Structure of high-risk papillomavirus type 31 E6 oncogenic protein and characterization of E6/E6AP/p53 complex formation.
Fiche publication
Date publication
octobre 2020
Journal
Journal of virology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MASSON Murielle, Dr TRAVE Gilles, Dr GOGL Gergo
Tous les auteurs :
Conrady MC, Suarez I, Gogl G, Frecot DI, Bonhoure A, Kostmann C, Cousido-Siah A, Mitschler A, Lim J, Masson M, Iftner T, Stubenrauch F, Trave G, Simon C
Lien Pubmed
Résumé
The degradation of p53 is a hallmark of "high-risk" HPV types of the alpha genus and HPV-related carcinogenicity. The oncoprotein E6 forms a ternary complex with the E3 ubiquitin ligase E6-associated protein (E6AP) and tumor suppressor protein p53 targeting p53 for ubiquitination. The extent of p53 degradation by different E6 proteins varies greatly, even for the closely-related HPV 16 and 31. 16E6 and 31E6 display high sequence identity (∼67 %). We report here for the first time the structure of HPV31 E6 bound to the LxxLL motif of E6AP. 16E6 and 31E6 are structurally very similar in agreement with the high sequence conservation. Both E6 proteins bind E6AP and degrade p53. However, the binding affinities of 31E6 to E6AP and p53, respectively, are reduced 2-fold and 5.4-fold as compared to 16E6. The affinity of E6-E6AP-p53 ternary complex formation parallels the efficacy of the subsequent reaction, namely degradation of p53. Therefore, closely-related E6 proteins addressing the same cellular targets may still diverge in their binding efficiencies, possibly explaining their different phenotypic or pathologic impact. Variations of carcinogenicity of Human papillomaviruses are related to variations of the E6 and E7 interactome. While different HPV species and genera are known to target distinct host proteins, the fine differences between E6 and E7 of closely-related HPV types, supposed to target the same cellular protein pools, remain to be addressed. We compare the oncogenic E6 proteins of the closely related "high-risk" HPV types 31 and 16 with regard to their structure and their efficiency of ternary complex formation with their cellular targets p53 and E6AP, which results in p53 degradation. We solved the crystal structure of 31E6 bound to the E6AP LxxLL-motif. 16E6 and 31E6 structures are highly similar but a few sequence variations lead to different protein contacts within the ternary complex and, as quantified here, an overall lower binding affinity of 31E6 compared with 16E6. These results align with the observed lower p53-degradation potential of 31E6.
Référence
J Virol. 2020 Oct 28;: