Gating of the CFTR Cl¯ channel by ATP-driven nucleotide-binding domain dimerisation

TC Hwang, DN Sheppard

Research output: Contribution to journalArticle (Academic Journal)peer-review

128 Citations (Scopus)

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) plays a fundamental role in fluid and electrolyte transport across epithelial tissues. Based on its structure, function and regulation, CFTR is an ATP-binding cassette (ABC) transporter. These transporters are assembled from two membrane-spanning domains (MSDs) and two nucleotide-binding domains (NBDs). In the vast majority of ABC transporters, the NBDs form a common engine that utilises the energy of ATP hydrolysis to pump a wide spectrum of substrates through diverse transmembrane pathways formed by the MSDs. By contrast, in CFTR the MSDs form a pathway for passive anion flow that is gated by cycles of ATP binding and hydrolysis by the NBDs. Here, we consider how the interaction of ATP with two ATP-binding sites, formed by the NBDs, powers conformational changes in CFTR structure to gate the channel pore. We explore how conserved sequences from both NBDs form ATP-binding sites at the interface of an NBD dimer and highlight the distinct roles that each binding site plays during the gating cycle. Knowledge of how ATP gates the CFTR Cl− channel is critical for understanding CFTR’s physiological role, its malfunction in disease and the mechanism of action of small molecules that modulate CFTR channel gating.
Translated title of the contributionGating of the CFTR Cl¯ channel by ATP-driven nucleotide-binding domain dimerisation
Original languageEnglish
Pages (from-to)2151 - 2161
Number of pages11
JournalJournal of Physiology
Volume587
DOIs
Publication statusPublished - May 2009

Bibliographical note

Publisher: Wiley-Blackwell
Other: Review

Fingerprint Dive into the research topics of 'Gating of the CFTR Cl¯ channel by ATP-driven nucleotide-binding domain dimerisation'. Together they form a unique fingerprint.

Cite this