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Updated: Jun 11, 2026
09:59
Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
The V510D suppressor mutation stabilizes DeltaF508-CFTR at the cell surface
Tip W Loo1, M Claire Bartlett, David M Clarke
1Departments of Medicine and Biochemistry, University of Toronto, Toronto, Ontario, Canada.
Biochemistry
|July 2, 2010
Summary
The V510D mutation in cystic fibrosis transmembrane conductance regulator (CFTR) protein helps correct the DeltaF508 mutation, improving protein folding and stability. This finding offers a new strategy for treating cystic fibrosis.
Area of Science:
- Molecular Biology
- Protein Folding
- Genetic Diseases
Background:
- Cystic fibrosis is caused by mutations in the CFTR gene.
- The common DeltaF508 mutation disrupts CFTR protein folding and stability.
- This leads to reduced protein maturation and function.
Purpose of the Study:
- To investigate mutations that can rescue DeltaF508-CFTR folding and stability.
- To identify specific amino acid substitutions that promote CFTR maturation.
- To understand the molecular mechanisms underlying CFTR folding rescue.
Main Methods:
- Site-directed mutagenesis of CFTR at the V510 position.
- Analysis of CFTR protein maturation and stability in cell models.
- Assessment of CFTR protein half-life at the cell surface.
- Investigating interactions between NBD1 and TMD2 domains.
Main Results:
- Acidic residue substitution at V510 (V510D, V510E) promoted DeltaF508-CFTR maturation.
- V510D mutation rescued maturation even without NBD2.
- V510D significantly increased the cell surface half-life of DeltaF508-CFTR.
- V510R/R1070D mutations also promoted maturation, suggesting a salt bridge interaction.
Conclusions:
- The V510D mutation in NBD1 promotes DeltaF508-CFTR maturation and stability.
- This rescue mechanism involves interactions with TMD2, potentially via a salt bridge with R1070.
- Targeting NBD1-TMD2 interactions offers a therapeutic strategy for cystic fibrosis.
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