Dissecting Henipavirus W proteins conformational and fibrillation properties: contribution of their N- and C-terminal constituent domains.

Giulia Pesce, Frank Gondelaud, Denis Ptchelkine, Christophe Bignon, Patrick Fourquet, Sonia Longhi
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Abstract

The Nipah and Hendra viruses are severe human pathogens. In addition to the P protein, their P gene also encodes the V and W proteins that share with P their N-terminal intrinsically disordered domain (NTD) and possess distinct C-terminal domains (CTDs). The W protein is a key player in the evasion of the host innate immune response. We previously showed that the W proteins are intrinsically disordered and can form amyloid-like fibrils. However, structural information on W CTD (CTDW) and its potential contribution to the fibrillation process is lacking. In this study, we demonstrate that CTDWS are disordered and able to form dimers mediated by disulfide bridges. We also show that the NTD and the CTDW interact with each other and that this interaction triggers both a gain of secondary structure and a chain compaction within the NTD. Finally, despite the lack of intrinsic fibrillogenic properties, we show that the CTDW favors the formation of fibrils by the NTD both in cis and in trans. Altogether, the results herein presented shed light on the molecular mechanisms underlying Henipavirus pathogenesis and may thus contribute to the development of targeted therapies.

剖析母鸡病毒 W 蛋白的构象和纤化特性:其 N 端和 C 端组成结构域的贡献。
尼帕病毒和亨德拉病毒是严重的人类病原体。除 P 蛋白外,它们的 P 基因还编码 V 蛋白和 W 蛋白,这两种蛋白与 P 蛋白共享 N 端内杂乱结构域(NTD),但具有不同的 C 端结构域(CTD)。W 蛋白是逃避宿主先天免疫反应的关键角色。我们以前曾发现,W 蛋白具有内在无序性,可以形成淀粉样纤维。然而,目前还缺乏 W CTD(CTDW)的结构信息及其对纤维化过程的潜在贡献。在这项研究中,我们证明了 CTDWS 是无序的,能够在二硫桥的介导下形成二聚体。我们还表明,NTD 和 CTDW 相互作用,这种作用会引发二级结构的增加和 NTD 内链的压实。最后,尽管缺乏内在的成纤特性,我们还是发现 CTDW 有利于 NTD 顺反向形成纤维。总之,本文所展示的结果揭示了母鸡病毒致病的分子机制,因此可能有助于靶向疗法的开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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