Identification of an ion channel-forming motif in the primary structure of CFTR, the cystic fibrosis chloride channel.

Synthetic peptides with sequences representingputative transmembrane (M) segments of CFTR (the cystic fibrosis transmembraneconductance regulator) were used as tools to identify the involvement of suchsegments in forming the ionic pore of the CFTR Cl- channel. Peptides withsequences corresponding to M2 and M6 form anion-selective channels afterreconstitution in lipid bilayers. In contrast, peptides with the sequences ofM1, M3, M4, and M5, or peptides of the same amino acid composition as M2 and M6but with scrambled sequences, do not form channels. Conductive heterooligomersof M2 and M6 exhibit a single channel conductance of 8 pS (in 0.15 M KCl) and a95% selectivity for anions over cations, properties that emulate both theconductance and the selectivity of the authentic CFTR channel. Theidentification of sequence-specific motifs that account for key functionalattributes of the CFTR channel suggests that such modules may representfundamental units of function and are plausible constituents of the pore-formingstructure of the CFTR Cl- channel.