Cystic fibrosis transmembrane conductance regulator (CFTR, also known as ABCC7) is an eukaryotic protein belonging to the ABC-C subfamily of the ABC transporter family. CFTR protein is a chloride ion channel controlled by phosphorylation. It has a major role in electrolyte and fluid secretion. CFTR is important in the determination of fluid flow, ion concentration and transepithelial salt transport. Dysfunction of the CFTR channel causes the life-threatening disease, cystic fibrosis, in which trans-epithelial ion transport is disrupted.
Cystic fibrosis transmembrane conductance regulator (CFTR, also known as ABCC7) is a chloride-conducting transmembrane protein consisting of 1480 amino acids, which belongs to the ABC-C subfamily of the ATP-binding cassette (ABC) transporter family. It possesses two nucleotide binding domains (NBDs), which bind ATP, form a transient interaction, and contribute strictly to regulate the channel gating and chloride ions flow along the electrochemical gradient. The overall structure of CFTR resembles a typical ABC transporter in the inward-facing conformation. The two transmembrane domains (TMDs) are domain-swapped such that TM 4-5 and TM 10-11 reach across the interface to pack against the other half of the molecule. The two cytosolic NBDs are separated by the mostly unstructured R domain wedged in between. It also contains an N-terminal interfacial structure never before seen in any of the ABC transporters, which we refer to as the lasso motif.
As an ion channel, the CFTR’s distinguishing feature is the ability to hydrolyze its bound ligand rather than respond to changes in bulk ligand concentrations as is done by all other known ligand-gated channels.
Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Cystic fibrosis (CF) is a common life-limiting disorder inherited in an autosomal recessive pattern and the most common lethal genetic disease in white populations. There are many ways to treat CF, such as correcting CFTR mutants, gene therapy, and organ transplantation. However, CFTR activators have the most promising applications, such as (Lumacaftor) as another inhibitor corrected CFTR mutations in CF by promoting maturation of the mutant CFTR (F508del-CFTR). IOWH032 is a synthetic CFTR inhibitor, which shows inhibitory activity against CFTR (T84-CFTR). GlyH-101 is a selective and reversible CFTR inhibitor, which can block cardiac I(Cl.PKA) channels2.
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1. Z Zhang, J Chen. (2016) Atomic Structure of the Cystic Fibrosis Transmembrane Conductance Regulator. Cell, 167(6), 1586-1597.
2. PP Barman, SC Choisy, HC Gadeberg, JC Hancox, AF James. (2011) Cardiac ion channel current modulation by the CFTR inhibitor GlyH-101. Biochem Biophys Res Commun, 408(1):12-17.
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