The role of CDK5 and GSK3B kinases in hyperphosphorylation of microtubule associated protein tau (MAPT) in Alzheimer's disease.
The role of CDK5 and GSK3B kinases in hyperphosphorylation of microtubule associated protein tau (MAPT) in Alzheimer's disease.
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DOI：
10.6026/97320630091023
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发表时间：
2013
期刊：
影响因子：
1.9
通讯作者：
Natarajan J
中科院分区：
文献类型：
--
作者：
Jayapalan S;Natarajan J
阿尔茨海默病是最常见的痴呆症。微管相关蛋白 tau (MAPT) 的异常过度磷酸化是阿尔茨海默病和相关 tau 病的标志之一。 CDK5 和 GSK3B 是两种主要的蛋白激酶，它们在 MAPT 异常过度磷酸化（导致阿尔茨海默病）中发挥重要作用。由于缺乏 MAPT-CDK5 和 MAPT-GSK3B 复合物的结构信息，我们采用分子建模来深入了解这两种酶对 MAPT 过度磷酸化的影响机制。首先对 MAPT 的三级结构进行建模并定义其活性区域。随后进行 MAPT 与 CDK5 和 GSK3B 激酶的分子对接和相互作用研究，以推断这些激酶在 MAPT 蛋白异常过度磷酸化中的作用。此外，我们还研究了 MAPT 和两种激酶的磷酸化位点和 ATP 结合位点等特征。 此外，我们计算了对接过程前后 MAPT 蛋白和两种激酶的稳定中心和稳定残基。总体结果表明，与 GSK3B 相比，CDK5 强烈参与 MAPT 的过度磷酸化。
Alzheimer's disease is the most common form of dementia. Abnormal hyperphosphorylation of Microtubule associated protein tau (MAPT) is one of the hallmarks of Alzheimer's disease and related tau pathies. CDK5 and GSK3B are the two main protein kinases that have an important role in the abnormal hyperphosphorylation of MAPT which leads to Alzheimer's disease. Structural information for both MAPT-CDK5 and MAPT-GSK3B complexes being absent, we resorted to molecular modeling for gaining insight into the mechanism of implication of hyperphosphorylation of MAPT by both enzymes. First the tertiary structure of MAPT was modeled and its active regions were defined. This was followed by molecular docking and interaction studies of MAPT with CDK5 and GSK3B kinases to infer the role of these kinases in abnormal hyperphosphorylation of MAPT protein. In addition, we have investigated the characteristic features such as phosphorylation sites and ATP binding sites of MAPT and two kinases. Further we computed the stabilization centers and stabilization residues of the MAPT protein and two kinases before and after docking process. The overall results portray that CDK5 is strongly involved in the hyperphosphorylation of MAPT when compared to GSK3B.