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Journal of Virology, August 2008, p. 7298-7305, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00772-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dimerization of the Papillomavirus E2 Protein Is Required for Efficient Mitotic Chromosome Association and Brd4 Binding{triangledown}

Juan Cardenas-Mora,{dagger},{ddagger} Jonathan E. Spindler,{dagger} Moon Kyoo Jang, and Alison A. McBride*

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Received 9 April 2008/ Accepted 15 May 2008

The E2 proteins of several papillomaviruses link the viral genome to mitotic chromosomes to ensure retention and the efficient partitioning of genomes into daughter cells following cell division. Bovine papillomavirus type 1 E2 binds to chromosomes in a complex with Brd4, a cellular bromodomain protein. Interaction with Brd4 is also important for E2-mediated transcriptional regulation. The transactivation domain of E2 is crucial for interaction with the Brd4 protein; proteins lacking or mutated in this domain do not interact with Brd4. However, we found that the C-terminal DNA binding/dimerization domain of E2 is also required for efficient binding to Brd4. Mutations that eliminated the DNA binding function of E2 had no effect on the ability of E2 to interact with Brd4, but an E2 protein with a mutation that disrupted C-terminal dimerization bound Brd4 with greatly reduced efficiency. Furthermore, E2 proteins in which the C-terminal domains were replaced with the dimeric DNA binding domain of EBNA-1 or Gal4 bound efficiently to the Brd4 protein, but the replacement of the E2 C-terminal domain with a monomeric red fluorescent protein did not rescue efficient Brd4 binding. Thus, E2 bound to Brd4 most efficiently as a dimer. To prove this finding further, the E2 DNA binding domain was replaced with an FKBP12-derived domain in which dimerization was regulated by a bivalent ligand. This fusion protein bound Brd4 efficiently only in the presence of the ligand, confirming that a dimer of E2 was required. Correspondingly, E2 proteins that could dimerize were able to bind to mitotic chromosomes much more efficiently than monomeric E2 polypeptides.

* Corresponding author. Mailing address: Laboratory of Viral Diseases, NIAID, NIH, Bethesda, MD 208920-0455. Phone: (301) 496-1370. Fax: (301) 480-1497. E-mail: amcbride{at}nih.gov

{triangledown} Published ahead of print on 21 May 2008.

{dagger} These authors made equal contributions to this work.

{ddagger} Present address: Purdue University, West Lafayette, Indiana.

Journal of Virology, August 2008, p. 7298-7305, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00772-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Poddar, A., Reed, S. C., McPhillips, M. G., Spindler, J. E., McBride, A. A. (2009). The Human Papillomavirus Type 8 E2 Tethering Protein Targets the Ribosomal DNA Loci of Host Mitotic Chromosomes. J. Virol. 83: 640-650 [Abstract] [Full Text]  


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