ATP-binding cassette family
||It has been suggested that this article be merged with ATP-binding cassette transporter. (Discuss) Proposed since December 2012.|
The ATP Binding Cassette Family, also known as the ABC Superfamily is the largest transporter protein family, includes several hundred different membrane transport proteins that utilize the energy of ATP to transport a specific substrate or group of substrates across the cell membrane. These substrates can be ions, sugars, amino acids, phospholipids, cholesterol, peptides, polysaccharides, proteins or other ligands. More than 100 ABC transporters are distributed from prokaryotes to humans. ABC genes are essential for many processes in the cell, and mutations in these genes cause or contribute to several human genetic diseases. 48 ABC genes have been reported in humans. Among these, 16 genes have been determined and 14 of these are related with diseases present in humans such as cystic fibrosis, adrenoleukodystrophy, Stargadt’s disease, drug-resistant tumors, Dubin-Johnson syndrome, Byler’s disease, progressive familiar intrahepatic cholestasis, X-linked sideroblastic anemia, ataxia, and persistent and hyperinsulimenic hypoglycemia in children. ABC transporters are also involved in multiple drug resistance, and this is how some of them were first identified. When the ABC transporter proteins are overexpressed in cancer cells they can export anticancer drugs and render tumors resistant.
The physiologic function of ABC transporters is not well known, and they are expressed constitutively in more than just cancer cells. It is known that ABC transporters bind ATP and use the energy from ATP hydrolysis to drive the transport of various molecules across the plasma membrane as well as intracellular membranes of the endoplasmic reticulum, peroxisome, and mitochondria. ABCD transporters are thought to participate in the absorption and secretion of endogenous and exogenous substances. There are normal ABC transporter cells found in digestive cells of the small intestine, large intestine, liver, and pancreas. They are also found in epithelial cells of the kidneys, adrenals, brain, and testes as well as endothelial cells found in the lining of blood vessels and lymphatic vessels. They can be thought of as a hydrophobic vacuum cleaner powered by ATP that expels nonpolar compounds from the lipid bilayer to the exterior.
All ABC transport proteins share a structural organization consisting of four core domains. These domains consist of two trans-membrane (T) domains and two cytosolic (A) domains. The T two domains alternate between an inward and outward facing orientation, and the alternation is powered by the hydrolysis of adenine triphosphate or ATP. ATP binds to the A subunits and it is then hydrolyzed to power the alternation, but the exact process by which this happens is not known. The four domains can be present in four separate polypeptides, which occur mostly in bacteria, or present in one or two multi-domain polypeptides. When the polypeptides are one domain, they are can be referred to as a full domain, and when they are two multi-domains they can be referred to as a half domain. The T domains are each built of typically 10 membrane spanning alpha helices, through which the transported substance can cross through the plasma membrane. Also, the structure of the T domains determines the specificity of each ABC protein. In the inward facing conformation, the binding site on the A domain is open directly to the surrounding aqueous solutions. This allows hydrophilic molecules to enter the binding site directly from the inner leaflet of the phospholipid bilayer. In addition, a gap in the protein is accessible directly from the hydrophobic core of the inner leaflet of the membrane bilayer. This allows hydrophobic molecules to enter the binding site directly from the inner leaflet of the phospholipid bilayer. After the ATP powered move to the outward facing conformation, molecules are released from the binding site and allowed to escape into the exoplasmic leaflet or directly into the extracellular medium.
Discovery of the first eukaryotic ABC transporter protein came from studies on tumor cells and cultured cells that exhibited resistance to several drugs with unrelated chemical structures. These cells were shown to express elevated levels of multidrug-resistance (MDR) transport protein which was originally called P-glycoprotein (P-gp), but it is also referred to as multidrug resistance protein 1 (MDR1) or ABCB1. This protein uses ATP hydrolysis, just like the other ABC transporters, to export a large variety of drugs from the cytosol to the extracellular medium. In multidrug-resistant cells, the MDR1 gene is frequently amplified in multidrug-resistant cells. This results in a large overproduction of the MDR1 protein. The substrates of mammalian ABCB1 are primarily planar, lipid-soluble molecules with one or more positive charges. All of these substrates compete with one another for transport, suggesting that they bind to the same or overlapping sites on the protein. Many of the drugs that are transported out by ABCB1 are small, nonpolar drugs that diffuse across the extracellular medium into the cytosol, where they block various cellular functions. Drugs such as colchicine and vinblastine, which block assembly of microtubules, freely cross the membrane into the cytosol, but the export of these drugs by ABCB1 reduces their concentration in the cell. Therefore, it takes a higher concentration of the drugs is required to kill the cells that express ABCB1 than those that do not express the gene.
