The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. These substrates include amino acids, lipids, inorganic ions, peptides, saccharides, peptides for antigen presentation, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. Human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease (Dean et al. 2001, Borst and Elferink 2002, Rees et al. 2009).
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Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I.; ''The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3.''; PubMedEurope PMCScholia
Lukacs GL, Mohamed A, Kartner N, Chang XB, Riordan JR, Grinstein S.; ''Conformational maturation of CFTR but not its mutant counterpart (delta F508) occurs in the endoplasmic reticulum and requires ATP.''; PubMedEurope PMCScholia
Hogue DL, Liu L, Ling V.; ''Identification and characterization of a mammalian mitochondrial ATP-binding cassette membrane protein.''; PubMedEurope PMCScholia
Ward CL, Omura S, Kopito RR.; ''Degradation of CFTR by the ubiquitin-proteasome pathway.''; PubMedEurope PMCScholia
DeStefano GM, Kurban M, Anyane-Yeboa K, Dall'Armi C, Di Paolo G, Feenstra H, Silverberg N, Rohena L, López-Cepeda LD, Jobanputra V, Fantauzzo KA, Kiuru M, Tadin-Strapps M, Sobrino A, Vitebsky A, Warburton D, Levy B, Salas-Alanis JC, Christiano AM.; ''Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth.''; PubMedEurope PMCScholia
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS, VX08-770-102 Study Group.; ''A CFTR potentiator in patients with cystic fibrosis and the G551D mutation.''; PubMedEurope PMCScholia
Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL.; ''Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.''; PubMedEurope PMCScholia
Soleimani M, Burnham CE.; ''Na+:HCO(3-) cotransporters (NBC): cloning and characterization.''; PubMedEurope PMCScholia
Frank NY, Margaryan A, Huang Y, Schatton T, Waaga-Gasser AM, Gasser M, Sayegh MH, Sadee W, Frank MH.; ''ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, Wang J, Sosa-Pineda B, Murti KG, Schuetz JD.; ''Identification of a mammalian mitochondrial porphyrin transporter.''; PubMedEurope PMCScholia
Borst P, Elferink RO.; ''Mammalian ABC transporters in health and disease.''; PubMedEurope PMCScholia
Wang N, Lan D, Gerbod-Giannone M, Linsel-Nitschke P, Jehle AW, Chen W, Martinez LO, Tall AR.; ''ATP-binding cassette transporter A7 (ABCA7) binds apolipoprotein A-I and mediates cellular phospholipid but not cholesterol efflux.''; PubMedEurope PMCScholia
El Khouri E, Le Pavec G, Toledano MB, Delaunay-Moisan A.; ''RNF185 is a novel E3 ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR).''; PubMedEurope PMCScholia
Picciotto MR, Cohn JA, Bertuzzi G, Greengard P, Nairn AC.; ''Phosphorylation of the cystic fibrosis transmembrane conductance regulator.''; PubMedEurope PMCScholia
Kaminski WE, Piehler A, Püllmann K, Porsch-Ozcürümez M, Duong C, Bared GM, Büchler C, Schmitz G.; ''Complete coding sequence, promoter region, and genomic structure of the human ABCA2 gene and evidence for sterol-dependent regulation in macrophages.''; PubMedEurope PMCScholia
Shen DW, Fojo A, Chin JE, Roninson IB, Richert N, Pastan I, Gottesman MM.; ''Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification.''; PubMedEurope PMCScholia
Morita SY, Terada T.; ''Molecular mechanisms for biliary phospholipid and drug efflux mediated by ABCB4 and bile salts.''; PubMedEurope PMCScholia
Ramjeesingh M, Ugwu F, Li C, Dhani S, Huan LJ, Wang Y, Bear CE.; ''Stable dimeric assembly of the second membrane-spanning domain of CFTR (cystic fibrosis transmembrane conductance regulator) reconstitutes a chloride-selective pore.''; PubMedEurope PMCScholia
Gloeckner CJ, Mayerhofer PU, Landgraf P, Muntau AC, Holzinger A, Gerber JK, Kammerer S, Adamski J, Roscher AA.; ''Human adrenoleukodystrophy protein and related peroxisomal ABC transporters interact with the peroxisomal assembly protein PEX19p.''; PubMedEurope PMCScholia
Kaminski WE, Orsó E, Diederich W, Klucken J, Drobnik W, Schmitz G.; ''Identification of a novel human sterol-sensitive ATP-binding cassette transporter (ABCA7).''; PubMedEurope PMCScholia
Oldfield S, Lowry C, Ruddick J, Lightman S.; ''ABCG4: a novel human white family ABC-transporter expressed in the brain and eye.''; PubMedEurope PMCScholia
Nasonkin I, Illing M, Koehler MR, Schmid M, Molday RS, Weber BH.; ''Mapping of the rod photoreceptor ABC transporter (ABCR) to 1p21-p22.1 and identification of novel mutations in Stargardt's disease.''; PubMedEurope PMCScholia
Sun H, Molday RS, Nathans J.; ''Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease.''; PubMedEurope PMCScholia
Zhao C, Haase W, Tampé R, Abele R.; ''Peptide specificity and lipid activation of the lysosomal transport complex ABCB9 (TAPL).''; PubMedEurope PMCScholia
Aubourg P, Mosser J, Douar AM, Sarde CO, Lopez J, Mandel JL.; ''Adrenoleukodystrophy gene: unexpected homology to a protein involved in peroxisome biogenesis.''; PubMedEurope PMCScholia
Abe-Dohmae S, Ikeda Y, Matsuo M, Hayashi M, Okuhira K, Ueda K, Yokoyama S.; ''Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate high density lipoprotein.''; PubMedEurope PMCScholia
Yamano G, Funahashi H, Kawanami O, Zhao LX, Ban N, Uchida Y, Morohoshi T, Ogawa J, Shioda S, Inagaki N.; ''ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells.''; PubMedEurope PMCScholia
Csere P, Lill R, Kispal G.; ''Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p.''; PubMedEurope PMCScholia
Dean M, Rzhetsky A, Allikmets R.; ''The human ATP-binding cassette (ABC) transporter superfamily.''; PubMedEurope PMCScholia
Petry F, Kotthaus A, Hirsch-Ernst KI.; ''Cloning of human and rat ABCA5/Abca5 and detection of a human splice variant.''; PubMedEurope PMCScholia
Sacksteder KA, Jones JM, South ST, Li X, Liu Y, Gould SJ.; ''PEX19 binds multiple peroxisomal membrane proteins, is predominantly cytoplasmic, and is required for peroxisome membrane synthesis.''; PubMedEurope PMCScholia
Osborne L, Knight R, Santis G, Hodson M.; ''A mutation in the second nucleotide binding fold of the cystic fibrosis gene.''; PubMedEurope PMCScholia
Kamijo K, Osumi T, Hashimoto T.; ''[PMP70, the 70-kDa peroxisomal membrane protein: a member of the ATP-binding cassette transporters].''; PubMedEurope PMCScholia
Holzinger A, Kammerer S, Berger J, Roscher AA.; ''cDNA cloning and mRNA expression of the human adrenoleukodystrophy related protein (ALDRP), a peroxisomal ABC transporter.''; PubMedEurope PMCScholia
Paytubi S, Wang X, Lam YW, Izquierdo L, Hunter MJ, Jan E, Hundal HS, Proud CG.; ''ABC50 promotes translation initiation in mammalian cells.''; PubMedEurope PMCScholia
Biswas EE, Biswas SB.; ''The C-terminal nucleotide binding domain of the human retinal ABCR protein is an adenosine triphosphatase.''; PubMedEurope PMCScholia
Vembar SS, Brodsky JL.; ''One step at a time: endoplasmic reticulum-associated degradation.''; PubMedEurope PMCScholia
Akiyama M, Sugiyama-Nakagiri Y, Sakai K, McMillan JR, Goto M, Arita K, Tsuji-Abe Y, Tabata N, Matsuoka K, Sasaki R, Sawamura D, Shimizu H.; ''Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer.''; PubMedEurope PMCScholia
Babenko AP, Gonzalez G, Aguilar-Bryan L, Bryan J.; ''Reconstituted human cardiac KATP channels: functional identity with the native channels from the sarcolemma of human ventricular cells.''; PubMedEurope PMCScholia
Fang Y, Morrell JC, Jones JM, Gould SJ.; ''PEX3 functions as a PEX19 docking factor in the import of class I peroxisomal membrane proteins.''; PubMedEurope PMCScholia
Wolters JC, Abele R, Tampé R.; ''Selective and ATP-dependent translocation of peptides by the homodimeric ATP binding cassette transporter TAP-like (ABCB9).''; PubMedEurope PMCScholia
Chloupková M, Reaves SK, LeBard LM, Koeller DM.; ''The mitochondrial ABC transporter Atm1p functions as a homodimer.''; PubMedEurope PMCScholia
Morita SY, Kobayashi A, Takanezawa Y, Kioka N, Handa T, Arai H, Matsuo M, Ueda K.; ''Bile salt-dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4.''; PubMedEurope PMCScholia
Piehler A, Kaminski WE, Wenzel JJ, Langmann T, Schmitz G.; ''Molecular structure of a novel cholesterol-responsive A subclass ABC transporter, ABCA9.''; PubMedEurope PMCScholia
Kapoor H, Koolwal A, Singh A.; ''Ivacaftor: a novel mutation modulating drug.''; PubMedEurope PMCScholia
Klugbauer N, Hofmann F.; ''Primary structure of a novel ABC transporter with a chromosomal localization on the band encoding the multidrug resistance-associated protein.''; PubMedEurope PMCScholia
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMedEurope PMCScholia
Rees DC, Johnson E, Lewinson O.; ''ABC transporters: the power to change.''; PubMedEurope PMCScholia
Tsuruoka S, Ishibashi K, Yamamoto H, Wakaumi M, Suzuki M, Schwartz GJ, Imai M, Fujimura A.; ''Functional analysis of ABCA8, a new drug transporter.''; PubMedEurope PMCScholia
Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM.; ''Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A).''; PubMedEurope PMCScholia
Paytubi S, Morrice NA, Boudeau J, Proud CG.; ''The N-terminal region of ABC50 interacts with eukaryotic initiation factor eIF2 and is a target for regulatory phosphorylation by CK2.''; PubMedEurope PMCScholia
Tammaro P, Ashcroft FM.; ''A mutation in the ATP-binding site of the Kir6.2 subunit of the KATP channel alters coupling with the SUR2A subunit.''; PubMedEurope PMCScholia
Engel T, Lorkowski S, Lueken A, Rust S, Schlüter B, Berger G, Cullen P, Assmann G.; ''The human ABCG4 gene is regulated by oxysterols and retinoids in monocyte-derived macrophages.''; PubMedEurope PMCScholia
Kaminski WE, Piehler A, Schmitz G.; ''Genomic organization of the human cholesterol-responsive ABC transporter ABCA7: tandem linkage with the minor histocompatibility antigen HA-1 gene.''; PubMedEurope PMCScholia
Jensen TJ, Loo MA, Pind S, Williams DB, Goldberg AL, Riordan JR.; ''Multiple proteolytic systems, including the proteasome, contribute to CFTR processing.''; PubMedEurope PMCScholia
Vaughan AM, Oram JF.; ''ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins.''; PubMedEurope PMCScholia
Gelman MS, Kannegaard ES, Kopito RR.; ''A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator.''; PubMedEurope PMCScholia
Liu LX, Janvier K, Berteaux-Lecellier V, Cartier N, Benarous R, Aubourg P.; ''Homo- and heterodimerization of peroxisomal ATP-binding cassette half-transporters.''; PubMedEurope PMCScholia
Kamisako T, Leier I, Cui Y, König J, Buchholz U, Hummel-Eisenbeiss J, Keppler D.; ''Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2.''; PubMedEurope PMCScholia
