Definition of a composite binding site for gp130 in human interleukin-6
Definition of a composite binding site for gp130 in human interleukin-6
复制标题
DOI：
10.1074/jbc.270.52.31249
复制
发表时间：
1995-12-29
影响因子：
4.8
通讯作者：
Savino, R
中科院分区：
文献类型：
--
作者：
Ciapponi, L;Graziani, R;Savino, R
螺旋状的细胞因子白细胞介素-6 （IL-6）组装了一个多蛋白受体复合物，激活细胞内信号传导的起始事件是IL-6/IL-6R α亚复合物与两条gp130链的结合，gp130的同二聚化由IL-6的两个不同且独立的区域，称为位点2和3触发。已经获得了几种IL-6拮抗剂，它们影响信号传导，但不影响IL-6。IL-6R亚复合物的形成。在本文中，我们详细分析了这些拮抗剂对gp130结合和二聚化的影响，并表明每种信号变体都影响gp130的体外二聚化，并且细胞生物活性的降低与gp130体外二聚化的降低精确平行。所有IL-6拮抗剂可分为两组，根据其与gp130相互作用的模式定位于位点2或3。我们发现位点3是一个很大的区域，它包括螺旋D开始的残基，空间上位于假定的AB环的残基两侧，位于细胞因子4-螺旋束的一端。有趣的是，在白血病抑制因子中，另一种通过gp130位点3发出信号的细胞因子在拓扑结构上是保守的，但已经进化到可以结合白血病抑制因子受体。
The helical cytokine interleukin-6 (IL-6) assembles a multiprotein receptor complex, The starting event in the activation of intracellular signaling is the binding of the IL-6/IL-6R alpha subcomplex to two gp130 chains, The homodimerization of gp130 is triggered by two distinct and independent regions of IL-6 called sites 2 and 3. Several IL-6 antagonists have been obtained that affect signaling, but not IL-6 . IL-6R alpha subcomplex formation. In this paper, we analyze in detail the impact of these antagonists on gp130 binding and dimerization and show that each signaling variant affects gp130 dimerization in vitro and that biological activity on cells decreases in precise parallel to the decrease in gp130 dimerization in vitro. All IL-6 antagonists can be classified into two groups, mapping at either site 2 or 3 in correspondence to their mode of interaction with gp130. We found that site 3 is a large region, which includes residues at the beginning of helix D spatially flanked by residues in the putative AB loop and located at one extremity of the cytokine 4-helix bundle. Interestingly, in leukemia inhibitory factor, another cytokine that signals through gp130, site 3, is topologically conserved but has evolved to bind leukemia inhibitory factor receptor.