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

Nature
Denise Martinez-ZapienKatia Zanier

Abstract

The p53 pro-apoptotic tumour suppressor is mutated or functionally altered in most cancers. In epithelial tumours induced by 'high-risk' mucosal human papilloma viruses, including human cervical carcinoma and a growing number of head-and-neck cancers, p53 is degraded by the viral oncoprotein E6 (ref. 2). In this process, E6 binds to a short leucine (L)-rich LxxLL consensus sequence within the cellular ubiquitin ligase E6AP. Subsequently, the E6/E6AP heterodimer recruits and degrades p53 (ref. 4). Neither E6 nor E6AP are separately able to recruit p53 (refs 3, 5), and the precise mode of assembly of E6, E6AP and p53 is unknown. Here we solve the crystal structure of a ternary complex comprising full-length human papilloma virus type 16 (HPV-16) E6, the LxxLL motif of E6AP and the core domain of p53. The LxxLL motif of E6AP renders the conformation of E6 competent for interaction with p53 by structuring a p53-binding cleft on E6. Mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation. The E6-binding site of p53 is distal from previously described DNA- and protein-binding surfaces of the core domain. This suggests that, in principle, E6 may avoid competition with cellular factors by targeting both free ...Continue Reading

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Citations

Jun 2, 2016·Cell Cycle·Gilles Travé, Katia Zanier
Apr 5, 2017·International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society·Eric J DevorKimberly K Leslie
Apr 5, 2017·Annual Review of Biochemistry·Ning Zheng, Nitzan Shabek
Jul 6, 2017·Viruses·Karin Hoppe-SeylerFelix Hoppe-Seyler
Jan 10, 2018·International Journal of Molecular Sciences·Elvira Regina Tamarozzi, Silvana Giuliatti
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Aug 9, 2018·PLoS Pathogens·Michelle AinouzeUzma Ayesha Hasan
Aug 10, 2018·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Sharbadeb KunduSankar Kumar Ghosh
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Oct 11, 2017·Biological Chemistry·Sonja Lorenz
Jun 3, 2020·Medicinal Research Reviews·Avinash KumarSuvarna G Kini

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Methods Mentioned

BETA
gel
isothermal titration
pull-down
pull-downs
FCS
transfection
Dynamic light scattering
gel filtration
electrophoresis

Software Mentioned

PHENIX
MOLPROBITY
Coot
Phaser
ImageQuant TL
HKL2000

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