Demirel O, Waibler Z, Kalinke U, Grünebach F, Appel S, Brossart P, Hasilik A, Tampé R, Abele R.; ''Identification of a lysosomal peptide transport system induced during dendritic cell development.''; PubMedEurope PMCScholia
Zhang F, Zhang W, Liu L, Fisher CL, Hui D, Childs S, Dorovini-Zis K, Ling V.; ''Characterization of ABCB9, an ATP binding cassette protein associated with lysosomes.''; PubMedEurope PMCScholia
Graf SA, Haigh SE, Corson ED, Shirihai OS.; ''Targeting, import, and dimerization of a mammalian mitochondrial ATP binding cassette (ABC) transporter, ABCB10 (ABC-me).''; PubMedEurope PMCScholia
Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH.; ''Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.''; PubMedEurope PMCScholia
Ousingsawat J, Kongsuphol P, Schreiber R, Kunzelmann K.; ''CFTR and TMEM16A are separate but functionally related Cl- channels.''; PubMedEurope PMCScholia
Ikeda Y, Abe-Dohmae S, Munehira Y, Aoki R, Kawamoto S, Furuya A, Shitara K, Amachi T, Kioka N, Matsuo M, Yokoyama S, Ueda K.; ''Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release.''; PubMedEurope PMCScholia
Zhang F, Hogue DL, Liu L, Fisher CL, Hui D, Childs S, Ling V.; ''M-ABC2, a new human mitochondrial ATP-binding cassette membrane protein.''; PubMedEurope PMCScholia
Stefková J, Poledne R, Hubácek JA.; ''ATP-binding cassette (ABC) transporters in human metabolism and diseases.''; PubMedEurope PMCScholia
Mitsuhashi N, Miki T, Senbongi H, Yokoi N, Yano H, Miyazaki M, Nakajima N, Iwanaga T, Yokoyama Y, Shibata T, Seino S.; ''MTABC3, a novel mitochondrial ATP-binding cassette protein involved in iron homeostasis.''; PubMedEurope PMCScholia
Vulevic B, Chen Z, Boyd JT, Davis W, Walsh ES, Belinsky MG, Tew KD.; ''Cloning and characterization of human adenosine 5'-triphosphate-binding cassette, sub-family A, transporter 2 (ABCA2).''; PubMedEurope PMCScholia
Deeley RG, Westlake C, Cole SP.; ''Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins.''; PubMedEurope PMCScholia
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M.; ''ABCA3 gene mutations in newborns with fatal surfactant deficiency.''; PubMedEurope PMCScholia
Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW.; ''Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.''; PubMedEurope PMCScholia
Ward CL, Kopito RR.; ''Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins.''; PubMedEurope PMCScholia
Kaminski WE, Wenzel JJ, Piehler A, Langmann T, Schmitz G.; ''ABCA6, a novel a subclass ABC transporter.''; PubMedEurope PMCScholia
Roerig P, Mayerhofer P, Holzinger A, Gärtner J.; ''Characterization and functional analysis of the nucleotide binding fold in human peroxisomal ATP binding cassette transporters.''; PubMedEurope PMCScholia
The exact roles of ABCA2 (Vulevic et al. 2001, Kaminski et al. 2001), ABCA6 (Kaminski & Wenzel et al. 2001), ABCA9 (Piehler et al. 2002) and ABCA10 (Wenzel et al. 2003), candidates for ABC lipid transporter-related activities, need to be elucidated. Even thought cholesterol-responsiveness has been noted in experimental systems, contribution of these proteins in regulation or in active transport is not yet clear.
The exact roles of ABCA2 (Vulevic et al. 2001, Kaminski et al. 2001), ABCA6 (Kaminski & Wenzel et al. 2001), ABCA9 (Piehler et al. 2002) and ABCA10 (Wenzel et al. 2003), candidates for ABC lipid transporter-related activities, need to be elucidated. Even thought cholesterol-responsiveness has been noted in experimental systems, contribution of these proteins in regulation or in active transport is not yet clear.
