Structural complementarity of Toll/interleukin-1 receptor domains in toll-like receptors and the adaptors Mal and MyD88
Structural complementarity of Toll/interleukin-1 receptor domains in toll-like receptors and the adaptors Mal and MyD88
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DOI：
10.1074/jbc.m301742200
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发表时间：
2003-10-17
影响因子：
4.8
通讯作者：
Gay, NJ
中科院分区：
文献类型：
--
作者：
Dunne, A;Ejdebäck, M;Gay, NJ
Toll/白细胞介素 1 受体 (TIR) 结构域是在 Toll 样受体/白细胞介素 1 受体超家族成员的细胞质尾部中发现的区域。该结构域对于信号传导至关重要，并且也存在于接头蛋白 Mal（MyD88 接头样）和 MyD88 中，其功能是将受体的激活与下游信号传导成分偶联。两个 Toll/白细胞介素 1 受体结构域的实验结构揭示了与细菌趋化蛋白 CheY 相似的 α-β 折叠，其他证据表明接头可以与受体及其自身产生异型相互作用。在这里，我们表明，Mal 和 MyD88 的纯化 TIR 结构域可以形成稳定的异二聚体，并且 Mal 同二聚体和寡聚体在 ATP 存在下解离。为了确定可能有助于信号复合物形成的结构特征，我们制作了人 Toll 样受体 4 (TLR4)、Mal 和 MyD88 的 TIR 结构域模型。我们发现，虽然整体折叠是守恒的，但静电表面电势是相当不同的。模型的对接研究表明，Mal 和 MyD88 与 TLR 2 和 4 的不同区域结合，这一发现与两个接头在信号传导中的协同作用一致。 Mal 和 MyD88 预计会在第三个非重叠位点相互作用，表明受体和接头可能形成异四聚体复合物。相互作用的理论模型得到谷胱甘肽 S-转移酶下拉和免疫共沉淀实验数据的支持。理论和实验数据均未表明 BB 环中保守的脯氨酸在 TLR4、Mal 和 MyD88 的关联中具有直接作用。最后，我们展示了果蝇蛋白 Tube 和 Mal 之间的序列关系，这可能表明这两个接头在果蝇和脊椎动物 Toll 途径中的功能等同。
The Toll/interleukin 1 receptor (TIR) domain is a region found in the cytoplasmic tails of members of the Toll-like receptor/interleukin-1 receptor superfamily. The domain is essential for signaling and is also found in the adaptor proteins Mal (MyD88 adaptor-like) and MyD88, which function to couple activation of the receptor to downstream signaling components. Experimental structures of two Toll/interleukin 1 receptor domains reveal a alpha-beta-fold similar to that of the bacterial chemotaxis protein CheY, and other evidence suggests that the adaptors can make heterotypic interactions with both the receptors and themselves. Here we show that the purified TIR domains of Mal and MyD88 can form stable heterodimers and also that Mal homodimers and oligomers are dissociated in the presence of ATP. To identify structural features that may contribute to the formation of signaling complexes, we produced models of the TIR domains from human Toll-like receptor 4 (TLR4), Mal, and MyD88. We found that although the overall fold is conserved the electrostatic surface potentials are quite distinct. Docking studies of the models suggest that Mal and MyD88 bind to different regions in TLRs 2 and 4, a finding consistent with a cooperative role of the two adaptors in signaling. Mal and MyD88 are predicted to interact at a third non-overlapping site, suggesting that the receptor and adaptors may form heterotetrameric complexes. The theoretical model of the interactions is supported by experimental data from glutathione S-transferase pull-downs and co-immunoprecipitations. Neither theoretical nor experimental data suggest a direct role for the conserved proline in the BB-loop in the association of TLR4, Mal, and MyD88. Finally we show a sequence relationship between the Drosophila protein Tube and Mal that may indicate a functional equivalence of these two adaptors in the Drosophila and vertebrate Toll pathways.