A C-TERMINAL MOTIF FOUND IN THE BETA(2)-ADRENERGIC RECEPTOR, P2Y1 RECEPTOR AND CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR DETERMINES BINDING TO THE NA+ H+ EXCHANGER REGULATORY FACTOR FAMILY OF PDZ PROTEINS/

The Na+/H+ exchanger regulatory factor (NHERF) binds to the tail of th e beta(2)-adrenergic receptor and plays a role in adrenergic regulatio n of Na+/H+ exchange, NHERF contains two PDZ domains, the first of whi ch is required for its interaction with the beta(2) receptor. Mutagene sis studies of the beta(2) receptor tail revealed that the optimal C-t erminal motif for binding to the first PDZ domain of NHERF is D-S/T-x- L, a motif distinct from those recognized by other PDZ domains. The fi rst PDZ domain of NHERF-2, a protein that is 52% identical to NHERF an d also known as E3KARP, SLP-1, and TKA-1, exhibits binding preferences very similar to those of the first PDZ domain of NHERF, The delineati on of the preferred binding motif for the first PDZ domain of the NHER F family of proteins allows for predictions for other proteins that ma y interact with NHERF or NHERF-2. For example, as would be predicted f rom the beta(2) receptor tail mutagenesis studies, NHERF binds to the tail of the purinergic P2Y1 receptor, a seven-transmembrane receptor w ith an intracellular C-terminal tail ending in D-T-S-L, NHERF also bin ds to the tail of the cystic fibrosis transmembrane conductance regula tor, which ends in D-T-R-L. Because the preferred binding motif of the first PDZ domain of the NHERF family of proteins is found at the C te rmini of a variety of intracellular proteins, NHERF and NHERF-2 may be multifunctional adaptor proteins involved in many previously unsuspec ted aspects of intracellular signaling.