Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex
Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex
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DOI：
10.1073/pnas.1417571112
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发表时间：
2015-03-03
影响因子：
11.1
通讯作者：
Remenyi, Attila
中科院分区：
文献类型：
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作者：
Alexa, Anita;Gogl, Gergo;Remenyi, Attila
丝裂原激活蛋白激酶 (MAPK) 结合并激活其下游激酶底物，即 MAPK 激活蛋白激酶 (MAPKAPK)。值得注意的是，细胞外信号调节激酶 2 (ERK2) 磷酸化核糖体 S6 激酶 1 (RSK1)，从而促进细胞生长。在这里，我们确定了 RSK1 构建体与其激活激酶复合物的晶体结构。该结构捕获处于预催化状态的激酶-激酶复合物，其中下游激酶 (RSK1) 的激活环面向酶 (ERK2) 的催化位点。分子动力学模拟被用来展示这种异二聚体如何转变为信号传导状态。该结构分析与 MAPK 的生化和细胞研究相结合。 MAPKAPK 信号传导表明，MAPK 结合线性基序（位于无序的激酶结构域延伸中）与 ERK2“对接”凹槽之间的相互作用在形成相遇复合体中发挥着主要作用。这种相互作用使激酶结构域在“重新调整”时保持接近，而通用激酶结构域表面接触使它们进入催化能力状态。
Mitogen-activated protein kinases (MAPKs) bind and activate their downstream kinase substrates, MAPK-activated protein kinases (MAPKAPKs). Notably, extracellular signal regulated kinase 2 (ERK2) phosphorylates ribosomal S6 kinase 1 (RSK1), which promotes cellular growth. Here, we determined the crystal structure of an RSK1 construct in complex with its activator kinase. The structure captures the kinase-kinase complex in a precatalytic state where the activation loop of the downstream kinase (RSK1) faces the enzyme's (ERK2) catalytic site. Molecular dynamics simulation was used to show how this heterodimer could shift into a signaling-competent state. This structural analysis combined with biochemical and cellular studies on MAPK. MAPKAPK signaling showed that the interaction between the MAPK binding linear motif (residing in a disordered kinase domain extension) and the ERK2 "docking" groove plays the major role in making an encounter complex. This interaction holds kinase domains proximal as they "readjust," whereas generic kinase domain surface contacts bring them into a catalytically competent state.