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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro
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No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro

机译：体外CDK5 / p25与CDK5 / p35的tau或组蛋白磷酸化动力学没有差异

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摘要

CDK5/p35 is a cyclin-dependent kinase essential for normal neuron function. Proteolysis of the p35 subunit in vivo results in CDK5/p25 that causes neurotoxicity associated with a number of neurode-generative diseases. Whereas the mechanism by which conversion of p35 to p25 leads to toxicity is unknown, there is common belief that CDK5/p25 is catalytically hyperactive compared to CDK5/p35. Here, we have compared the steady-state kinetic parameters of CDK5/p35 and CDK5/p25 towards both histone H1, the best known substrate for both enzymes, and the microtubule-associated protein, tau, a physiological substrate whose in vivo phosphorylation is relevant to Alzheimer's disease. We show that the kinetics of both enzymes are the same towards either substrate in vitro. Furthermore, both enzymes display virtually identical kinetics towards individual phosphorylation sites in tau monitored by NMR. We conclude that conversion of p35 to p25 does not alter the catalytic efficiency of the CDK5 catalytic subunit by using histone H1 or tau as substrates, and that neurotoxicity associated with CDK5/p25 is unlikely attributable to CDK5 hyperactivation, as measured in vitro.
机译：CDK5 / p35是细胞周期蛋白依赖性激酶，对正常神经元功能至关重要。体内p35亚基的蛋白水解作用会导致CDK5 / p25引起与许多神经退行性疾病相关的神经毒性。虽然尚不清楚p35转化为p25导致毒性的机理，但普遍认为，与CDK5 / p35相比，CDK5 / p25具有催化活性。在这里，我们比较了CDK5 / p35和CDK5 / p25对两种组蛋白H1（两种酶的最著名底物）和微管相关蛋白tau（一种与体内磷酸化相关的生理底物）的稳态动力学参数阿尔茨海默氏病。我们显示两种酶的动力学在体外对任一底物都相同。此外，两种酶都显示出通过NMR监测的tau中各个磷酸化位点的动力学基本相同。我们得出的结论是，通过使用组蛋白H1或tau作为底物，p35到p25的转化不会改变CDK5催化亚基的催化效率，并且与CDK5 / p25相关的神经毒性不太可能归因于CDK5的过度活化，如体外测定。

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  • 作者

    Dylan W. Peterson; D. Michael Ando; Daryl A. Taketa; Hongjun Zhou; Fredrick W. Dahlquist; John Lew;

  • 作者单位

    Departments of Molecular, Cellular, and Developmental Biology University of California, Santa Barbara, CA 93106;

    rnDepartments of Molecular, Cellular, and Developmental Biology University of California, Santa Barbara, CA 93106;

    rnDepartments of Molecular, Cellular, and Developmental Biology University of California, Santa Barbara, CA 93106;

    rnDepartments of Molecular, Cellular, and Developmental Chemistry, University of California, Santa Barbara, CA 93106;

    rnDepartments of Molecular, Cellular, and Developmental Chemistry, University of California, Santa Barbara, CA 93106;

    rnDepartments of Molecular, Cellular, and Developmental Biology University of California, Santa Barbara, CA 93106;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    alzheimer's disease; neurotoxicity; NMR; protein kinase; proteolysis;

    机译：阿尔茨海默氏病;神经毒性NMR;蛋白激酶蛋白水解;

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