Vaccinia virus proteins A52 and B14 Share a Bcl-2-like fold but have evolved to inhibit NF-kappaB rather than apoptosis.
Vaccinia virus proteins A52 and B14 Share a Bcl-2-like fold but have evolved to inhibit NF-kappaB rather than apoptosis.
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DOI：
10.1371/journal.ppat.1000128
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发表时间：
2008-08-15
期刊：
影响因子：
6.7
通讯作者：
Grimes JM
中科院分区：
文献类型：
--
作者：
Graham SC;Bahar MW;Cooray S;Chen RA;Whalen DM;Abrescia NG;Alderton D;Owens RJ;Stuart DI;Smith GL;Grimes JM
牛痘病毒（VACV）是痘病毒的原型，编码许多调节宿主对感染的反应的蛋白。两种这样的蛋白质B14和A52在感染细胞内起作用以抑制NF-κB的活化，从而阻断促炎细胞因子的产生。我们已经解决了A52和B14的晶体结构，分别在1.9纳米和2.7纳米分辨率。引人注目的是，这两种蛋白都采用Bcl-2样折叠，尽管与其他病毒或细胞Bcl-2样蛋白没有显著的序列相似性。与先前描述的细胞和病毒Bcl-2样蛋白不同，A52和B14缺乏用于结合来自促凋亡Bcl-2样蛋白的BH 3肽的表面沟，并且它们不调节凋亡。对32种细胞和病毒Bcl-2样蛋白结构的基于结构的系统发育分析表明，A52和B14彼此之间以及与VACV N1和粘液瘤病毒M11之间的关系比与其他病毒或细胞Bcl-2样蛋白之间的关系更密切。这表明痘病毒的祖先获得了编码Bcl-2样蛋白的基因，并且在进化过程中，基因复制事件使病毒能够利用这种Bcl-2支架来干扰不同的宿主信号传导途径。细胞对病毒感染具有强大的防御能力，但病毒已经进化出复杂的对抗措施来逃避这种防御。用于根除天花的疫苗牛痘病毒有大约200个基因，其中许多编码蛋白质，帮助病毒逃避宿主的免疫防御。这篇文章涉及牛痘病毒蛋白A52和B14，它们阻断导致NF-κB转录因子激活的信号传导途径，从而降低宿主对感染的免疫应答。通过解决A52和B14的三维结构，我们发现它们非常类似于一个细胞和病毒蛋白家族（Bcl-2家族），通常用于调节细胞凋亡（细胞自杀的过程，从而阻止感染它们的任何病毒的复制）。然而，A52和B14都不调节细胞凋亡。通过比较三维结构，我们表明，牛痘病毒Bcl-2样蛋白更密切地类似于彼此比其他细胞或病毒Bcl-2样蛋白。这表明，牛痘病毒的祖先从其宿主获得了编码Bcl-2样蛋白的基因，随着时间的推移，该基因已被复制并适应病毒内的不同功能。
Vaccinia virus (VACV), the prototype poxvirus, encodes numerous proteins that modulate the host response to infection. Two such proteins, B14 and A52, act inside infected cells to inhibit activation of NF-κB, thereby blocking the production of pro-inflammatory cytokines. We have solved the crystal structures of A52 and B14 at 1.9 Å and 2.7 Å resolution, respectively. Strikingly, both these proteins adopt a Bcl-2–like fold despite sharing no significant sequence similarity with other viral or cellular Bcl-2–like proteins. Unlike cellular and viral Bcl-2–like proteins described previously, A52 and B14 lack a surface groove for binding BH3 peptides from pro-apoptotic Bcl-2–like proteins and they do not modulate apoptosis. Structure-based phylogenetic analysis of 32 cellular and viral Bcl-2–like protein structures reveals that A52 and B14 are more closely related to each other and to VACV N1 and myxoma virus M11 than they are to other viral or cellular Bcl-2–like proteins. This suggests that a progenitor poxvirus acquired a gene encoding a Bcl-2–like protein and, over the course of evolution, gene duplication events have allowed the virus to exploit this Bcl-2 scaffold for interfering with distinct host signalling pathways. Cells possess formidable defences against virus infection, but viruses have evolved sophisticated counter-measures to evade such defences. Vaccinia virus, the vaccine used to eradicate smallpox, has about 200 genes, and many of these encode proteins that help the virus evade the host's immune defences. This paper concerns the vaccinia virus proteins A52 and B14, which block signalling pathways leading to the activation of the NF-κB transcription factor and thereby diminish the host immune response to infection. By solving the three-dimensional structures of A52 and B14, we show that they closely resemble a family of cellular and viral proteins (the Bcl-2 family) that usually function to regulate apoptosis (a process by which cells commit suicide, thereby stopping the replication of any viruses with which they are infected). However, neither A52 nor B14 regulate apoptosis. By comparing three-dimensional structures, we show that vaccinia virus Bcl-2–like proteins more closely resemble each other than they do other cellular or viral Bcl-2–like proteins. This suggests that an ancestor of vaccinia virus acquired a gene encoding a Bcl-2–like protein from its host and, over time, this gene has been copied and adapted for different functions within the virus.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.4
作者：
Gedey, Roderick;Jin, Xiao-Lu;Shisler, Joanna L.
通讯作者：
Shisler, Joanna L.
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
DOI：
10.1073/pnas.0711573105
发表时间：
2008-02-12
影响因子：
11.1
作者：
Assarsson, Erika;Greenbaum, Jason A.;Sette, Alessandro
通讯作者：
Sette, Alessandro