Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Cytokine. 2018 Oct;110:428-434. doi: 10.1016/j.cyto.2018.05.011. Epub 2018 May 19.
Gp130 is the common receptor within the Interleukin 6 cytokine family. Gp130 consists of 6 extracellular domains followed by a small stalk region connecting the last extracellular domain with the trans-membrane domain. Whereas the first three extracellular domains bind to IL-6-type cytokines, the domains 4-6 are needed for correct positioning of the intracellular domains to facilitate Janus kinase activation after cytokine binding. Interestingly, deletion within the cytokine-binding domain resulted in cytokine-independent constitutive activation of mutant gp130 receptors. Here, we tested the hypothesis, if deletions of the stalk region and/or domains 4-6 of gp130 might also result in constitutive receptor activation. Shortening of the stalk region of gp130 alone did, however, not result in constitutive receptor activation, whereas a gp130 receptor deletion variant only consisting of the three N-terminal cytokine binding domains but lacking all FNIII domains was biologically inactive. Importantly, combined deletion of the three FNIII domains plus shortening of the stalk region of gp130 resulted in ligand-independent, constitutive receptor activation of gp130.
Gp130 是白细胞介素 6 细胞因子家族中的通用受体。Gp130 由 6 个细胞外结构域组成，其后是一个小的茎区，将最后一个细胞外结构域与跨膜结构域连接起来。虽然前三个细胞外结构域结合白细胞介素 6 型细胞因子，但 4-6 个结构域对于正确定位细胞内结构域以促进细胞因子结合后的 Janus 激酶激活是必需的。有趣的是，细胞因子结合结构域内的缺失导致突变 gp130 受体的细胞因子非依赖性组成型激活。在这里，我们检验了这样一个假设，即 gp130 的茎区和/或结构域 4-6 的缺失是否也可能导致组成型受体激活。然而，gp130 茎区的缩短本身并没有导致组成型受体激活，而仅由三个 N 端细胞因子结合结构域组成但缺乏所有 FNIII 结构域的 gp130 受体缺失变体在生物学上是无活性的。重要的是，gp130 的三个 FNIII 结构域和茎区的联合缺失导致 gp130 的配体非依赖性、组成型受体激活。
