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首页> 外文期刊>Journal of Molecular Biology >The High-Risk HPV16 E7 Oncoprotein Mediates Interaction between the Transcriptional Coactivator CBP and the Retinoblastoma Protein pRb
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The High-Risk HPV16 E7 Oncoprotein Mediates Interaction between the Transcriptional Coactivator CBP and the Retinoblastoma Protein pRb

机译：高风险HPV16 E7癌蛋白介导转录共激活因子CBP和成视网膜细胞瘤蛋白pRb之间的相互作用。

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摘要

The oncoprotein E7 from human papillomavirus (HPV) strains that confer high cancer risk mediates cell transformation by deregulating host cellular processes and activating viral gene expression through recruitment of cellular proteins such as the retinoblastoma protein (pRb) and the cyclic-AMP response element binding binding protein (CBP) and its paralog p300. Here we show that the intrinsically disordered N-terminal region of E7 from high-risk HPV16 binds the TAZ2 domain of CBP with greater affinity than E7 from low-risk HPV6b. HPV E7 and the tumor suppressor p53 compete for binding to TAZ2. The TAZ2 binding site in E7 overlaps the LxCxE motif that is crucial for interaction with pRb. While TAZ2 and pRb compete for binding to a monomeric E7 polypeptide, the full-length E7 dimer mediates an interaction between TAZ2 and pRb by promoting formation of a ternary complex. Cell-based assays show that expression of full-length HPV16 E7 promotes increased pRb acetylation and that this response depends both on the presence of CBP/p300 and on the ability of E7 to form a dimer. These observations suggest a model for the oncogenic effect of high-risk HPV16 E7. The disordered region of one E7 molecule in the homodimer interacts with the pocket domain of pRb, while the same region of the other E7 molecule binds the TAZ2 domain of CBP/p300. Through its ability to dimerize, E7 recruits CBP/p300 and pRb into a ternary complex, bringing the histone acetyltransferase domain of CBP/p300 into proximity to pRb and promoting acetylation, leading to disruption of cell cycle control. (C) 2014 Elsevier Ltd. All rights reserved.
机译：来自人类乳头瘤病毒（HPV）株的癌蛋白E7具有高癌症风险，可通过调控宿主细胞过程并通过募集细胞蛋白（例如成视网膜细胞瘤蛋白（pRb）和环状AMP应答元件结合）来激活病毒基因表达，从而介导细胞转化蛋白（CBP）及其旁系同源物p300。在这里，我们显示来自高风险HPV16的E7的内在无序N末端区域与来自低风险HPV6b的E7的亲和力更大，以CBP的TAZ2域结合。 HPV E7和肿瘤抑制因子p53竞争与TAZ2的结合。 E7中的TAZ2结合位点与LxCxE基序重叠，这对于与pRb相互作用至关重要。尽管TAZ2和pRb竞争结合单体E7多肽，但全长E7二聚体通过促进三元复合物的形成介导TAZ2和pRb之间的相互作用。基于细胞的分析表明，全长HPV16 E7的表达可促进pRb乙酰化的增强，并且这种反应取决于CBP / p300的存在以及E7形成二聚体的能力。这些观察结果提出了高风险HPV16 E7致癌作用的模型。同型二聚体中一个E7分子的无序区域与pRb的口袋结构域相互作用，而另一个E7分子的相同区域则与CBP / p300的TAZ2结构域结合。通过其二聚能力，E7将CBP / p300和pRb募集到三元复合物中，使CBP / p300的组蛋白乙酰基转移酶结构域接近pRb并促进乙酰化，从而破坏细胞周期控制。 （C）2014 Elsevier Ltd.保留所有权利。

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