50] Overexpression, purification, and function of first nucleotide-binding fold of cystic fibrosis transmembrane conductance regulator

Abstract

Cystic fibrosis (CF) is the most common lethal autosomal recessive genetic disease in the Caucasian population. The disease results from mutations in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein comprised of 1480 amino acid residues. CFTR embraces two transmembrane domains, each having six putative membrane-spanning segments; two nucleotide-binding folds, NBF1 and NBF2, each possessing a Walker A and B nucleotide-binding consensus sequence, and a regulatory (R) domain having numerous acidic and basic amino acid residues as well as serine and threonine residues that can be phosphorylated by some cAMP dependent protein kinases. Mutations in CFTR occur within or near the two NBFs. Most patients with cystic fibrosis have at least one allele in which the codon for phenylalanine-508 in NBF1 is deleted. The interaction of intracellular adenosine triphosphate (ATP) with NBF1 (or NBF2) may be essential for chloride channel activation.