EFFECTS OF THE DELTA-F508 MUTATION ON THE STRUCTURE, FUNCTION, AND FOLDING OF THE 1ST NUCLEOTIDE-BINDING DOMAIN OF CFTR

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 (DELTAF508) 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 beta-stranded structure in solution. The DELTAF508 mutation causes a diminution in the amount of beta-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 DELTAF508 is a stability, or protein-folding mutant. Here we review these results and discuss their implications for interpreting the behavior of DELTAF508 in situ and for the rational design of new CF drugs.