Domain III from class II fusion proteins functions as a dominant-negative inhibitor of virus membrane fusion.
Domain III from class II fusion proteins functions as a dominant-negative inhibitor of virus membrane fusion.
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DOI：
10.1083/jcb.200507075
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发表时间：
2005-10-10
影响因子：
7.8
通讯作者：
Kielian, Margaret
中科院分区：
文献类型：
--
作者：
Liao, Maofu;Kielian, Margaret
甲病毒和黄病毒通过结构相似的病毒融合蛋白介导的低pH依赖性膜融合反应来感染细胞。在融合过程中，这些 II 类病毒融合蛋白三聚并重新折叠形成发夹样结构，其中结构域 III 和茎区向后折叠至目标膜插入融合肽。我们证明外源结构域 III 可以作为甲病毒和黄病毒膜融合和感染的显性失活抑制剂。结构域 III 与融合蛋白稳定结合，从而防止折返反应并阻断融合的脂质混合步骤。我们的数据揭示了存在相对较长寿命的核心三聚体中间体，结构域 III 与该中间体相互作用以启动膜融合。这些新型 II 类融合蛋白抑制剂在病毒属内表现出交叉抑制作用，表明结构域 III-核心三聚体相互作用可以作为抗病毒试剂开发的新靶点。
Alphaviruses and flaviviruses infect cells through low pH-dependent membrane fusion reactions mediated by their structurally similar viral fusion proteins. During fusion, these class II viral fusion proteins trimerize and refold to form hairpin-like structures, with the domain III and stem regions folded back toward the target membrane-inserted fusion peptides. We demonstrate that exogenous domain III can function as a dominant-negative inhibitor of alphavirus and flavivirus membrane fusion and infection. Domain III binds stably to the fusion protein, thus preventing the foldback reaction and blocking the lipid mixing step of fusion. Our data reveal the existence of a relatively long-lived core trimer intermediate with which domain III interacts to initiate membrane fusion. These novel inhibitors of the class II fusion proteins show cross-inhibition within the virus genus and suggest that the domain III–core trimer interaction can serve as a new target for the development of antiviral reagents.