Multiple WW domains, but not the C2 domain, are required for inhibition of the epithelial Na+ channel by human Nedd4.

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