ArticleCommunications biology2018
A minimal helical-hairpin motif provides molecular-level insights into misfolding and pharmacological rescue of CFTR.
Article in Communications biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Advancements in Single-Molecule Fluorescence Detection Techniques and Their Expansive Applications in Drug Discovery and Neuroscience.Biosensors · 2025Review
- Functional Consequences of CFTR Interactions in Cystic Fibrosis.International journal of molecular sciences · 2024Review
- Folding speeds of helical membrane proteins.Biochemical Society transactions · 2024Review
- Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.Molecules (Basel, Switzerland) · 2024Review
- An automated single-molecule FRET platform for high-content, multiwell plate screening of biomolecular conformations and dynamics.Nature communications · 2023Article
- Robust membrane protein tweezers reveal the folding speed limit of helical membrane proteins.eLife · 2023Article
- One Size Does Not Fit All: The Past, Present and Future of Cystic Fibrosis Causal Therapies.Cells · 2022Review
- Fast slow folding of an outer membrane porin.Proceedings of the National Academy of Sciences of the United States of America · 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
- Heat treatment of thioredoxin fusions increases the purity of α-helical transmembrane protein constructs.Protein science : a publication of the Protein Society · 2021Article
- Single-Molecular Förster Resonance Energy Transfer Measurement on Structures and Interactions of Biomolecules.Micromachines · 2021Review
- SDS-induced multi-stage unfolding of a small globular protein through different denatured states revealed by single-molecule fluorescence.Chemical science · 2020Article
- 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
- CFTR transmembrane segments are impaired in their conformational adaptability by a pathogenic loop mutation and dynamically stabilized by Lumacaftor.The Journal of biological chemistry · 2020Article
- Site-Directed Fluorescence Approaches for Dynamic Structural Biology of Membrane Peptides and Proteins.Frontiers in molecular biosciences · 2019Review
Corrections and comments
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Our meagre understanding of CFTR misfolding and its reversal by small-molecule correctors hampers the development of mechanism-based therapies of cystic fibrosis. Here we exploit a helical-hairpin construct-the simplest proxy of membrane-protein tertiary contacts-containing CFTR's transmembrane helices 3 and 4 and its corresponding disease phenotypic mutant V232D to gain molecular-level insights into CFTR misfolding and drug rescue by the corrector Lumacaftor. Using a single-molecule FRET approach to study hairpin conformations in lipid bilayers, we find that the wild-type hairpin is well folded, whereas the V232D mutant assumes an open conformation in bilayer thicknesses mimicking the endoplasmic reticulum. Addition of Lumacaftor reverses the aberrant opening of the mutant hairpin to restore a compact state as in the wild type. The observed membrane escape of the V232D hairpin and its reversal by Lumacaftor complement cell-based analyses of the full-length protein, thereby providing in vivo and in vitro correlates of CFTR misfolding and drug-action mechanisms.
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Registered trials
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