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Publication Detail
CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Vergani P, Lockless SW, Nairn AC, Gadsby DC
  • Publisher:
    Nature Publishing Group
  • Publication date:
    24/02/2005
  • Pagination:
    876, 880
  • Journal:
    Nature
  • Volume:
    433
  • Issue:
    7028
  • Print ISSN:
    0028-0836
  • Keywords:
    thermodynamic double-mutant cycle, ATP binding cassette transporters, ion channel gating
  • Addresses:
    paola.vergani@rockefeller.edu
Abstract
ABC (ATP-binding cassette) proteins constitute a large family of membrane proteins that actively transport a broad range of substrates. Cystic fibrosis transmembrane conductance regulator (CFTR), the protein dysfunctional in cystic fibrosis, is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing of the pore have been linked to ATP binding and hydrolysis at CFTR's two nucleotide-binding domains, NBD1 and NBD2 (see, for example, refs 1, 2). Isolated NBDs of prokaryotic ABC proteins dimerize upon binding ATP, and hydrolysis of the ATP causes dimer dissociation. Here, using single-channel recording methods on intact CFTR molecules, we directly follow opening and closing of the channel gates, and relate these occurrences to ATP-mediated events in the NBDs. We find that energetic coupling between two CFTR residues, expected to lie on opposite sides of its predicted NBD1-NBD2 dimer interface, changes in concert with channel gating status. The two monitored side chains are independent of each other in closed channels but become coupled as the channels open. The results directly link ATP-driven tight dimerization of CFTR's cytoplasmic nucleotide-binding domains to opening of the ion channel in the transmembrane domains. This establishes a molecular mechanism, involving dynamic restructuring of the NBD dimer interface, that is probably common to all members of the ABC protein superfamily.
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