Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL
Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL
复制标题
DOI：
10.1074/jbc.m403434200
复制
发表时间：
2004-07-23
影响因子：
4.8
通讯作者：
Tong, L
中科院分区：
文献类型：
--
作者：
Khan, JA;Brint, EK;Tong, L
Toll/白细胞介素-1受体（TIR）结构域保守存在于Toll样受体（TLRs）和白细胞介素-1受体（IL-1Rs）的胞内区域以及一些细胞质适配器分子中。该结构域在这些受体的信号转导中起着至关重要的作用。在这里，我们报道了人类IL-1RAPL的TIR结构域在2.3埃分辨率下的晶体结构，这是IL-1R超家族的第一个TIR结构域。该TIR结构域与TLR1和TLR2结构域存在较大的结构差异。IL-1RAPL中的螺旋α had与TLR1或TLR2中的等效物几乎垂直。BB环在第8位和第10位的苏基之间含有IL-1RAPL特有的氢键。这些结构域之间的结构和序列多样性可能对这些受体信号转导的特异性很重要。在晶体中观察到IL-1RAPL的TIR结构域的二聚体，尽管该结构域在溶液中是单体的。二聚体界面上的残基大多是IL-1RAPL所特有的，这与该受体独特的功能作用是一致的。我们的功能研究表明，IL-1RAPL可以激活JNK，但不能激活ERK或p38 MAP激酶，而它的同源物TIGIRR不能激活JNK。缺失诱变研究表明，IL-1RAPL激活JNK并不依赖于其TIR结构域的完整性，这表明通过该受体的信号传导机制不同。
The Toll/interleukin-1 receptor (TIR) domain is conserved in the intracellular regions of Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) as well as in several cytoplasmic adapter molecules. This domain has crucial roles in signal transduction by these receptors for host immune response. Here we report the crystal structure at 2.3-Angstrom resolution of the TIR domain of human IL-1RAPL, the first structure of a TIR domain of the IL-1R superfamily. There are large structural differences between this TIR domain and that of TLR1 and TLR2. Helix alphaD in IL-1RAPL is almost perpendicular to its equivalent in TLR1 or TLR2. The BB loop contains a hydrogen bond unique to IL-1RAPL between Thr residues at the 8th and 10th positions. The structural and sequence diversity among these domains may be important for specificity in the signal transduction by these receptors. A dimer of the TIR domain of IL-1RAPL is observed in the crystal, although this domain is monomeric in solution. Residues in the dimer interface are mostly unique to IL-1RAPL, which is consistent with the distinct functional roles of this receptor. Our functional studies show IL-1RAPL can activate JNK but not the ERK or the p38 MAP kinases, whereas its close homolog, TIGIRR, cannot activate JNK. Deletion mutagenesis studies show that the activation of JNK by IL-1RAPL does not depend on the integrity of its TIR domain, suggesting a distinct mechanism of signaling through this receptor.