Linked Life Data

10360942

Source:http://linkedlifedata.com/resource/pubmed/id/10360942

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
1999-7-2
pubmed:databankReference
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
38
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7453-61
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1999
pubmed:articleTitle
Cystic fibrosis transmembrane conductance regulator: solution structures of peptides based on the Phe508 region, the most common site of disease-causing DeltaF508 mutation.
pubmed:affiliation
Department of Biological Chemistry, Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205-2185, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't