Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53.
Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53.
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HPV介导的p53降解所需的E6/E6AP/p53复合物的结构。
DOI：
10.1038/nature16481
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发表时间：
2016-01-28
期刊：
影响因子：
64.8
通讯作者：
Zanier K
中科院分区：
文献类型：
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作者：
Martinez-Zapien D;Ruiz FX;Poirson J;Mitschler A;Ramirez J;Forster A;Cousido-Siah A;Masson M;Vande Pol S;Podjarny A;Travé G;Zanier K
p53促凋亡肿瘤抑制因子在大多数癌症中突变或功能改变。在由“高危”粘膜人乳头瘤病毒（hrm-HPV）诱导的上皮肿瘤中，包括人宫颈癌和越来越多的头颈癌，p53被病毒癌蛋白E6降解。在此过程中，E6结合到细胞泛素连接酶E6 AP内的短LxxLL共有序列。随后，E6/E6 AP异二聚体募集并降解p53。E6和E6 AP都不能单独募集p53，并且E6、E6 AP和p53的精确组装模式是未知的。在这里，我们解决了三元复合物的晶体结构，包括全长HPV 16 E6，E6 AP的LxxLL基序和p53的核心结构域。E6 AP的LxxLL基序通过在E6上构建p53结合裂缝而使E6的构象能够与p53相互作用。E6-p53界面关键位置的突变破坏了p53降解。p53的E6结合位点远离先前描述的核心结构域的DNA和蛋白质结合表面。这表明，原则上，E6可以通过靶向游离和结合的p53分子来避免与细胞因子的竞争。E6/E6 AP/p53复合物代表了病毒劫持泛素介导的蛋白降解途径和p53肿瘤抑制途径的原型。本结构提供了一个框架，用于设计针对HPV介导的肿瘤发生的抑制性治疗策略。
The p53 pro-apoptotic tumor suppressor is mutated or functionally altered in most cancers. In epithelial tumors induced by “high-risk” mucosal Human Papillomaviruses (hrm-HPVs), including human cervical carcinoma and a growing number of head-and-neck cancers , p53 is degraded by the viral oncoprotein E6 . In this process, E6 binds to a short LxxLL consensus sequence within the cellular ubiquitin ligase E6AP . Subsequently, the E6/E6AP heterodimer recruits and degrades p53 . Neither E6 nor E6AP are separately able to recruit p53 , and the precise mode of assembly of E6, E6AP and p53 is unknown. Here, we solved the crystal structure of a ternary complex comprising full-length HPV16 E6, the LxxLL motif of E6AP and the core domain of p53. The LxxLL motif of E6AP renders the conformation of E6 competent for interaction with p53 by structuring a p53-binding cleft on E6. Mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation. The E6-binding site of p53 is distal from previously described DNA- and protein-binding surfaces of the core domain. This suggests that, in principle, E6 may avoid competition with cellular factors by targeting both free and bound p53 molecules. The E6/E6AP/p53 complex represents a prototype of viral hijacking of both the ubiquitin-mediated protein degradation pathway and the p53 tumor suppressor pathway. The present structure provides a framework for the design of inhibitory therapeutic strategies against HPV-mediated oncogenesis.