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FUNCTION Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis (PubMed:26823428). Mediates the transport of chloride ions across the cell membrane (PubMed:10792060, PubMed:11524016, PubMed:11707463, PubMed:12519745, PubMed:12529365, PubMed:12588899, PubMed:12727866, PubMed:15010471, PubMed:17036051, PubMed:1712898, PubMed:17182731, PubMed:19398555, PubMed:19621064, PubMed:22178883, PubMed:25330774, PubMed:26846474, PubMed:28087700, PubMed:8910473, PubMed:9804160). Possesses an intrinsic ATPase activity and utilizes ATP to gate its channel; the passive flow of anions through the channel is gated by cycles of ATP binding and hydrolysis by the ATP-binding domains (PubMed:11524016, PubMed:15284228, PubMed:26627831, PubMed:8910473). The ion channel is also permeable to HCO(3)(-); selectivity depends on the extracellular chloride concentration (PubMed:15010471, PubMed:19019741). In vitro, mediates ATP-dependent glutathione flux (PubMed:12727866). Exerts its function also by modulating the activity of other ion channels and transporters (PubMed:12403779, PubMed:22121115, PubMed:22178883, PubMed:27941075). Plays an important role in airway fluid homeostasis (PubMed:16645176, PubMed:19621064, PubMed:26823428). Contributes to the regulation of the pH and the ion content of the airway surface fluid layer and thereby plays an important role in defense against pathogens (PubMed:14668433, PubMed:16645176, PubMed:26823428). Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex (PubMed:17182731, PubMed:17434346, PubMed:27941075). Inhibits the activity of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:17182731). Inhibits the activity of the ENaC channel containing subunits SCNN1D, SCNN1B and SCNN1G, but not of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:17182731, PubMed:27941075). May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7 (PubMed:12403779). Can inhibit the chloride channel activity of ANO1 (PubMed:22178883). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (PubMed:19923167, PubMed:27714810, PubMed:29393851).CATALYTIC ACTIVITY ATP + H2O + closed Cl(-) channel = ADP + phosphate + open Cl(-) channel.CATALYTIC ACTIVITY chloride(in) = chloride(out)CATALYTIC ACTIVITY hydrogencarbonate(in) = hydrogencarbonate(out)CATALYTIC ACTIVITY ATP + H2O = ADP + phosphate + H(+)BIOPHYSICOCHEMICAL PROPERTIES Monomer; does not require oligomerization for channel activity (PubMed:11524016). May form oligomers in the membrane (PubMed:11524016). Interacts with SLC26A3, SLC26A6 and SHANK2 (By similarity). Interacts with NHERF1 and MYO6 (PubMed:11304524, PubMed:12403779, PubMed:15247260). Interacts (via C-terminus) with GOPC (via PDZ domain); this promotes CFTR internalization and thereby decreases channel activity (PubMed:11707463, PubMed:16331976). Interacts with SLC4A7 through NHERF1 (PubMed:12403779). Found in a complex with MYO5B and RAB11A (PubMed:17462998). Interacts with ANO1 (PubMed:22178883). Interacts with SLC26A8 (PubMed:22121115). Interacts with AHCYL1; the interaction increases CFTR activity (By similarity). Interacts with CSE1L (PubMed:20933420). The core-glycosylated form interacts with GORASP2 (via PDZ GRASP-type 1 domain) in respone to ER stress (PubMed:21884936). Interacts with MARCHF2; the interaction leads to CFTR ubiquitination and degradation (PubMed:23818989). Interacts with ADGRG2 (PubMed:29393851).INTERACTION The channel is internalized from the cell surface into an endosomal recycling compartment, from where it is recycled to the cell membrane (PubMed:17462998, PubMed:19398555, PubMed:20008117). In the oviduct and bronchus, detected on the apical side of epithelial cells, but not associated with cilia (PubMed:22207244). In Sertoli cells, a processed product is detected in the nucleus (By similarity). ER stress induces GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of core-glycosylated CFTR to cell membrane (PubMed:21884936).ALTERNATIVE PRODUCTS Expressed in the respiratory airway, including bronchial epithelium, and in the female reproductive tract, including oviduct (at protein level) (PubMed:15716351, PubMed:22207244). Detected in pancreatic intercalated ducts in the exocrine tissue, on epithelial cells in intralobular striated ducts in sublingual salivary glands, on apical membranes of crypt cells throughout the small and large intestine, and on the reabsorptive duct in eccrine sweat glands (PubMed:1284548, PubMed:28130590). Detected on the equatorial segment of the sperm head (at protein level) (PubMed:19923167). Detected in nasal and bronchial superficial epithelium (PubMed:15716351). Expressed by the central cells on the sebaceous glands, dermal adipocytes and, at lower levels, by epithelial cells (PubMed:28130590).DOMAIN Binds and hydrolyzes ATP via the two cytoplasmic ABC transporter nucleotide-binding domains (PubMed:15284228). The two ATP-binding domains interact with each other, forming a head-to-tail dimer (PubMed:17036051). Normal ATPase activity requires interaction between the two domains (PubMed:15284228). The first ABC transporter nucleotide-binding domain has no ATPase activity by itself (By similarity).DOMAIN The PDZ-binding motif mediates interactions with GOPC and with the SLC4A7, NHERF1/EBP50 complex.DOMAIN The R region is intrinsically disordered (PubMed:10792060, PubMed:17660831). It mediates channel activation when it is phosphorylated, but not in the absence of phosphorylation (PubMed:10792060).PTM N-glycosylated.PTM Phosphorylated; cAMP treatment promotes phosphorylation and activates the channel (PubMed:12588899, PubMed:17036051, PubMed:8910473). Dephosphorylation decreases the ATPase activity (in vitro) (PubMed:8910473). Phosphorylation at PKA sites activates the channel (PubMed:10792060, PubMed:12519745, PubMed:12588899, PubMed:25330774). Phosphorylation at PKC sites enhances the response to phosphorylation by PKA (PubMed:12588899). Phosphorylated by AMPK; this inhibits channel activity (PubMed:12519745).PTM Ubiquitinated, leading to its degradation in the lysosome (PubMed:19398555, PubMed:23818989). Deubiquitination by USP10 in early endosomes enhances its endocytic recycling to the cell membrane (PubMed:19398555). Ubiquitinated by RNF185 during ER stress (PubMed:24019521). Ubiquitinated by MARCHF2 (PubMed:23818989).DISEASE The disease is caused by variants affecting the gene represented in this entry. There is some evidence that the functional defect caused by the most common variant Phe-508 DEL can be corrected by the binding to the snake phospholipase A2 crotoxin basic subunit CB. This toxin both disrupts the Phe-508 DEL-cytokeratin 8 complex, allowing for the escape from degradation, and increases the chloride channel current (PubMed:27241308).DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS Exon 9 splicing depends upon 2 polymorphic tracts within intron 8, a T(n) tract and TG(n) tract, where the number of T and/or TG repeats affect the extent of correct splicing of exon 9. Low numbers of T residues and high numbers of TG repeats give rise to less efficient splicing. Transcripts that lack exon 9 sequences fail to mature. Causes congenital bilateral absence of the vas deferens (CBAVD).MISCELLANEOUS Alternative acceptor site favored by mutation in an exonic splicing enhancer (ESE). Causes cystic fibrosis (CF).SIMILARITY Belongs to the ABC transporter superfamily. ABCC family. CFTR transporter (TC 3.A.1.202) subfamily.ONLINE INFORMATION CFTR entryONLINE INFORMATION Database for mutations in ABC proteins
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