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Originally published In Press as doi:10.1074/jbc.M011487200 on May 18, 2001

J. Biol. Chem., Vol. 276, Issue 30, 28321-28326, July 27, 2001
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Multiple WW Domains, but Not the C2 Domain, Are Required for Inhibition of the Epithelial Na+ Channel by Human Nedd4*

Peter M. SnyderDagger §, Diane R. OlsonDagger , Fiona J. McDonald, and Daniel B. BucherDagger

From the Dagger  Department of Internal Medicine and Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242, and  Department of Physiology, University of Otago, Dunedin, New Zealand

The epithelial Na+ channel (ENaC) absorbs Na+ across the apical membrane of epithelia. The activity of ENaC is controlled by its interaction with Nedd4; mutations that disrupt this interaction increase Na+ absorption, causing an inherited form of hypertension (Liddle's syndrome). Nedd4 contains an N-terminal C2 domain, a C-terminal ubiquitin ligase domain, and multiple WW domains. The C2 domain is thought to be involved in the Ca2+-dependent localization of Nedd4 at the cell surface. However, we found that the C2 domain was not required for human Nedd4 (hNedd4) to inhibit ENaC in both Xenopus oocytes and Fischer rat thyroid epithelia. Rather, hNedd4 lacking the C2 domain inhibited ENaC more potently than wild-type hNedd4. Earlier work indicated that the WW domains bind to PY motifs in the C terminus of ENaC. However, it is not known which WW domains mediate this interaction. Glutathione S-transferase-fusion proteins of WW domains 2-4 each bound to alpha , beta , and gamma ENaC in vitro. The interactions were abolished by mutation of two residues. WW domain 3 (but not the other WW domains) was both necessary and sufficient for the binding of hNedd4 to alpha ENaC. WW domain 3 was also required for the inhibition of ENaC by hNedd4; inhibition was nearly abolished when WW domain 3 was mutated. However, the interaction between ENaC and WW domain 3 alone was not sufficient for inhibition. Moreover, inhibition was decreased by mutation of WW domain 2 or WW domain 4. Thus, WW domains 2-4 each participate in the functional interaction between hNedd4 and ENaC in intact cells.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by the Roy J. Carver Charitable Trust, the National Heart, Lung, and Blood Institute (Grants HL-58812 and HL-03575), and the National Institute of Diabetes and Digestive and Kidney Diseases (Grant DK-52617), National Institutes of Health. To whom correspondence should be addressed: 371 EMRB, Dept. of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail: psnyder@blue.weeg.uiowa.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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