The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1 alpha receptor, confers chemokine selectivity - Evidence for a two-step mechanism for MCP-1 receptor activation
The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1 alpha receptor, confers chemokine selectivity - Evidence for a two-step mechanism for MCP-1 receptor activation
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DOI：
10.1074/jbc.271.32.19084
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发表时间：
1996-08-09
影响因子：
4.8
通讯作者：
Charo, IF
中科院分区：
文献类型：
--
作者：
Monteclaro, FS;Charo, IF
趋化因子MCP-1（单核细胞趋化蛋白）和MIP-1 α为了鉴定参与决定配体特异性的受体结构域，我们构建了一系列嵌合MCP-1和RANTES，（在激活时调节，正常T细胞表达和分泌的）/MIP-1 α受体，其氨基末端和三个细胞外环中的每一个逐渐互换。放射性标记的MCP-1以高亲和力结合野生型MCP-1受体，但不结合RANTES/MLP-1 α受体（C-C CKR-1），保留MCP-1受体的氨基末端延伸的嵌合体以高亲和力结合MCP-1。相反，嵌合MCP-1受体，其中野生型氨基末端被RANTES/MIP-1 α：这些数据表明MCP-1受体的氨基末端对于配体的高亲和力结合是必需的，使用RANTES/MIP-1 α：受体，放射性标记的MIP-1 α以高亲和力结合表达RANTES/MIP-1 α受体细胞外环的嵌合体，与MCP-1受体相反;对于MCP-1，而不是RANTES/MIP-1 α受体，野生型氨基末端的存在也显著降低了最大信号传导所需的配体浓度。我们得出结论，MCP-1受体的氨基末端延伸，而不是RANTES/MIP-1 α受体，在配体结合和信号转导中起关键作用。这些数据揭示了两种C-C趋化因子受体之间的显著功能差异，并提示MCP-1受体活化的两步机制。
The chemoattractant cytokines, MCP-1 (monocyte chemoattractant protein) and MIP-1 alpha (macrophage inflammatory protein), are recognized by highly homologous but distinct receptors, To identify receptor domains involved ill determining ligand specificity, we created a series of chimeric MCP-1 and RANTES (regulated on activation, normal T cell expressed and secreted)/MIP-1 alpha receptors that progressively interchanged the amino terminus and each of the three extracellular loops. Radiolabeled MCP-1 bound with high affinity to the wild-type MCP-1 receptor, but not to the RANTES/MLP-1 alpha receptor (C-C CKR-1), Chimeras that retained the amino-terminal extension of the MCP-I receptor bound MCP-1 with high affinity, In contrast, chimeric MCP-I receptors, in which the wild-type amino terminus was replaced with the corresponding portion of the RANTES/MIP-1 alpha: receptor, bound MIP-1 with low affinity, These data indicate that the amino terminus of the MCP-1 receptor is necessary for high affinity binding of the ligand, Very different results were obtained using the RANTES/MIP-1 alpha: receptor, Radiolabeled MIP-1 alpha bound with high affinity to chimeras that expressed the extracellular loops of the RANTES/MIP-1 alpha receptor, In contrast to the MCP-1 receptor; substitution of the wild-type amino-terminal extension had little or no effect on MIP-1 alpha binding, For the MCP-1, but not the RANTES/MIP-1 alpha receptor, the presence of the wild-type amino terminus also significantly lowered the ligand concentration required for maximal signaling, We conclude that the amino-terminal extension of the MCP-1 receptor, but not the RANTES/MIP-1 alpha receptor, is critically involved in ligand binding and signal transduction. These data reveal significant functional differences between the two C-C chemokine receptors and suggest a two-step mechanism for activation of the MCP-1 receptor.