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首页> 外文期刊>Molecular and Cellular Biology >Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding.
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Human interleukin-3 (IL-3) induces disulfide-linked IL-3 receptor alpha- and beta-chain heterodimerization, which is required for receptor activation but not high-affinity binding.

机译：人白介素3（IL-3）诱导二硫键连接的IL-3受体α和β链异二聚，这是受体激活所必需的，但不是高亲和力结合。

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The human interleukin-3 receptor (IL-3R) is a heterodimer that comprises an IL-3 specific alpha chain (IL-3R alpha) and a common beta chain (beta C) that is shared with the receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5. These receptors belong to the cytokine receptor superfamily, but they are structurally and functionally more related to each other and thus make up a distinct subfamily. Although activation of the normal receptor occurs only in the presence of ligand, the underlying mechanisms are not known. We show here that human IL-3 induces heterodimerization of IL-3R alpha and beta c and that disulfide linkage of these chains is involved in receptor activation but not high-affinity binding. Monoclonal antibodies (MAb) to IL-3R alpha and beta c were developed which immunoprecipitated, in the absence of IL-3, the respective chains from cells labelled with 125I on the cell surface. However, in the presence of IL-3, each MAb immunoprecipitated both IL-3R alpha and beta c. IL-3-induced receptor dimers were disulfide and nondisulfide linked and were dependent on IL-3 interacting with both IL-3R alpha and beta c. In the presence of IL-3 and under nonreducing conditions, MAb to either IL-3R alpha or beta c immunoprecipitated complexes with apparent molecular weights of 215,000 and 245,000 and IL-3R alpha and beta c monomers. Preincubation with iodoacetamide prevented the formation of the two high-molecular-weight complexes without affecting noncovalent dimer formation or high-affinity IL-3 binding. Two-dimensional gel electrophoresis and Western blotting (immunoblotting) demonstrated the presence of both IL-3R alpha and beta c in the disulfide-linked complexes. IL-3 could also be coimmunoprecipitated with anti-IL-3R alpha or anti-beta c MAB, but it was not covalently attached to the receptor. Following IL-3 stimulation, only the disulfide-linked heterodimers exhibited reactivity with antiphosphotyrosine antibodies, with beta c but not IL-3R alpha being the phosphorylated species. A model of IL-3R activation is proposed which may be also applicable to the related GM-CSF and IL-5 receptors.
机译：人白介素3受体（IL-3R）是一种异二聚体，它包含IL-3特异性α链（IL-3Rα）和与粒细胞-巨噬细胞集落-受体共享的共同β链（βC）。刺激因子（GM-CSF）和IL-5。这些受体属于细胞因子受体超家族，但它们在结构和功能上彼此更相关，因此构成了一个独特的亚家族。尽管正常受体的激活仅在配体存在下发生，但其潜在机制尚不清楚。我们在这里显示人IL-3诱导IL-3Rα和βc的异二聚化，并且这些链的二硫键参与受体激活，但不参与高亲和力结合。已开发出针对IL-3Rα和βc的单克隆抗体（MAb），在没有IL-3的情况下，它们会从细胞表面被125 I标记的细胞免疫沉淀出相应的链。但是，在存在IL-3的情况下，每个MAb都会免疫沉淀IL-3Rα和βc。 IL-3诱导的受体二聚体是二硫键和非二硫键连接的，并且依赖于IL-3与IL-3Rα和βc的相互作用。在IL-3存在下且在非还原条件下，表观分子量为215,000和245,000的IL-3Rα或βc免疫沉淀复合物的单克隆抗体以及IL-3Rα和βc单体。与碘乙酰胺的预温育可防止两种高分子量复合物的形成，而不会影响非共价二聚体的形成或高亲和力的IL-3结合。二维凝胶电泳和Western印迹（免疫印迹）表明，二硫键连接的复合物中同时存在IL-3Rα和βc。 IL-3也可以与抗IL-3Rα或抗βc MAB进行免疫共沉淀，但未与受体共价连接。在IL-3刺激后，只有二硫键连接的异二聚体与抗磷酸酪氨酸抗体表现出反应性，βc却不与IL-3Rα磷酸化。提出了IL-3R激活的模型，该模型也可适用于相关的GM-CSF和IL-5受体。

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