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Type: Journal article
Title: All three WW domains of murine Nedd4 are involved in the regulation of epithelial sodium channels by intracellular Na⁺
Other Titles: All three WW domains of murine Nedd4 are involved in the regulation of epithelial sodium channels by intracellular Na(+)
Author: Harvey, K.
Dinudom, A.
Komwatanat, P.
Jolliffe, C.
Day, M.
Parasivam, G.
Cook, D.
Kumar, S.
Citation: Journal of Biological Chemistry, 1999; 274(18):12525-12530
Issue Date: 1999
ISSN: 0021-9258
Statement of
Kieran F. Harvey, Anuwat Dinudom, Permsak Komwatana, Corina N. Jolliffe, Margot L. Day, Gayathri Parasivam, David I. Cook and Sharad Kumar
Abstract: The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of alpha, beta, and gamma subunits. The carboxyl terminus of each ENaC subunit contains a PPxY motif which is necessary for interaction with the WW domains of the ubiquitin-protein ligase, Nedd4. Disruption of this interaction, as in Liddle's syndrome where mutations delete or alter the PY motif of either the beta or gamma subunits, results in increased ENaC activity. We have recently shown using the whole-cell patch clamp technique that Nedd4 mediates the ubiquitin-dependent down-regulation of Na+ channel activity in response to increased intracellular Na+. In this paper, we demonstrate that WW domains 2 and 3 bind alpha-, beta-, and gamma-ENaC with varying degrees of affinity, whereas WW domain 1 does not bind to any of the subunits. We further show using whole-cell patch clamp techniques that Nedd4-mediated down-regulation of ENaC in mouse mandibular duct cells involves binding of the WW domains of Nedd4 to three distinct sites. We propose that Nedd4-mediated down-regulation of Na+ channels involves the binding of WW domains 2 and 3 to the Na+ channel and of WW domain 1 to an unknown associated protein.
Keywords: Epithelium
Ubiquitin-Protein Ligases
Sodium Channels
Recombinant Fusion Proteins
Amino Acid Sequence
Protein Binding
Sequence Homology, Amino Acid
Molecular Sequence Data
Epithelial Sodium Channels
DOI: 10.1074/jbc.274.18.12525
Appears in Collections:Aurora harvest 4
Medicine publications

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