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Cited by 375Cystic Fibrosis Research AdvancesIon Transport and Channel RegulationGenetic and Kidney Cyst Diseases

CFTR: folding, misfolding and correcting the ΔF508 conformational defect

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Lukacs, Gergely L., Verkman, A.S.·2012·Trends in Molecular Medicine
DOI 10.1016/j.molmed.2011.10.003PMC PMC3643519
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Abstract

Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is caused by loss-of-function mutations of the CF transmembrane conductance regulator (CFTR), a cyclic AMP-regulated plasma membrane chloride channel. The most common mutation, deletion of phenylalanine 508 (ΔF508), impairs CFTR folding and, consequently, its biosynthetic and endocytic processing as well as chloride channel function. Pharmacological treatments may target the ΔF508 CFTR structural defect directly by binding to the mutant protein and/or indirectly by altering cellular protein homeostasis (proteostasis) to promote ΔF508 CFTR plasma membrane targeting and stability. This review discusses recent basic research aimed at elucidating the structural and trafficking defects of ΔF508 CFTR, a prerequisite for the rational design of CF therapy to correct the loss-of-function phenotype.

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Authors
Lukacs, G. L., & Verkman, A. S.
Affiliations
University of California, San Francisco (US)
Corresponding author
Verkman, A.S.
Venue
Trends in Molecular Medicine
Publisher
Elsevier BV
Published
2012-02
Volume
18
Issue
2
Pages
81-91
ISSN
1471-4914 (ISSN-L)
DOI
10.1016/j.molmed.2011.10.003
PMC
PMC3643519
OpenAlex
W2058169488
Cited by
375
References
1
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FWCI
4.70
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Molecular Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Cystic Fibrosis Foundation
  • Cystic Fibrosis Foundation Therapeutics
  • Canada Research Chairs
  • National Institutes of Health
  • Health Canada
  • Canadian Institutes of Health Research
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075302, 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
CFTR, cystic fibrosis, F508del mutation, protein folding, protein misfolding, chloride channels, proteostasis, protein trafficking, plasma membrane targeting, CFTR correctors, CFTR modulators
MeSH terms
Animals, Cystic Fibrosis, Humans, Models, Molecular, Mutation, Protein Folding, Cystic Fibrosis Transmembrane Conductance Regulator, Protein Transport, Drug Discovery

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