Practice question

Cystic fibrosis most common lethal autosomal recessive disorder in Caucasian populations results from mutations in CFTR gene on chromosome 7q31.2 encoding cystic fibrosis transmembrane conductance regulator. Biochemical classification places CFTR within C subfamily of ATP binding cassette transporters ABCC7 despite functional divergence. Topology includes two membrane spanning domains each six helices forming anion selective pore, two nucleotide binding domains NBD1 and NBD2 containing Walker motifs and LSGGQ signature dimerizing upon ATP binding, and unique regulatory R domain with multiple PKA phosphorylation sites controlling gating. Unlike typical ABC exporter that alternates access to pump substrates, CFTR functions as low conductance chloride channel allowing passive efflux of Cl- and HCO3- down electrochemical gradient when phosphorylated R domain permits NBD dimerization and ATP binding opens pore. Most common mutation deletion Phe508 in NBD1 impairs folding trafficking degraded by ER quality control. Potentiators ivacaftor increase open probability, correctors lumacaftor aid folding. Hence defective protein belongs to ABC transporter family.