The human gene ABCB6 encodes a mitochondrial half-type ATP-binding cassette (ABC) protein MTABC3 which is uniquely located on the outer mitochondrial membrane and is functional as a homodimer (Krishnamurthy et al. 2006). It plays a crucial role in heme synthesis by mediating porphyrin uptake into mitochondria (Mitsuhashi et al. 2000, Krishnamurthy et al. 2006).
The multidrug resistance associated protein (MRPs) subfamily of the ABC transporter family can transport a wide and diverse range of organic anions that can be endogenous compounds and xenobiotics and their metabolites. All human MRPs (except MRP9) can mediate these transport reactions (Deeley et al. 2006). Separately, specific reactions have also been annotated to describe the roles of ABCC4 in platelet dense granule assembly, of ABCC1 in LTC4 export (an aspect of leukotriene synthesis), and of ABCC3 in bile salt efflux.
Human ABCG4 shows sequence homology to the Drosophila white gene, the product of which must dimerise to become functionally active. ABCG4 is closely related to ABCG1 with 74% identity and is thus thought to play a role in the efflux of excess cholesterol (Engel et al. 2001). Northern Blot analysis shows that ABCG4 is expressed specifically in brain and the eye (Oldfield et al. 2002).
Some members of the ABC transporter superfamily are able to mediate the efflux of a broad range of cytotoxic drugs from cells, leading to the name multidrug resistance (MDR) proteins (Seeger and van Veen 2009). The ABCB1 (P-glycoprotein 1[PGP], multidrug resistance protein 1 [MRP1]) is the most characterised MDR (Shen et al. 1986, Gottesman & Pastan 1988). ABCB5 (Frank et al. 2005) and ABCA8 (Tsuruoka et al. 2002) are newer members of MDRs.
Rhodopsin (RHO) is localised to both the disc membrane and the plasma membrane of rod outer segments (ROS). All-trans-retinal (atRAL) released from rhodopsin during the bleaching process, needs to translocate to the cytosol for reduction to all-trans-retinol (atROL) via all-trans-retinol dehydrogenases. Although atRAL can diffuse through membranes unaided, there exists an ABC transporter on disc membranes which may facilitate the transport of excess atRAL. Retinal-specific ATP-binding cassette transporter (ABCA4, ABCR) is the only ABC transporter which mediates the transport of retinoids (Biswas & Biswas 2000). Studies using bovine ABCA4 demonstrates atRAL transport (Sun et al. 1999). Human ABCR was found to be identical to the ABC transporter linked to Stargardt's disease type 1 (STGD1, MIM:248200), a cause of macular degeneration in childhood (Nasonkin et al. 1998).
The complex of ATP-binding cassette sub-family G members 5 and 8 (ABCG5:ABCG8) in the plasma membrane mediates the ATP-dependent export of cytosolic sterols (cholesterol and phytosterols). Mutations affecting the ABCG5/8 proteins are associated with the accumulation of high levels of cholesterol and phytosterols in the body, demonstrating the specificity and physiological importance of this process (Berge et al. 2000). Human ABCG5/8 has not been studied in detail, but the homologous mouse protein complex mediate ATP-dependent sterol export (Wang et al. 2006). The mouse proteins localize to the apical plasma membranes of enterocytes and hepatocytes, consistent with the hypothesis that in vivo ABCG5/8 mediates sterol export into the gut lumen and from hepatocytes into the bile (Graf et al. 2003).
In an ATP-dependent reaction, ABCG1 mediates the movement of intracellular cholesterol to the extracellular face of the plasma membrane. In a tissue culture model system, the active form of ABCG1 is predominantly a tetramer (Vuaghan and Oram 2005). The number of lipid molecules transported per ATP consumed is not known.
ABCA7 has the ability to bind apolipoproteins and promote efflux of cellular phospholipids and may have a possible role in cellular phospholipid metabolism in peripheral tissues. Like many other ABC-transporters, the exact role of ABCA7 is waiting to be elucidated.
Mitochondrial ABC transporters are thought to play a key role in iron metabolism and heme biosynthesis. All mitochondrial ABC transporters described to date are of the half-transporter type and would probably function as dimers (Ramjeesingh et al. 2003) but their dimerization partners have not yet been identified. ABC7 is the functional human orthologue of yeast Atm1p (Csere et al. 1998), is predicted to dimerize in the same way as Atm1p (Chloupková et al. 2004) and is probably involved in iron homeostasis. Defects in ABCB7 are the cause of X-linked sideroblastic anemia with ataxia (ASAT) [MIM:301310] (Allikmets et al. 1999). Human genes ABCB8 and ABCB10 encode mABC1 and mABC2 respectively (Hogue et al. 1999, Zhang et al 2000 respectively). They would be expected to dimerize, as demonstrated for mABC2 (Graf et al. 2004). Both are believed to have similar functionality to ABC7 although this has not been demonstrated yet.
The 70-kDa peroxisomal membrane protein (PMP70) and the adrenoleukodystrophy protein (ALDP aka ABCD1) are half ATP binding cassette (ABC) transporters in the peroxisome membrane. They are involved in metabolic transport of long and very long chain fatty acids into peroxisomes. Mutations in the ALD gene result in the X-linked neurodegenerative disorder adrenoleukodystrophy (ALD; MIM:300100). ABCD1 deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients with ALD have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. In addition to ABCD1, other genes and environmental factors determine clinical features of ALD (Kemp et al. 2012, Berger et al. 2014).
PEX19 is a chaperone protein that binds a broad spectrum of peroxisomal membrane proteins (PMPs), and interacts with regions of PMPs required for their targeting to peroxisomes. PEX3 is required for PEX19 to dock at peroxisomes, interacts specifically with the docking domain of PEX19, and is required for recruitment of the PEX19 docking domain to peroxisomes. The ABC transporters D1, D2 and D3 must first form dimers to become fully functional (Liu et al.1999) which then can bind with PEX19.
Regulation of epithelial chloride flux, which is defective in patients with cystic fibrosis, may be mediated by phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR) by cyclic AMP-dependent protein kinase (PKA) or protein kinase C (PKC). CFTR regulates both HCO(3)(-) secretion and HCO(3)(-) salvage in secretory epithelia.
ATP-binding cassette sub-family B member 9 (ABCB9, aka lysosomal ABC transporter associated with antigen processing-like, TAPL) is a homodimeric ATP-dependent low affinity peptide transporter (Wolters et al. 2005), localised on the lysosomal membrane (Zhang et al. 2000). It is able to transport a broad spectrum of peptides (from 6mer up to at least 59mer peptides, optimum of 23mers) from the cytosol to the lysosomal lumen. ABCB9 favours positively charged, aromatic or hydrophobic residues in the N- and C-terminal positions whereas negatively charged residues and asparagine and methionine residues are not favoured (Wolters et al. 2005, Demirel et al. 2007, Zhao et al. 2008). The reaction described here shows the transport of the optimum 23mer peptide.
ATP-binding cassette sub-family F member 1 (ABCF1 aka ABC50) is unlike most ABC proteins in that it does not possess membrane-spanning domains. ABCF1 interacts with eukaryotic initiation factor 2 complex (EIF2S1:EIF2S2:EIF2S3), a key player in translation initiation and control and in ribosome regulation. ABCF1 is predominantly located in the cytosol, whereas a smaller amount is also found in the nucleoplasm but not in the nucleolus. Knockout of ABCF1 impaired translation of both cap-dependent and cap-independent reporters, consistent with a positive role for ABCF1 in the function of the EIF2 complex (Paytubi et al. 2008, Paytubi et al. 2009).
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11) is an inward rectifier potassium channel, favouring potassium flow into the cell rather than out of it. KCNJ11 can complex with ATP-binding cassette sub-family member 9 (ABCC9) to form cardiac and smooth muscle-type K+(ATP) channels. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (Babenko et al. 1998, Tammaro & Ashcroft 2007).
