Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization

Vivian Saridakis; Yi Sheng; Feroz Sarkari; Melissa N Holowaty; Kathy Shire; Tin Nguyen; Rongguang G Zhang; Jack Liao; Weontae Lee; Aled M Edwards; Cheryl H Arrowsmith; Lori Frappier

doi:10.1016/j.molcel.2005.02.029

Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization

Mol Cell. 2005 Apr 1;18(1):25-36. doi: 10.1016/j.molcel.2005.02.029.

Authors

Vivian Saridakis¹, Yi Sheng, Feroz Sarkari, Melissa N Holowaty, Kathy Shire, Tin Nguyen, Rongguang G Zhang, Jack Liao, Weontae Lee, Aled M Edwards, Cheryl H Arrowsmith, Lori Frappier

Affiliation

¹ Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

PMID: 15808506
DOI: 10.1016/j.molcel.2005.02.029

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Apoptosis
Binding Sites
Crystallography, X-Ray
Endopeptidases / chemistry*
Endopeptidases / metabolism*
Epstein-Barr Virus Nuclear Antigens / chemistry*
Epstein-Barr Virus Nuclear Antigens / metabolism*
Escherichia coli / genetics
Herpesvirus 4, Human / genetics
Herpesvirus 4, Human / metabolism
Humans
Kinetics
Models, Molecular
Molecular Sequence Data
Peptide Fragments / chemistry
Protein Conformation
Protein Structure, Tertiary
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Tumor Suppressor Protein p53 / chemistry*
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin Thiolesterase
Ubiquitin-Specific Peptidase 7

Substances

Epstein-Barr Virus Nuclear Antigens
Peptide Fragments
Recombinant Fusion Proteins
Tumor Suppressor Protein p53
Endopeptidases
USP7 protein, human
Ubiquitin Thiolesterase
Ubiquitin-Specific Peptidase 7
EBV-encoded nuclear antigen 1

Associated data

PDB/1YY6
PDB/1YZE