Requirements for efficient correction of ΔF508 CFTR revealed by analyses of evolved sequences
Open accessAbstract
Misfolding of ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR) underlies pathology in most CF patients. F508 resides in the first nucleotide-binding domain (NBD1) of CFTR near a predicted interface with the fourth intracellular loop (ICL4). Efforts to identify small molecules that restore function by correcting the folding defect have revealed an apparent efficacy ceiling. To understand the mechanistic basis of this obstacle, positions statistically coupled to 508, in evolved sequences, were identified and assessed for their impact on both NBD1 and CFTR folding. The results indicate that both NBD1 folding and interaction with ICL4 are altered by the ΔF508 mutation and that correction of either individual process is only partially effective. By contrast, combination of mutations that counteract both defects restores ΔF508 maturation and function to wild-type levels. These results provide a mechanistic rationale for the limited efficacy of extant corrector compounds and suggest approaches for identifying compounds that correct both defective steps.
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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 [14]
The Introduction (page unavailable) reports that single ΔF508 correctors reached only about 15% of wild-type efficacy, and the Discussion (page unavailable) links limited correction of individual folding defects to limited CFTR maturation and function. The paper does not report the magnitude of clinical improvements with a single corrector or compare clinical outcomes with its degree of correction; it expresses concern about whether that degree of correction would provide therapeutic benefit. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCorrection 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 [20]
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Cites
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- Authors
- Mendoza, J. L., Schmidt, A., Li, Q., Nuvaga, E., Barrett, T., Bridges, R. J., Feranchak, A. P., Brautigam, C. A., & Thomas, P. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Rosalind Franklin University of Medicine and Science (US)
- Corresponding author
- Thomas, Philip J.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 148
- Issue
- 1-2
- Pages
- 164-174
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3266553
- OpenAlex
- W2158288696
- Cited by
- 261
- References
- 1
- Citations by year
- 2026: 2 · 2025: 13 · 2024: 11 · 2023: 13 · 2022: 12 · 2021: 13 · 2020: 21 · 2019: 12 · 2018: 28 · 2017: 21 · 2016: 13 · 2015: 27 · 2014: 34 · 2013: 24 · 2012: 17
- FWCI
- 25.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 563 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK049835, DK49835, R01DK076638, DK76638)
- National Institute of Dental and Craniofacial Research (DE 12309, R01DE012309)
- 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 › Molecular Biology › Protein Structure and Dynamics
- Keywords
- F508del mutation, CFTR, cystic fibrosis, protein misfolding, NBD1, protein folding, protein maturation
- MeSH terms
- Animals, Cystic Fibrosis, Humans, Models, Molecular, Suppression, Genetic, Protein Structure, Tertiary, Protein Folding, ATP-Binding Cassette Transporters, Cystic Fibrosis Transmembrane Conductance Regulator, Mice
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