Protein kinase CK2, cystic fibrosis transmembrane conductance regulator, and the deltaF508 mutation: F508 deletion disrupts a kinase-binding site.
Deletion of phenylalanine 508 (DeltaF508) from the first nucleotide-binding domain (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common mutation in cystic fibrosis. The F508 region lies within a surface-exposed loop that has not been assigned any interaction with associated proteins. Here we demonstrate that the pleiotropic protein kinase CK2 that controls protein trafficking, cell proliferation, and development binds wild-type CFTR near F508 and phosphorylates NBD1 at Ser-511 in vivo and that mutation of Ser-511 disrupts CFTR channel gating. Importantly, the interaction of CK2 with NBD1 is selectively abrogated by the DeltaF508 mutation without disrupting four established CFTR-associated kinases and two phosphatases. Loss of CK2 association is functionally corroborated by the insensitivity of DeltaF508-CFTR to CK2 inhibition, the absence of CK2 activity in DeltaF508 CFTR-expressing cell membranes, and inhibition of CFTR channel activity by a peptide that mimics the F508 region of CFTR (but not the equivalent DeltaF508 peptide). Disruption of this CK2-CFTR association is the first described DeltaF508-dependent protein-protein interaction that provides a new molecular paradigm in the most frequent form of cystic fibrosis.
Treharne
Kate J
KJ
Department of Maternal and Child Health Sciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, United Kingdom.
Crawford
Russell M
RM
Xu
Zhe
Z
Chen
Jeng-Haur
JH
Best
O Giles
OG
Schulte
Eva A
EA
Gruenert
Dieter C
DC
Wilson
Stuart M
SM
Sheppard
David N
DN
Kunzelmann
Karl
K
Mehta
Anil
A
D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D045744:Cell Line, Tumor; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D014982:Xenopus laevis
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D047390:Casein Kinase II