ArticleJournal of molecular biology2015
Restoration of NBD1 thermal stability is necessary and sufficient to correct ∆F508 CFTR folding and assembly.
Article in Journal of molecular biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- A cell-permeable nanobody to restore F508del cystic fibrosis transmembrane conductance regulator activity.Nature chemical biology · 2026Article
- p.Phe508del-CFTR Trafficking: A Protein Quality Control Perspective Through UPR, UPS, and Autophagy.International journal of molecular sciences · 2025Review
- Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review.Current issues in molecular biology · 2025Review
- ATP-dependent thermoring basis for the heat unfolding of the first nucleotide-binding domain isolated from human CFTR.Research square · 2024Article
- Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling.Nature communications · 2023Article
- Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators.Science (New York, N.Y.) · 2022Article
- A small molecule high throughput screening platform to profile conformational properties of nascent, ribosome-bound proteins.Scientific reports · 2022Article
- Nanomechanics combined with HDX reveals allosteric drug binding sites of CFTR NBD1.Computational and structural biotechnology journal · 2022Article
- Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.Cellular and molecular life sciences : CMLS · 2021Article
- A topological switch in CFTR modulates channel activity and sensitivity to unfolding.Nature chemical biology · 2021Article
- Stability Prediction for Mutations in the Cytosolic Domains of Cystic Fibrosis Transmembrane Conductance Regulator.Journal of chemical information and modeling · 2021Article
- New insights into structure and function of bis-phosphinic acid derivatives and implications for CFTR modulation.Scientific reports · 2021Article
- Towards next generation therapies for cystic fibrosis: Folding, function and pharmacology of CFTR.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2020Review
- Disease-relevant mutations alter amino acid co-evolution networks in the second nucleotide binding domain of CFTR.PloS one · 2020Article
- Domain-interface dynamics of CFTR revealed by stabilizing nanobodies.Nature communications · 2019Article
- Differential Scanning Fluorimetry and Hydrogen Deuterium Exchange Mass Spectrometry to Monitor the Conformational Dynamics of NBD1 in Cystic Fibrosis.Methods in molecular biology (Clifton, N.J.) · 2019Article
- Ligand binding to a remote site thermodynamically corrects the F508del mutation in the human cystic fibrosis transmembrane conductance regulator.The Journal of biological chemistry · 2018Article
- Structure-guided combination therapy to potently improve the function of mutant CFTRs.Nature medicine · 2018Article
- Combining theoretical and experimental data to decipher CFTR 3D structures and functions.Cellular and molecular life sciences : CMLS · 2018Article
- ΔF508-CFTR Modulator Screen Based on Cell Surface Targeting of a Chimeric Nucleotide Binding Domain 1 Reporter.SLAS discovery : advancing life sciences R & D · 2018Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) (ABCC7), unique among ABC exporters as an ion channel, regulates ion and fluid transport in epithelial tissues. Loss of function due to mutations in the cftr gene causes cystic fibrosis. The most common cystic-fibrosis-causing mutation, the deletion of F508 (ΔF508) from the first nucleotide binding domain (NBD1) of CFTR, results in misfolding of the protein and clearance by cellular quality control systems. The ΔF508 mutation has two major impacts on CFTR: reduced thermal stability of NBD1 and disruption of its interface with membrane-spanning domains (MSDs). It is unknown if these two defects are independent and need to be targeted separately. To address this question, we varied the extent of stabilization of NBD1 using different second-site mutations and NBD1 binding small molecules with or without NBD1/MSD interface mutation. Combinations of different NBD1 changes had additive corrective effects on ∆F508 maturation that correlated with their ability to increase NBD1 thermostability. These effects were much larger than those caused by interface modification alone and accounted for most of the correction achieved by modifying both the domain and the interface. Thus, NBD1 stabilization plays a dominant role in overcoming the ΔF508 defect. Furthermore, the dual target approach resulted in a locked-open ion channel that was constitutively active in the absence of the normally obligatory dependence on phosphorylation by protein kinase A. Thus, simultaneous targeting of both the domain and the interface, as well as being non-essential for correction of biogenesis, may disrupt normal regulation of channel function.
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