CFTR | Cystic Fibrosis Transmembrane Conductance Regulator | ATP-Binding Cassette Sub-family C Member 7
ABC binding cassette superfamily of primary active transporters
- ABCA - (ABC1) subfamily including 13 members (ABCA1 - ABCA13)
- ABCB - Multidrig Resistance (MDR)/(TAP) subfamily including 11 members (ABCB1 - ABCB11)
- ABCC - (CFTR)/Multidrug Resistance Protein (MRP) subfamily including 12 members (ABCC1 - ABCC12)
- ABCD - Adrenoleukodystrophy (ALD) subfamily including 4 members (ABCD1 - ABCD4)
- ABCE - Oligoadenylate Binding Protein (OABP) subfamily including 1 member (ABCE1)
- ABCF - Nonmembrane ABC Protein (GCN20) subfamily including 3 members (ABCF1 - ABCF3)
- ABCG - Half Transporters (WHITE) subfamily including 5 members (ABCG1, ABCG2, ABCG4, ABCG5, ABCG8)
ABC transporters often contain multiple subunits. The common feature of all ABC transporters is that they consist of two distinct domains:
- The TMD ( transmembrane domain), also known as membrane-spanning domain (MSD) or integral membrane (IM) domain, consists of alpha helices, embedded in the membrane bilayer. It recognizes a variety of substrates and undergoes conformational changes to transport the substrate across the membrane. The sequence and architecture of TMDs is variable, reflecting the chemical diversity of substrates that can be translocated.
- The NBD (nucleotide-binding domain) or ATP-binding cassette (ABC) domain (membrane-associated AAA ATPases), is located in the cytoplasm and has a highly conserved sequence. The ATPase subunits utilize the energy of ATP binding and hydrolysis to provide the energy needed for the translocation of substrates across membranes, either for uptake or for export.
CFTR Background Information
CFTR, also called Cystic fibrosis transmembrane conductance regulator, is a ATP-gated, phosphorylation-regulated epithelial cell membrane chloride channel belonging to the ATP-binding cassette (ATP transporter) subfamily C. CFTR is involved in normal fluid transport across various epithelia. Mutations of the gene can cause cystic fibrosis.
The protein consists of five domains. There are two transmembrane domains, each with six spans of alpha helices. These are each connected to a nucleotide binding domain (NBD) in the cytoplasm. The first NBD is connected to the second transmembrane domain by a regulatory "R" domain that is a unique feature of CFTR, not present in other ABC transporters. The ion channel only opens when its R-domain has been phosphorylated by PKA and ATP is bound at the NBDs. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain.
Respiratory airway: bronchial epithelium; female reproductive tract; pancreatic intercalated ducts in the exocrine tissue; epithelial cells in intralobular striated ducts, sublingual salivary glands, apical membranes of crypt cells throughout the small and large intestine, reabsorptive duct in eccrine sweat glands, the equatorial segment of the sperm head, nasal superficial epithelium. central cells on the sebaceous glands
Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis: It mediates the transport of chloride ions across the cell membrane. In addition, CFTR effects several other conductances via the regulation of: epithelial Na channel (ENaC), calcium activated chloride channels (CaCC), volume regulated anion channel (VRAC), outwardly rectifying chloride channel (ORCC), renal outer medullary potassium channel (ROMK2),. CFTR furthermore regulates TRPV4. The activities of CFTR and the chloride-bicarbonate exchangers SLC26A3 (DRA) and SLC26A6 (PAT1) are mutually enhanced by a physical association between the regulatory (R) domain of CFTR and the STAS domain of the SCL26 transporters, an effect facilitated by PKA-mediated phosphorylation of the R domain of CFTR
Multiple kinases can activate the CFTR chloride channel but only protein kinase A-dependent activation of CFTR has been described in detail. First the R domain is phosphorylated by cAMP-dependent protein kinase A (PKA). This allows binding of ATP to nucleotide binding domain 1. When ATP is hydrolyzed by NBD1, the channel opens and anions can flow, according to the electrochemical gradient, through the pore formed by the transmembrane domains. When the R domain is fully phosphorylated, the second nucleotide-binding domain can bind ATP. This event stabilizes the open state of the chloride channel and results in longer openings. When in a next step ATP is hydrolyzed at NBD2 and ADP and Pi are released from both NBDs, the channel will close again
Cystic fibrosis (CF) is caused by mutations of CFTR. Cystic Fibrosis is a common generalized disorder of the exocrine glands which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes. It is the most common genetic disease in Caucasians, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. Congenital bilateral absence of the vas deferens (CBAVD) is caused by mutations of CFTR. It causes sterility in men and could represent an incomplete form of cystic fibrosis, as the majority of men suffering from cystic fibrosis lack the vas deferens.
Monomer; does not require oligomerization for channel activity. Interacts with SLC26A3, SLC26A6, SLC26A8, SLC4A7, SLC9A3R1, SHANK2, MYO5B, MYO6, GOPC, RAB11A, ANO1, AHCYL1, CSE1L, GORASP2, MRP4 (Multidrug resistance-associated protein 4)
forskolin, cAMP, Glibenclamide, GlyH 101, Fluoride
Patch Clamp: whole cell, room temperature
Reviews and Links
- Dean et al. (2001) The Human ATP-binding Cassette (ABC) Transporter Superfamily. J. Lipid Res. 42:1007–1017.
Transporter classification database:
Data and Applications