Function of CFTR Protein: Ion Transport

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporter superfamily that plays a critical role in fluid and electrolyte transport across epithelial tissues. CFTR is composed of two membrane-spanning domain (MSD)- nucleotide-binding domain (NBD) motifs linked by a unique regulatory (R) domain. The MSDs assemble to form a transmembrane pore with deep intracellular and shallow extracellular vestibules that funnel anions towards a selectivity filter, which determines the permeation properties of CFTR.Anion flow through the CFTR pore is powered by cycles of ATP binding and hydrolysis at two ATP-binding sites. Stable ATP binding occurs at one ATP-binding site (site 1), whereas rapid ATP turnover occurs at the other (site 2).These ATP-binding sites are located at the interface of the two NBDs, which are themselves organized as a head-to-tail dimer. The R domain contains multiple consensus phosphorylation sites on the surface of an unstructured domain. Phosphorylation of the R domain stimulates CFTR function by enhancing ATP-dependent channel gating at the NBDs.Thus, CFTR is an anion channel with exquisite regulation. Malfunction of CFTR in cystic fibrosis has profound consequences for transepithelial ion transport.