UniProt functional annotation for P26361



	UniProt functional annotation for P26361

UniProt code: P26361.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

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:20231442, PubMed:22265409). Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer. Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7. Can inhibit the chloride channel activity of ANO1 (By similarity). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (PubMed:21976599). {ECO:0000250|UniProtKB:P13569, ECO:0000269|PubMed:19033647, ECO:0000269|PubMed:20231442, ECO:0000269|PubMed:21976599, ECO:0000269|PubMed:22265409, ECO:0000269|PubMed:26823428}.

Catalytic activity: Reaction=ATP + H(2)O + closed Cl(-) channel = ADP + phosphate + open Cl(-) channel.; EC=5.6.1.6; Evidence={ECO:0000250|UniProtKB:P13569};

Subunit: Monomer; does not require oligomerization for channel activity. May form oligomers in the membrane (By similarity). Interacts with SLC26A3, SLC26A6 and SLC9A3R1 (PubMed:21976599). Interacts with SHANK2 (By similarity). Interacts with MYO6 (By similarity). Interacts (via C-terminus) with GOPC (via PDZ domain); this promotes CFTR internalization and thereby decreases channel activity. Interacts with SLC4A7 through SLC9A3R1. Found in a complex with MYO5B and RAB11A. Interacts with ANO1. Interacts with SLC26A8 (By similarity). Interacts with AHCYL1; the interaction increases CFTR activity (PubMed:19033647, PubMed:23542070). Interacts with CSE1L (By similarity). The core- glycosylated form interacts with GORASP2 (via PDZ GRASP-type 1 domain) in respone to ER stress (By similarity). {ECO:0000250|UniProtKB:P13569, ECO:0000250|UniProtKB:P34158, ECO:0000269|PubMed:19033647, ECO:0000269|PubMed:21976599, ECO:0000269|PubMed:23542070}.

Subcellular location: Apical cell membrane {ECO:0000269|PubMed:20231442, ECO:0000269|PubMed:21884936}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P13569}. Early endosome membrane {ECO:0000250|UniProtKB:P13569}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P13569}. Cell membrane {ECO:0000269|PubMed:20231442, ECO:0000269|PubMed:22265409}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P13569}. Recycling endosome membrane {ECO:0000250|UniProtKB:P13569}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P13569}. Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P13569}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P13569}. Nucleus {ECO:0000250|UniProtKB:P34158}. Note=The channel is internalized from the cell surface into an endosomal recycling compartment, from where it is recycled to the cell membrane. In the oviduct and bronchus, detected on the apical side of epithelial cells, but not associated with cilia. In Sertoli cells, a processed product is detected in the nucleus. ER stress induces GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of core-glycosylated CFTR to cell membrane (PubMed:21884936). {ECO:0000250|UniProtKB:P13569, ECO:0000250|UniProtKB:P34158, ECO:0000269|PubMed:21884936}.

Tissue specificity: Expressed in the epididymis (at protein level) (PubMed:30659401). In the initial segment of the epididymis, detected on both the luminal and basolateral sides of the ducts where it is expressed in the duct columnar cells as well as in the interstitial smooth muscle cells (PubMed:30659401). Expressed in sperm in the caput (PubMed:30659401). In the cauda, detected along the luminal border but not continuously and is also expressed on the basolateral surface (PubMed:30659401). Within the caudal lumen, detected on sperm (PubMed:30659401). Isoform 1: Expressed in a variety of epithelial tissues including colon, kidney, lung, small intestine, pancreatic duct and testis (PubMed:7691356). Isoform 2: Expressed only in testis (PubMed:7691356). Isoform 3: Expressed only in testis (PubMed:7691356). {ECO:0000269|PubMed:30659401, ECO:0000269|PubMed:7691356}.

Domain: Binds and hydrolyzes ATP via the two cytoplasmic ABC transporter nucleotide-binding domains. The two ATP-binding domains interact with each other, forming a head-to-tail dimer. Normal ATPase activity requires interaction between the two domains (By similarity). The first ABC transporter nucleotide-binding domain has no ATPase activity by itself (PubMed:14685259, PubMed:15619636). {ECO:0000250|UniProtKB:P13569, ECO:0000269|PubMed:14685259, ECO:0000269|PubMed:15619636}.

Domain: The PDZ-binding motif mediates interactions with GOPC and with the SLC4A7, SLC9A3R1/EBP50 complex. {ECO:0000250|UniProtKB:P13569}.

Domain: The disordered R region mediates channel activation when it is phosphorylated, but not in the absence of phosphorylation. {ECO:0000250|UniProtKB:P13569}.

Ptm: N-glycosylated. {ECO:0000250|UniProtKB:P13569}.

Ptm: Phosphorylated; cAMP treatment promotes phosphorylation and activates the channel. Dephosphorylation decreases the ATPase activity (in vitro). Phosphorylation at PKA sites activates the channel. Phosphorylation at PKC sites enhances the response to phosphorylation by PKA. Phosphorylated by AMPK; this inhibits channel activity. {ECO:0000250|UniProtKB:P13569}.

Ptm: Ubiquitinated, leading to its degradation in the lysosome. Deubiquitination by USP10 in early endosomes enhances its endocytic recycling to the cell membrane. Ubiquitinated by RNF185 during ER stress. {ECO:0000250|UniProtKB:P13569}.

Disruption phenotype: Mice are born at the expected Mendelian rate, but about 80% die within two to five days after birth due to peritonitis (PubMed:7685652). Those that survive fail to thrive, appear runted and weigh about half as much as wild-type littermates (PubMed:7685652). Many of the surviving pups die when they start ingesting solid food, due to intestinal blockage caused by excessive mucus accumulation (PubMed:7685652). None survive for more than about 45 days after birth (PubMed:7685652). Intestinal crypts in the jejunum and ileum are filled with excessive mucus (PubMed:7685652). Excessive accumulation of mucus is also seen in colon (PubMed:7685652). In contrast, their lungs do not present pathological mucus accumulation (PubMed:7685652). Likewise, only five out of ten animals show dilatation and blockage of several small pancreatic ducts (PubMed:7685652). Besides, mutant mice present defects in their lacrimal glands that make them more susceptible to develop eye infections (PubMed:7685652). In caecum epithelium, forskolin-sensitive ion transport is nearly abolished (PubMed:7685652). {ECO:0000269|PubMed:7685652}.

Similarity: Belongs to the ABC transporter superfamily. ABCC family. CFTR transporter (TC 3.A.1.202) subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



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:20231442, PubMed:22265409). Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Contributes to the regulation of the pH and the ion content of the epithelial fluid layer. Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7. Can inhibit the chloride channel activity of ANO1 (By similarity). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (PubMed:21976599). {ECO:0000250\|UniProtKB:P13569, ECO:0000269\|PubMed:19033647, ECO:0000269\|PubMed:20231442, ECO:0000269\|PubMed:21976599, ECO:0000269\|PubMed:22265409, ECO:0000269\|PubMed:26823428}.