Multidrug resistance protein 3 (ATP-binding cassette sub-family B member 4, ABCB4 aka MDR3) mediates the ATP-dependent export of organic anions and drugs from hepatocytes into the canalicular lumen in the presence of bile salts. ABCB4 is especially important for the export of phospholipids such as phosphatidylcholine (PC) from the plasma membrane of hepatocytes (Morita et al. 2007). Biliary phospholipids associate with bile salts and cholesterol in mixed micelles, thereby reducing the detergent activity and cytotoxicity of bile salts and preventing cholesterol crystallisation. Thus, ABCB4 plays a crucial role in bile formation and lipid homeostasis (Morita & Terada 2014).
Cystic fibrosis transmembrane conductance regulator (CFTR) is a low conductance chloride-selective channel that mediates the transport of chloride ions in human airway epithelial cells which plays a key role in maintaining homoeostasis of epithelial secretions in the lungs. Defects in CFTR can cause cystic fibrosis (CF; MIM:602421), a common generalised disorder in Caucasians affecting the exocrine glands. CF results in an ionic imbalance that impairs clearance of secretions, not only in the lung, but also in the pancreas, gastrointestinal tract and liver (Riordan et al. 1999, Ousingsawat et al. 2011).
Cystic fibrosis transmembrane conductance regulator (CFTR) is a low conductance chloride-selective channel that mediates the transport of chloride ions in human airway epithelial cells which plays a key role in maintaining homoeostasis of epithelial secretions in the lungs. Defects in CFTR can cause cystic fibrosis (CF; MIM:602421), a common generalised disorder in Caucasians affecting the exocrine glands. CF results in an ionic imbalance that impairs clearance of secretions, not only in the lung, but also in the pancreas, gastrointestinal tract and liver. Wide-ranging manifestations of the disease include chronic lung disease, exocrine pancreatic insufficiency, blockage of the terminal ileum, male infertility and salty sweat.
The class 3 mutations of CFTR such as G551D strongly decrease the time spent by CFTR in the open state (a gating defect). Results from 2-phase clinical trials using VX-770 (aka Ivacaftor), a CFTR potentiator, showed an increased CFTR channel open probability in G551D patients. Ivacaftor use showed improvements in CFTR and lung function of patients with at least one G551D allele (Accurso et al. 2010, Ramsey et al. 2011, Kapoor et al. 2014). In 2012, the FDA approved Ivacaftor (under the trade name Kalydeco) for use in cystic fibrosis patients with the G551D mutation (Ledford 2012).
Defects in cystic fibrosis transmembrane conductance regulator (CFTR) can cause cystic fibrosis (CF; MIM:602421), a common generalised disorder in Caucasians affecting the exocrine glands. CF results in an ionic imbalance that impairs clearance of secretions, not only in the lung, but also in the pancreas, gastrointestinal tract and liver. Wide-ranging manifestations of the disease include chronic lung disease, exocrine pancreatic insufficiency, blockage of the terminal ileum, male infertility and salty sweat. The class 3 mutations of CFTR such as G551D strongly decrease the time spent by CFTR in the open state (a gating defect). Results from 2-phase clinical trials using VX-770 (aka Ivacaftor), a CFTR potentiator, showed an increased CFTR channel open probability in G551D patients. Ivacaftor use showed improvements in CFTR and lung function of patients with at least one G551D allele (Accurso et al. 2010, Ramsey et al. 2011, Kapoor et al. 2014). In 2012, the FDA approved Ivacaftor (under the trade name Kalydeco) for use in cystic fibrosis patients with the G551D mutation (Ledford 2012).
Canalicular multispecific organic anion transporter 1 (ABCC2 aka multidrug resistance-associated protein 2, MRP2), in addition to transporting many organic anions, mediates the ATP-dependent transport of glutathione and glucuronate conjugates from hepatocytes into bile. In the reaction annotated here, ABCC2 specifically transports, with high affinity and efficiency, mono- and di-glucuronated bilirubin into bile (Kamisako et al. 1999). Bilirubin, the end product of heme breakdown, is an important constituent of bile and is responsible for its characteristic colour.
