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Lookup NU author(s): Dr Michael Gray
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Background: Deletion of phenylalanine-508 (Delta F508) from the first nucleotide-binding domain (NBD1) in the wild-type cystic fibrosis (CF) transmembrane-conductance regulator (wtCFTR) causes CF. However, the mechanistic relationship between Delta F508-CFTR and the diversity of CF disease is unexplained. The surface location of F508 on NBD1 creates the potential for protein-protein interactions and nearby, lies a consensus sequence (SYDE) reported to control the pleiotropic protein kinase CK2. Methods: Electrophysiology, immunofluorescence and biochemistry applied to CFTR-expressing cells, Xenopus oocytes, pancreatic ducts and patient biopsies. Results: Irrespective of PKA activation, CK2 inhibition (ducts, oocytes, cells) attenuates CFTR-dependent Cl- transport, closing wtCFTR in cellattached membrane patches. CK2 and wtCFTR coprecipitate and CK2 co-localized with wtCFTR (but not Delta F508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and Delta F508-CFTR expressing oocytes, only Delta F508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the Delta F508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not Delta F508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by Delta F508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR. Copyright (C) 2009 S. Karger AG, Basel
Author(s): Treharne KJ, Xu Z, Chen JH, Best OG, Cassidy DM, Gruenert DC, Hegyi P, Gray MA, Sheppard DN, Kunzelmann K, Mehta A
Publication type: Article
Publication status: Published
Journal: Cellular Physiology and Biochemistry
Year: 2009
Volume: 24
Issue: 5-6
Pages: 347-360
ISSN (print): 1015-8987
ISSN (electronic): 1421-9778
Publisher: S. Karger AG
URL: http://dx.doi.org/10.1159/000257427
DOI: 10.1159/000257427
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