Evaluation of the Interaction of Cyclin-Dependent Kinase 5 with Activator p25 and with p25-Derived Inhibitor CIP
Evaluation of the Interaction of Cyclin-Dependent Kinase 5 with Activator p25 and with p25-Derived Inhibitor CIP
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DOI：
10.1089/cmb.2009.0202
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发表时间：
2010-05-01
影响因子：
1.7
通讯作者：
Pant, Harish C.
中科院分区：
文献类型：
--
作者：
Cardone, Antonio;Albers, R. Wayne;Pant, Harish C.
一个高亲和力的抑制蛋白称为CIP，产生的小截短的p35，实验确定。P35是细胞周期蛋白依赖性激酶cdk 5的生理激活剂。P25来源于“应激”神经元内p35的蛋白水解截短，并且它与特定神经元蛋白的过度磷酸化有关，通常发生在神经退行性疾病如阿尔茨海默氏症中。在这里，我们报告的cdk 5-p25和cdk 5-CIP复合物的结合机制的研究。这提供了对蛋白质CIP的抑制活性的来源的更好理解。我们使用一种基于几何的技术来测试假设，即p25的截断增加了CIP的灵活性，从而防止cdk 5达到其活性构象。我们的研究是基于一个基于几何的对齐算法，它对齐两个给定的蛋白质构象相对于他们的接口。我们的研究结果支持的灵活性假设，并将被用作有针对性的分子动力学模拟的基础。
A high-affinity inhibitor protein called CIP, produced by small truncations of p35, was experimentally identified. P35 is a physiological activator of the cyclin-dependent kinase cdk5. P25 is derived from proteolytic truncation of p35 within "stressed" neurons, and it is associated with the hyperphosphorylation of specific neuronal proteins, typically occurring in neurodegenerative diseases such as Alzheimer's. Here, we report a study of the binding mechanisms of the cdk5-p25 and cdk5-CIP complexes. This provides a better understanding of the source of the inhibitory activity of the protein CIP. We use a geometry-based technique to test the hypothesis that p25's truncation increases the flexibility of CIP and thus prevents cdk5 from reaching its active conformation. Our study is based on a geometry-based alignment algorithm, which aligns two given protein conformations with respect to their interfaces. Our results support the flexibility hypothesis and will be used as a basis for targeted molecular dynamics simulations.