Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant

A. Bellomaria, Gaetano Barbato, G. Melino, M. Paci, Sonia Melino

Research output: Contribution to journalArticle

Abstract

The E3 ubiquitin ligase Itch mediates the degradation of the p63 protein. Itch contains four WW domains which are pivotal for the substrate recognition process. Indeed, this domain is implicated in several signalling complexes crucially involved in human diseases including Muscular Dystrophy, Alzheimer's Disease and Huntington Disease. WW domains are highly compact protein-protein binding modules that interact with short proline-rich sequences. The four WW domains present in Itch belong to the Group I type, which binds polypeptides with a PY motif characterized by a PPxY consensus sequence, where x can be any residue. Accordingly, the Itch-p63 interaction results from a direct binding of Itch-WW2 domain with the PY motif of p63. Here, we report a structural analysis of the Itch-p63 interaction by fluorescence, CD and NMR spectroscopy. Indeed, we studied the in vitro interaction between Itch-WW2 domain and p63(534-551), an 18-mer peptide encompassing a fragment of the p63 protein including the PY motif. In addition, we evaluated the conformation and the interaction with Itch-WW2 of a site specific mutant of p63, I549T, that has been reported in both Hay-Wells syndrome and Rapp-Hodgkin syndrome. Based on our results, we propose an extended PP xY motif for the Itch recognition motif (P-P-P-Y-x(4)-[ST]-[ILV]) , which includes these C-terminal residues to the PPxY motif.

Original languageEnglish
Pages (from-to)3730-3739
Number of pages10
JournalCell Cycle
Volume9
Issue number18
DOIs
Publication statusPublished - Sep 15 2010

Keywords

  • Cell death
  • E3 ubiquitin ligases
  • Ectodermal dysplasia
  • HECT
  • Itch
  • p53 family
  • p63
  • Rapp-hodgkin syndrome

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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