与HPV16-E6和p53复合的E6AP的结构揭示了对E3酶激活重要的新型有序域
Sebastian Kenny1, Shalini Iyer1, Clinton A Gabel2
1Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
Structure (London, England : 1993)
|January 16, 2025
概括
高风险的人类乳头瘤病毒E6针对p53瘤抑制剂. Cryo-EM揭示了E6AP酶如何与E6和p53相互作用,详细介绍了E6AP在泛素转移和E6保护中的N终端域作用.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 高风险的人类乳头瘤病毒 (HPV) E6瘤蛋白向细胞p53瘤抑制蛋白进行降解.
- 了解E6AP无素结合酶机制,包括基质定位和E6保护是不完整的.
研究的目的:
- 阐明E6AP/E6/p53复合体形成和E6AP酶激活的结构基础.
- 了解E6AP是如何调解p53的泛化,并保护E6免受自我泛化.
主要方法:
- 确定了E6AP/E6/p53复合体的冷电子显微镜 (cryo-EM) 结构.
- 利用体内模型来分析三分子复杂相互作用.
- 确定了控制E6AP酶活性的关键结构相互作用.
主要成果:
- 冷-EM结构揭示了E6AP,E6和p53.3的精确排列方式.
- 在E6AP的N端有序域 (NOD) 中,一个终端α螺旋与HECT域相互作用.
- 这种NOD螺旋对E6AP结合酶功能至关重要,增强E6-E6AP结合,调节p53识别,并保护E6免受无处不在.
结论:
- E6AP的N端有序域在E6AP/E6/p53复合体中起着关键的调节作用.
- 结构洞察力解释了E6AP针对p53降解的机制,同时保护HPV E6.
- 这项工作为了解病毒蛋白相互作用和开发向治疗提供了基础.
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