AN APICAL PDZ PROTEIN ANCHORS THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR TO THE CYTOSKELETON

The function of the cystic fibrosis transmembrane conductance regulato r (CFTR) as a Cl- channel in the apical membrane of epithelial cells i s extensively documented. However, less is known about the molecular d eterminants of CFTR residence in the apical membrane, basal regulation of its Cl- channel activity, and its reported effects on the function of other transporters. These aspects of CFTR function likely require specific interactions between CFTR and unknown proteins in the apical compartment of epithelial cells. Here we report that CFTR interacts wi th the recently discovered protein, EBP50 GERM-binding phosphoprotein 50). EBP50 is concentrated at the apical membrane in human airway epit helial cells, in vivo, and CFTR and EBP50 associate in in vitro bindin g assays. The CFTR-EBP50 interaction requires the COOH-terminal DTRL s equence of CFTR and utilizes either PDZ1 or PDZ2 of EBP50, although bi nding to PDZ1 is of greater affinity. Through formation of a complex, the intel action between CFTR and EBP50 may influence the stability an d/or regulation of CFTR Cl- channel function in the cell membrane and provides a potential mechanism through which CFTR can affect the activ ity of other apical membrane proteins.