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VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1
- Source :
- Molecular Biology of the Cell
- Publication Year :
- 2013
- Publisher :
- The American Society for Cell Biology, 2013.
-
Abstract
- Misfolding of cystic fibrosis transmembrane conductance regulator protein (CFTR) causes the fatal lung disease cystic fibrosis. VX-809 was developed to suppress disease-related folding defects in CFTR. VX-809 suppresses folding defects in CFTR by modulating the conformation of membrane-spanning domain 1. VX-808 is thereby able to partially restore function to F508del-CFTR and other disease-related mutants.<br />Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
Protein Folding
Cystic Fibrosis
Protein Conformation
Regulator
Mutation, Missense
Aminopyridines
Cystic Fibrosis Transmembrane Conductance Regulator
medicine.disease_cause
Cystic fibrosis
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Protein structure
medicine
Humans
Benzodioxoles
Molecular Biology
030304 developmental biology
0303 health sciences
Mutation
biology
Lumacaftor
Cell Biology
Articles
respiratory system
medicine.disease
Cystic fibrosis transmembrane conductance regulator
Transmembrane protein
digestive system diseases
3. Good health
Cell biology
respiratory tract diseases
Protein Structure, Tertiary
Biochemistry
chemistry
Cell Biology of Disease
030220 oncology & carcinogenesis
biology.protein
Protein folding
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 19394586 and 10591524
- Volume :
- 24
- Issue :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecular Biology of the Cell
- Accession number :
- edsair.doi.dedup.....1fa760baf2e280c127123b8cef7c0924