ArticleThe Journal of biological chemistry2014
An electrostatic interaction at the tetrahelix bundle promotes phosphorylation-dependent cystic fibrosis transmembrane conductance regulator (CFTR) channel opening.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Novel gain-of-function mutants identify a critical region within CFTR membrane-spanning domain 2 controlling cAMP-dependent and ATP-independent channel activation.Cellular and molecular life sciences : CMLS · 2024Article
- Comparing ATPase activity of ATP-binding cassette subfamily C member 4, lamprey CFTR, and human CFTR using an antimony-phosphomolybdate assay.Frontiers in pharmacology · 2024Article
- Expression of gain-of-function CFTR in cystic fibrosis airway cells restores epithelial function better than wild-type or codon-optimized CFTR.Molecular therapy. Methods & clinical development · 2023Article
- Optimization of CFTR gating through the evolution of its extracellular loops.The Journal of general physiology · 2023Article
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
- Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond.eLife · 2021Article
- The molecular evolution of function in the CFTR chloride channel.The Journal of general physiology · 2021Article
- Identification of binding sites for ivacaftor on the cystic fibrosis transmembrane conductance regulator.iScience · 2021Article
- 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
- Slowing ribosome velocity restores folding and function of mutant CFTR.The Journal of clinical investigation · 2019Article
- VX-770-mediated potentiation of numerous human CFTR disease mutants is influenced by phosphorylation level.Scientific reports · 2019Article
- Bacterial Sphingomyelinase is a State-Dependent Inhibitor of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR).Scientific reports · 2017Article
- Current insights into the role of PKA phosphorylation in CFTR channel activity and the pharmacological rescue of cystic fibrosis disease-causing mutants.Cellular and molecular life sciences : CMLS · 2017Review
- Molecular modelling and molecular dynamics of CFTR.Cellular and molecular life sciences : CMLS · 2017Review
- Analysis of cystic fibrosis-associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases.JCI insight · 2016Article
- Article
- Positioning of extracellular loop 1 affects pore gating of the cystic fibrosis transmembrane conductance regulator.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Channel Gating Regulation by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) First Cytosolic Loop.The Journal of biological chemistry · 2016Article
- Murine and human CFTR exhibit different sensitivities to CFTR potentiators.American journal of physiology. Lung cellular and molecular physiology · 2015Article
- Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS.The Journal of biological chemistry · 2015Article
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3 authors.
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Abstract
The CFTR channel is an essential mediator of electrolyte transport across epithelial tissues. CFTR opening is promoted by ATP binding and dimerization of its two nucleotide binding domains (NBDs). Phosphorylation of its R domain (e.g. by PKA) is also required for channel activity. The CFTR structure is unsolved but homology models of the CFTR closed and open states have been produced based on the crystal structures of evolutionarily related ABC transporters. These models predict the formation of a tetrahelix bundle of intracellular loops (ICLs) during channel opening. Here we provide evidence that residues E267 in ICL2 and K1060 in ICL4 electrostatically interact at the interface of this predicted bundle to promote CFTR opening. Mutations or a thiol modifier that introduced like charges at these two positions substantially inhibited ATP-dependent channel opening. ATP-dependent activity was rescued by introducing a second site gain of function (GOF) mutation that was previously shown to promote ATP-dependent and ATP-independent opening (K978C). Conversely, the ATP-independent activity of the K978C GOF mutant was inhibited by charge- reversal mutations at positions 267 or 1060 either in the presence or absence of NBD2. The latter result indicates that this electrostatic interaction also promotes unliganded channel opening in the absence of ATP binding and NBD dimerization. Charge-reversal mutations at either position markedly reduced the PKA sensitivity of channel activation implying strong allosteric coupling between bundle formation and R domain phosphorylation. These findings support important roles of the tetrahelix bundle and the E267-K1060 electrostatic interaction in phosphorylation-dependent CFTR gating.
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