BACKGROUND 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. RESULTS 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. CONCLUSIONS 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.

中文翻译：

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鼠疫耶尔森氏菌V抗原（LcrV）和人类Toll样受体2（TLR2）之间的相互作用在一个模型化的蛋白质复合物中和潜在的机理见解。

背景技术鼠疫耶尔森氏菌是鼠疫的病原体，能够抑制白细胞的免疫反应以逃避吞噬作用。发现V抗原（LcrV）通过与人Toll样受体2（TLR2）结合而参与此过程。由于缺乏结构信息，该LcrV和TLR2介导的免疫应答抑制的详细机制尚待充分阐明。结果在这项工作中，通过蛋白质结构建模，我们能够构建鼠疫耶尔森菌LcrV和人TLR2的异四聚体的结构模型。分子动力学模拟表明该结构在水生环境中的稳定性。LcrV模型具有哑铃状结构，具有两个球状结构域（N端的G1和远离膜的G2），并与卷曲螺旋接头（CCL）域相连。两个马蹄形TLR2亚基形成V形结构，彼此不直接接触，并通过LcrV同型二聚体固定在一起。在该结构模型中，G1和CCL结构域均参与LcrV同型二聚体的形成，而所有三个结构域均参与LcrV-TLR2结合。基于该异四聚体结构模型，提出了一种机制模型：LcrV同二聚体分离TLR2亚基以抑制TLR2的二聚化和随后的信号转移以进行免疫应答。而LcrV也可能抑制TLR2与其他TLRs异源二聚体的形成，并导致免疫应答抑制。结论这项工作建立了鼠疫耶尔森菌LcrV和人TLR2的异四聚体结构模型。对这种建模结构的分析显示了其在水生环境中的稳定性以及LcrV域和残基在蛋白质-蛋白质相互作用中的作用。基于该异四聚体结构模型，提出了LcrV在鼠疫耶尔森氏菌发病机理中作用的机制模型。这项工作提供了LcrV功能的假设，进一步的实验验证可以阐明LcrV在人类免疫应答抑制中的作用。