ArticleProceedings of the National Academy of Sciences of the United States of America2005
Normal gating of CFTR requires ATP binding to both nucleotide-binding domains and hydrolysis at the second nucleotide-binding domain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 87 citations in OpenAlex.
- Etiology of Colitis-Complex Diarrhea in Growing Pigs: A Review.Animals : an open access journal from MDPI · 2021Review
- Article
- G551D mutation impairs PKA-dependent activation of CFTR channel that can be restored by novel GOF mutations.American journal of physiology. Lung cellular and molecular physiology · 2020Article
- Disease-relevant mutations alter amino acid co-evolution networks in the second nucleotide binding domain of CFTR.PloS one · 2020Article
- An Intriguing Involvement of Mitochondria in Cystic Fibrosis.Journal of clinical medicine · 2019Review
- Molecular dynamics simulation study on the structural instability of the most common cystic fibrosis-associated mutant ΔF508-CFTR.Biophysics and physicobiology · 2018Article
- Molecular Mechanism of Action of Trimethylangelicin Derivatives as CFTR Modulators.Frontiers in pharmacology · 2018Article
- Stabilization of a nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator yields insight into disease-causing mutations.The Journal of biological chemistry · 2017Article
- Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis.Scientific reports · 2017Article
- The gating of the CFTR channel.Cellular and molecular life sciences : CMLS · 2017Review
- Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators.PloS one · 2016Article
- Deletion of Phenylalanine 508 in the First Nucleotide-binding Domain of the Cystic Fibrosis Transmembrane Conductance Regulator Increases Conformational Exchange and Inhibits Dimerization.The Journal of biological chemistry · 2015Article
- Effects of protein sources and levels in antibiotic-free diets on diarrhea, intestinal morphology, and expression of tight junctions in weaned piglets.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2015Article
- The cystic fibrosis transmembrane conductance regulator is an extracellular chloride sensor.Pflugers Archiv : European journal of physiology · 2015Article
- Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia.The Journal of biological chemistry · 2015Article
- Conserved allosteric hot spots in the transmembrane domains of cystic fibrosis transmembrane conductance regulator (CFTR) channels and multidrug resistance protein (MRP) pumps.The Journal of biological chemistry · 2014Article
- Interference with ubiquitination in CFTR modifies stability of core glycosylated and cell surface pools.Molecular and cellular biology · 2014Article
- Ethanol and its non-oxidative metabolites profoundly inhibit CFTR function in pancreatic epithelial cells which is prevented by ATP supplementation.Pflugers Archiv : European journal of physiology · 2014Article
- ATP binding to two sites is necessary for dimerization of nucleotide-binding domains of ABC proteins.Biochemical and biophysical research communications · 2014Article
- The deviant ATP-binding site of the multidrug efflux pump Pdr5 plays an active role in the transport cycle.The Journal of biological chemistry · 2013Article
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3 authors at 2 institutions in 1 country.
Funding
Abstract
ATP interacts with the two nucleotide-binding domains (NBDs) of CFTR to control gating. However, it is unclear whether gating involves ATP binding alone, or also involves hydrolysis at each NBD. We introduced phenylalanine residues into nonconserved positions of each NBD Walker A motif to sterically prevent ATP binding. These mutations blocked [alpha-(32)P]8-N(3)-ATP labeling of the mutated NBD and reduced channel opening rate without changing burst duration. Introducing cysteine residues at these positions and modifying with N-ethylmaleimide produced the same gating behavior. These results indicate that normal gating requires ATP binding to both NBDs, but ATP interaction with one NBD is sufficient to support some activity. We also studied mutations of the conserved Walker A lysine residues (K464A and K1250A) that prevent hydrolysis. By combining substitutions that block ATP binding with Walker A lysine mutations, we could differentiate the role of ATP binding vs. hydrolysis at each NBD. The K1250A mutation prolonged burst duration; however, blocking ATP binding prevented the long bursts. These data indicate that ATP binding to NBD2 allowed channel opening and that closing was delayed in the absence of hydrolysis. The corresponding NBD1 mutations showed relatively little effect of preventing ATP hydrolysis but a large inhibition of blocking ATP binding. These data suggest that ATP binding to NBD1 is required for normal activity but that hydrolysis has little effect. Our results suggest that both NBDs contribute to channel gating, NBD1 binds ATP but supports little hydrolysis, and ATP binding and hydrolysis at NBD2 are key for normal gating.
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