CFTR: Effect of ICL2 and ICL4 amino acids in close spatial proximity on the current properties of the channel

BackgroundCFTR is the only ABC transporter functioning as a chloride (Cl−) channel. We studied molecular determinants, which might distinguish CFTR from standard ABC transporters, and focused on the interface formed by the intracellular loops from the membrane spanning domains.MethodsResidues from ICL2 and ICL4 in close proximity were targeted, and their involvement in the functioning of CFTR was studied by whole cell patch clamp recording.ResultsWe identified 2 pairs of amino acids, at the extremity of the bundle formed by the four intracellular loops, whose mutation i) decreases the Cl− current of CFTR (couple E267-K1060) or ii) increases it with a change of the electrophysiological signature (couple S263-V1056).ConclusionsThese results highlight the critical role of these ICL residues in the assembly of the different domains and/or in the Cl− permeation pathway of CFTR.