Cystic fibrosis transmembrane conductance regulator (CFTR) (CFTR)

The Cystic fibrosis transmembrane conductance regulator (CFTR) is a plasma membrane glycoprotein composed of 1,480 amino acids forming two transmembrane domains (TMD1 and TMD2), two nucleotide-binding domains (NBD1 and NBD2), and a unique regulatory (R) domain, functioning as an ATP- and phosphorylation-gated anion channel that conducts chloride and bicarbonate ions across epithelial cell membranes in organs such as the lungs, pancreas, and intestines. Encoded by the CFTR gene on chromosome 7q31.2, CFTR operates as a member of the ABC transporter superfamily but uniquely serves as an ion channel rather than an active transporter, with activity requiring PKA-mediated phosphorylation of the R domain (up to six sites) to relieve autoinhibition and ATP binding to NBDs for dimerization and pore opening. Loss-of-function mutations in over 2,000 identified variants (classified into six types based on processing, trafficking, or gating defects) cause cystic fibrosis, the most common lethal genetic disease in Caucasians, leading to mucus accumulation, chronic infections, and organ failure due to impaired anion secretion and dehydration of airway surfaces. Cryo-EM structures of human CFTR reveal conformational changes from a dephosphorylated inward-facing state to a phosphorylated ATP-bound outward-open state, with TM8 breaks facilitating gating and specific residues lining the positively charged pore. Therapeutically, CFTR modulators like ivacaftor (potentiator), lumacaftor/tezacaftor/elexacaftor (correctors), and combinations (e.g., Trikafta) target specific mutations (e.g., F508del, G551D), dramatically improving lung function and survival in ∼90% of patients, though challenges persist for rare mutations and complete correction.

Other names

CFTR gene productABC-C7ABCC7

Potentiation of channel gating (increases open probability in phosphorylated state), Correction of protein folding and trafficking defects (Class II mutations), Stabilization of NBD dimer and promotion of conformational changes for anion conduction