC proteins can induce non-apoptotic cell death selectively in some tumour cells harbouring activating mutations in the RAS-RAF-MEK pathway (Yagoda et al., 2007).
It forms a 19-stranded beta barrel with the first and last strand parallel. The hydrophobic outside perimeter of the barrel is covered by detergent molecules in a beltlike fashion (Hiller et al., 2010). In the presence of cholesterol, recombinant VDAC-1 can form voltage-gated channels in phospholipid bilayers similar to those of the native protein. The NMR measurements revealed the binding sites of VDAC-1 for the Bcl-2 protein, Bcl-x(L), for reduced beta-nicotinamide adenine dinucleotide, and for cholesterol. Bcl-x(L) interacts with the VDAC barrel laterally at strands 17 and 18 (Hiller et al., 2008). The position of the voltage-sensing N-terminal segment is oriented against the interior wall, causing a partial narrowing at the center of the pore. This segment is ideally positioned to regulate the conductance of ions and metabolites passing through the VDAC pore (Ujwal et al., 2008).
Mitochondria import 90-99% of their proteins from the cytosol. Three protein families including Sam50, VDAC and Tom40 together with Mdm10 compose the set of integral beta-barrel proteins embedded in the mitochondrial outer membrane in S. cerevisiae (MOM) (Zeth 2010). The 16-stranded Sam50 protein forms part of the sorting and assembly machinery (SAM) and shows a clear evolutionary relationship to members of the bacterial Omp85 family (1.B.33). VDAC and Tom40 both adopt the same fold with 19 probable TMSs. Tom40 is in the TOM complex (3.A.8). Models of Tom40 and Sam50 have been developed using X-ray structures of related proteins. These models have been analyzed with respect to properties such as conservation and charge distribution yielding features related to their individual functions (Zeth 2010).
The gene for VDAC1 in humans is over-expressed in many cancer types, and silencing of VDAC1 expression inhibits tumor development. Along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death (Shoshan-Barmatz et al. 2015).
Under cellular stress, human VDACs hetero-oligomerize and coaggregate with proteins that can form amyloidogenic and neurodegenerative deposits, implicating a role for VDACs in proteotoxicity. Gupta and Mahalakshmi 2019 mapped aggregation-prone regions of human VDACs, using isoform 3 as the model VDAC, and showed that the region comprising strands beta7-beta9 is aggregation prone. An alpha1-beta7-beta9 interaction (involving the hVDAC3 N-terminal alpha1 helix) can lower protein aggregation, whereas perturbations of this interaction promote VDAC aggregation. hVDAC3 aggregation proceeds via a partially unfolded structure.
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Voltage-dependent anion channel-1 (VDAC1; OMP2; Por1) porin. It is a component of the mitochondrial permeability transition pore (mPTP) which includes cyclophilin D, VDAC and the adenine nucleotide translocator (TC subfamily 2.A.29.1) (Austin et al. 2013). Mitochondrial synthesis of cardiolipin (CL) and phosphatidylethanolamine requires the transport of their precursors, phosphatidic acid and phosphatidylserine, respectively, to the mitochondrial inner membrane. The Ups1-Mdm35 and Ups2-Mdm35 complexes transfer phosphatidic acid and phosphatidylserine, respectively, between the mitochondrial outer and inner membranes. A Ups1-independent CL accumulation pathway requires several mitochondrial proteins with unknown functions including Mdm31. Miyata et al. 2018 identified VDAC1 (Por1) as a protein that interacts with both Mdm31 and Mdm35. Depletion of the porins Por1 and Por2 destabilized Ups1 and Ups2, decreased CL levels by ~90%, and caused loss of Ups2-dependent phosphatidylethanolamine synthesis, but did not affect Ups2-independent phosphatidylethanolamine synthesis in mitochondria. Por1 mutations that affected its interactions with Mdm31 and Mdm35, but not respiratory growth, also decreased CL levels. Using HeLa cells, the authors showed that mammalian porins also function in mitochondrial CL metabolism. Thus, yeast porins function in mitochondrial phospholipid metabolism, and porin-mediated regulation of CL metabolism appears to be evolutionarily conserved.
