Journal
BIOCHEMISTRY
Volume 49, Issue 30, Pages 6352-6357Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi100807h
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Funding
- Canadian Institutes for Health Research [62832]
- Canadian Research Chair in Membrane Biology
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Deletion of Phe508 (Delta F508) in the first nucleotide-binding domain (NBD1) of CFTR causes cystic fibrosis. The mutation severely reduces the stability and folding of the protein, by disrupting interactions between NBD1 and the second transmembrane domain (TMD2). We found that replacement of Val510 with acidic residues (but not neutral or positive residues) promoted maturation of Delta F508-CFTR with V510D more efficiently than V510E. Promotion of Delta F508-CFTR maturation did not require NBD2 as introduction of V510D into a Delta NBD2/Delta F508-CFTR mutant restored maturation to levels similar to that of full-length protein. The V510D mutation increased the half-life of mature Delta F508-CFTR at the cell surface by about 5-fold to resemble the half-life of wild-type CFTR. It was also observed that introduction of the V510R/R1070D mutations into Delta F508-CFTR also promoted maturation whereas the V510D/R1070A mutations did not. We propose that the V510D mutation in NBD1 promotes maturation and stabilizes Delta F508-CFTR at the cell surface through formation of a salt bridge with Arg1070 in TMD2.
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