This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zhang, Y.
Right arrow Articles by Chen, X. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhang, Y.
Right arrow Articles by Chen, X. S.

 Previous Article  |  Next Article 

Journal of Virology, April 2007, p. 3618-3626, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02044-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Structures of a Human Papillomavirus (HPV) E6 Polypeptide Bound to MAGUK Proteins: Mechanisms of Targeting Tumor Suppressors by a High-Risk HPV Oncoprotein{triangledown}

Yi Zhang,1,{dagger} Jhimli Dasgupta,1,{dagger} Runlin Z. Ma,2 Lawrence Banks,3 Miranda Thomas,3 and Xiaojiang S. Chen1*

Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089,1 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China,2 International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy3

Received 19 September 2006/ Accepted 13 December 2006

Human papillomavirus (HPV) E6 oncoprotein targets certain tumor suppressors such as MAGI-1 and SAP97/hDlg for degradation. A short peptide at the C terminus of E6 interacts specifically with the PDZ domains of these tumor suppressors, which is a property unique to high-risk HPVs that are associated with cervical cancer. The detailed recognition mechanisms between HPV E6 and PDZ proteins are unclear. To understand the specific binding of cellular PDZ substrates by HPV E6, we have solved the crystal structures of the complexes containing a peptide from HPV18 E6 bound to three PDZ domains from MAGI-1 and SAP97/Dlg. The complex crystal structures reveal novel features of PDZ peptide recognition that explain why high-risk HPV E6 can specifically target these cellular tumor suppressors for destruction. Moreover, a new peptide-binding loop on these PDZs is identified as interacting with the E6 peptide. Furthermore, we have identified an arginine residue, unique to high-risk HPV E6 but outside the canonical core PDZ recognition motif, that plays an important role in the binding of the PDZs of both MAGI-I and SAP97/Dlg, the mutation of which abolishes E6's ability to degrade the two proteins. Finally, we have identified a dimer form of MAGI-1 PDZ domain 1 in the cocrystal structure with E6 peptide, which may have functional relevance for MAGI-1 activity. In addition to its novel insights into the biochemistry of PDZ interactions, this study is important for understanding HPV-induced oncogenesis; this could provide a basis for developing antiviral and anticancer compounds.

* Corresponding author. Mailing address: Molecular and Computational Biology, University of Southern California, 1050 Childs Way, MCB201, Los Angeles, CA 90089. Phone: (213) 740-5487. Fax: (213) 740-0493. E-mail: xiaojiac{at}usc.edu.

{triangledown} Published ahead of print on 31 January 2007.

{dagger} These authors contributed to the work equally.

Journal of Virology, April 2007, p. 3618-3626, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02044-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lee, M., Vasioukhin, V. (2008). Cell polarity and cancer - cell and tissue polarity as a non-canonical tumor suppressor. J. Cell Sci. 121: 1141-1150 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»