Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53

Nature

Volumn 529, Issue 7587, 2016, Pages 541-545

  Martinez Zapien, Denise ^a   Ruiz, Francesc Xavier ^b   Poirson, Juline ^a   Mitschler, André ^b   Ramirez, Juan ^a   Forster, Anne ^a   Cousido Siah, Alexandra ^b   Masson, Murielle ^a   Pol, Scott Vande ^c   Podjarny, Alberto ^b   Travé, Gilles ^a   Zanier, Katia ^a  

^a Institut de Recherche de l'Ecole de Biotechnologie de Strasbourg   (France)

^b UNIVERSITÉ DE STRASBOURG   (France)

^c UNIVERSITY OF VIRGINIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN E6; PROTEIN E6AP; PROTEIN P53; UNCLASSIFIED DRUG; VIRUS PROTEIN;

CANCER; CHEMICAL BINDING; DEGRADATION; ENZYME ACTIVITY; GENE EXPRESSION; METABOLISM; MUTATION; PROTEIN; TUMOR; VIRUS;

ARTICLE; BINDING SITE; CHEMICAL MUTAGENESIS; CRYSTAL STRUCTURE; HUMAN PAPILLOMAVIRUS TYPE 16; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN DEGRADATION; PROTEIN DNA BINDING; PROTEIN DOMAIN; PROTEIN MOTIF; PROTEIN PROTEIN INTERACTION; PROTEIN QUATERNARY STRUCTURE; PROTEIN TARGETING;

HUMAN PAPILLOMAVIRUS;

EID: 84964301688     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature16481     Document Type: Article

References (37)

