A PDZ-binding motif is essential but not sufficient to localize the C terminus of CFTR to the apical membrane

Localization of ion channels and transporters to the correct membrane of po larized epithelia is important for vectorial ion, movement. Prior studies h ave shown that the cytoplasmic carboxyl terminus of the cystic fibrosis tra nsmembrane conductance regulator (CFTR) is involved in the apical localizat ion of this protein. Here we show that the C-terminal tail alone, or when f used to the green fluorescent protein (GFP), can localize to the apical pla sma membrane, despite the absence of transmembrane domains. Co-expression o f the G terminus with full-length CFTR results in redistribution of CFTR fr om apical to basolateral membranes, indicating that both proteins interact with the same target at the apical membrane. Amino acid substitution and de letion analysis confirms the importance of a PDZ-binding motif D-T-R-L> for apical localization. However, two other G-terminal regions, encompassing a mino acids 1370-1394 and 1404-1425 of human CFTR, are also required for loc alizing to the apical plasma membrane. Based on these results, we propose a model of polarized distribution of CFTR, which includes a mechanism of sel ective retention of this protein in the apical plasma membrane and stresses the requirement for other C-terminal sequences in addition to a PDZ-bindin g motif.