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.
Highlights
The p53 tumor-suppressor protein is a sequence-specific transcription factor that responds to a wide variety of cellular stress signals [1,2,3]
The residues mediating peptide recognition in TRAF6, Arg392, Phe471, and Tyr473, are missing in the herpesvirus-associated ubiquitin-specific protease (HAUSP) N-terminal domain structure [34] (Figure 1B). These observations indicate that the HAUSP tumor necrosis factor–receptor associated factor (TRAF)-like domain may represent a new type of peptide-binding motif in the TRAF family
Structural Basis of p53 Recognition by HAUSP We previously showed that the HAUSP TRAF-like domain stably interacts with a C-terminal peptide fragment of p53 and that deletion of 11 amino acids in p53 resulted in a complete loss of interaction with HAUSP [29]
Summary
The p53 tumor-suppressor protein is a sequence-specific transcription factor that responds to a wide variety of cellular stress signals [1,2,3]. P53 is maintained at a low level mainly through MDM2-mediated ubiquitylation and subsequent degradation [7,8,9]. The C-terminal RING-finger motif of MDM2 promotes p53 ubiquitylation [10,15], and targets MDM2 itself for auto-ubiquitylation and subsequent degradation [10,15]. The MDM2 gene is a transcriptional target of p53 [17,18,19], so activation of the MDM2 gene by p53 would lead to repression of p53 activity The existence of this auto-regulatory feedback loop between MDM2 and p53 adds a complex feature to the p53–MDM2 pathway and makes MDM2 one of the most important regulators of p53 activity
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