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首页> 外文期刊>Biochemistry >Activation Mechanism of CDK2: Role of Cyclin Binding versus Phosphorylation.
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Activation Mechanism of CDK2: Role of Cyclin Binding versus Phosphorylation.

机译：CDK2的激活机制：细胞周期蛋白结合与磷酸化的作用。

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摘要

Activation of the cyclin-dependent kinases is a two-step process involving cyclin binding followed by phosphorylation at a conserved threonine residue within the kinase activation loop. In this study, we describe the separate roles of cyclin A binding versus phosphorylation in the overall activation mechanism of CDK2. Interaction of CDK2 with cyclin A results in a partially active complex that is moderately defective in the binding of the protein substrate, but not ATP, and severely defective in both phosphoryl group transfer and turnover. Alternatively, phosphorylation of the CDK2 monomer also results in a partially activated species, but one that is severely (>/=480-fold) defective in substrate binding exclusively. Catalytic turnover in the phosphorylated CDK2 monomer is largely unimpaired ( approximately 8-fold lower). Our data support a model for the activation of CDK2 in vivo, in which interaction of unphosphorylated CDK2 with cyclin A serves to configure the active site for ground-state binding of both ATP and the protein substrate, and further aligns ATP in the transition state for phosphoryl transfer. Optimizing the alignment of protein substrates in the phosphoryl transfer reaction is the principal role of phosphorylation at Thr(160).
机译：细胞周期蛋白依赖性激酶的激活是一个两步过程，涉及细胞周期蛋白结合，然后在激酶激活环内保守的苏氨酸残基处进行磷酸化。在这项研究中，我们描述了细胞周期蛋白A结合与磷酸化在CDK2总体激活机制中的独立作用。 CDK2与细胞周期蛋白A的相互作用产生了部分活性的复合物，该复合物在蛋白质底物的结合中适度存在缺陷，但在ATP中没有，在磷酰基转移和周转方面均存在严重缺陷。备选地，CDK2单体的磷酸化也导致部分活化的物质，但是仅在底物结合方面严重（＞ / ＝ 480倍）缺陷的物质。磷酸化CDK2单体的催化转化率基本不受损害（降低约8倍）。我们的数据支持体内CDK2激活的模型，其中未磷酸化的CDK2与细胞周期蛋白A的相互作用可为ATP和蛋白质底物的基态结合配置活性位点，并进一步使ATP处于过渡态磷酰基转移。在磷酸基转移反应中优化蛋白质底物的排列是Thr（160）处磷酸化的主要作用。

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