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). ABC transporters are involved in tumour resistance, cystic fibrosis, bacterial multidrug resistance and a range of other inherited human diseases. In biology, extant taxon is commonly used in discussions of living and fossil species. ... In biological taxonomy, a phylum (Greek plural: phyla) is a taxon in the rank below kingdom and above class. ... Prokaryotes (pro-KAR-ee-oht) (from Old Greek pro- before + karyon nut or kernel, referring to the cell nucleus, + suffix -otos, pl. ... A transmembrane protein is a protein that spans the entire biological membrane. ... The cell membrane (also called the plasma membrane, plasmalemma or phospholipid bilayer) is a semipermeable lipid bilayer common to all living cells. ... Santorio Santorio (1561-1636) in his steelyard balance, from Ars de statica medecina, first published 1614 Metabolism (from μεταβολισμος(metavallo), the Greek word for change), in the most general sense, is the ingestion and breakdown of complex compounds, coupled... Figure 1: Basic lipid structure. ... Sterols are a subgroup of steroids with a hydroxyl group in the 3-position of the A-ring. ... This article does not cite any references or sources. ...

Function

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. More recently ABC-transporters have been shown to exist within the placenta, indicating they could play a protective role for the developing fetus against xenobiotics^{[citation needed]}. The cell membrane (also called the plasma membrane, plasmalemma or phospholipid bilayer) is a semipermeable lipid bilayer common to all living cells. ... Drawing of a cell membrane A component of every biological cell, the cell membrane (or plasma membrane) is a thin and structured bilayer of phospholipid and protein molecules that envelopes the cell. ... The endoplasmic reticulum or ER is an organelle found in all eukaryotic cells that is an interconnected network of tubules, vesicles and cisternae that is responsible for several specialized functions: Protein translation, folding, and transport of proteins to be used in the cell membrane (e. ... In cell biology, a mitochondrion is an organelle found in the cells of most eukaryotes. ... The placenta is an ephemeral (temporary) organ present in female placental vertebrates during gestation (pregnancy), but a placenta has evolved independently also in other animals as well, for instance scorpions and velvet worms. ... A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. ...

The range of transported compounds includes:

• Lipids and sterols;
• Ions and small molecules.
• Drugs;
• Large polypeptides.

Figure 1: Basic lipid structure. ... Sterols are a subgroup of steroids with a hydroxyl group in the 3-position of the A-ring. ... This article is about the electrically charged particle. ... This article does not cite any references or sources. ... Peptides are the family of molecules formed from the linking, in a defined order, of various amino acids. ...

Structure

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. Other conserved motifs include the Q-loop, the his-loop, the pro-loop and the D-loop. 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-.

Many ABC transporters may be classified as 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. However though these are the most common domain organisations, others exist. For instance many bacterial importers are composed of four polypeptides. Every possible organisation for these domains has been observed (Higgins, 1992).

Method of Operation

The mechanism of ABC transporters has not been fully identified. It is known that when an ATP molecule binds to each cassette of an ABC-transporter, it induces a conformational change in which the NBFs interact more closely. This is communicated to the TMs, which shift to re-orientate the translocation pathway. This action is called the power stroke. In this conformation, the substrate binding is lower affinity, and so the substrates can be released. Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... A power stroke is, in general, the stroke of a cyclic motor which generates force. ...

Particular areas of controversy include the roles of ATP binding, ATP hydrolysis and the subsequent dissociation of the ADP and Pi. Also unclear is how communication between the NBFs and the TMs takes place.

Role in Multidrug Resistance

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. Multidrug resistance is the ability of pathologic cells to withstand chemicals that are designed to aid in the eradication of such cells. ... P-glycoproteins are a type of protein that appear to have developed as a mechanism to protect the body from harmful substances by acting as efflux transporters. ...

It is unclear exactly how these proteins can translocation such a wide variety of drugs, however one model (the hydrophobic vacuum cleaner model) states that in P-glycoprotein the drugs are bound indiscriminately from the lipid phase based on their hydrophobicity.

Subfamilies

Human Subfamilies

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

A full list of human ABC transporters can be found at [2]. ABCB5 [ATP-Binding Cassette Subfamily B (MDR/TAP) Member 5] is a human ABC transporter and P-glycoprotein family member principally expressed in physiological skin and human malignant melanoma. ... The protein encoded by the ABCC6 gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ... Basic structure of a peroxisome Electron micrograph of a section of a liver cell showing glycogen deposits as accumulations of electron dense particles (arrows). ... ABCD1 is a gene associated with adrenoleukodystrophy. ... Cap badge of the Rhodesian Light Infantry. ...

Prokaryotic Subfamilies

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]

Images

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

References

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 links

• UMich Orientation of Proteins in Membranes families/superfamily-17 - Calculated position of BtuCD transporter in membrane
• UMich Orientation of Proteins in Membranes families/superfamily-18 - Calculated position of multidrug transporter sav1866 in membrane
• UMich Orientation of Proteins in Membranes families/superfamily-198 - Calculated position of molybdate uptake transporter in membrane
• MeSH ATP-Binding+cassette+transporters