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PMID:11149908
| Citation |
Kamynina, E, Debonneville, C, Bens, M, Vandewalle, A and Staub, O (2001) A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J. 15:204-214 |
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| Abstract |
Liddle's syndrome is a form of inherited hypertension linked to mutations in the genes encoding the epithelial Na+ channel (ENaC). These mutations alter or delete PY motifs involved in protein-protein interactions with a ubiquitin-protein ligase, Nedd4. Here we show that Na+ transporting cells, derived from mouse cortical collecting duct, express two Nedd4 proteins with different structural organization and characteristics of ENaC regulation: 1) the classical Nedd4 (herein referred to as Nedd4-1) containing one amino-terminal C2, three WW, and one HECT-ubiquitin protein ligase domain and 2) a novel Nedd4 protein (Nedd4-2), homologous to Xenopus Nedd4 and comprising four WW, one HECT, yet lacking a C2 domain. Nedd4-2, but not Nedd4-1, inhibits ENaC activity when coexpressed in Xenopus oocytes and this property correlates with the ability to bind to ENaC, as only Nedd4-2 coimmunoprecipitates with ENaC. Furthermore, this interaction depends on the presence of at least one PY motif in the ENaC complex and on WW domains 3 and 4 in Nedd4-2. Thus, these results suggest that the novel suppressor protein Nedd4-2 is the regulator of ENaC and hence a potential susceptibility gene for arterial hypertension. |
| Links |
PubMed Online version:10.1096/fj.00-0191com |
| Keywords |
Amino Acid Motifs; Amino Acid Sequence; Animals; Binding Sites; Calcium-Binding Proteins/chemistry; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/metabolism; Cloning, Molecular; Endosomal Sorting Complexes Required for Transport; Ligases/chemistry; Ligases/genetics; Ligases/metabolism; Mice; Molecular Sequence Data; Mutation; Oocytes/drug effects; Oocytes/metabolism; Protein Binding; Protein Isoforms/chemistry; Protein Isoforms/genetics; Protein Isoforms/metabolism; Protein Structure, Tertiary; RNA, Messenger/analysis; RNA, Messenger/genetics; Rats; Sequence Alignment; Sodium Channel Blockers; Sodium Channels/metabolism; Ubiquitin-Protein Ligases; Xenopus laevis |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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