Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity.
Conformational adaptation of Asian macaque TRIMCyp directs lineage specific antiviral activity.
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DOI：
10.1371/journal.ppat.1001062
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发表时间：
2010-08-19
期刊：
影响因子：
6.7
通讯作者：
Towers GJ
中科院分区：
文献类型：
--
作者：
Ylinen LM;Price AJ;Rasaiyaah J;Hué S;Rose NJ;Marzetta F;James LC;Towers GJ
TRIMCyps是在新世界和旧大陆灵长类动物中独立出现的抗逆转录病毒蛋白。所有TRIMCyps都包含一个与TRIM5α的三方结构域融合的CypA结构域，但它们具有不同的慢病毒特异性，使HIV-1限制在新世界猫头鹰猴中，HIV-2限制在旧世界恒河猴中。在这里，我们提供的证据表明，亚洲猕猴TRIMCyps已经获得了在不同慢病毒谱系之间转换限制特异性的变化，从而产生针对不同病毒的物种特异性等位基因。结构、热力学和病毒限制性内切分析表明，在猕猴TRIMCyp进化的早期，Cyp结构域R69H发生了单一突变，将限制性内切特异性扩展到非洲绿猴、黑白鹭和黑猩猩的慢病毒谱系。随后的突变增强了对特定病毒的限制，但代价是丧失了广泛的特异性。我们揭示了支架突变E143K是如何改变特异性的，它改变了表面静电并将构象变化传播到活性位点。我们的研究结果表明，尽管在目前的猕猴种群中没有慢病毒感染的报道，但慢病毒可能是亚洲猕猴的重要病原体。在哺乳动物的进化过程中，逆转录病毒一直在不断地感染它们，导致它们进化出防御机制来保护自己。其中一种机制利用称为限制因子的细胞内抗病毒分子。限制性内切因子序列在灵长类动物的进化过程中发生了变化，这表明逆转录病毒与其宿主之间的持续斗争正如红皇后假说所描述的那样。TRIM5是一个重要的限制因子，能够保护一些猴子而不是人类免受HIV感染。某些猴子通过将病毒结合的B30.2结构域与通过反转录转位插入TRIM5位点的亲环蛋白a结构域交换，从而修饰了它们的TRIM5基因。这导致一种TRIMCyp蛋白的表达，这种蛋白具有抗病毒活性，可以对抗招募亲环蛋白的病毒，如HIV-1。似乎亲环蛋白制造了一个特别灵活的病毒结合域，能够限制来自灵长类动物和猫的不同慢病毒。在这里，我们描述了亲环蛋白-衣壳相互作用的分子细节，重点是来自Macaca Fascicularis的TRIMCyp蛋白。使用结构/功能方法，我们可以显示TRIMCyp序列的适应性变化如何在不同灵长类慢病毒谱系成员之间切换特异性的分子细节。将这些变化映射到猕猴的系统发育上，揭示了TRIMCyp进化的历史，该历史指导了对各种不同慢病毒的限制。
TRIMCyps are anti-retroviral proteins that have arisen independently in New World and Old World primates. All TRIMCyps comprise a CypA domain fused to the tripartite domains of TRIM5α but they have distinct lentiviral specificities, conferring HIV-1 restriction in New World owl monkeys and HIV-2 restriction in Old World rhesus macaques. Here we provide evidence that Asian macaque TRIMCyps have acquired changes that switch restriction specificity between different lentiviral lineages, resulting in species-specific alleles that target different viruses. Structural, thermodynamic and viral restriction analysis suggests that a single mutation in the Cyp domain, R69H, occurred early in macaque TRIMCyp evolution, expanding restriction specificity to the lentiviral lineages found in African green monkeys, sooty mangabeys and chimpanzees. Subsequent mutations have enhanced restriction to particular viruses but at the cost of broad specificity. We reveal how specificity is altered by a scaffold mutation, E143K, that modifies surface electrostatics and propagates conformational changes into the active site. Our results suggest that lentiviruses may have been important pathogens in Asian macaques despite the fact that there are no reported lentiviral infections in current macaque populations. Retroviruses have constantly been infecting mammals throughout their evolution, causing them to evolve defensive mechanisms to protect themselves. One of these mechanisms utilises intracellular antiviral molecules referred to as restriction factors. Restriction factor sequences have changed through primate evolution, suggesting an ongoing battle between retroviruses and their hosts as described by the Red Queen hypothesis. TRIM5 is an important restriction factor able to protect some monkeys, but not humans, from HIV infection. Certain monkeys have modified their TRIM5 genes by swapping the virus binding B30.2 domain with a cyclophilin A domain inserted into the TRIM5 locus by retrotransposition. This leads to expression of a TRIMCyp protein with antiviral activity against viruses, such as HIV-1, that recruit cyclophilins. It appears that cyclophilin makes a particularly flexible virus-binding domain able to restrict divergent lentiviruses from primates as well as cats. Here we characterise the molecular details of Cyclophilin-Capsid interactions focusing on TRIMCyp proteins from Macaca Fascicularis. Using a structure/function approach we can show the molecular details of how adaptive changes in the TRIMCyp sequence switch specificity between members of different primate lentiviral lineages. Mapping these changes onto the macaque phylogeny reveals a history of TRIMCyp evolution that directs restriction to a variety of diverse lentiviruses.
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