To solve the problems associated with multidrug-resistance by MDR1, different types of drugs can be used or the ABC transporters themselves must be inhibited. For other types of drugs to work they must bypass the resistance mechanism, which is the ABC transporter. To do this other anticancer drugs can be utilized such as alkylating drugs (cyclophosphamide), antimetabolites (5-fluorouracil), and the anthracycline modified drugs (annamycin and doxorubicin-peptide). These drugs would not function as a substrate of ABC transporters, and would thus not be transported. The other option is to use a combination of ABC inhibitory drugs and the anticancer drugs at the same time. This would reverse the resistance to the anticancer drugs so that they could function as intended. The substrates that reverse the resistance to anticancer drugs are called chemosensitizers.
The ABCA subfamily is composed of 12 full transporters split into two subgroups. The first subgroup consists of seven genes that map to six different chromosomes. These are ABCA1-4, A7, A12, and A13. The other subgroup consists of ABCA5-6, and A8-10. All of subgroup 2 is organized into a head to tail cluster of chromosomes on chromosome 17q24. Genes in this second subgroup are distinguished from ABCA1-like genes by having 37-38 exons as opposed to the 50 exons in ABCA1. The ABCA1 subgroup is implicated in the development of genetic diseases. In the recessive Tangier’s disease, the ABCA1 protein is mutated. Also, the ABCA4 maps to a region of chromosome 1p21 that contains the gene for Stargardt’s disease. This gene is found to be highly expressed in rod photoreceptors and is mutated in Stargardt’s disease, recessive retinitis pigmentism, and the majority of recessive cone-rod dystrophy.
The ABCB subfamily is composed of four full transporters and two half transporters. This is the only human subfamily to have both half and full types of transporters. ABCB1 was discovered as a protein overexpressed in certain drug resistant tumor cells. It is expressed primarily in the blood brain barrier and liver and is thought to be involved in protecting cells from toxins. Cells that overexpress this protein exhibit multi-drug resistance.
Subfamily ABCC contains thirteen members and nine of these transporters are referred to as the Multidrug Resistance Proteins (MRPs). The MRP proteins are found throughout nature and they mediate many important functions. They are known to be involved in ion transport, toxin secretion, and signal transduction. Of the nine MRP proteins, four of them, MRP4, 5, 8, 9, (ABCC4, 5, 11, and 12), have a typical ABC structure with four domains, comprising two membrane spanning domains, with each spanning domain followed by a nucleotide binding domain. These are referred to as short MRPs. The remaining 5 MRP’s (MRP1, 2, 6, 7 (ABCC1, 2, 3, 6 and 10) are known as long MRPs and feature an additional fifth domain at their N terminus.
The sulfonylurea receptors (SUR), involved in insulin secretion, neuronal function, and muscle function, are also part of this family of proteins. Mutations in SUR proteins are a potential cause of Neonatal diabetes mellitus. SUR is also the binding site for drugs such as sulfonylureas and potassium-channel openers activators such as diazoxide.
The ABCD subfamily consists of four genes that encode half transporters expressed exclusively in the peroxisome. ABCD1 is responsible for the X-linked form of Adrenoleukodystrophy (ALD) which is a disease characterized by neurodegeneration and adrenal deficiency that typically is initiated in late childhood. The cells of ALD patients feature accumulation of unbranched saturated fatty acids, but the exact role of ABCD1 in the process is still undetermined. In addition, the function of other ABCD genes have yet to be determined but have been thought to exert related functions in fatty acid metabolism.
ABCE and ABCF
Both of these subgroups are composed of genes that have ATP binding domains that are closely related to other ABC transporters, but these genes do not encode for trans-membrane domains. ABCE consists of only one member, OABP or ABCE1, which is known to recognize certain oligodendrocytes produced in response to certain viral infections. Each member of the ABCF subgroup consist of a pair of ATP binding domains.
Six half transporters with ATP binding sites on the N terminus and trans-membrane domains at the C terminus make up the ABCG subfamily. This orientation is opposite of all other ABC genes. There are only 5 ABCG genes in the human genome, but there are 15 in the Drosophelia genome and 10 in yeast. The ABCG2 gene was discovered in cell lines selected for high level resistance for mitoxantrone and no expression of ABCB1 or ABCC1. ABCG2 can export anthrocycline anticancer drugs, as well as topotecan, mitoxantrone, or doxorubicin as substrates. Chromosomal translocations have been found to cause the ABCG2 amplification or rearrangement found in resistant cell lines. The normal function of ABCG2 is not known.
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