Nominé Yves, Masson Murielle, Charbonnier Sebastian, Zanier Katia, Ristriani Tutik, Deryckère François, Sibler Annie-Paule, Desplancq Dominique, Atkinson Robert Andrew, Weiss Etienne, Orfanoudakis Georges, Kieffer Bruno, Travé Gilles
Equipe Oncoprotéine, UMR CNRS 7100, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sebastien Brant, BP 10413, 67412 Illkirch Cedex, France.
Mol Cell. 2006 Mar 3;21(5):665-78. doi: 10.1016/j.molcel.2006.01.024.
Oncoprotein E6 is essential for oncogenesis induced by human papillomaviruses (HPVs). The solution structure of HPV16-E6 C-terminal domain reveals a zinc binding fold. A model of full-length E6 is proposed and analyzed in the context of HPV evolution. E6 appears as a chameleon protein combining a conserved structural scaffold with highly variable surfaces participating in generic or specialized HPV functions. We investigated surface residues involved in two specialized activities of high-risk genital HPV E6: p53 tumor suppressor degradation and nucleic acid binding. Screening of E6 surface mutants identified an in vivo p53 degradation-defective mutant that fails to recruit p53 to ubiquitin ligase E6AP and restores high p53 levels in cervical carcinoma cells by competing with endogeneous E6. We also mapped the nucleic acid binding surface of E6, the positive potential of which correlates with genital oncogenicity. E6 structure-function analysis provides new clues for understanding and counteracting the complex pathways of HPV-mediated pathogenesis.
癌蛋白E6对于人乳头瘤病毒（HPV）诱导的肿瘤发生至关重要。HPV16-E6 C末端结构域的溶液结构揭示了一种锌结合折叠。提出了全长E6的模型，并在HPV进化的背景下进行了分析。E6表现为一种变色龙蛋白，它结合了保守的结构支架和参与一般或特殊HPV功能的高度可变表面。我们研究了与高危生殖器HPV E6的两种特殊活性相关的表面残基：p53肿瘤抑制因子降解和核酸结合。对E6表面突变体的筛选鉴定出一种体内p53降解缺陷型突变体，该突变体无法将p53募集到泛素连接酶E6AP，并通过与内源性E6竞争来恢复宫颈癌细胞中的高p53水平。我们还绘制了E6的核酸结合表面，其正电位与生殖器致癌性相关。E6结构-功能分析为理解和对抗HPV介导的发病机制的复杂途径提供了新线索。