Outer membrane porin, VDAC of 346 aas. This protein may function in the thylacoid membrane of the chloroplast as a non-selective voltage-indiependent porin (see TC# 1.B.8.8.7 and Kojima et al. 2018).
Mitochondrial outer membrane voltage-dependent anion-selective channel protein 2, VDAC-2 of 294 aas. Protein:micelle ratios and cysteine residues in the protein influence VDAC2 stability and unfolding rates (Maurya and Mahalakshmi 2014). VDAC-2 performs a different subset of regulatory functions than VDAC1. It has anti-apoptotic features and contributes to gametogenesis.It may also regulate ROS, steroidogenesis and mitochondria-associated endoplasmic reticulum membrane regulatory pathways (Maurya and Mahalakshmi 2015). Plays a role in mitochondrial import of Bak and tBid-induced apoptosis (Naghdi et al. 2015). VDAC2 plasticity and stability in the mitochondrial outer membrane are modulated by physical properties of the bilayer (Srivastava et al. 2018).
Mitochondrial outer membrane porin, PorA or VDAC (Troll et al. 1992).
VDAC1 of 276 aas, one of five isoforms. A knock out mutation (Δvdac1) resulted in abnormal ovule formation during female gametogenesis, and both the mitochondrial transmembrane potential and ATP synthesis were reduced (Pan et al. 2014).
Non-selective channel of the thylakoid membrane of 275 aas and one TMSs, CpTPOR (Kojima et al. 2018). The channels are large enough for permeation of small organic compounds (e.g. carbohydrates and amino acids with Mr < 1500). The pore has an estimated radius of ∼1.3 nm and exhibits a typical single-channel conductance of 1.8 nS in 1 m KCl with infrequent closing transitions. CpTPOR exhibits no obvious selectivity for anions and no voltage-dependent gating. It presumably enables rapid transfer of various metabolites between the lumen and stroma (Kojima et al. 2018).
VDAC2 of 281 aas, 1 N-terminal α-TMS and 19 β-TMSs. Forms channels much like those of VDAC1 (Guardiani et al. 2018).
Outer membrane porin, VDAC3 (HSR2) of 274 aas. This protein may function in the thylacoid membrane of the chloroplast as a non-selective voltage-indiependent porin (see TC# 1.B.8.8.7 and Kojima et al. 2018).
VDAC3 porin. The human orthologue forms small pores in membranes (Checchetto et al. 2014). VDAC3 is a sensor of the oxidative state in the mitochondrial intermembrane space, and cysteyl residue modification appears to play a role (Reina et al. 2016).
VDAC1 porin. > 99% identical to human (P21796) and mouse (60932) VDAC1. Mammals possess three VDACs (VDAC1, 2 and 3) encoded by three genes, but they are all similar in sequence (~60-70% identical) (Messina et al., 2011). The 3-d structure of the human VDAC1 is known (PDB ID 2JK4; Bayrhuber et al. 2008). Reviewed by Shoshan-Barmatz et al. 2015. VDAC1 is found both in mitochondria and the plasma membrane (Lawen et al. 2005) where it may cause cytoplasmic ATP loss.. It may be involved in cancer (Shoshan-Barmatz et al. 2017) and Alzheimer's disease (AD) (Shoshan-Barmatz et al. 2018). Along with its low toxicity profile and high antioxidant activity, the gallic acid derivative, AntiOxBEN3, strongly inhibits calcium-dependent mitochondrial permeability transition pore (mPTP) opening (Teixeira et al. 2018). VDAC dimerization plays a role in mitochondrial metabolic regulation and apoptosis in response to cytosolic acidification during cellular stress, and E73 is involved (Bergdoll et al. 2018). Inhibiting VDAC1 overproduction and plasma membrane insertion in β-cells preserves insulin secretion in diabetes (Zhang et al. 2018).
