Roessler E, Grant A, Ju G, Tsudo M, Sugamura K, Waldmann T A
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3344-7. doi: 10.1073/pnas.91.8.3344.
The interleukin 2 (IL-2) receptor (IL-2R) is a multisubunit receptor that includes three major IL-2 binding subunits, the IL-2R alpha, beta, and gamma chains. We have detected and analyzed cooperative interactions between the IL-2R alpha and beta chains (IL-2R alpha and IL-2R beta, respectively) in COS cells transfected with cDNAs encoding the IL-2R alpha, the IL-2R beta, or both cDNAs. We demonstrated that IL-2 F42A, an analog that fails to bind to the isolated IL-2R alpha subunit and would be predicted by the hierarchical affinity-conversion model to have impaired binding to cells expressing both chains, instead readily binds to the IL-2R alpha/beta heterodimer in COS cells. Furthermore, this binding is abolished by the antibody HIEI that separates the two IL-2R subunits. The monoclonal antibodies anti-Tac and Mik-beta 1 directed at the IL-2-binding sites on IL-2R alpha and IL-2R beta, respectively, block ligand binding to the heterodimer. This binding pattern is inconsistent with the strict hierarchical affinity-conversion model that mandates an initial binding of IL-2 to IL-2R alpha followed by binding of the IL-2/IL-2R alpha complex to IL-2R beta. Instead, our results support an alternative model of preformed complexes of IL-2R beta with other IL-2R subunits. In this alternative model, IL-2R alpha and -beta exist in part as preformed complexes in which the affinity of IL-2R beta for IL-2 is altered by the proximity of IL-2R alpha, through mechanisms that do not require the prior binding of IL-2 to IL-2R alpha.
白细胞介素2（IL-2）受体（IL-2R）是一种多亚基受体，包括三个主要的IL-2结合亚基，即IL-2Rα、β和γ链。我们在转染了编码IL-2Rα、IL-2Rβ或两者cDNA的COS细胞中检测并分析了IL-2Rα和β链（分别为IL-2Rα和IL-2Rβ）之间的协同相互作用。我们证明，IL-2 F42A是一种不能与分离的IL-2Rα亚基结合的类似物，根据分级亲和力转换模型预测，它与表达两条链的细胞的结合会受损，但它却能轻易地与COS细胞中的IL-2Rα/β异二聚体结合。此外，将两个IL-2R亚基分开的抗体HIEI可消除这种结合。分别针对IL-2Rα和IL-2Rβ上IL-2结合位点的单克隆抗体抗-Tac和Mik-β1可阻断配体与异二聚体的结合。这种结合模式与严格的分级亲和力转换模型不一致，该模型要求IL-2首先与IL-2Rα结合，然后IL-2/IL-2Rα复合物再与IL-2Rβ结合。相反，我们的结果支持IL-2Rβ与其他IL-2R亚基预先形成复合物的另一种模型。在这种替代模型中，IL-2Rα和-β部分以预先形成的复合物形式存在，其中IL-2Rβ对IL-2的亲和力通过IL-2Rα的接近而改变，其机制不需要IL-2预先与IL-2Rα结合。
