病毒编码的肿瘤坏死因子受体CrmE的结构

Structure of CrmE, a virus-encoded tumour necrosis factor receptor.

作者信息

Graham Stephen C, Bahar Mohammad W, Abrescia Nicola G A, Smith Geoffrey L, Stuart David I, Grimes Jonathan M

机构信息

Division of Structural Biology, Wellcome Trust Centre for Human Genetics and Oxford Protein Production Facility Roosevelt Drive, Headington, Oxford OX3 7BN, UK.

出版信息

J Mol Biol. 2007 Sep 21;372(3):660-71. doi: 10.1016/j.jmb.2007.06.082. Epub 2007 Jul 3.

DOI:10.1016/j.jmb.2007.06.082

PMID:17681535

Abstract

Vaccinia virus (VACV), the smallpox vaccine, encodes many proteins that subvert the host immune response. One of these, cytokine response modifier E (CrmE), is secreted by infected cells and protects these cells from apoptotic challenge by tumour necrosis factor alpha (TNFalpha). We have expressed recombinant CrmE from VACV strain Lister in Escherichia coli, shown that the purified protein is monomeric in solution and competent to bind TNFalpha, and solved the structure to 2.0 A resolution. This is the first structure of a virus-encoded tumour necrosis factor receptor (TNFR). CrmE shares significant sequence similarity with mammalian type 2 TNF receptors (TNFSFR1B, p75; TNFR type 2). The structure confirms that CrmE adopts the canonical TNFR fold but only one of the two "ligand-binding" loops of TNFRSF1A is conserved in CrmE, suggesting a mechanism for the higher affinity of poxvirus TNFRs for TNFalpha over lymphotoxin-alpha. The roles of dimerisation and pre-ligand-assembly domains (PLADs) in poxvirus and mammalian TNFR activity are discussed.

摘要

牛痘病毒（VACV），即天花疫苗，编码许多能够破坏宿主免疫反应的蛋白质。其中一种细胞因子反应调节因子E（CrmE）由受感染细胞分泌，可保护这些细胞免受肿瘤坏死因子α（TNFα）引发的凋亡挑战。我们已在大肠杆菌中表达了来自VACV株李斯特菌的重组CrmE，证明纯化后的蛋白质在溶液中为单体形式且能够结合TNFα，并解析出其结构，分辨率达到2.0埃。这是病毒编码的肿瘤坏死因子受体（TNFR）的首个结构。CrmE与哺乳动物2型肿瘤坏死因子受体（TNFSFR1B，p75；TNFR 2型）具有显著的序列相似性。该结构证实CrmE采用了典型的TNFR折叠，但TNFRSF1A的两个“配体结合”环中只有一个在CrmE中保守，这表明痘病毒TNFR对TNFα的亲和力高于淋巴毒素α的一种机制。文中还讨论了二聚化和配体预组装结构域（PLADs）在痘病毒和哺乳动物TNFR活性中的作用。