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Nat Struct Mol Biol. 2006 Mar;13(3):285-91. Epub 2006 Feb 12.

Molecular recognition of p53 and MDM2 by USP7/HAUSP.

Author information

1
Ontario Cancer Institute, Department of Medical Biophysics, 101 College Street, Toronto, Ontario, Canada M5G 1L7.

Abstract

The ubiquitin-specific protease, USP7, has key roles in the p53 pathway whereby it stabilizes both p53 and MDM2. We show that the N-terminal domain of USP7 binds two closely spaced 4-residue sites in both p53 and MDM2, falling between p53 residues 359-367 and MDM2 residues 147-159. Cocrystal structures with USP7 were determined for both p53 peptides and for one MDM2 peptide. These peptides bind the same surface of USP7 as Epstein-Barr nuclear antigen-1, explaining the competitive nature of the interactions. The structures and mutagenesis data indicate a preference for a P/AXXS motif in peptides that bind USP7. Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial. These results help to elucidate the mechanism of substrate recognition by USP7 and the regulation of the p53 pathway.

PMID:
16474402
DOI:
10.1038/nsmb1067
[Indexed for MEDLINE]

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