Abstract

Papillomaviruses cause epithelial tumors including cervical cancer, which is a leading cause of cancer deaths in women and is an AIDS-associated malignancy. The papillomavirus E6 oncoprotein plays a critical role in virus replication and is essential in the development of cervical cancer. A molecular structure of E6 is critical for the design of therapeutic strategies. Unfortunately, elucidating the structure of the E6 protein has remained elusive for decades because the physical properties of E6 have frustrated structural studies. This application has overcome these difficulties and will solve the solution structure of E6 by NMR techniques. The structural features of E6 at the atomic level will be correlated to its multiple biological functions.

Public Health Relevance

Papillomaviruses cause numerous cancers, including cervical cancer, because they make a protein called E6 that helps make normal cells into cancerous cells. Understanding the atomic structure of E6 will aid our understanding of how E6 works, and could lead to drugs that act against E6 and thereby against cervical cancer. This application will solve the atomic structure of E6 and perform experiments to show how the E6 structure participates in causing cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134737-04
Application #
8446155
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$374,788
Indirect Cost
$84,671

  Institution

Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904

  Publications

Webb Strickland, Sydney; Brimer, Nicole; Lyons, Charles et al. (2018) Human Papillomavirus E6 interaction with cellular PDZ domain proteins modulates YAP nuclear localization. Virology 516:127-138
Suarez, Irina; Trave, Gilles (2018) Structural Insights in Multifunctional Papillomavirus Oncoproteins. Viruses 10:
Martinez-Zapien, Denise; Ruiz, Francesc Xavier; Poirson, Juline et al. (2016) Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529:541-5
Strickland, Sydney Webb; Vande Pol, Scott (2016) The Human Papillomavirus 16 E7 Oncoprotein Attenuates AKT Signaling To Promote Internal Ribosome Entry Site-Dependent Translation and Expression of c-MYC. J Virol 90:5611-5621
Vande Pol, Scott (2015) Papillomavirus E6 Oncoproteins Take Common Structural Approaches to Solve Different Biological Problems. PLoS Pathog 11:e1005138
Vincentelli, Renaud; Luck, Katja; Poirson, Juline et al. (2015) Quantifying domain-ligand affinities and specificities by high-throughput holdup assay. Nat Methods 12:787-93
Ramírez, Juan; Recht, Raphaël; Charbonnier, Sebastian et al. (2015) Disorder-to-order transition of MAGI-1 PDZ1 C-terminal extension upon peptide binding: thermodynamic and dynamic insights. Biochemistry 54:1327-37
Ramirez, Juan; Poirson, Juline; Foltz, Clémence et al. (2015) Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand. Angew Chem Int Ed Engl 54:7958-62
Brimer, Nicole; Wade, Ramon; Vande Pol, Scott (2014) Interactions between E6, FAK, and GIT1 at paxillin LD4 are necessary for transformation by bovine papillomavirus 1 E6. J Virol 88:9927-33
Zanier, Katia; Stutz, Christina; Kintscher, Susanne et al. (2014) The E6AP binding pocket of the HPV16 E6 oncoprotein provides a docking site for a small inhibitory peptide unrelated to E6AP, indicating druggability of E6. PLoS One 9:e112514

Showing the most recent 10 out of 21 publications