Role of the UPS in Liddle syndrome.
Hypertension is a serious medical problem affecting a large population worldwide. Liddle syndrome is a hereditary form of early onset hypertension caused by mutations in the epithelial Na+ channel (ENaC). The mutated region, called the PY (Pro-Pro-x-Tyr) motif, serves as a binding site for Nedd4-2, an E3 ubiquitin ligase from the HECT family. Nedd4-2 binds the ENaC PY motif via its WW domains, normally leading to ENaC ubiquitylation and endocytosis, reducing the number of active channels at the plasma membrane. In Liddle syndrome, this endocytosis is impaired due to the inability of the mutated PY motif in ENaC to properly bind Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na+ (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Small molecules/compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve to alleviate hypertension. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
Rotin
Daniela
D
Program in Cell Biology, The Hospital for Sick Children, and Biochemistry Department, University of Toronto, Ontario, M5G 1X8, Canada. drotin@sickkids.ca
D000818:Animals; D004705:Endocytosis; D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008024:Ligands; D000075702:Nedd4 Ubiquitin Protein Ligases; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013577:Syndrome; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; D008024:Ligands; D025801:Ubiquitin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex