Receptor recognition sites of cytokines are organized as exchangeable modules -: Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6
Receptor recognition sites of cytokines are organized as exchangeable modules -: Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6
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DOI：
10.1074/jbc.274.17.11859
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发表时间：
1999-04-23
影响因子：
4.8
通讯作者：
Rose-John, S
中科院分区：
文献类型：
--
作者：
Kallen, KJ;Grötzinger, J;Rose-John, S
白细胞介素-6（IL-6）和睫状神经营养因子（CNTF）是IL-6型神经和造血细胞因子家族的“4-螺旋束”细胞因子，IL-6通过诱导gp 130同源二聚体（例如，IL-6），而CNTF和白血病抑制因子（LIF）通过gp 130和LIF受体（LIFR）的异源二聚体进行信号传导。尽管IL-6和CNTF结合相同的受体成分（gp 130）和相似的蛋白质结构，但它们只有6%的序列相同性。利用分子模拟，我们确定了一个假定的LIFR结合表位的CNTF，由三个不同的区域组成（C-末端A-螺旋/N-末端AB环，BC环，C-末端CD-环/N-末端D-螺旋），IL-6上相应的gp 130结合位点与该表位交换，所得的IL-6/CNTF嵌合体在没有LIFR的细胞上失去了通过gp 130发出信号的能力，但获得了通过gp 130/LIFR异源二聚体和STATE在应答细胞上发出信号的能力。除了确定一个特定的LIFR结合表位的CNTF，我们的研究结果表明，细胞因子的受体识别位点组织为模块，即使是有限的序列同源性细胞因子之间的可交换的。
Interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) are "4-helical bundle" cytokines of the IL-6 type family of neuropoietic and hematopoietic cytokines, IL-6 signals by induction of a gp130 homodimer (eg. IL-6), whereas CNTF and leukemia inhibitory factor (LIF) signal via a heterodimer of gp130 and LIF receptor (LIFR). Despite binding to the same receptor component (gp130) and a similar protein structure, IL-6 and CNTF share only 6% sequence identity. Using molecular modeling we defined a putative LIFR binding epitope on CNTF that consists of three distinct regions (C-terminal A-helix/N-terminal AB loop, BC loop, C-terminal CD-loop/N-terminal D-helix), A corresponding gp130-binding site on IL-6 was exchanged with this epitope, The resulting IL-6/CNTF chimera lost the capacity to signal via gp130 on cells without LIFR, but acquired the ability to signal via the gp130/LIFR heterodimer and STATE on responsive cells. Besides identifying a specific LIFR binding epitope on CNTF, our results suggest that receptor recognition sites of cytokines are organized as modules that are exchangeable even between cytokines with limited sequence homology.