1cky
CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR: SOLUTION STRUCTURES OF PEPTIDES BASED ON THE PHE508 REGION, THE MOST COMMON SITE OF DISEASE-CAUSING DELTA-F508 MUTATION
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OverviewOverview
Most cases of cystic fibrosis (CF), a common inherited disease of, epithelial cell origin, are caused by the deletion of Phe508 located in, the first nucleotide-binding domain (NBF1) of the protein called CFTR, (cystic fibrosis transmembrane conductance regulator). To gain greater, insight into the structure within the Phe508 region of the wild-type, protein and the change in structure that occurs when this residue is, deleted, we conducted nuclear magnetic resonance (NMR) studies on, representative synthetic 26 and 25 amino acid peptide segments. 2D 1H NMR, studies at 600 MHz of the 26-residue peptide consisting of Met498 to, Ala523 in 10% DMSO, pH 4.0, at 25 degrees C show a continuous but labile, helix from Gly500 to Lys522, based on both NH-NH(i,i+1) and, alphaH-NH(i,i+1) NOEs. Phe508 within this helix shows only short-range (i, </=i + 2) NOEs. The corresponding 25-residue peptide lacking Phe508 also, forms a labile helix from Gly500 to Lys522. However, the relative, intensities of the NH-NH(i, i+1)/alphaH-NH(i,i+1) NOEs, fewer, intermediate-range NOEs, and downfield alphaH and NH chemical shifts, indicate a lower helical propensity of the 25-mer between residues 505 and, 517, surrounding the missing residue, Phe508. 2D 1H NMR studies of both, peptides in saturating (43%) TFE reveal stable alpha-helices from Gly500, to Lys522, based on NH-NH(i,i+1,2,3), alphaH-NH(i,i+2,3,4), alphaH-betaH(i,i+3), and weak alphaH-NH(i,i+1) NOEs. However, downfield, shifts of the alphaH resonances from residues Gly500 to Ile507 and fewer, intermediate-range NOEs suggest a less stable alpha-helix in the 25-mer, even in saturating TFE. These findings show that the Phe508-containing, region of CFTR has a propensity to form an alpha-helix, which is, destabilized by the DeltaF508 mutation found in most patients with CF., These studies have direct relevance to better understanding the CFTR, misfolding problem associated with CF and to identifying chemical agents, which correct this problem.
About this StructureAbout this Structure
1CKY is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.
ReferenceReference
Cystic fibrosis transmembrane conductance regulator: solution structures of peptides based on the Phe508 region, the most common site of disease-causing DeltaF508 mutation., Massiah MA, Ko YH, Pedersen PL, Mildvan AS, Biochemistry. 1999 Jun 8;38(23):7453-61. PMID:10360942
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