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Cited by 280Cystic Fibrosis Research AdvancesProtein Structure and DynamicsHeat shock proteins research

Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function

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Rabeh, Wael M., Bossard, Florian, Xu, Haijin, Okiyoneda, Tsukasa, Bagdany, Miklos, Mulvihill, Cory M., Du, Kai, di Bernardo, Salvatore +4 more·2012·Cell
DOI 10.1016/j.cell.2011.11.024PMC PMC3431169
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Abstract

The folding and misfolding mechanism of multidomain proteins remains poorly understood. Although thermodynamic instability of the first nucleotide-binding domain (NBD1) of ΔF508 CFTR (cystic fibrosis transmembrane conductance regulator) partly accounts for the mutant channel degradation in the endoplasmic reticulum and is considered as a drug target in cystic fibrosis, the link between NBD1 and CFTR misfolding remains unclear. Here, we show that ΔF508 destabilizes NBD1 both thermodynamically and kinetically, but correction of either defect alone is insufficient to restore ΔF508 CFTR biogenesis. Instead, both ΔF508-NBD1 energetic and the NBD1-MSD2 (membrane-spanning domain 2) interface stabilization are required for wild-type-like folding, processing, and transport function, suggesting a synergistic role of NBD1 energetics and topology in CFTR-coupled domain assembly. Identification of distinct structural deficiencies may explain the limited success of ΔF508 CFTR corrector molecules and suggests structure-based combination corrector therapies. These results may serve as a framework for understanding the mechanism of interface mutation in multidomain membrane proteins.

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  • The magnitude of clinical improvements with single corrector combinations was consistent with the degree of correction of F508del-CFTR by a single CFTR corrector.

    “Given the multiple defects in F508del-CFTR affecting processing and trafficking, the magnitude of clinical improvements was consistent with the degree of correction of F508del-CFTR by a single CFTR corrector.13,14”

    From Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial (2019) · cites this paper as [13]

    The Introduction and Discussion describe modest correction of ΔF508-CFTR by individual corrector molecules and link that limitation to multiple folding defects. They do not compare the degree of molecular correction with the magnitude of clinical improvements, so the clinical-consistency part of the claim is unsupported by this paper. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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 [18]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • 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 [18]

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Cited by

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Authors
Rabeh, W. M., Bossard, F., Xu, H., Okiyoneda, T., Bagdany, M., Mulvihill, C. M., Du, K., di Bernardo, S., Liu, Y., Konermann, L., Roldan, A., & Lukacs, G. L.
Affiliations
  • McGill University (CA)
  • Western University (CA)
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2012-01
Volume
148
Issue
1-2
Pages
150-163
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2011.11.024
PMC
PMC3431169
OpenAlex
W1995692151
Cited by
280
References
1
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Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Canadian Institutes of Health Research
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK075302, R01DK075302)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
ΔF508-CFTR, cystic fibrosis, protein misfolding, CFTR correctors, protein topology
MeSH terms
Humans, Models, Molecular, Mutation, Protein Structure, Tertiary, Protein Folding, Cystic Fibrosis Transmembrane Conductance Regulator

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