title: Effects of the delta F508 mutation on the structure, function, and folding of the first nucleotide-binding domain of CFTR.
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 (delta F508) 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 delta F508 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 delta F508 is a stability, or protein-folding mutant. Here we review these results and discuss their implications for interpreting the behavior of delta F508 in situ and for the rational design of new CF drugs.
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
authors.forename: P J
authors.initials: PJ
authors.lastname: Thomas
authors.forename: P L
authors.initials: PL
authors.lastname: Pedersen
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D009711:Nucleotides / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017384:Sequence Deletion
chemical_list: C505032:CFTR protein, human; D007473:Ion Channels; D008565:Membrane Proteins; D009711:Nucleotides; D010446:Peptide Fragments; D019005:Cystic Fibrosis Transmembrane Conductance Regulator