对于HPV介导的p53降解所需的E6/E6AP/p53复合物的结构
Denise Martinez-Zapien1, Francesc Xavier Ruiz2, Juline Poirson1
1Equipe labellisée Ligue, Biotechnologie et signalisation cellulaire UMR 7242, Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, BP 10413, F-67412 Illkirch, France.
Nature
|January 21, 2016
概括
人类乳头瘤病毒 (HPV) 基蛋白E6劫持了E6相关蛋白1 (E6AP) 基酶以降解p53瘤抑制剂. 晶体结构揭示了E6如何与p53结合,从而实现对HPV驱动的癌症的治疗策略.
科学领域:
- 分子生物学
- 病毒学
- 结构生物学
背景情况:
- 这种p53瘤抑制剂对亡至关重要,并且在癌症中经常发生变化.
- 高风险的人类乳头瘤病毒 (HPV) 使用病毒蛋白E6来降解p53.
- E6需要E6相关蛋白1 (E6AP) 来招募和降解p53,但组装机制尚不清楚.
研究的目的:
- 阐明HPV-16E6,E6AP和p53之间三元复合的结构基础.
- 了解E6如何通过E6AP促进p53的降解.
- 为开发针对HPV诱导的治疗干预提供结构基础.
主要方法:
- 全长HPV-16 E6,E6AP LxxLL动机和p53核心域复合物的晶体结构的确定.
- 针对位点的突变发生,以研究E6-p53相互作用界面.
主要成果:
- 晶体结构显示了三元复合体,显示E6AP LxxLL图案诱导了E6中的p53结合裂.
- 在E6-p53接口的突变性消除了p53降解.
- p53上的E6结合位与其DNA和蛋白质结合表面不同,这表明E6可以向各种p53形式.
结论:
- 复杂的E6/E6AP/p53结构解释了病毒对ubiquitin-proteasome系统和p53通路的颠覆.
- 这种结构洞察对于设计抑制剂来对抗HPV介导的癌症发展至关重要.
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