Molecular physiology and pharmacology of the CFTR chloride channel
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Cystic fibrosis transmembrane conductance regulator (CFTR) is the only ATP binding cassette (ABC) protein that functions as an ion channel. The clinical importance of CFTR lies in the fact that its malfunction causes the lethal genetic disease, cystic fibrosis (CF). Like other ABC proteins, CFTR contains four canonical domains— two transmembrane domains (TMDs) that form the ion permeation pathway and two nucleotide binding domains (NBDs) that utilize the free energy from ATP-hydrolysis to drive the gating cycle. The prevailing model in the field dictates that ATP hydrolysis and the gating cycle are strictly coupled. In this study, we have identified a post-hydrolytic state by using non-hydrolytic ATP analogs as baits. As this state may accommodate an ATP molecule to initiate another hydrolysis reaction without the necessity of gate closure, a non-integral stoichiometry between ATP hydrolysis and gating cycle is posited. This hypothesis was reaffirmed by studying a mutant CFTR that allows us to visualize ATP hydrolysis. Based on our new findings, we proposed an energetic coupling model for CFTR gating. Importantly, understanding the gating mechanism of CFTR may help us to decipher the pathogenesis of CF at a molecular level. We discovered that the most common CF-associated mutant, ΔF508-CFTR, destabilizes the NBD dimer, which likely links to its low open probability. Furthermore, the energetic coupling model could explain the action of the now clinically applied CF potentiator, Vx-770 (Kalydeco).
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