Abstract
The fatal autosomal recessive disease cystic fibrosis (CF) is caused by mutations in the gene which encodes the cystic fibrosis transmembrane conductance regulator (CFTR). Many of these disease-causing mutations, including the deletion of F508 (ΔF508) which accounts for approximately 70% of the disease alleles, occur in one of the two consensus nucleotide binding sequences. Peptide studies have directly demonstrated that the N-terminal nucleotide binding sequences bind adenine nucleotides. Structurally, circular dichroism spectropolarimetry indicates that this region of CFTR assumes a β-stranded structure in solution. The ΔF508 mutation causes a diminution in the amount of β-stranded structure and a concomitant increase in the amount of random coil structure present, indicating that either the mutant peptide has a different native structure or that the conformational equilibrium is shifted toward a more disordered form. Furthermore, the mutant peptide is more sensitive to denaturation, indicating that ΔF508 is a stability, or protein-folding mutant. Here we review these results and discuss their implications for interpreting the behavior of ΔF508 in situ and for the rational design of new CF drugs.
Original language | English (US) |
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Pages (from-to) | 11-19 |
Number of pages | 9 |
Journal | Journal of Bioenergetics and Biomembranes |
Volume | 25 |
Issue number | 1 |
DOIs | |
State | Published - Feb 1993 |
Externally published | Yes |
Keywords
- Cystic fibrosis
- cystic fibrosis transmembrane conductance regulator
- genetic disease
- mutant
- nucleotide binding
- peptides
- protein folding
- secondary structure
ASJC Scopus subject areas
- Physiology
- Cell Biology