Cystic Fibrosis and the CFTR Anion Channels

Cystic fibrosis transmembrane conductance regulator (CFTR), an odd offspring of the ATP-binding cassette (ABC) transporter superfamily, plays a major role in modulating transepithelial water and salt movements in epithelia-lining organs such as the airways and the gastrointestinal tract. Hyperactivation of CFTR causes secretory diarrhea, whereas loss of CFTR function leads to severe damage to the lung in patients with the genetic disease cystic fibrosis. Decades of research on this chloride channel protein is propelled by both its clinical significance and its unique position at the evolutionary crossroads of ion channels and active transporters. Here, we strive to give readers a broad coverage of the structure–function relationships of CFTR with an emphasis on the phosphorylation-dependent activation of its function, and the structural mechanisms for gating and permeation of an activated CFTR. The chapter highlights the recent breakthroughs in the determination of CFTR’s cryo-EM structures, and discusses a number of unresolved controversies and unanswered questions. The chapter ends with a glance over the molecular mechanism underpinning pathogenic mutations in CFTR and the pharmacology of CFTR modulators, areas that not only hold the promise for an ultimate cure for cystic fibrosis but also shed light on the fundamental mechanisms of CFTR function.