Interactions between Yersinia pestis V-antigen (LcrV) and human Toll-like receptor 2 (TLR2) in a modelled protein complex and potential mechanistic insights
Interactions between Yersinia pestis V-antigen (LcrV) and human Toll-like receptor 2 (TLR2) in a modelled protein complex and potential mechanistic insights
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鼠疫耶尔森氏菌 V 抗原 (LcrV) 和人 Toll 样受体 2 (TLR2) 在模型蛋白复合物中的相互作用以及潜在的机制见解
DOI：
10.1186/s12865-019-0329-5
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发表时间：
2019
期刊：
影响因子：
3
通讯作者：
Hai Xu
中科院分区：
文献类型：
--
作者：
T. Wei;J. Gong;Guojing Qu;Mingyu Wang;Hai Xu
鼠疫耶尔森氏菌是鼠疫的病原体，能够抑制白色血细胞的免疫反应以逃避吞噬。发现V抗原（LcrV）通过与人Toll样受体2（TLR 2）结合而参与该过程。然而，由于缺乏结构信息，LcrV和TLR 2介导的免疫应答抑制背后的详细机制尚未完全阐明。在这项工作中，与蛋白质结构建模，我们能够构建一个结构模型的异源四聚体Y。鼠疫LcrV和人TLR 2。分子动力学模拟结果表明，该结构在水环境中是稳定的。LcrV模型具有哑铃状结构，其中两个球结构域（在N-末端的G1和远离膜的G2）与卷曲螺旋接头（CCL）结构域连接。两个马蹄形TLR 2亚基形成V形结构，彼此不直接接触，并通过LcrV同源二聚体保持在一起。在该结构模型中，G1和CCL结构域均参与LcrV同源二聚体的形成，而所有三个结构域均参与LcrV-TLR 2结合。基于这种异源四聚体结构模型提出了一种机制模型：LcrV同源二聚体分离TLR 2亚基，抑制TLR 2的二聚化和随后的免疫应答信号传递;而LcrV也可以抑制TLR 2与其他TLRs形成异源二聚体，导致免疫应答抑制。Y.鼠疫LcrV和人TLR 2在这项工作中建模。对该模型结构的分析表明其在水生环境中的稳定性以及LcrV结构域和残基在蛋白质-蛋白质相互作用中的作用。LcrV在Y.基于这种异源四聚体结构模型提出了鼠疫的致病机理。本研究为LcrV的功能提供了一个假说，进一步的实验验证可能阐明LcrV在人类免疫反应抑制中的作用。
Yersinia pestis, the etiological pathogen of plague, is capable of repressing the immune response of white blood cells to evade phagocytosis. The V-antigen (LcrV) was found to be involved in this process by binding to human Toll-like Receptor 2 (TLR2). The detailed mechanism behind this LcrV and TLR2 mediated immune response repression, however, is yet to be fully elucidated due to the lack of structural information. In this work, with protein structure modelling, we were able to construct a structure model of the heterotetramer of Y. pestis LcrV and human TLR2. Molecular dynamics simulation suggests the stability of this structure in aquatic environment. The LcrV model has a dumbbell-like structure with two globule domains (G1 at N-terminus and G2 away from membrane) connected with a coiled-coil linker (CCL) domain. The two horseshoe-shape TLR2 subunits form a V-shape structure, are not in direct contact with each other, and are held together by the LcrV homodimer. In this structure model, both the G1 and CCL domains are involved in the formation of LcrV homodimer, while all three domains are involved in LcrV-TLR2 binding. A mechanistic model was proposed based on this heterotetrameric structure model: The LcrV homodimer separates the TLR2 subunits to inhibit the dimerization of TLR2 and subsequent signal transfer for immune response; while LcrV could also inhibit the formation of heterodimers of TLR2 with other TLRs, and leads to immune response repression. A heterotetrameric structure of Y. pestis LcrV and human TLR2 was modelled in this work. Analysis of this modelled structure showed its stability in aquatic environments and the role of LcrV domains and residues in protein-protein interaction. A mechanistic model for the role of LcrV in Y. pestis pathogenesis is raised based on this heterotetrameric structure model. This work provides a hypothesis of LcrV function, with which further experimental validation may elucidate the role of LcrV in human immune response repression.
DOI：
10.1107/s1744309113008579
发表时间：
2013-05-01
影响因子：
0.9
作者：
Chaudhury, Sukanya;Battaile, Kevin P.;De Guzman, Roberto N.
通讯作者：
De Guzman, Roberto N.