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Cited by 378Cystic Fibrosis Research AdvancesIon Transport and Channel RegulationGenetic and Kidney Cyst Diseases

Mechanism-based corrector combination restores ΔF508-CFTR folding and function

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Okiyoneda, Tsukasa, Veit, Guido, Dekkers, Johanna F, Bagdany, Miklos, Soya, Naoto, Xu, Haijin, Roldan, Ariel, Verkman, Alan S +5 more·2013·Nature Chemical Biology
DOI 10.1038/nchembio.1253PMC PMC3840170
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Abstract

The most common cystic fibrosis mutation, ΔF508 in nucleotide binding domain 1 (NBD1), impairs cystic fibrosis transmembrane conductance regulator (CFTR)-coupled domain folding, plasma membrane expression, function and stability. VX-809, a promising investigational corrector of ΔF508-CFTR misprocessing, has limited clinical benefit and an incompletely understood mechanism, hampering drug development. Given the effect of second-site suppressor mutations, robust ΔF508-CFTR correction most likely requires stabilization of NBD1 energetics and the interface between membrane-spanning domains (MSDs) and NBD1, which are both established primary conformational defects. Here we elucidate the molecular targets of available correctors: class I stabilizes the NBD1-MSD1 and NBD1-MSD2 interfaces, and class II targets NBD2. Only chemical chaperones, surrogates of class III correctors, stabilize human ΔF508-NBD1. Although VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional plasma membrane expression of ΔF508-CFTR also requires compounds that counteract the NBD1 and NBD2 stability defects in cystic fibrosis bronchial epithelial cells and intestinal organoids. Thus, the combination of structure-guided correctors represents an effective approach for cystic fibrosis therapy.

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  • Rescuing structural defects of NBD1-MSDs and NBD2-domain interfaces, as well as NBD1 stability by type I, II, and III correctors, reinstated folding for F508del-CFTR and a subset of rare folding mutants located in MSD1, MSD2, and NBD2 domains.

    “This hypothesis gained traction by demonstrating that rescuing the structural defects of the NBD1-MSDs and NBD2-domain interfaces — as well as the NBD1 stability by type I, II, and III correctors, respectively — reinstated folding for not only the F508del-CFTR (18, 19, 21), but also a subset of rare folding mutants located in the MSD1, MSD2, and NBD2 domains (21).”

    From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [19]

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  • Correction of distinct folding defects is required to robustly restore mutant channel folding.

    “it was suggested that the correction of distinct folding defects is required to robustly restore the mutant channel folding (18–20).”

    From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [19]

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Authors
Okiyoneda, T., Veit, G., Dekkers, J. F., Bagdany, M., Soya, N., Xu, H., Roldan, A., Verkman, A. S., Kurth, M., Simon, A., Hegedus, T., Beekman, J. M., & Lukacs, G. L.
Affiliations
  • McGill University (CA)
  • University Medical Center Utrecht (NL)
  • University of California, San Francisco (US)
  • University of California, Davis (US)
ORCID
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2013-05-12
Volume
9
Issue
7
Pages
444-454
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/nchembio.1253
PMC
PMC3840170
OpenAlex
W2151837778
Cited by
378
References
2
Citations by year
2026: 9 · 2025: 15 · 2024: 25 · 2023: 17 · 2022: 33 · 2021: 26 · 2020: 26 · 2019: 28 · 2018: 46 · 2017: 23 · 2016: 40 · 2015: 34 · 2014: 48 · 2013: 8
FWCI
32.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Repository of the Academy's Library (Library of the Hungarian Academy of Sciences) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Japan Society for the Promotion of Science (25893275)
  • National Institute of General Medical Sciences (P41GM089153, GM089153)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075302, DK072517, P30DK072517)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
cystic fibrosis, ΔF508-CFTR, CFTR correctors, lumacaftor, second-site suppressor mutations, chemical chaperones, protein folding, plasma membrane expression, missense mutations, intestinal organoids, bronchial epithelial cells, structure-based drug design
MeSH terms
Aminopyridines, Animals, Binding Sites, Bronchi, Cell Membrane, Cystic Fibrosis, Endoplasmic Reticulum, Epithelial Cells, Glycosylation, Cricetinae, Humans, Mutation, Nucleotides, Recombinant Proteins, Protein Structure, Tertiary, Protein Folding, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles

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