Structure of the human papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor

doi:10.1074/jbc.M508455200

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Papers In Press, published online ahead of print October 24, 2005
J. Biol. Chem, 10.1074/jbc.M508455200
Submitted on August 2, 2005
Revised on October 5, 2005
Accepted on October 24, 2005

Structure of the human papillomavirus E7 oncoprotein and its mechanism for inactivation of the retinoblastoma tumor suppressor

Xin Liu, Adrienne Clements, Kehao Zhao, and Ronen Marmorstein

The Wistar Institute, Philadelphia, PA 19104

Corresponding Author: marmor{at}wistar.org

The E7 oncoprotein from human papillomavirus (HPV) mediates cell transformation, in part, by binding to the human pRb tumor suppressor protein and E2F transcription factors, resulting in the dissociation of pRb from E2F transcription factors and the premature cell progression into the S-phase of the cell cycle. This activity is mediated by the LXCXE motif and the CR3 zinc-binding domain of the E7 protein. In this study we report the X-ray crystal structure of the CR3 region of HPV E7 and a structure-based mutational analysis to investigate its mode of pRb and E2F-binding and E2F displacement from pRb. The structure reveals a novel zinc bound E7-CR3 obligate homodimer that contains 2 surface patches of sequence conservation. Mutation of residues within these patches reveals that one patch is required for pRb-binding while the other is required for E2F-binding. We also show that both E7-mediated interactions are required to disrupt pRb/E2F complexes. Based on these studies we present a mechanistic model for how E7 displaces E2F from pRb. Since the CR3 region of HPV E7 has no detectable homology to other human proteins, the structure-function studies presented here provides an avenue for developing small molecule compounds that inhibit HPV-E7-mediated cell transformation.

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