Efficiency of signalling through cytokine receptors depends critically on receptor orientation
Efficiency of signalling through cytokine receptors depends critically on receptor orientation
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DOI：
10.1038/26773
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发表时间：
1998-10-01
期刊：
影响因子：
64.8
通讯作者：
Stroud, RM
中科院分区：
文献类型：
--
作者：
Syed, RS;Reid, SW;Stroud, RM
人促红细胞生成素是前体细胞分化和增殖为红细胞所必需的造血细胞因子(1)。它通过结合和定位两个细胞表面促红细胞生成素受体(EPORs)来激活细胞，从而触发细胞内的磷酸化级联反应(2)。在细胞增殖试验中，当促红细胞生成素浓度为10 pm时，可诱发半最大反应(参考文献1)。3)，促红细胞生成素-EPOR结合部位1的K-d值为10(-2)(K-d约为1 NM)，以及促红细胞生成素-EPOR结合部位2的K-d为10(-5)(K-d约为1µM)(4)。细胞表面受体的总半数结合浓度(IC50)与0.18 nM促红细胞生成素相似，表明在10 PM促红细胞生成素存在下，只有6%的受体会被结合。其他使受体二聚化的有效促红细胞生成素类似配体可以引起相同的细胞反应(5，6)，但效率要低得多，需要接近其K-d值的浓度(类似于0.1µM)。红细胞生成素与红细胞生成素受体的胞外配体结合域的晶体结构由两种晶型在1.9埃处测定，表明促红细胞生成素施加了一个独特的120度角关系和方向，负责通过细胞内激酶途径进行最佳信号传递。
Human erythropoietin is a haematopoietic cytokine required for the differentiation and proliferation of precursor cells into red blood cells(1). It activates cells by binding and orientating two cell-surface erythropoietin receptors (EPORs) which trigger an intracellular phosphorylation cascade(2). The half-maximal response in a cellular proliferation assay is evoked at an erythropoietin concentration of 10 pM (ref. 3), 10(-2) of its K-d value for erythropoietin-EPOR binding site 1 (K-d approximate to 1 nM), and 10(-5) of the K-d for erythropoietin-EPOR binding site 2 (K-d approximate to 1 mu M)(4). Overall half-maximal binding (IC50) of cell-surface receptors is produced with similar to 0.18 nM erythropoietin, indicating that only similar to 6% of the receptors would be bound in the presence of 10 pM erythropoietin. Other effective erythropoietin-mimetic ligands that dimerize receptors can evoke the same cellular responses(5,6) but much less efficiently, requiring concentrations close to their K-d values (similar to 0.1 mu M). The crystal structure of erythropoietin complexed to the extracellular ligand-binding domains of the erythropoietin receptor, determined at 1.9 Angstrom from two crystal forms, shows that erythropoietin imposes a unique 120 degrees angular relationship and orientation that is responsible for optimal signalling through intracellular kinase pathways.