CFTR: An ion channel with a transporter-type energy-coupling mechanism

343 C o m m e n t a r y Once, as a medical student, I learned from a pathology textbook that CFTR is a chloride ion channel—a unique one that I should keep in mind because its failure causes the life-threatening human genetic disease cystic fibro-sis. It was several years later, after I began studying CFTR, that I saw the other side of its uniqueness. It is the only known ion channel in an enormous transporter family, namely the ATP-binding cassette (ABC) protein family. Classical wisdom has been that the logic of transporters and ion channels is vastly different in thermodynamic essence. There is hence an intriguing question: how closely is CFTR function linked to ABC transporter mechanisms? An article in this issue of the Journal by Jih et al. greatly advances our understanding of this topic by demonstrating that CFTR unidirection-ally cycles through chloride-conducting (open) and non-conducting (closed) states using the free energy of ATP hydrolysis. Readers interested in this topic are also referred to an elegant work published recently by Csanády et al. (2010). ABC transporters are thermodynamic engines in nature. They are designed to transfer the free energy of ATP hydrolysis to the uphill movement of substrates across a membrane in which a chemical potential difference is created and maintained. Recent crystallographic studies of ABC proteins (Oldham et al., 2008; Rees et al., 2009) nicely show that this free energy transfer process can be achieved by a conformational coupling mechanism (Tanford, 1983): conformational changes in the cytoplasmic nucleotide-binding domains (NBDs), resulting from ATP binding and hydrolysis, are coupled to the rearrangements in the transmembrane helices, leading to a change in accessibility of the substrate-binding site from one side of the membrane to the other. In this mechanism, the essentially irreversible ATP hydrolysis step, which drives the alternating exposure of substrates, effectively ensures a one-direction translocation of sub-strates against the chemical gradient. On the other hand, the CFTR channel, although equipped with all molecular components of ABC family members, catalyzes downhill diffusion of chloride ions. For such a passive transport system, there is no obvious need for external energy input (e.g., ATP hydrolysis). It is therefore unclear if the operation of CFTR, like other ABC transporters, requires strict coupling between the substrate translocation pathway and the ATP catalytic cycle. In fact, the opening and closing of ion-conducting pathways for channels are usually found to represent conformational …