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ATP-binding cassette transporter genes

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ATP-binding cassette transporter genes (ABC-transporter genes) are a superfamily of genes which encode the ABC-transporter proteins. They are one of the largest, and most ancient families with representatives in all extant phyla from prokaryotes to humans. [1]. These are transmembrane proteins that function in the transport of a wide variety of substrates across extra- and intracellular membranes, including metabolic products, lipids and sterols, and drugs. Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding domain(s), also known as nucleotide-binding folds (NBFs).

FunctionEdit

ABC-transporters utilize the energy of ATP hydrolysis to transport various substrates across cellular membranes. Within bacteria, ABC-transporters mainly pump essential compounds such as sugars, vitamins, and metal ions into the cell. Within eukaryotes, ABC-transporters mainly transport molecules to the outside of the plasma membrane or into membrane-bound organelles such as the endoplasmic reticulum, mitochondria, etc.

The range of transported compounds includes:

StructureEdit

Typical ABC-transporters will contain two transmembrane domains (TMs), each of which consists of α-helices which cross the phospholipid bilayer multiple times. These helices form between six to eleven (usually six) membrane-spanning regions. These transmembrane domains provide the specificity for the substrate, and prevent unwanted molecules from using the transporter. In between the TMs is a ligand binding-domain, which is on the extracellular side of the protein for importers and on the cytoplasmic side for exporters.

All ABC proteins also contain either one or two ATP-binding domain(s), (nucleotide-binding folds (NBFs)) and are located on the cytoplasm side of the membrane. These folds are divided into parts or motifs, called Walker A and Walker B, which are separated by approximately 90-120 amino acids. In addition, there is a third short and highly conserved motif (called LSGGQ motif, C motif, or "signature" motif) located after the Walker B motif. Unlike the Walker A and Walker B motifs, which are found in other proteins which hydrolyze ATP, the signature motif is unique to ABC transporters. These folds form the “cassettes” which the protein family is named after. The transmembrane domains and nucleotide-binding folds are often arranged in the order NH3+-TM-NBF-TM-NBF-COO-.

ABC transporters may be classified as either half transporters or full transporters. Full transporters consist of the typical two TMs and NBFs. Half transporters consist of only one TM and one NBF and must combine with another half transporter to gain functionability. Half transporters can thus form homodimers if two identical ABC transporters join, and heterodimers if two unlike ABC transporters join.

Method of OperationEdit

When an ATP molecule binds to each cassette of an ABC-transporter, it induces a conformational change in which the NBFs and TMs shift to reveal a cavity called the translocation pathway. When the translocation pathway opens, molecules which were previously bound to the ligand binding-domain are free to travel through the pathway. This action is called the power stroke.

Role in Multidrug ResistanceEdit

ABC transporters are known to play a crucial role in the development of multidrug resistance (MDR). In MDR, patients who are on medication eventually develop resistance to not only the drug they are taking, but to several different types of drugs. This is caused by several factors, one of which is increased excretion of the drug from the cell by ABC transporters. For example, the ABCB1 protein (P-glycoprotein) functions in pumping tumor suppression drugs out of the cell. Pgp also called MDR1, ABCB1, is the prototype of ABC transporters and also the most extensively studied gene. Pgp is known to transport organic cationic or neutral compounds. A few ABCC family members, also known as MRP, have also been demonstrated to confer MDR to organic anion compounds. The best studied member in ABCG family is ABCG2, also known as BCRP (breast cancer resistance protein) confer resistance to most of Topoisomerase I or II inhibitors such as topotecan, irinotecan and doxorobicin.

SubfamiliesEdit

Human SubfamiliesEdit

There are 50 known ABC transporters present in humans, which are classified into seven families by the Human Genome Organization.

  • ABCA: . Some of the largest transporters are located here (over 2,100 amino acids long). Responsible for the transportation of cholesterol and lipids, among other things. Five of them are located in a cluster in the 17q24 chromosome.
  • ABCB: Consists of 4 full and 7 half transporters. Some are located in the blood-brain barrier, liver, mitochondria and transports peptides and bile, for example. (Example: ABCB5.)
  • ABCC: Consists of 12 full transporters. Used in ion transport, cell-surface receptors, toxin secretion. (Example: ABCC6.) Includes the CFTR protein, which causes cystic fibrosis when deficient.
  • ABCD: Consists of 4 half transporters, which are all used in peroxisomes.
  • ABCE/ABCF: Consists of 1 ABCE and 3 ABCF proteins. These are not actually transporters but are merely ATP-binding domains which were derived from the ABC family but without the transmembrane domains. These proteins mainly regulate protein synthesis or expression.
  • ABCG: Consists of 6 “reverse” half-transporters, with the NBF at the NH3+ end and the TM at the COO- end. Transports lipids, bile, cholesterol, and other steroids.

