Center for Nanoscience, Ludwig-Maximilians-Universität München, 80799 Munich, Germany.
J Struct Biol. 2010 Mar;169(3):323-30. doi: 10.1016/j.jsb.2009.12.007. Epub 2009 Dec 16.
Toll-like receptors (TLRs) belong to the Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) superfamily which is defined by a common cytoplasmic Toll/interleukin-1 receptor (TIR) domain. TLRs recognize pathogen-associated molecular patterns and initiate an intracellular kinase cascade to trigger an immediate defensive response. SIGIRR (single immunoglobulin interleukin-1 receptor-related molecule), another member of the TLR/IL-1R superfamily, acts as a negative regulator of MyD88-dependent TLR signaling. It attenuates the recruitment of MyD88 adaptors to the receptors with its intracellular TIR domain. Thus, SIGIRR is a highly important molecule for the therapy of autoimmune diseases caused by TLRs. So far, the structural mechanism of interactions between SIGIRR, TLRs and adaptor molecules is unclear. To develop a working hypothesis for this interaction, we constructed three-dimensional models for the TIR domains of TLR4, TLR7, MyD88 and SIGIRR based on computational modeling. Through protein-protein docking analysis, we developed models of essential complexes involved in the TLR4 and 7 signaling and the SIGIRR inhibiting processes. We suggest that SIGIRR may exert its inhibitory effect through blocking the molecular interface of TLR4, TLR7 and the MyD88 adaptor mainly via its BB-loop region.
Toll 样受体（TLRs）属于 Toll 样受体/白细胞介素-1 受体（TLR/IL-1R）超家族，该超家族的特征是具有共同的细胞质 Toll/白细胞介素-1 受体（TIR）结构域。TLRs 识别病原体相关分子模式，并启动细胞内激酶级联反应，触发即刻防御反应。SIGIRR（单一免疫球蛋白白细胞介素-1 受体相关分子）是 TLR/IL-1R 超家族的另一个成员，作为 MyD88 依赖性 TLR 信号的负调节剂。它通过其细胞内 TIR 结构域来减弱 MyD88 衔接子与受体的募集。因此，SIGIRR 是治疗 TLR 引起的自身免疫疾病的重要分子。到目前为止，SIGIRR、TLRs 和衔接子分子之间相互作用的结构机制尚不清楚。为了为此相互作用建立一个工作假设，我们基于计算建模构建了 TLR4、TLR7、MyD88 和 SIGIRR 的 TIR 结构域的三维模型。通过蛋白质-蛋白质对接分析，我们开发了涉及 TLR4 和 7 信号转导以及 SIGIRR 抑制过程的必需复合物模型。我们认为，SIGIRR 可能通过其 BB-环区域主要阻断 TLR4、TLR7 和 MyD88 衔接子的分子界面来发挥其抑制作用。
