In vitro CFTR folding assays.

Abstract

Cystic fibrosis (CF), a severe autosomal recessive disorder, is marked by reduced regulated chloride conductance across the apical membrane of affected epithelia. This reduction is attributable to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which acts as an ATP-dependent cAMP-regulated chloride channel. As shown in Fig. 1, CFTR is a multidomain membrane protein composed of five functional domains: two nucleotide-bind-ing domains (NBD), two transmembrane domains (TMD), and a regulatory domain (R). The most prevalent cystic fibrosis-causing mutation is the deletion of the F508 residue in NBD1 of CFTR (,). This deletion affects the ability of the domain, and thus the CFTR protein, to fold into its native state (), leading to its retention in the endoplasmic reticulum (ER) and subsequent degradation (). Open image in new window Fig. 1. Schematic of the cystic fibrosis transmembrane conductance regulator. CFTR is comprised of two transmembrane domains (TMD1 and TMD2), two nucleotide-binding domains (NBD-1 and NBD-2), and a cytosolic regulatory domain (R). The nucleotide-binding domains contain the Walker A and B consensus sequences common to nucleotide-binding proteins as well as the C consensus sequence. The most prevalent CF-causing mutation, the deletion of F508, is located in NBD-1 between the A and C consensus sites.