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首页> 美国卫生研究院文献>other >A Docking Site in MKK4 Mediates High Affinity Binding to JNK MAPKs and Competes with Similar Docking Sites in JNK Substrates
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A Docking Site in MKK4 Mediates High Affinity Binding to JNK MAPKs and Competes with Similar Docking Sites in JNK Substrates

机译：MKK4中的对接位点介导与JNK MAPK的高亲和力结合并与JNK底物中的类似对接位点竞争

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摘要

Specific docking interactions between MAPKs and their activating MAPK kinases (MKKs or MEKs) are crucial for efficient and accurate signal transmission. Here, we report the identification of a MAPK-docking site, or “D-site,” in the N terminus of human MKK4/JNKK1. This docking site conforms to the consensus sequence for known D-sites in other MKKs and contains the first of the two cleavage sites for anthrax lethal factor protease that have been found in the N terminus of MKK4. This docking site was both necessary and sufficient for the high affinity binding of the MAPKs JNK1, JNK2, JNK3, p38α, and p38β to MKK4. Mutations that altered conserved residues in this docking site reduced JNK/p38 binding. In addition, a peptide version of this docking site, as well as a peptide version of the JNK-binding site of the JIP-1 scaffold protein, inhibited both MKK4/JNK binding and MKK4-mediated phosphorylation of JNK1. These same peptides also inhibited JNK2-mediated phosphorylation of c-Jun and ATF2, suggesting that transcription factors, MKK4, and the JIP scaffold compete for docking to JNK. Finally, the selectivity of the MKK4, MEK1, and MEK2 D-sites for JNK versus ERK was quantified. The MEK1 and MEK2 D-sites displayed a strong selectivity for their cognate MAPK (ERK2) versus a non-cognate MAPK (JNK). In contrast, the MKK4 D-site exhibited only limited selectivity for JNK versus ERK.
机译：MAPK及其激活的MAPK激酶（MKK或MEK）之间的特定对接相互作用对于有效和准确的信号传输至关重要。在这里，我们报告在人MKK4 / JNKK1的N末端有一个MAPK停靠位点或“ D-位点”的鉴定。该停靠位点与其他MKK中已知D位点的共有序列一致，并且包含已在MKK4 N端发现的炭疽致死因子蛋白酶的两个切割位点中的第一个。该停靠位点对于MAPK JNK1，JNK2，JNK3，p38α和p38β与MKK4的高亲和力结合既必要又充分。改变该对接位点中保守残基的突变降低了JNK / p38结合。此外，此停靠位点的肽版本以及JIP-1支架蛋白的JNK结合位点的肽版本均抑制MKK4 / JNK结合和MKK4介导的JNK1磷酸化。这些相同的肽还抑制c-Jun和ATF2的JNK2介导的磷酸化，表明转录因子MKK4和JIP支架竞争对接JNK。最后，量化了JNK对ERK的MKK4，MEK1和MEK2 D位点的选择性。与非同源MAPK（JNK）相比，MEK1和MEK2 D位点对它们的同源MAPK（ERK2）具有很强的选择性。相反，MKK4 D位点对JNK与ERK的选择性只有有限的选择性。

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