Harvard-MIT Division of Health Sciences and Technology, Koch Institute for Integrative Cancer Research, and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Innate Immun. 2011 Dec;17(6):548-57. doi: 10.1177/1753425910377099. Epub 2010 Aug 10.
The Yersinia outer protein (Yop) M effector from the Yersinia pestis bacterium is well-known for being a critical virulence determinant; however, structural insight vis-à-vis its role in Y. pestis pathogenesis has been elusive. Here, we investigate the intact sequence of the YopM protein through our recently developed fold identification and homology modeling tools, and analyze the immune modulatory potential of its constituent domains. We identify a putative novel E3 ligase (NEL) domain towards the C-terminal tail of YopM and characterize its active site, to show that YopM could function as an autoregulated bacterial type E3 ubiquitin ligase. We further identify unreported NEL domains in several other bacteria and note remarkable similarity in sequence, structure, surface, and electrostatics for the family of NEL-containing bacterial effectors that suggests conserved function and potentially similar host targets for these proteins. Based on these observations and recent empirical evidence for degradation of the human proteins HLA-DR, thioredoxin, and NEMO/IKKγ by other members of the NEL-containing bacterial family, we discuss the potential for YopM to modulate a wide spectrum of immune signal transduction pathways. The key immune modulatory effects highlighted are suppression of MHC class II antigen presentation, dampening of nuclear factor (NF)-κB mediated inflammatory response, and intonation of mitogen-activated protein kinase (MAPK) signaling. Additionally, our analysis of the modeled YopM LRR domain reveals structural features akin to the Toll-like receptor 4 (TLR4) LRR motif. We propose that YopM LRR could be a 'molecular mimic' of TLR4 LRR, permitting reduced immunogenicity and potentially mitigating bacterial lipopolysaccharide surveillance of the innate immune system. Our identification and characterization of the YopM NEL domain, taken together with our analysis of the YopM LRR domain, provides plausible insight into subversion of host immunity by Y. pestis YopM and perhaps could set the stage for design of new therapeutic opportunities.
鼠疫耶尔森氏菌的耶尔森氏外蛋白 (Yop) M 效应子是众所周知的关键毒力决定因素；然而，其在鼠疫耶尔森氏菌发病机制中的作用的结构见解一直难以捉摸。在这里，我们通过我们最近开发的折叠识别和同源建模工具研究了完整的 YopM 蛋白序列，并分析了其组成结构域的免疫调节潜力。我们在 YopM 的 C 末端尾部发现了一个假定的新型 E3 连接酶 (NEL) 结构域，并对其活性位点进行了表征，表明 YopM 可以作为一种自我调节的细菌型 E3 泛素连接酶发挥作用。我们进一步在其他几种细菌中鉴定出未报告的 NEL 结构域，并注意到含有 NEL 的细菌效应子家族的这些结构域在序列、结构、表面和静电特性方面具有显著的相似性，这表明它们具有保守的功能，并且可能对这些蛋白质的宿主靶标具有相似性。基于这些观察结果以及最近关于其他 NEL 结构域细菌家族成员降解人类蛋白质 HLA-DR、硫氧还蛋白和 NEMO/IKKγ 的经验证据，我们讨论了 YopM 调节广泛的免疫信号转导途径的潜力。突出的关键免疫调节作用包括抑制 MHC Ⅱ类抗原呈递、抑制核因子 (NF)-κB 介导的炎症反应以及诱导丝裂原激活蛋白激酶 (MAPK) 信号转导。此外，我们对建模的 YopM LRR 结构域的分析揭示了与 Toll 样受体 4 (TLR4) LRR 基序相似的结构特征。我们提出，YopM LRR 可能是 TLR4 LRR 的“分子模拟物”，可降低免疫原性，并可能减轻固有免疫系统对细菌脂多糖的监测。我们对 YopM NEL 结构域的鉴定和表征，以及我们对 YopM LRR 结构域的分析，为鼠疫耶尔森氏菌 YopM 对宿主免疫的颠覆提供了合理的见解，并且可能为设计新的治疗机会奠定了基础。
