The ΔF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR
Abstract
Misfolding accounts for the endoplasmic reticulum-associated degradation of mutant cystic fibrosis transmembrane conductance regulators (CFTRs), including deletion of Phe508 (DeltaF508) in the nucleotide-binding domain 1 (NBD1). To study the role of Phe508, the de novo folding and stability of NBD1, NBD2 and CFTR were compared in conjunction with mutagenesis of Phe508. DeltaF508 and amino acid replacements that prevented CFTR folding disrupted the NBD2 fold and its native interaction with NBD1. DeltaF508 caused limited alteration in NBD1 conformation. Whereas nonpolar and some aliphatic residues were permissive, charged residues and glycine compromised the post-translational folding and stability of NBD2 and CFTR. The results suggest that hydrophobic side chain interactions of Phe508 are required for vectorial folding of NBD2 and the domain-domain assembly of CFTR, representing a combined co- and post-translational folding mechanism that may be used by other multidomain membrane proteins.
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The cooperative F508del-CFTR domain misfolding can be robustly reversed by allosteric pharmacochaperones that synergistically stabilize NBD1 unfolding intermediates and the MSD1 by type III (VX-445) and type I (VX-661) correctors, respectively.
“These observations illustrate that the cooperative F508del-CFTR domain misfolding (10, 11, 51) can be robustly reversed by allosteric pharmacochaperones that synergistically stabilize NBD1 unfolding intermediates and the MSD1 by type III (VX-445) and type I (VX-661) correctors, respectively.”
From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [10]
F508del impairs NBD1 stability and the coupled or cooperative domain folding of CFTR.
“F508del impairs the NBD1 stability and the coupled or cooperative domain folding of the channel (9–11).”
From Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination (2020) · cites this paper as [10]
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Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
Van Goor, F., Hadida, S., Grootenhuis, P. D. J., Burton, B., Stack, J. H., Straley, K. S., Decker, C. J., Miller, M., McCartney, J., Olson, E. R., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105787108 · Cited by 1,088 · see citing works
Veit, G., Roldan, A., Hancock, M. A., Da Fonte, D. F., Xu, H., Hussein, M., Frenkiel, S., Matouk, E., Velkov, T., & Lukacs, G. L. (2020) · JCI Insight · doi:10.1172/jci.insight.139983 · Cited by 250 · see citing works
Tropak, M. B., Blanchard, J. E., Withers, S. G., Brown, E. D., & Mahuran, D. (2007) · Chemistry & Biology · doi:10.1016/j.chembiol.2006.12.006 · Cited by 105 · see citing works
- Authors
- Du, K., Sharma, M., & Lukacs, G. L.
- Affiliations
- University of Toronto (CA)
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2004-12-26
- Volume
- 12
- Issue
- 1
- Pages
- 17-25
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W1996779865
- Cited by
- 356
- References
- 0
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 11 · 2023: 12 · 2022: 13 · 2021: 15 · 2020: 16 · 2019: 19 · 2018: 14 · 2017: 14 · 2016: 14 · 2015: 14 · 2014: 25 · 2013: 14 · 2012: 24
- FWCI
- 11.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cystic Fibrosis Foundation
- National Institutes of Health
- Canadian Institutes of Health Research
- 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
- cystic fibrosis, CFTR, F508del mutation, NBD1, post-translational folding, domain-domain interactions, protein misfolding, ER-associated degradation, hydrophobic interactions, protein stability
- MeSH terms
- Animals, Binding Sites, Cell Line, Cystic Fibrosis, Cricetinae, Humans, Peptide Hydrolases, Phenylalanine, Protein Processing, Post-Translational, Sequence Deletion, Protein Folding, Cystic Fibrosis Transmembrane Conductance Regulator
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