Protein kinase CK2, Cystic Fibrosis Transmembrane Conductance Regulator, and the F508 mutation - F508 Deletion Disrupts a Kinase-Binding Site

KJ Treharne, Russell Mckenzie Crawford, Z Xu, J-H Chen, OG Best, EA Schulte, DC Gruenert, SM Wilson, K Kunzelmann, DN Sheppard, A Mehta

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Deletion of phenylalanine 508 ( Delta F508) 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 Delta F508 mutation without disrupting four established CFTR-associated kinases and two phosphatases. Loss of CK2 association is functionally corroborated by the insensitivity of Delta F508-CFTR to CK2 inhibition, the absence of CK2 activity in Delta F508 CFTR-expressing cell membranes, and inhibition of CFTR channel activity by a peptide that mimics the F508 region of CFTR ( but not the equivalent Delta F508 peptide). Disruption of this CK2-CFTR association is the first described Delta F508-dependent protein-protein interaction that provides a new molecular paradigm in the most frequent form of cystic fibrosis.

Original languageEnglish
Pages (from-to)10804-10813
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number14
DOIs
Publication statusPublished - 6 Apr 2007

Keywords

  • POLYAMINE METABOLISM
  • CHAPERONE CALNEXIN
  • MOLECULAR-BASIS
  • WILD-TYPE
  • CFTR
  • PHOSPHORYLATION
  • CELLS
  • CHANNEL
  • INHIBITION
  • ALPHA

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