ArticleThe Journal of biological chemistry2011
Thermally unstable gating of the most common cystic fibrosis mutant channel (ΔF508): "rescue" by suppressor mutations in nucleotide binding domain 1 and by constitutive mutations in the cytosolic loops.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Chronic and acute modulator treatment restore wild-type-like activity and stability to the primary cystic fibrosis-causingProceedings of the National Academy of Sciences of the United States of America · 2026Article
- The F508del-CFTR trafficking correctors elexacaftor and tezacaftor are CFTR-independent CaRespiratory research · 2024Article
- Cystic Fibrosis Modulator Therapies: Bridging Insights from CF to other Membrane Protein Misfolding Diseases.Israel journal of chemistry · 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
- A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR.British journal of pharmacology · 2022Article
- Functional stability of CFTR depends on tight binding of ATP at its degenerate ATP-binding site.The Journal of physiology · 2021Article
- CFTR Lifecycle Map-A Systems Medicine Model of CFTR Maturation to Predict Possible Active Compound Combinations.International journal of molecular sciences · 2021Article
- Ubiquitination of disease-causing CFTR variants in a microsome-based assay.Analytical biochemistry · 2020Article
- Slowing ribosome velocity restores folding and function of mutant CFTR.The Journal of clinical investigation · 2019Article
- Short-term consequences of F508del-CFTR thermal instability on CFTR-dependent transepithelial currents in human airway epithelial cells.Scientific reports · 2019Article
- Differential thermostability and response to cystic fibrosis transmembrane conductance regulator potentiators of human and mouse F508del-CFTR.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- Structural mechanisms for defective CFTR gating caused by the Q1412X mutation, a severe Class VI pathogenic mutation in cystic fibrosis.The Journal of physiology · 2019Article
- Partial rescue of F508del-cystic fibrosis transmembrane conductance regulator channel gating with modest improvement of protein processing, but not stability, by a dual-acting small molecule.British journal of pharmacology · 2018Article
- Substitution of Yor1p NBD1 residues improves the thermal stability of Human Cystic Fibrosis Transmembrane Conductance Regulator.Protein engineering, design & selection : PEDS · 2017Article
- Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell.Nature communications · 2017Article
- Two Small Molecules Restore Stability to a Subpopulation of the Cystic Fibrosis Transmembrane Conductance Regulator with the Predominant Disease-causing Mutation.The Journal of biological chemistry · 2017Article
- Development of Automated Patch Clamp Technique to Investigate CFTR Chloride Channel Function.Frontiers in pharmacology · 2017Article
- Analysis of cystic fibrosis-associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases.JCI insight · 2016Article
- Potentiation of ΔF508- and G551D-CFTR-Mediated Cl- Current by Novel Hydroxypyrazolines.PloS one · 2016Article
- A synonymous codon change alters the drug sensitivity of ΔF508 cystic fibrosis transmembrane conductance regulator.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
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Authors and funding
5 authors.
Funding
Abstract
Most cystic fibrosis (CF) cases are caused by the ΔF508 mutation in the CF transmembrane conductance regulator (CFTR), which disrupts both the processing and gating of this chloride channel. The cell surface expression of ΔF508-CFTR can be "rescued" by culturing cells at 26-28 °C and treating cells with small molecule correctors or intragenic suppressor mutations. Here, we determined whether these various rescue protocols induce a ΔF508-CFTR conformation that is thermally stable in excised membrane patches. We also tested the impact of constitutive cytosolic loop mutations that increase ATP-independent channel activity (K978C and K190C/K978C) on ΔF508-CFTR function. Low temperature-rescued ΔF508-CFTR channels irreversibly inactivated with a time constant of 5-6 min when excised patches were warmed from 22 °C to 36.5 °C. A panel of CFTR correctors and potentiators that increased ΔF508-CFTR maturation or channel activity failed to prevent this inactivation. Conversely, three suppressor mutations in the first nucleotide binding domain rescued ΔF508-CFTR maturation and stabilized channel activity at 36.5 °C. The constitutive loop mutations increased ATP-independent activity of low temperature-rescued ΔF508-CFTR but did not enhance protein maturation. Importantly, the ATP-independent activities of these ΔF508-CFTR constructs were stable at 36.5 °C, whereas their ATP-dependent activities were not. Single channel recordings of this thermally stable ATP-independent activity revealed dynamic gating and unitary currents of normal amplitudes. We conclude that: (i) ΔF508-CFTR gating is highly unstable at physiologic temperature; (ii) most rescue protocols do not prevent this thermal instability; and (iii) ATP-independent gating and the pore are spared from ΔF508-induced thermal instability, a finding that may inform alternative treatment strategies.
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