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首页> 外文期刊>Molecular and Cellular Biology >A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer.
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A dominant negative inhibitor indicates that monocyte chemoattractant protein 1 functions as a dimer.

机译：显性负抑制剂表示单核细胞趋化蛋白1发挥二聚体的功能。

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Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine family of proinflammatory cytokines, all of which share a high degree of amino acid sequence similarity. Aberrant expression of chemokines occurs in a variety of diseases that have an inflammatory component, such as atherosclerosis. Although structural analyses indicate that chemokines form homodimers, there is controversy about whether dimerization is necessary for activity. To address this question for MCP-1, we obtained evidence in four steps. First, coprecipitation experiments demonstrated that MCP-1 forms dimers at physiological concentrations. Second, chemically cross-linked MCP-1 dimers attract monocytes in vitro with a 50% effective concentration of 400 pM, identical to the activity of non-cross-linked MCP-1. Third, an N-terminal deletion variant of MCP-1 (called 7ND) that inhibits MCP-1-mediated monocyte chemotaxis specifically forms heterodimers with wild-type MCP-1. Finally, although 7ND inhibits wild-type MCP-1 activity, it has no effect on cross-linked MCP-1. These results indicate that 7ND is a dominant negative inhibitor, implying that MCP-1 activates its receptor as a dimer. In addition, chemical cross-linking restores activity to an inactive N-terminal insertional variant of MCP-1, further supporting the need for dimerization. Since the reported Kd for MCP-1 monomer dissociation is much higher than its 50% effective concentration or Kd for receptor binding, active dimer formation may require high local concentrations of MCP-1. Our data further suggest that the dimer interface can be a target for MCP-1 inhibitory drugs.
机译：单核细胞趋化蛋白1（MCP-1）是促炎细胞因子趋化因子家族的成员，它们均具有高度的氨基酸序列相似性。趋化因子的异常表达发生在多种具有炎症成分的疾病中，例如动脉粥样硬化。尽管结构分析表明趋化因子形成同型二聚体，但对于是否需要二聚作用才存在争议。为了解决MCP-1的这个问题，我们分四步获得了证据。首先，共沉淀实验表明MCP-1在生理浓度下会形成二聚体。第二，化学交联的MCP-1二聚体以50％的有效浓度400 pM在体外吸引单核细胞，与非交联的MCP-1的活性相同。第三，抑制MCP-1介导的单核细胞趋化性的MCP-1的N端缺失变体（称为7ND）与野生型MCP-1特异性形成异二聚体。最后，尽管7ND抑制了野生型MCP-1活性，但对交联的MCP-1没有影响。这些结果表明7ND是主要的阴性抑制剂，这表明MCP-1将其受体激活为二聚体。另外，化学交联将活性恢复为MCP-1的非活性N末端插入变体，进一步支持了二聚化的需求。由于报告的MCP-1单体解离Kd远远高于其50％有效浓度或受体结合Kd，因此形成有效的二聚体可能需要高浓度的MCP-1。我们的数据进一步表明，二聚体界面可以成为MCP-1抑制药物的靶标。

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