Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1: Implications for EBV-mediated immortalization
Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1: Implications for EBV-mediated immortalization
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DOI：
10.1016/j.molcel.2005.02.029
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发表时间：
2005-04-01
期刊：
影响因子：
16
通讯作者：
Frappier, L
中科院分区：
文献类型：
--
作者：
Saridakis, V;Sheng, Y;Frappier, L
USP 7/HAUSP是p53和Mdm 2的关键调节因子，并被EB病毒（EBV）的EB核抗原1（EBNA 1）蛋白靶向。我们已经确定了单独的USP 7的p53结合结构域的晶体结构，并结合到EBNA 1肽。该结构域是一个八链β夹心结构，类似于TNF-受体相关因子的TRAF-C结构域，尽管肽结合模式与先前观察到的TRAF-肽相互作用序列（DPGEGPS）和结合肽的构象显著不同。通过EBNA 1和p53结合的USP 7的NMR化学位移分析表明，p53与EBNA 1结合相同的口袋，但与USP 7的接触范围较小。功能研究表明，EBNA 1与USP 7结合可以通过降低p53水平来保护细胞免受凋亡攻击。这些数据为理解EBNA 1如何有助于EB病毒感染细胞的存活提供了结构和概念框架。
USP7/HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV). We have determined the crystal structure of the p53 binding domain of USP7 alone and bound to an EBNA1 peptide. This domain is an eight-stranded beta sandwich similar to the TRAF-C domains of TNF-receptor associated factors, although the mode of peptide binding differs significantly from previously observed TRAF-peptide interactions in the sequence (DPGEGPS) and the conformation of the bound peptide. NMR chemical shift analyses of USP7 bound by EBNA1 and p53 indicated that p53 binds the same pocket as EBNA1 but makes less extensive contacts with USP7. Functional studies indicated that EBNA1 binding to USP7 can protect cells from apoptotic challenge by lowering p53 levels. The data provide a structural and conceptual framework for understanding how EBNA1 might contribute to the survival of Epstein-Barr virus-infected cells.