期刊
EMBO JOURNAL
卷 29, 期 1, 页码 263-277出版社
WILEY
DOI: 10.1038/emboj.2009.329
关键词
CFTR; coupling helix 1; NBD1; NMR spectroscopy; phosphorylation
资金
- Pharmaceuticals, Inc.
- Cystic Fibrosis Foundation Therapeutics
- Canadian Institutes of Health Research
- Robert Welch Foundation [I-1284]
- NIH [DK49385]
- Cystic Fibrosis Foundation
- Canadian Cystic Fibrosis Foundation
The most common cystic fibrosis (CF)-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is deletion of Phe508 (Delta F508) in the first of two nucleotide-binding domains (NBDs). Nucleotide binding and hydrolysis at the NBDs and phosphorylation of the regulatory (R) region are required for gating of CFTR chloride channel activity. We report NMR studies of wild-type and Delta F508 murine CFTR NBD1 with the C-terminal regulatory extension (RE), which contains residues of the R region. Interactions of the wild-type NBD1 core with the phosphoregulatory regions, the regulatory insertion (RI) and RE, are disrupted upon phosphorylation, exposing a potential binding site for the first coupling helix of the N-terminal intracellular domain (ICD). Phosphorylation of Delta F508 NBD1 does not as effectively disrupt interactions with the phosphoregulatory regions, which, along with other structural differences, leads to decreased binding of the first coupling helix. These results provide a structural basis by which phosphorylation of CFTR may affect the channel gating of full-length CFTR and expand our understanding of the molecular basis of the DF508 defect. The EMBO Journal (2010) 29, 263-277. doi: 10.1038/emboj.2009.329; Published online 19 November 2009
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