Enzymological Aspects Of Neural Functions

神经功能的酶学方面

• 批准号: 7594636
• 负责人: ROBERT W ALBERS
• 金额: $ 28.15万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594636
• 关键词: Affinity; Biological; Biological Assay; Complex; Cultured Cells; Cyclin-Dependent Kinases; Cyclins; Enzymes; Family; Goals; Lead; Modification; Molecular; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Pathology; Peptides; Phosphotransferases; Physiological; Protein Fragment; Protein Kinase; Proteins; Regulation; Stress; System; Transfection; Work; base; conformational conversion; enzyme mechanism; inhibitor/antagonist; interest; member; practical application; prevent; tau Proteins

We are examining the mechanism of cdk5 kinase activation and inhibition. The interaction of this kinase with its different activator proteins and fragments thereof produce complex effects on its biological activity. We have described a fragment (CIP) of the cdk5-activator protein, p35, that produces high-affinity inhibition of cdk5 by selective competition with the p25 activator protein. The p25 form of the cdk5 activator appears in neurons under stress, induces hyperphosphorylation of the microtubule associated protein, tau, and transfection with the inhibitor peptide can prevent this in neuronal cell culture assays (Zheng et al, 2005). We are currently engaged in studies to further define the mechanism of this selective inhibition. Cdk5 is a member of the cyclin-dependent kinase family. Although cdk5 activator proteins are not cyclins, the activator interfaces with the kinases in this family are largely similar and they induce similar conformational transitions. Thus we are also exploring computational means to obtain information about the interactions of CIP and related inhibitors with the cdk5 kinase.

我们正在研究CDK5激酶激活和抑制的机制。该激酶与其不同激活蛋白及其片段的相互作用对其生物学活性产生了复杂的影响。我们已经描述了CDK5激活蛋白P35的片段（CIP），该片段通过与P25激活蛋白的选择性竞争可产生CDK5的高亲和力抑制作用。 CDK5活化剂的p25形式出现在胁迫下的神经元中，诱导微管相关蛋白，tau的高磷酸化，而用抑制剂肽转染可以在神经元细胞培养分析中预防这种磷酸化（Zheng等人，2005年）。 目前，我们正在研究进一步定义这种选择性抑制的机制。 CDK5是Cyclin依赖性激酶家族的成员。 尽管CDK5激活蛋白不是细胞周期蛋白，但该家族中与激酶的激活剂界面在很大程度上相似，它们会诱导类似的构象转变。 因此，我们还在探索计算方法，以获取有关CIP和相关抑制剂与CDK5激酶相互作用的信息。