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Solution structure of a Nedd4 WW domain-ENaC peptide complex
V Kanelis1, D Rotin, J D Forman-Kay
1Programmes in Structural Biology and Biochemistry, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Nature Structural Biology
|April 27, 2001
Summary
Nedd4 WW domain binds betaENaC via a novel helical turn, revealing insights into Liddle syndrome. This structure clarifies how Nedd4 regulates epithelial sodium channels and offers a molecular basis for hypertension.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Nedd4 is a ubiquitin ligase that interacts with the epithelial sodium channel (ENaC).
- This interaction is crucial for regulating ENaC cell surface stability.
- Mutations in the Nedd4 binding site on betaENaC cause Liddle syndrome, a form of hypertension.
Purpose of the Study:
- To determine the solution structure of the Nedd4 WW domain in complex with the betaENaC PY motif.
- To elucidate the molecular mechanisms of Nedd4-ENaC interaction.
- To provide structural insights into the pathogenesis of Liddle syndrome.
Main Methods:
- Solution NMR spectroscopy was used to determine the structure.
- The complex studied was the third WW domain of Nedd4 and the betaENaC PY motif-containing peptide (betaP2).
Main Results:
- The Nedd4 WW domain binds the betaENaC PY motif (betaP2).
- The PPPN sequence adopts a polyproline type II helical conformation.
- Unexpectedly, the C-terminal YDSL sequence forms a helical turn, with both tyrosine and leucine residues contacting the WW domain.
Conclusions:
- The Nedd4 WW domain-betaENaC structure reveals a novel binding mode compared to other WW domain interactions.
- This finding expands the understanding of WW domain-ligand recognition.
- The structure provides a molecular basis for Liddle syndrome, linked to impaired Nedd4 binding to ENaC.