Cloned (Comment) | Organism |
---|---|
recombinant expression of wild-type and mutant enzymes in CHO cells | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
G551D | third most common pathogenic naturally occuring mutation of the enzyme, mutant G551D shows a significantly decreased open probability caused by failure of the mutant channel to respond to ATP. The CFTR-targeted drug, VX-770 (Ivacaftor) potentiates G551D-CFTR function in vitro by boosting its open probability, in the presence of VX-770, G551D-CFTR becomes responsive to ATP, albeit with an unusual time course. A sudden removal of ATP in excised inside-out patches containing the mutant enzyme elicits an initial increase in macroscopic G551D-CFTR current followed by a slow decrease, in contrast to wild-type channels. The stimulatory effect of ATP is abolished by the G551D mutation despite a normal surface expression of the mutant proteins. The two ATP-binding sites in the G551D mutant mediate opposite effects on channel gating. Introduction of mutations that specifically alter ATP-binding affinity in either nucleotide-binding domain (NBD1 or NBD2) into the G551D background, the disease-associated mutation converts site 2, formed by the head subdomain of NBD2 and the tail subdomain of NBD1, into an inhibitory site, whereas site 1 remains stimulatory | Homo sapiens |
G551D/Y1219F | increased ATP washout compared to mutant G551D | Homo sapiens |
G551D/Y1219G | increased ATP washout compared to mutant G551D | Homo sapiens |
G551D/Y1219I | increased ATP washout compared to mutant G551D | Homo sapiens |
G551E | site-directed mutagenesis, the mutant exhibits a similar phenotype like mutant G551D | Homo sapiens |
G551K | site-directed mutagenesis, the mutant does not exhibit a similar phenotype like mutant G551D | Homo sapiens |
G551S | site-directed mutagenesis, the mutant does not exhibit a similar phenotype like mutant G551D | Homo sapiens |
W401G/G551D | acceleration of the slow-phase current decay by the W401G mutation | Homo sapiens |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
cell surface | - |
Homo sapiens | 9986 | - |
plasma membrane | - |
Homo sapiens | 5886 | - |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Mg2+ | required | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
ATP + H2O + closed Cl- channel | Homo sapiens | - |
ADP + phosphate + open Cl- channel | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P13569 | - |
- |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
ATP + H2O + closed Cl- channel | - |
Homo sapiens | ADP + phosphate + open Cl- channel | - |
? |
Synonyms | Comment | Organism |
---|---|---|
CFTR | - |
Homo sapiens |
pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
---|---|---|---|
7.4 | - |
assay at | Homo sapiens |
General Information | Comment | Organism |
---|---|---|
malfunction | cystic fibrosis, one of the most common lethal genetic diseases, is caused by loss-of-function mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel. The third most common pathogenic mutation, a glycine-to-aspartate mutation at position 551 (G551D) shows a significantly decreased open probability caused by failure of the mutant channel to respond to ATP. The CFTR-targeted drug, VX-770 (Ivacaftor), which potentiates G551D-CFTR function in vitro by boosting its Po, is approved by the american food and drug administration to treat cystic fibrosis patients carrying this mutation | Homo sapiens |
physiological function | the cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a chloride channel, which is gated by ATP when phosphorylated | Homo sapiens |