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Inhibition of Protein Kinase CK2 Closes the CFTR Cl- Channel, but has no Effect on the Cystic Fibrosis Mutant ΔF508-CFTRTreharne K.J. · Xu Z.1 · Chen J.-H.1 · Best O.G.1 · Cassidy D.M.1 · Gruenert D.C.2 · Hegyi P.3 · Gray M.A.4 · Sheppard D.N.1 · Kunzelmann K.5,* · Mehta A.*
Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, University of Dundee, Ninewells Hospital, Dundee,1Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, University Walk, Bristol2California Pacific Medical Centre Research Institute, San Francisco; Department of Laboratory Medicine, University of California, San Francisco, Department of Medicine, University of Vermont School of Medicine, Burlington,3First Department of Medicine, University of Szeged, Szeged,4Institute for Cell and Molecular Biosciences, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne,5Institut für Physiologie, Universität Regensburg, Regensburg,*KK and AM are co-last authors Corresponding Author
Prof. Dr. Karl Kunzelmann
Institut für Physiologie, Universität Regensburg
Universitaetstrasse 31, 93053 Regensburg (Germany)
Tel. +499419434302, Fax: +499419434315
Background: Deletion of phenylalanine-508 (ΔF508) 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 ΔF508-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 cell-attached membrane patches. CK2 and wtCFTR co-precipitate and CK2 co-localized with wtCFTR (but not ΔF508-CFTR) in apical membranes of human airway biopsies. Comparing wild-type and ΔF508CFTR expressing oocytes, only ΔF508-CFTR Cl- currents were insensitive to two CK2 inhibitors. Furthermore, wtCFTR was inhibited by injecting a peptide mimicking the F508 region, whereas the ΔF508-equivalent peptide had no effect. Conclusions: CK2 controls wtCFTR, but not ΔF508-CFTR. Others find that peptides from the F508 region of NBD1 allosterically control CK2, acting through F508. Hence, disruption of CK2-CFTR interaction by ΔF508-CFTR might disrupt multiple, membrane-associated, CK2-dependent pathways, creating a new molecular disease paradigm for deleted F508 in CFTR.
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