A full list of human ABC transporters can be found at [2].

Prokaryotic SubfamiliesEdit

Importers

  • Carbohydrate Uptake Transporter-1 (CUT1)
  • Carbohydrate Uptake Transporter-2 (CUT2)
  • Polar Amino Acid Uptake Transporter (PAAT)
  • Peptide/Opine/Nickel Uptake Transporter (PepT)
  • Hydrophobic Amino Acid Uptake Transporter (HAAT)
  • Sulfate/Tungstate Uptake Transporter (SulT)
  • Phosphate Uptake Transporter (PhoT)
  • Molybdate Uptake Transporter (MolT)
  • Phosphonate Uptake Transporter (PhnT)
  • Ferric Iron Uptake Transporter (FeT)
  • Polyamine/Opine/Phosphonate Uptake Transporter (POPT)
  • Quaternary Amine Uptake Transporter (QAT)
  • Vitamin B12 Uptake Transporter (B12T)
  • Iron Chelate Uptake Transporter (FeCT)
  • Manganese/Zinc/Iron Chelate Uptake Transporter (MZT)
  • Nitrate/Nitrite/Cyanate Uptake Transporter (NitT)
  • Taurine Uptake Transporter (TauT)
  • Cobalt Uptake Transporter (CoT)
  • Thiamin Uptake Transporter (ThiT)
  • Brachyspira Iron Transporter (BIT)
  • Siderophore-Fe3+ Uptake Transporter (SIUT)
  • Nickel Uptake Transporter (NiT)
  • Nickel/Cobalt Uptake Transporter (NiCoT)
  • Methionine Uptake Transporter (MUT)
  • Lipid Exporter (LipidE)

Exporters

  • Capsular Polysaccharide Exporter (CPSE)
  • Lipooligosaccharide Exporter (LOSE)
  • Lipopolysaccharide Exporter (LPSE)
  • Teichoic Acid Exporter (TAE)
  • Drug Exporter-1 (DrugE1)
  • Lipid Exporter (LipidE)
  • Putative Heme Exporter (HemeE)
  • β-Glucan Exporter (GlucanE)
  • Protein-1 Exporter (Prot1E)
  • Protein-2 Exporter (Prot2E)
  • Peptide-1 Exporter (Pep1E)
  • Peptide-2 Exporter (Pep2E)
  • Peptide-3 Exporter (Pep3E)
  • Probable Glycolipid Exporter (DevE)
  • Na+ Exporter (NatE)
  • Microcin B17 Exporter (McbE)
  • Drug Exporter-2 (DrugE2)
  • Microcin J25 Exporter (McjD)
  • Drug/Siderophore Exporter-3 (DrugE3)
  • (Putative) Drug Resistance ATPase-1 (Drug RA1)
  • (Putative) Drug Resistance ATPase-2 (Drug RA2)
  • Macrolide Exporter (MacB)
  • Peptide-4 Exporter (Pep4E)
  • 3-component Peptide-5 Exporter (Pep5E)
  • Lipoprotein Translocase (LPT)
  • β-Exotoxin I Exporter (βETE)
  • AmfS Peptide Exporter (AmfS-E)
  • SkfA Peptide Exporter (SkfA-E)
  • CydDC Cysteine Exporter (CydDC-E)

[3]

ImagesEdit

A wealth of high-resolution structures of ABC proteins have been produced in recent years. [4]

References Edit

  1. ^  Jones, P. M.; George, A. M.; Cellular and Molecular Life Sciences. 2004, 61, 682-699.
  2. ^  Dean, Michael. The Human ATP-Binding Cassette (ABC) Transporter Superfamily. Bethesda (MD):National Library of Medicine (US), NCBI; 2002 November.
  3. ^  Szentpétery, Z.; Kern, A.; Liliom, K.; Sarkadi, B.; Váradi, A.; Bakos, E.; J. Biol. Chem. 2004, 279, 41670-41678. [5]
  4. ^  ABC Nomenclature Committee. ABC-Transporter Genes nomenclature scheme, enacted October 22, 1999. Verified availability August 2, 2005.
  5. ^  Fitzgerald, M. L.; Okuhira, K.; Short, G. F.; Manning, J. J.; Bell, S. A.; Freeman, M. W.; J. Biol. Chem. 2004, 279, 48477-48485.
  6. ^  Wain, H. M.; White, J. A.; Povey, S. [6]
  7. ^  Saier MH Jr.; Microbiol Mol Biol Rev., 2000, 64(2), 354-411 TCDB
  8. ^  Deeley, R. G. [7]

External linksEdit

- Calculated position of BtuCD transporter  in membrane
- Calculated position of multidrug transporter sav1866 in membrane
- Calculated position of molybdate uptake transporter in membrane


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