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Structural Basis of Competitive Recognition of p53 and MDM2 by HAUSP/USP7: Implications for the Regulation of the p53-MDM2 Pathway.
- Source :
-
PLoS Biology . Feb2006, Vol. 4 Issue 2, pe27. 12p. 6 Diagrams, 4 Charts. - Publication Year :
- 2006
-
Abstract
- Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), a deubiquitylating enzyme of the ubiquitin-specific processing protease family, specifically deubiquitylates both p53 and MDM2, hence playing an important yet enigmatic role in the p53-MDM2 pathway. Here we demonstrate that both p53 and MDM2 specifically recognize the N-terminal tumor necrosis factor-receptor associated factor (TRAF)-like domain of HAUSP in a mutually exclusive manner. HAUSP preferentially forms a stable HAUSP-MDM2 complex even in the presence of excess p53. The HAUSP-binding elements were mapped to a peptide fragment in the carboxy-terminus of p53 and to a short-peptide region preceding the acidic domain of MDM2. The crystal structures of the HAUSP TRAF-like domain in complex with p53 and MDM2 peptides, determined at 2.3-Å and 1.7-Å resolutions, respectively, reveal that the MDM2 peptide recognizes the same surface groove in HAUSP as that recognized by p53 but mediates more extensive interactions. Structural comparison led to the identification of a consensus peptide-recognition sequence by HAUSP. These results, together with the structure of a combined substrate-binding-and-deubiquitylation domain of HAUSP, provide important insights into regulation of the p53-MDM2 pathway by HAUSP. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15449173
- Volume :
- 4
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- PLoS Biology
- Publication Type :
- Academic Journal
- Accession number :
- 19804788
- Full Text :
- https://doi.org/10.1371/journal.pbio.0040027