Access

Letters to Nature

Nature 433, 876-880 (24 February 2005) | doi:10.1038/nature03313; Received 11 October 2004; Accepted 22 December 2004

Open Innovation Challenges

CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains

Paola Vergani1, Steve W. Lockless2, Angus C. Nairn3,4 & David C. Gadsby1

  1. Laboratory of Cardiac/Membrane Physiology,
  2. Laboratory of Molecular Neurobiology and Biophysics, and
  3. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USA
  4. Department of Psychiatry, Yale University, New Haven, Connecticut 06519, USA

Correspondence to: Paola Vergani1David C. Gadsby1 Correspondence and requests for materials should be addressed to D.C.G. (Email: gadsby@rockefeller.edu) or to P.V. (Email: paola.vergani@rockefeller.edu).

Top

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 dissociation3, 4, 5. 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 coupling6 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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.

NEWS AND VIEWS

Structural biology The ABC of a versatile engine

Nature News and Views (17 Dec 1998)

The ABCs of trans(porter) inhibition

Nature Chemical Biology News and Views (01 Aug 2008)

See all 3 matches for News And Views