Cystic fibrosis transmembrane conductance regulator (CFTR): Making an ion channel out of an active transporter structure

Abstract

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a member of the ATP-binding cassette (ABC) family of membrane transport proteins, most members of which function as ATP-dependent pumps. CFTR is unique among human ABC proteins in functioning not as a pump, but as an ion channel. Recent structural data has indicated that CFTR shares broadly similar overall architecture and ATP-dependent conformational changes as other ABC proteins. Functional investigations suggest that CFTR has a unique open portal connecting the cytoplasm to the transmembrane channel pore, that allows for a continuous pathway for Cl ions to cross the membrane in one conformation. This lateral portal may be what allows CFTR to function as an ion channel rather than as a pump, suggesting a plausible mechanism by which channel function may have evolved in CFTR.

Omnipresent Maxwell's demons orchestrate information management in living cells

“…Indeed, a variety of ABC transporters have their second ATP-binding site degenerate. They have a role restricted to management of a gating process, which can be seen as the consequence of a 'broken pump' where ATP hydrolysis is now purely informational, controlling energy-dependent gating [for example for ion transport (Linsdell, 2018)]. In the context of this work, this is an exceptionally fit illustration of the trapdoor process of a MxD, which can thus monitor the energy availability in the cell (ATP/ADP ratio, Fig.…”

Research advances in molecular mechanisms underlying the pathogenesis of cystic fibrosis: From technical improvement to clinical applications (Review)

“…Biological functions of CFTR. The CFTR protein is positioned in the cell membrane (29) and is associated with proteins involved in the active transportation of material through the cell membrane (12,30). Specifically, CFTR regulates the movement of Cl -.…”

“…Specifically, CFTR regulates the movement of Cl -. Therefore, defects in CFTR gene can render the CFTR protein absent or dysfunctional, thereby blocking the transportation of Clto the cell surface (29,30). Additionally, aside from Cl -, CFTR regulates the epithelial Na channel (31).…”

“…In the lungs, accumulated mucus can become infested with bacteria and the chronic inflammation leads to pneumonia, resulting in deterioration with life-threatening difficulties in breathing. Given the molecular mechanisms of the deficiency of CFTR, the common symptoms of CF include severe cough and shortness of breath; however, CF can also lead to abnormal bowel movements, difficulty in gaining weight and infertility (12,29).…”

“…The misfolded protein will be prevented from migrating to the cell membrane. In Class 3 mutations, channels in the CFTR protein are not properly opened due to gate defect (29,32,34). For the Class 4 mutation, while the CFTR protein is responsive to cell signaling, it is misshapen, resulting in a limited flow of Clions.…”