VDAC porin. The open state has a weak anion selectivity whereas the closed state is cation-selective.
Voltage-dependent anion-selective porin1 (Porin-1, VDAC or Por-1) (De Pinto et al. 1989; Aiello et al., 2004) (one of three paralogues). Mutations in VDAC leads to neurologic dysfunction and male infertility in Drosophila (Graham et al., 2010). Porin 1 is abundantly expressed in both male and female germ cell tissues; Porin 2 is abundant in testis but in small amounts in ovaries. The immuno-histological stain of ovaries shows that Porin isoform 1 is selectively targeted to follicular cells while Porin isoform 2 is present in mitochondria of the epithelial sheath cells of the ovariole (Guarino et al. 2006; Specchia et al. 2008).
Voltage-independent, cation-selective porin2 (Porin-2 or Por-2) (converted to anion selective by changing Glu-66 and Glu-163 to lysines; Aiello et al., 2004). One of three paralogues (Craigen and Graham, 2008). Porin 1 is abundantly expressed in both male and female germ cell tissues; Porin 2 is abundant in testis but in small amounts in ovaries. The immuno-histological stain of ovaries shows that Porin 1 is selectively targeted to follicular cells while Porin 2 is present in mitochondria of the epithelial sheath cells of the ovariole (Specchia et al. 2008).
Rice VDAC4. Channels formed in planar bilayers exhibit large conductance (4.6 ± 0.3 nS in 1 M KCl), strong voltage dependence and weak anion selectivity. The open state of the channel is permeable to ATP (Godbole et al. 2011).
Mitochondrial outer membrane porin, VDAC, of 292 aas (De Pinto et al. 1989).
19 β-stranded barrel translocase across the outer membrane, Tom40 (Pfam Porin 3 Superfamily).
Entamoeba histolytica, an anaerobic intestinal parasite causing dysentery and extra-intestinal abscesses in humans, possesses highly reduced and divergent mitochondrion-related organelles (MROs) called mitosomes. This organelle lacks many features associated with canonical aerobic mitochondria and even other MROs such as hydrogenosomes. The Entamoeba mitosome has been found to have a compartmentalized sulfate activation pathway, which has a role in amebic stage conversion. It also features a unique shuttle system that delivers proteins from the cytosol to the mitosome. Only Entamoeba mitosomes possess a novel subclass of β-barrel outer membrane protein called MBOMP30.The mitosome protein import complex consisting of at least two proteins, TOM40, which provides the channel, and TOM60, which seems to be necessary for protein import (Makiuchi et al. 2013; Santos et al. 2016).
Mitochondrial porin of 305aas (Porin3_VDAC superfamily). Exhibits the properties of a voltage-dependent general diffusion porin with cation-selectivity and a pore diameter of 1.3 nm (Ludwig et al. 1989).
The Mdm10 protein of 493 aas, a putative eukaryotic porin. It belongs to the eukaryotic porin 3 superfamily together with VDAC and Tom40 (Flinner et al. 2013). This protein is also listed under TC# 1.B.33.3.1 and TC#9.B.58.1.1 as part of two complexes: the mitochondrial Sorting and Assembly Machinery (SAM) and the TULIP complex, respectively.
Pore-forming β-barrel porin of 308 aas in hydrogenosomes, Tom40-1 (Makki et al. 2019).
Pore-forming β-barrel porin of 290 aas, present in hydrogenosomes, Tom40-2 (Makki et al. 2019).
Pore-forming β-barrel porin of 305 aas in hydrogenosomes, Tom40-3 (Makki et al. 2019).
Pore-forming β-barrel porin of 296 aas in hydrogenosomes, Tom40-4 (Makki et al. 2019).
Pore-forming β-barrel porin of 397 aas in hydrogenosomes, Tom40-5 (Makki et al. 2019).
Pore-forming β-barrel porin of 298 aas in hydrogenosomes, Tom40-6 (Makki et al. 2019).

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 V. 
 V.