Structure of the p53 Binding Domain of HAUSP/USP7 Bound to Epstein-Barr Nuclear Antigen 1

Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada
Molecular Cell (Impact Factor: 14.02). 05/2005; 18(1):25-36. DOI: 10.1016/j.molcel.2005.02.029
Source: PubMed


USP7/HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV). We have determined the crystal structure of the p53 binding domain of USP7 alone and bound to an EBNA1 peptide. This domain is an eight-stranded beta sandwich similar to the TRAF-C domains of TNF-receptor associated factors, although the mode of peptide binding differs significantly from previously observed TRAF-peptide interactions in the sequence (DPGEGPS) and the conformation of the bound peptide. NMR chemical shift analyses of USP7 bound by EBNA1 and p53 indicated that p53 binds the same pocket as EBNA1 but makes less extensive contacts with USP7. Functional studies indicated that EBNA1 binding to USP7 can protect cells from apoptotic challenge by lowering p53 levels. The data provide a structural and conceptual framework for understanding how EBNA1 might contribute to the survival of Epstein-Barr virus-infected cells.

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Available from: Lori Frappier, Dec 16, 2015
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    • "Inactivation experiments in mice confirmed that regulation of p53 is a crucial, but not the only, function of USP7 (Kon et al., 2010, 2011). Targeting of USP7 by the viral EBNA1 protein or cellular TSPYL5 suppresses p53 function (Saridakis et al., 2005; Epping et al., 2011). USP7 activity may promote tumor suppression in breast cancer through the p53 pathway (Epping et al., 2011). "
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    • "There are several mechanisms by which EBV could increase the risk of malignant transformation of infected cells. It was found that viral proteins inhibit apoptosis [16-18], affect the JAK/STAT pathway [19-22], promote epigenetic changes [23-25], and undermine the immune defense mechanisms [26] (see Table 1 for details). "
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    • "In vivo EBNA1 has not been reported to lower Mdm2 levels, but has been confirmed to lower p53 levels at least in some cell backgrounds. For example, expression of EBNA1 but not a USP7-binding mutant of EBNA1 in U2OS cells was shown to reduce the accumulation of p53 in response to DNA damage and subsequent apoptosis [153]. Similarly, EBNA1 expression in CNE2 nasopharyngeal carcinoma (NPC) cells decreased the accumulation of p53 in response to DNA damage [156], and the presence of EBNA1 or EBV in AGS or SCM1 gastric carcinoma cells decreased the steady-state levels of p53 [135, 157]. "
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    ABSTRACT: Epstein-Barr virus (EBV) is a widespread human herpes virus that immortalizes cells as part of its latent infection and is a causative agent in the development of several types of lymphomas and carcinomas. Replication and stable persistence of the EBV genomes in latent infection require the viral EBNA1 protein, which binds specific DNA sequences in the viral DNA. While the roles of EBNA1 were initially thought to be limited to effects on the viral genomes, more recently EBNA1 has been found to have multiple effects on cellular proteins and pathways that may also be important for viral persistence. In addition, a role for EBNA1 in lytic infection has been recently identified. The multiple roles of EBNA1 in EBV infection are the subject of this paper.
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