Catalytic activity:		Reaction=ATP + H(2)O + closed Cl(-) channel = ADP + phosphate + open Cl(-) channel.; EC=5.6.1.6; Evidence={ECO:0000250\|UniProtKB:P13569};
Subunit:		Monomer; does not require oligomerization for channel activity. May form oligomers in the membrane (By similarity). Interacts with SLC26A3, SLC26A6 and SLC9A3R1 (PubMed:21976599). Interacts with SHANK2 (By similarity). Interacts with MYO6 (By similarity). Interacts (via C-terminus) with GOPC (via PDZ domain); this promotes CFTR internalization and thereby decreases channel activity. Interacts with SLC4A7 through SLC9A3R1. Found in a complex with MYO5B and RAB11A. Interacts with ANO1. Interacts with SLC26A8 (By similarity). Interacts with AHCYL1; the interaction increases CFTR activity (PubMed:19033647, PubMed:23542070). Interacts with CSE1L (By similarity). The core- glycosylated form interacts with GORASP2 (via PDZ GRASP-type 1 domain) in respone to ER stress (By similarity). {ECO:0000250\|UniProtKB:P13569, ECO:0000250\|UniProtKB:P34158, ECO:0000269\|PubMed:19033647, ECO:0000269\|PubMed:21976599, ECO:0000269\|PubMed:23542070}.
Subcellular location:		Apical cell membrane {ECO:0000269\|PubMed:20231442, ECO:0000269\|PubMed:21884936}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P13569}. Early endosome membrane {ECO:0000250\|UniProtKB:P13569}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P13569}. Cell membrane {ECO:0000269\|PubMed:20231442, ECO:0000269\|PubMed:22265409}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P13569}. Recycling endosome membrane {ECO:0000250\|UniProtKB:P13569}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P13569}. Endoplasmic reticulum membrane {ECO:0000250\|UniProtKB:P13569}; Multi-pass membrane protein {ECO:0000250\|UniProtKB:P13569}. Nucleus {ECO:0000250\|UniProtKB:P34158}. Note=The channel is internalized from the cell surface into an endosomal recycling compartment, from where it is recycled to the cell membrane. In the oviduct and bronchus, detected on the apical side of epithelial cells, but not associated with cilia. In Sertoli cells, a processed product is detected in the nucleus. ER stress induces GORASP2-mediated unconventional (ER/Golgi-independent) trafficking of core-glycosylated CFTR to cell membrane (PubMed:21884936). {ECO:0000250\|UniProtKB:P13569, ECO:0000250\|UniProtKB:P34158, ECO:0000269\|PubMed:21884936}.
Tissue specificity:		Expressed in the epididymis (at protein level) (PubMed:30659401). In the initial segment of the epididymis, detected on both the luminal and basolateral sides of the ducts where it is expressed in the duct columnar cells as well as in the interstitial smooth muscle cells (PubMed:30659401). Expressed in sperm in the caput (PubMed:30659401). In the cauda, detected along the luminal border but not continuously and is also expressed on the basolateral surface (PubMed:30659401). Within the caudal lumen, detected on sperm (PubMed:30659401). Isoform 1: Expressed in a variety of epithelial tissues including colon, kidney, lung, small intestine, pancreatic duct and testis (PubMed:7691356). Isoform 2: Expressed only in testis (PubMed:7691356). Isoform 3: Expressed only in testis (PubMed:7691356). {ECO:0000269\|PubMed:30659401, ECO:0000269\|PubMed:7691356}.
Domain:		Binds and hydrolyzes ATP via the two cytoplasmic ABC transporter nucleotide-binding domains. The two ATP-binding domains interact with each other, forming a head-to-tail dimer. Normal ATPase activity requires interaction between the two domains (By similarity). The first ABC transporter nucleotide-binding domain has no ATPase activity by itself (PubMed:14685259, PubMed:15619636). {ECO:0000250\|UniProtKB:P13569, ECO:0000269\|PubMed:14685259, ECO:0000269\|PubMed:15619636}.
Domain:		The PDZ-binding motif mediates interactions with GOPC and with the SLC4A7, SLC9A3R1/EBP50 complex. {ECO:0000250\|UniProtKB:P13569}.
Domain:		The disordered R region mediates channel activation when it is phosphorylated, but not in the absence of phosphorylation. {ECO:0000250\|UniProtKB:P13569}.
Ptm:		N-glycosylated. {ECO:0000250\|UniProtKB:P13569}.
Ptm:		Phosphorylated; cAMP treatment promotes phosphorylation and activates the channel. Dephosphorylation decreases the ATPase activity (in vitro). Phosphorylation at PKA sites activates the channel. Phosphorylation at PKC sites enhances the response to phosphorylation by PKA. Phosphorylated by AMPK; this inhibits channel activity. {ECO:0000250\|UniProtKB:P13569}.
Ptm:		Ubiquitinated, leading to its degradation in the lysosome. Deubiquitination by USP10 in early endosomes enhances its endocytic recycling to the cell membrane. Ubiquitinated by RNF185 during ER stress. {ECO:0000250\|UniProtKB:P13569}.
Disruption phenotype:		Mice are born at the expected Mendelian rate, but about 80% die within two to five days after birth due to peritonitis (PubMed:7685652). Those that survive fail to thrive, appear runted and weigh about half as much as wild-type littermates (PubMed:7685652). Many of the surviving pups die when they start ingesting solid food, due to intestinal blockage caused by excessive mucus accumulation (PubMed:7685652). None survive for more than about 45 days after birth (PubMed:7685652). Intestinal crypts in the jejunum and ileum are filled with excessive mucus (PubMed:7685652). Excessive accumulation of mucus is also seen in colon (PubMed:7685652). In contrast, their lungs do not present pathological mucus accumulation (PubMed:7685652). Likewise, only five out of ten animals show dilatation and blockage of several small pancreatic ducts (PubMed:7685652). Besides, mutant mice present defects in their lacrimal glands that make them more susceptible to develop eye infections (PubMed:7685652). In caecum epithelium, forskolin-sensitive ion transport is nearly abolished (PubMed:7685652). {ECO:0000269\|PubMed:7685652}.
Similarity:		Belongs to the ABC transporter superfamily. ABCC family. CFTR transporter (TC 3.A.1.202) subfamily. {ECO:0000305}.