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PLoS Pathog:伪狂犬病毒囊膜糖蛋白 gD 识别受体 nectin- 1 的分子机制

2017-06-13 佚名 微生物研究所

图:伪狂犬病毒 gD 与猪 nectin-1 的复合物结构疱疹病毒膜融合需要多个病毒蛋白与多个细胞表面受体参与,相互协调才能完成,整个过程极其复杂。病毒表面糖蛋白 D (gD) 与宿主细胞受体的识别是α- 疱疹病毒感染初期的必不可少的步骤。在迄今已鉴定的 gD 受体中,细胞黏附分子 nectin- 1 参与了多种α- 疱疹病毒入侵宿主细胞的过程,被认为是最有效的 gD 受体。因此,gD 识别 ne


图:伪狂犬病毒 gD 与猪 nectin-1 的复合物结构

疱疹病毒膜融合需要多个病毒蛋白与多个细胞表面受体参与,相互协调才能完成,整个过程极其复杂。病毒表面糖蛋白 D (gD) 与宿主细胞受体的识别是α- 疱疹病毒感染初期的必不可少的步骤。在迄今已鉴定的 gD 受体中,细胞黏附分子 nectin- 1 参与了多种α- 疱疹病毒入侵宿主细胞的过程,被认为是最有效的 gD 受体。因此,gD 识别 nectin- 1 的分子机制成为α- 疱疹病毒研究领域的一个重要科学问题。

中国科学院微生物研究所高福团队与严景华课题组在前期研究中已经解析了 I 和 II 型单纯疱疹病毒(HSV)gD 与其受体 nectin- 1 的复合物结构,发现 HSV gD 蛋白结合于 nectin- 1 分子二聚化的接触面上。这一结合模式破坏了 nectin- 1 自身的二聚化,进而削弱了细胞粘附,有利于病毒入侵(Nature Communications2011;Journal of Virology 2014)。同时还阐明了 HSV 病毒另一关键糖蛋白 gB 与受体 PILRa 相互作用机制(PNAS 2014)。

猪伪狂犬病病毒(Pseudorabies virus, PRV)与 HSV 同属 α 疱疹病毒。HSV 是 Simplexvirus 属成员,而 PRV 是 Varicellovirus 病毒属成员。有研究表明 PRV 同样可以利用 nectin- 1 作为受体,然而其分子机制不清楚。另外,PRV 感染宿主是猪,那么它能否结合 HSV 的受体,如人源 nectin-1、HVEM 等,进而存在感染人的风险呢?

团队系统地研究了 PRV gD 与 nectin- 1 的相互作用,证明了 PRV 可以感染人源和猪源 nectin- 1 过表达的细胞,并且 PRV gD 对两种来源的 nectin- 1 亲和力基本相同,这警示人们要防范 PRV 感染人的风险。研究进一步解析了 PRV gD 胞外域及其与 nectin- 1 复合体晶体结构。结构显示 PRV gD 的空间结构与 HSV 非常相似,尽管其序列同源性只有 22%,与 HSV gD 结构不同的是,PRV gD N- 末端的 loop 区比较短,而这个区域正好是 HSV gD 结合另一个受体 HVEM 的位置,这也就解释了为什么 PRV 不能用 HVEM 做受体的机制。复合体结构表明 PRV gD 以与 HSV 相同的模式结合 nectin-1,然而,在 PRV gD 与 nectin- 1 结合界面处有多个独有的特征,这些特征促使 PRV 配体利用不同于 HSV gD 的氨基酸残基与 nectin- 1 相互作用。该项研究不仅揭示了 PRV gD 与 nectin- 1 的相互作用分子机制,而且丰富了人们对α- 疱疹病毒亚科的受体结合模式的理解,也会为开发抑制伪狂犬病毒融合的小分子药物奠定理论基础。

该研究成果近期发表在 PLOS Pathogens 杂志上。中科院微生物所和广西大学联合培养博士生李安、四川大学教授逯光文为共享第一作者,微生物所高福、严景华和广西大学教授罗廷荣为论文共同通讯作者。该研究得到了国家重点研发计划项目和多项国家自然科学基金项目的资助。

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    2017-06-14 stupidox

    学习了,谢谢。

    0

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    2017-06-13 sillywu

    这是猪病啊,这里现在这么兼容并包了呀

    0

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    2017-06-13 楠博One

    发现病毒对症研究有效果的药物

    0

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    2017-06-13 菊花小王子

    不错

    0

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