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PLoS Pathog:研究发现EB病毒如何“接管”我们细胞的基因调节机制

来源:生物谷 2014-04-13 21:44

2014年4月12日讯 /生物谷BIOON/--近日,蒙特利尔大学研究人员已经发现EB病毒 (EBV)的一个组成部分如何“接管”我们的细胞基因调节机制,使病毒自身能够得到复制。EBV病毒引起各种疾病,例如霍奇金淋巴瘤和Burkitt's淋巴瘤等。

在感染期间,EB病毒利用先进的战略“颠覆”人类细胞。该病毒在人体细胞之外不能存活,为此,它们已经开发策略,以模仿人类细胞功能的关键组成部分如RNA聚合酶。

James Omichinski博士解释:运用结构生物学在原子水平揭开EBV病毒与人类细胞相互作用的细节,使我们能够了解病毒如何攻克人类防御系统。有了这方面的知识,对发展病毒感染的新治疗方法至关重要。

采用先进的核磁共振技术,科学家研究EBV病毒EBNA2蛋白如何结合到TFIIH复合体蛋白质中的某一蛋白,帮助调节另一种蛋白RNA聚合酶II,RNA聚合酶II是负责控制我们大部分基因的分子。Omichinski博士解释:我们解开了这些蛋白质之间的相互作用的分子细节。

为了揭示这个相互作用的分子细节,主要作者Philippe Chabot用稳定的同位素标记EBNA2蛋白和TFIIH,利用核磁共振光谱测定相互作用的分子结构。这项工作的一个直接好处是,EBNA2蛋白和TFIIH之间的互动可能是药物开发的靶标,在未来可以更好地治疗EBV病毒所造成的疾病。

这项研究结果发表在PLOS Pathogens杂志上。(生物谷Bioon.com)

 

doi:10.1371/journal.ppat.1004042
Structural and Functional Characterization of a Complex between the Acidic Transactivation Domain of EBNA2 and the Tfb1/p62 Subunit of TFIIH

Philippe R.et al.

Infection with the Epstein-Barr virus (EBV) can lead to a number of human diseases including Hodgkin's and Burkitt's lymphomas. The development of these EBV-linked diseases is associated with the presence of nine viral latent proteins, including the nuclear antigen 2 (EBNA2). The EBNA2 protein plays a crucial role in EBV infection through its ability to activate transcription of both host and viral genes. As part of this function, EBNA2 associates with several host transcriptional regulatory proteins, including the Tfb1/p62 (yeast/human) subunit of the general transcription factor IIH (TFIIH) and the histone acetyltransferase CBP(CREB-binding protein)/p300, through interactions with its C-terminal transactivation domain (TAD). In this manuscript, we examine the interaction of the acidic TAD of EBNA2 (residues 431–487) with the Tfb1/p62 subunit of TFIIH and CBP/p300 using nuclear magnetic resonance (NMR) spectroscopy, isothermal titration calorimeter (ITC) and transactivation studies in yeast. NMR studies show that the TAD of EBNA2 binds to the pleckstrin homology (PH) domain of Tfb1 (Tfb1PH) and that residues 448–471 (EBNA2448–471) are necessary and sufficient for this interaction. NMR structural characterization of a Tfb1PH-EBNA2448–471 complex demonstrates that the intrinsically disordered TAD of EBNA2 forms a 9-residue α-helix in complex with Tfb1PH. Within this helix, three hydrophobic amino acids (Trp458, Ile461 and Phe462) make a series of important interactions with Tfb1PH and their importance is validated in ITC and transactivation studies using mutants of EBNA2. In addition, NMR studies indicate that the same region of EBNA2 is also required for binding to the KIX domain of CBP/p300. This study provides an atomic level description of interactions involving the TAD of EBNA2 with target host proteins. In addition, comparison of the Tfb1PH-EBNA2448–471 complex with structures of the TAD of p53 and VP16 bound to Tfb1PH highlights the versatility of intrinsically disordered acidic TADs in recognizing common target host proteins.

 

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