A di-leucine motif and an upstream serine in the interleukin-6 (IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor
A di-leucine motif and an upstream serine in the interleukin-6 (IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor
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DOI：
10.1074/jbc.271.10.5487
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发表时间：
1996-03-08
影响因子：
4.8
通讯作者：
Graeve, L
中科院分区：
文献类型：
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作者：
Dittrich, E;Haft, CR;Graeve, L
白介素 6 (IL-6) 受体复合物由两个不同的亚基组成，即 IL-6 结合蛋白 (IL-6R，gp80) 和信号转导成分 gp130。我们之前的研究表明，gp130 胞内结构域内的 10 个氨基酸序列 TQPLLDSEER 对于 IL-6 的有效内化至关重要。由于该序列包含假定的双亮氨酸内化基序，因此我们通过构建两个额外的缺失和一系列点突变体进一步分析了该区域。对这些突变体的分析表明，双亮氨酸对（Leu-145 和 Leu-146）对于配体内化至关重要，而亮氨酸 145 对交换的弹性较差。此外，当研究由Tac抗原与gp130的六肽STQPLL融合组成的嵌合蛋白（Tac-STQPLL）时，我们发现该序列足以介导嵌合体的内吞作用和溶酶体靶向。对二亮氨酸基序上游三个丝氨酸残基的突变分析表明，丝氨酸 139 突变为丙氨酸使初始内化率降低了 50%。这一发现表明丝氨酸磷酸化可能对于快速内吞作用很重要。
The interleukin-6 (IL-6) receptor complex is composed of two different subunits, the IL-6 binding protein (IL-6R, gp80) and the signal transducing component gp130. Our previous studies revealed that the 10-amino acid sequence TQPLLDSEER within the intracellular domain of gp130 is crucial for the efficient internalization of IL-6. Since this sequence contains a putative dileucine internalization motif, we further analyzed this region by constructing two additional deletions and a series of point mutants. Analyses of these mutants showed that the di-leucine pair (Leu-145 and Leu-146) is essential for ligand internalization, with leucine 145 being less resilient to exchanges. Furthermore, when a chimeric protein (Tac-STQPLL) composed of the Tac antigen fused to the hexapeptide STQPLL of gp130 was studied, we found that this sequence is sufficient to mediate endocytosis and lysosomal targeting of the chimera. Mutational analysis of three serine residues upstream of the di-leucine motif revealed that mutation of serine 139 to an alanine reduces the initial internalization rate by 50%. This finding suggests that a serine phosphorylation may be important for rapid endocytosis.