Effects of the ΔF508 mutation on the structure, function, and folding of the first nucleotide-binding domain of CFTR

Philip J. Thomas, Peter L. Pedersen

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)11-19
Number of pages9
JournalJournal of Bioenergetics and Biomembranes
Volume25
Issue number1
DOIs
StatePublished - Feb 1993

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Cystic Fibrosis Transmembrane Conductance Regulator
Nucleotides
Cystic Fibrosis
Peptides
Mutation
Adenine Nucleotides
Sequence Deletion
Protein Folding
Circular Dichroism
Alleles
Pharmaceutical Preparations
Genes

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

Cite this

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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.",
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AU - Pedersen, Peter L.

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N2 - 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.

AB - 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.

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