Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation.

The epithelial Na(+) channel (ENaC) is regulated via PY motif-WW domain interaction by the mouse (m) ubiquitin-protein ligase mNedd4-2 but not by its close relative mNedd4-1. Whereas mNedd4-1 is composed of one C2, three WW, and one HECT domain, mNedd4-2 comprises four WW domains and one HECT domain. Both proteins ...
have human (h) homologs, hNedd4-1 and hNedd4-2; however, both of them include four WW domains. Therefore, we characterized hNedd4-1 and hNedd4-2 in Xenopus laevis oocytes with respect to ENaC binding and interaction. We found that hNedd4-2 binds to and abrogates ENaC activity, whereas hNedd4-1 does not coimmunoprecipitate with ENaC and has only modest effects on ENaC activity. Structure-function studies revealed that the C2 domain of hNedd4-1 prevents this protein from downregulating ENaC and that WW domains 3 and 4, involved in interaction with ENaC, do not by themselves provide specificity for ENaC recognition. Taken together, our data demonstrate that hNedd4-2 inhibits ENaC, implying that this protein is a modulator of salt homeostasis, whereas hNedd4-1 is not primarily involved in ENaC regulation.
Mesh Terms:
Animals, Binding Sites, Calcium-Binding Proteins, Endosomal Sorting Complexes Required for Transport, Epithelial Sodium Channel, Female, Gene Expression Regulation, Humans, Ligases, Mice, Oocytes, Organ Specificity, Protein Binding, Recombinant Proteins, Sodium Channels, Ubiquitin-Protein Ligases, Xenopus laevis
Am. J. Physiol. Renal Physiol.
Date: Sep. 01, 2001
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