ATP-binding cassette sub-family A member 12 (ABCA12) is thought to function as an epidermal keratinocyte lipid transporter. Lipids such as glucosylceramides and gangliosides form extracellular lipid layers in the stratum corneum of the epidermis, essential for skin barrier function (Akiyama et al. 2005). Mutations in ABCA12 can cause autosomal recessive congenital ichthyoses (ARCI).
ATP-binding cassette sub-family A member 3 (ABCA3) plays an important role in the formation of pulmonary surfactant, probably by transporting phospholipids such as phosphatidylcholine (PC) and phosphatidylglycerol (PG) from the ER membrane to lamellar bodies (LBs). PC and PG are the major phospholipid constituents of pulmonary surfactant. LBs are the surfactant storage organelles of type II epithelial cells from where phospholipids can be secreted together with surfactant proteins (SFTPs) into the alveolar airspace (Klugbauer & Hofmann 1996, Yamano et al. 2001). Defects in ABCA3 are the cause of pulmonary surfactant metabolism dysfunction type 3 (SMDP3; MIM:610921) (Shulenin et al. 2004).
The ABC transporter subfamily A member ABCA5 is thought to mediate cholesterol (CHOL) efflux from lysosomes (Petry et al. 2003). ABCA5 defects are associated with autosomal recessive congenital generalised hypertrichosis terminalis (CGHT; MIM:135400). Lysosomal function is reduced with an accumulation of autophagosomes and their cargo as well as increased endolysosomal cholesterol in CGHT keratinocytes, resulting in hair overgrowth (DeStefano et al. 2014).
Retrotranslocation of the misfolded CFTR likely depends on the ERAD ATPase VCP (reviewed in Vembar and Brodsky, 2008; Pranke and Sermet-Gaudelus, 2014).
RNF5 and RNF185 ubiquitinate misfolded CFTR as part of the retrotranslocon that targets the receptor for degradation through the ERAD pathway. Both depletion of the E3 ligases by siRNA and expression of a catalytically inactive form of the enzyme strongly inhibits CFTR degradation (El Khouri et al, 2013; Younger et al, 2006).
Up to two thirds of wild-type CFTR is targeted for co-translational degradation by the ERAD pathway due to inefficient folding (Jensen et al, 1995; Ward et al, 1994; Ward et al, 1995; Gelman et al, 2002; Lukacs et al, 1994). Misfolded CFTR is ubiquitinated in the ER by E3 ligases RNF5 and RNF185, likely as part of a mulitprotein retrotranslocation complex containing the hexameric ATPase VCP and various scaffolding and structural proteins (reviewed in Vembar and Brodsky, 2008). Consistent with this, RNF185 interacts directly both with CFTR and with other components of the ERAD machinery, including E2 proteins, ERLIN and DERLIN proteins (Younger et al, 2006; El Khouri et al, 2013).
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride ion channel that undergoes multiple folding processes and post-translational modifications during its biosynthesis. 60-80% of CFTR protein encoded by the wild-type (WT) gene is successfully modified and transits the secretory system to the plasma membrane. The remaining misfolded protein is targeted for degradation by the ER, lysosomes or autophagy (reviewed in Pranke and Sermet-Gaudelus, 2014)
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The class 3 mutations of CFTR such as G551D strongly decrease the time spent by CFTR in the open state (a gating defect). Results from 2-phase clinical trials using VX-770 (aka Ivacaftor), a CFTR potentiator, showed an increased CFTR channel open probability in G551D patients. Ivacaftor use showed improvements in CFTR and lung function of patients with at least one G551D allele (Accurso et al. 2010, Ramsey et al. 2011, Kapoor et al. 2014). In 2012, the FDA approved Ivacaftor (under the trade name Kalydeco) for use in cystic fibrosis patients with the G551D mutation (Ledford 2012).