Papillomaviruses cause benign and malignant epitheliomas in vertebrates, and are grouped into genera of related viruses. Alpha genus HPV's cause anogenital and head and neck cancers that arise from the influence of the virally encoded E6 and E7 oncoproteins. Beta genus HPV types are associated with cutaneous squamous cell carcinomas in immunosuppressed patients, and other HPV types can cause disabling warts in immunosuppressed and HIV infected persons. The action of the virally encoded E6 oncoprotein is critical for the production of both benign epitheliomas and cancers in all HPV types, and the cancer phenotype can be inhibited if E6 expression is inhibited. Therefore, an understanding of the structure of E6 and how E6 interacts with its cellular targets is critical to potential interventions. In the first award cycle of this renewal application, we defined the three dimensional molecular structure of E6 proteins bound to their cellular targets, which is a finding that had been sought for decades. In addition, this application elucidated a newly described cellular target of beta genus E6 called MAML1. MAML1 is a transcriptional coactivator of Notch signaling, so discovery of this association is an important advance in understanding the biology of both human (MAML is the target of E6 proteins in the beta and mu genera) and animal E6 proteins. When E6 proteins bind their cellular targets (called LxxLL docking motifs in the target protein), they undergo an allosteric change in shape to interact with additional proteins such as the p53 tumor suppressor. In this renewal application, we will extend the analysis of E6 structure to additional E6 proteins of medical importance, determine at the molecular level how E6 interacts with additional cellular proteins such as the p53 tumor suppressor, and determine the surface domains of E6 that are required for critical aspects of the papillomavirus life cycle.
Human papillomaviruses cause genital cancer (cervix and anal) and cancers of the head and neck. The virus produces E6 and E7 oncoproteins that cause the cancer. This application has elucidated the structure of two E6 proteins, and now continues to define the structure of additional E6 proteins, and will determine how E6 interacts with other cellular proteins to cause cancer. Understanding the structure of E6 and how E6 interacts with other proteins could facilitate the design of compounds to treat cancers caused by HPV.
|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:|
|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|
|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|
|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