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

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287 Citations (Scopus)


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 β 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.

Original languageEnglish
Pages (from-to)25-36
Number of pages12
JournalMolecular Cell
Issue number1
Publication statusPublished - 2005 Apr 1

Bibliographical note

Funding Information:
We thank the Oxford Protein Production Facility, University of Oxford for performing initial crystal screens with USP7 and Dr. Dinesh Christendat for help with X-ray data collection. We also thank Dr. J. Lukin for assistance with NMR analysis, Cheryl Smith for FACS analysis, Dr. Sam Benchimol for cell lines and antibodies, Dr. Jaap Middeldorp for EBNA1 antibody, and Dr. Alan Davidson for use of his spectrofluorometer. This work was funded by the Canadian Cancer Society through grants to L.F. and C.H.A. from the National Cancer Institute of Canada (NCIC). V.S. was supported by a Natural Sciences and Engineering Council of Canada postdoctoral fellowship and Y.S. was supported by a fellowship from the NCIC.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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