Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein: MODULATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALING CASCADE IN A CALCIUM-DEPENDENT WAY
Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein: MODULATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALING CASCADE IN A CALCIUM-DEPENDENT WAY
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DOI：
10.1074/jbc.m115.684928
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发表时间：
2016-01-01
影响因子：
4.8
通讯作者：
Nyitray, Laszlo
中科院分区：
文献类型：
--
作者：
Gogl, Gergo;Alexa, Anita;Nyitray, Laszlo
丝裂原活化蛋白激酶（MAPK）促进MAPK活化的蛋白激酶活化。在负责细胞生长的MAPK途径中，ERK 2启动RSK 1上的第一个磷酸化事件，其在恶性黑素瘤中被Ca 2+结合S100蛋白抑制。在这里，我们提出了一个详细的体外生物化学和结构表征的S100 B-RSK 1相互作用。S100 B与RSK 1的钙/钙调蛋白依赖性蛋白激酶（CaMK）型结构域的Ca 2+依赖性结合使人想起钙调蛋白与CaMK II的结合。尽管S100 B-RSK 1和钙调素-CAMK II系统在功能上明显不同，但它们证明了不相关的细胞内Ca 2+结合蛋白如何影响含CaMK结构域的蛋白激酶的活性。我们的晶体学、小角X射线散射和NMR分析显示，S100 B与RSK 1肽配体形成模糊复合物。基于快速动力学实验，我们得出结论，结合涉及构象选择和诱导拟合步骤。这种相互作用的结构基础的知识可以促进黑色素瘤的治疗靶向。
Mitogen-activated protein kinases (MAPK) promote MAPK-activated protein kinase activation. In the MAPK pathway responsible for cell growth, ERK2 initiates the first phosphorylation event on RSK1, which is inhibited by Ca2+-binding S100 proteins in malignant melanomas. Here, we present a detailed in vitro biochemical and structural characterization of the S100B-RSK1 interaction. The Ca2+-dependent binding of S100B to the calcium/calmodulin-dependent protein kinase (CaMK)-type domain of RSK1 is reminiscent of the better known binding of calmodulin to CaMKII. Although S100B-RSK1 and the calmodulin-CAMKII system are clearly distinct functionally, they demonstrate how unrelated intracellular Ca2+-binding proteins could influence the activity of the CaMK domain-containing protein kinases. Our crystallographic, small angle x-ray scattering, and NMR analysis revealed that S100B forms a fuzzy complex with RSK1 peptide ligands. Based on fast-kinetics experiments, we conclude that the binding involves both conformation selection and induced fit steps. Knowledge of the structural basis of this interaction could facilitate therapeutic targeting of melanomas.