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Journal of Virology, May 2008, p. 4853-4861, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02388-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dimerization of the Human Papillomavirus Type 16 E2 N Terminus Results in DNA Looping within the Upstream Regulatory Region{triangledown}

Elena E. Hernandez-Ramon,1,{dagger} Julie E. Burns,1* Wenke Zhang,2,{ddagger} Hannah F. Walker,1 Stephanie Allen,2 Alfred A. Antson,3 and Norman J. Maitland1

YCR Cancer Research Unit, Department of Biology (Area 13), University of York, Heslington, York, YO10 5DD United Kingdom,1 Laboratory of Biophysics and Surface Analysis, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD United Kingdom,2 York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York, YO10 5DD United Kingdom3

Received 5 November 2007/ Accepted 15 February 2008

Papillomavirus E2 proteins play a central role in regulating viral gene expression and replication. DNA-binding activity is associated with the C-terminal domain of E2, which forms a stable dimer, while the N-terminal domain is responsible for E2's replication and transactivation functions. The crystal structure of the latter domain revealed a second dimerization interface on E2 which may be responsible for DNA loop formation in the regulatory region of the human papillomavirus (HPV) genome. We investigated the biological significance of the N-terminal dimerization by introducing single amino acid substitutions into the dimerization interface. As expected, these substitutions did not influence the C-terminal dimerization and DNA-binding functions of E2. However, the mutations led to reduced transactivation of a synthetic E2-responsive reporter gene, while HPV DNA replication was unaffected. The effect of the mutations on DNA looping was visualized by atomic force microscopy. While wild-type E2 was able to generate DNA loops, all three mutant E2 proteins were defective in this ability. Our results suggest that N-terminal dimerization plays a role in E2-mediated transactivation, probably via DNA looping, a common mechanism for remote regulation of gene transcription.

* Corresponding author. Mailing address: YCR Cancer Research Unit, Department of Biology (Area 13), University of York, Heslington, York, YO10 5DD United Kingdom. Phone: 44 1904 328707. Fax: 44 1904 328710. E-mail: jeb10{at}york.ac.uk

{triangledown} Published ahead of print on 12 March 2008.

{dagger} Present address: Genomic Medicine Unit, Hospital General de México, Dr. Balmis 148, Col. Doctores, Del. Cuauhtémoc, México D.F., CP 06726 Mexico.

{ddagger} Present address: State Key Lab for Supramolecular Structure and Materials, Jilin University, 2699 Qianjin Street, Changchun, 130012 People's Republic of China.

Journal of Virology, May 2008, p. 4853-4861, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02388-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cardenas-Mora, J., Spindler, J. E., Jang, M. K., McBride, A. A. (2008). Dimerization of the Papillomavirus E2 Protein Is Required for Efficient Mitotic Chromosome Association and Brd4 Binding. J. Virol. 82: 7298-7305 [Abstract] [Full Text]  


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