1i5h

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SOLUTION STRUCTURE OF THE RNEDD4 WWIII DOMAIN-RENAC BP2 PEPTIDE COMPLEX

Overview

Nedd4 is a ubiquitin protein ligase composed of a C2 domain, three (or, four) WW domains and a ubiquitin ligase Hect domain. Nedd4 was, demonstrated to bind the epithelial sodium channel (alphabetagammaENaC), by association of its WW domains with PY motifs (XPPXY) present in each, ENaC subunit, and to regulate the cell surface stability of the channel., The PY motif of betaENaC is deleted or mutated in Liddle syndrome, a, hereditary form of hypertension caused by elevated ENaC activity. Here we, report the solution structure of the third WW domain of Nedd4 complexed to, the PY motif-containing region of betaENaC (TLPIPGTPPPNYDSL, referred to, as betaP2). A polyproline type II helical conformation is adopted by the, PPPN sequence. Unexpectedly, the C-terminal sequence YDSL forms a helical, turn and both the tyrosine and the C-terminal leucine contact the WW, domain. This is unlike other proline-rich peptides complexed to WW, domains, which bind in an extended conformation and lack molecular, interactions with residues C-terminal to the tyrosine or the structurally, equivalent residue in non-PY motif WW domain targets. The Nedd4 WW, domain-ENaC betaP2 peptide structure expands our understanding of the, mechanisms involved in WW domain-ligand recognition and the molecular, basis of Liddle syndrome.

About this Structure

1I5H is a Protein complex structure of sequences from Rattus norvegicus. Full crystallographic information is available from OCA.

Reference

Solution structure of a Nedd4 WW domain-ENaC peptide complex., Kanelis V, Rotin D, Forman-Kay JD, Nat Struct Biol. 2001 May;8(5):407-12. PMID:11323714

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