1. Bosch, F. X. et al. Comprehensive control of human papillomavirus infections and related diseases. Vaccine 31 (Suppl. 7), H1-H31 (2013).
2. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129-1136 (1990).
3. Huibregtse, J. M., Scheffner, M. & Howley, P. M. Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol. Cell. Biol. 13, 4918-4927 (1993).
4. Scheffner, M., Nuber, U. & Huibregtse, J. M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature 373, 81-83 (1995).
5. Ansari, T., Brimer, N. & Vande Pol, S. B. Peptide interactions stabilize and restructure human papillomavirus type 16 E6 to interact with p53. J. Virol. 86, 11386-11391 (2012).
6. Davey, N. E., Travé, G. & Gibson, T. J. How viruses hijack cell regulation. Trends Biochem. Sci. 36, 159-169 (2011).
7. Vande Pol, S. B. & Klingelhutz, A. J. Papillomavirus E6 oncoproteins. Virology 445, 115-137 (2013).
8. Zanier, K. et al. Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins. Science 339, 694-698 (2013).
9. Gu, J., Rubin, R. M. & Yuan, Z. M. A sequence element of p53 that determines its susceptibility to viral oncoprotein-targeted degradation. Oncogene 20, 3519-3527 (2001).
10. Li, X. & Coffino, P. High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation. J. Virol. 70, 4509-4516 (1996).
11. Bernard, X. et al. Proteasomal degradation of p53 by human papillomavirus E6 oncoprotein relies on the structural integrity of p53 core domain. PLoS ONE 6, e25981 (2011).
12. Zanier, K. et al. Solution structure analysis of the HPV16 E6 oncoprotein reveals a self-association mechanism required for E6-mediated degradation of p53. Structure 20, 604-617 (2012).
13. Ronchi, V. P., Klein, J. M., Edwards, D. J. & Haas, A. L. The active form of E6-associated protein (E6AP)/UBE3A ubiquitin ligase is an oligomer. J. Biol. Chem. 289, 1033-1048 (2014).
14. Ristriani, T., Fournane, S., Orfanoudakis, G., Travé, G. & Masson, M. A single-codon mutation converts HPV16 E6 oncoprotein into a potential tumor suppressor, which induces p53-dependent senescence of HPV-positive HeLa cervical cancer cells. Oncogene 28, 762-772 (2009).
15. Fu, L. et al. Degradation of p53 by human Alphapapillomavirus E6 proteins shows a stronger correlation with phylogeny than oncogenicity. PLoS ONE 5, e12816 (2010).
16. Mesplède, T. et al. p53 degradation activity, expression, and subcellular localization of E6 proteins from 29 human papillomavirus genotypes. J. Virol. 86, 94-107 (2012).
17. Hiller, T., Poppelreuther, S., Stubenrauch, F. & Iftner, T. Comparative analysis of 19 genital human papillomavirus types with regard to p53 degradation, immortalization, phylogeny, and epidemiologic risk classification. Cancer Epidemiol. Biomark. Prev. 15, 1262-1267 (2006).
18. Foster, S. A., Demers, G. W., Etscheid, B. G. & Galloway, D. A. The ability of human papillomavirus E6 proteins to target p53 for degradation in vivo correlates with their ability to abrogate actinomycin D-induced growth arrest. J. Virol. 68, 5698-5705 (1994).
19. Cooper, B. et al. Requirement of E6AP and the features of human papillomavirus E6 necessary to support degradation of p53. Virology 306, 87-99 (2003).
20. Liu, Y. et al. Multiple functions of human papillomavirus type 16 E6 contribute to the immortalization of mammary epithelial cells. J. Virol. 73, 7297-7307 (1999).
21. Nakagawa, S. et al. Mutational analysis of human papillomavirus type 16 E6 protein: transforming function for human cells and degradation of p53 in vitro. Virology 212, 535-542 (1995).
22. Zanier, K. et al. 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 (2014).
23. Stutz, C. et al. Intracellular analysis of the interaction between the human papillomavirus type 16 E6 oncoprotein and inhibitory peptides. PLoS ONE 10, e0132339 (2015).
24. Hengstermann, A., Linares, L. K., Ciechanover, A., Whitaker, N. J. & Scheffner, M. Complete switch from Mdm2 to human papillomavirus E6-mediated degradation of p53 in cervical cancer cells. Proc. Natl Acad. Sci. USA 98, 1218-1223 (2001).
25. Lilyestrom, W., Klein, M. G., Zhang, R., Joachimiak, A. & Chen, X. S. Crystal structure of SV40 large T-antigen bound to p53: interplay between a viral oncoprotein and a cellular tumor suppressor. Genes Dev. 20, 2373-2382 (2006).
26. Scheffner, M., Takahashi, T., Huibregtse, J. M., Minna, J. D. & Howley, P. M. Interaction of the human papillomavirus type 16 E6 oncoprotein with wild-type and mutant human p53 proteins. J. Virol. 66, 5100-5105 (1992).
27. Cherry, J. J. et al. Structure based identification and characterization of flavonoids that disrupt human papillomavirus-16 E6 function. PLoS ONE 8, e84506 (2013).
28. Malecka, K. A. et al. Identification and characterization of small molecule human papillomavirus E6 inhibitors. ACS Chem. Biol. 9, 1603-1612 (2014).
29. Moon, A. F., Mueller, G. A., Zhong, X. & Pedersen, L. C. A synergistic approach to protein crystallization: combination of a fixed-arm carrier with surface entropy reduction. Protein Sci. 19, 901-913 (2010).
30. Otwinowski, Z. & Minor, W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326 (1997).
31. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658-674 (2007).
32. Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213-221 (2010).
33. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126-2132 (2004).
34. Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12-21 (2010).
35. DeLano, W. L. The PyMOL molecular graphics system (DeLano Scientific, 2002).
36. Cassonnet, P. et al. Benchmarking a luciferase complementation assay for detecting protein complexes. Nature Methods 8, 990-992 (2011).
37. Wang, Y., Rosengarth, A. & Luecke, H. Structure of the human p53 core domain in the absence of DNA. Acta Crystallogr. D 63, 276-281 (2007).