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EBP50 is a Na⁺/H⁺ exchange regulatory cofactor, called NHE-RF or NHERF-1, of 358 aas (Slc9 isoform A3, regulatory factor 3). It is an adaptor protein that organizes a number of cell receptors and channels (Li et al., 2005). It contains two PDZ domains that bind to the cytoplasmic domains of a number of membrane channels and receptors. The carboxyl terminus of NHERF interacts with the FERM domain (a domain shared by protein 4.1, ezrin, radixin, and moesin) of a family of actin-binding proteins called the ezrin-radixin-moesin family (TC #8.A.25). NHERF enhances the channel activities of cystic fibrosis transmembrane conductance regulator (CFTR) (TC #3.A.1.202.1). Binding of the FERM domain of ezrin to NHERF regulates the cooperative binding of NHERF to bring two cytoplasmic tails of CFTR into spatial proximity to each other. Ezrin binding activates the second PDZ domain of NHERF to interact with the cytoplasmic tails of CFTR (C-CFTR), so as to form a specific 2:1:1 (C-CFTR)₂·NHERF·ezrin ternary complex. EPP50 is required both for plasma membrane localization and for maximal activation of CFTR (Broere et al., 2007). Without ezrin binding, the cytoplasmic tail of CFTR only interacts strongly with the first amino-terminal PDZ domain to form a 1:1 C-CFTR·NHERF complex. Because of the concentrated distribution of ezrin and NHERF in the apical membrane regions of epithelial cells and the diverse binding partners for the NHERF PDZ domains, the regulation of NHERF by ezrin may be employed as a general mechanism to assemble channels and receptors in the membrane cytoskeleton (Li et al., 2005).