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A more recent version of this article appeared on June 1, 2006
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Submitted on September 16, 2005
Revised on February 28, 2006
Accepted on March 6, 2006
*Departments of Physiology and Medicine, Gastroenterology Division and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; Unite Mixte de Recherche 144, Centre National de la Recherche Scientifique/Institut Curie, 75248 Paris Cedex 05, France; Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322
Monitoring Editor: Anthony Bretscher
Based on physiological studies, the epithelial brush border (BB) Na+/H+ antiporter3 (NHE3) appears to associate with the actin cytoskeleton both by binding to and independently of the PDZ domain containing proteins NHERF1 and NHERF2. We now show that NHE3 directly binds ezrin at a site in its C-terminus between aa 475-589 which is separate from the PDZ interacting domain. This is an area predicted to be 
-helical, with a positive aa cluster on one side (K516, R520, and R527). Point mutations of these positively charged aa reduced (NHE3 double mutant (R520F, R527F)) or totally abolished (NHE3 triple mutant (K516Q, R520F, K 527F)) ezrin binding. Functional consequences of these NHE3 point mutants included (a) A marked decrease in surface amount with a greater decrease in NHE3 activity. (b) Decreased surface expression due to decreased rates of exocytosis and plasma membrane delivery of newly synthesized NHE3, with normal total expression levels and endocytosis rates. (c) A longer plasma membrane half-life of mutant NHE3 with normal total half-life. (d) Decreased BB mobile fraction of NHE3 double mutant. These results show that NHE3 binds ezrin directly as well as indirectly and suggest that the former is related to (a) The exocytic trafficking of and plasma membrane delivery of newly synthesized NHE3 which determines the amount of plasma membrane NHE3 and partially determines NHE3 activity, and (b) BB mobility of NHE3 which may increase its delivery from microvilli to the intervillus clefts, perhaps for NHE3 regulated endocytosis.
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