TY - JOUR
T1 - A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein
AU - Cutting, Garry R.
AU - Kasch, Laura M.
AU - Rosenstein, Beryl J.
AU - Zielenski, Julian
AU - Tsui, Lap Chee
AU - Antonarakis, Stylianos E.
AU - Kazazian, Haig H.
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 1990
Y1 - 1990
N2 - THE gene responsible for cystic fibrosis (CF) has recently been identified and is predicted to encode a protein of 1,480 ami no acids called the CF transmembrane conductance regulator (CFTR)1,2. Several functional regions are thought to exist in the CFTR protein, including two areas for ATP-binding, termed nucleotide-binding folds (NBFs), a regulatory (R) region that has many possible sites for phosphor} lation by protein kinases A and C, and two hydro-phobic regions that probably interact with cell membranes2. The most common CF gene mutation leads to omission of phenv lalanine residue 508 in the putative first NBF, indicating that this region is functionally important2-4. To determine whether other mutations occur in the NBFs of CFTR, we determined the nucleotide sequences of exons 9, 10, 11 and 12 (encoding the first NBF) and exons 20, 21 and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American-black CF patients. One cluster of four mutations was discovered in a 30-base-pair region of exon 11. Three of these mutations cause amino-acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins and ATP-binding membrane-associated transport proteins. The fourth mutation creates a premature termination signal. These mutations reveal a functionally important region in the CFTR protein and provide further evidence that CFTR is a member of the family of ATP-dependent transport proteins2,5.
AB - THE gene responsible for cystic fibrosis (CF) has recently been identified and is predicted to encode a protein of 1,480 ami no acids called the CF transmembrane conductance regulator (CFTR)1,2. Several functional regions are thought to exist in the CFTR protein, including two areas for ATP-binding, termed nucleotide-binding folds (NBFs), a regulatory (R) region that has many possible sites for phosphor} lation by protein kinases A and C, and two hydro-phobic regions that probably interact with cell membranes2. The most common CF gene mutation leads to omission of phenv lalanine residue 508 in the putative first NBF, indicating that this region is functionally important2-4. To determine whether other mutations occur in the NBFs of CFTR, we determined the nucleotide sequences of exons 9, 10, 11 and 12 (encoding the first NBF) and exons 20, 21 and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American-black CF patients. One cluster of four mutations was discovered in a 30-base-pair region of exon 11. Three of these mutations cause amino-acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins and ATP-binding membrane-associated transport proteins. The fourth mutation creates a premature termination signal. These mutations reveal a functionally important region in the CFTR protein and provide further evidence that CFTR is a member of the family of ATP-dependent transport proteins2,5.
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U2 - 10.1038/346366a0
DO - 10.1038/346366a0
M3 - Article
C2 - 1695717
AN - SCOPUS:0025310336
SN - 0028-0836
VL - 346
SP - 366
EP - 369
JO - Nature
JF - Nature
IS - 6282
ER -