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

摘要: 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 cervical carcinoma and a growing number of head-and-neck cancers, degraded the viral oncoprotein E6 (ref. 2). this process, binds to short leucine (L)-rich LxxLL consensus sequence within cellular ubiquitin ligase E6AP. Subsequently, E6/E6AP heterodimer recruits degrades 4). Neither nor E6AP are separately able recruit (refs 3, 5), precise mode assembly E6, unknown. Here we solve crystal structure ternary complex comprising full-length virus type 16 (HPV-16) motif core domain p53. renders conformation competent for interaction with structuring p53-binding cleft on E6. Mutagenesis critical positions at E6-p53 interface disrupts degradation. E6-binding site distal from previously described DNA- protein-binding surfaces domain. This suggests that, principle, may avoid competition factors targeting both free bound molecules. E6/E6AP/p53 represents prototype hijacking ubiquitin-mediated protein degradation pathway pathway. present provides framework design inhibitory therapeutic strategies against oncogenesis mediated virus.