Truncation of CDK5 activator p35 induces intensive phosphorylation of Ser202/Thr205 of human tau
| Autor: | Taro Saito, Toshio Hashiguchi, Mitsuko Hashiguchi, Shin-ichi Hisanaga |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Threonine
Insecta Time Factors Tau protein Blotting Western Hyperphosphorylation Nerve Tissue Proteins tau Proteins Biochemistry Cell Line Serine Animals Humans Protein Isoforms Trypsin Kinase activity Phosphorylation Molecular Biology Neurons biology Cell Death Activator (genetics) Chemistry Cyclin-dependent kinase 5 Calpain Cell Biology eye diseases Recombinant Proteins Kinetics Tubulin nervous system biology.protein Plasmids Protein Binding |
| Zdroj: | The Journal of biological chemistry. 277(46) |
| ISSN: | 0021-9258 |
| Popis: | Hyperphosphorylated tau is a major component of neurofibrillary tangles, one of the hallmarks of Alzheimer's disease. CDK5 is a kinase that phosphorylates the tau protein, and its endogenous activator, p35, regulates its activity. Recently, calpain was found to digest p35 to its truncated product, p25. Several lines of evidence suggest that p25-CDK5 has much more powerful kinase activity and that it may cause abnormal hyperphosphorylation of tau. In this study, we have examined the kinetic characteristics of in vitro phosphorylation of the longest isoform of human tau by CDK5 and its activators using recombinant proteins. Although the kinase activity of CDK5 in phosphorylating tau was significantly higher in the presence of p25, the affinity of CDK5 for tau was not different. Phosphopeptide mapping revealed enhanced phosphorylation of Ser(202)/Thr(205) residues by p25-CDK5 (amino acid residues of tau are numbered according to the longest isoform of human tau). These results suggest that cleavage of p35 to p25 greatly enhances the kinase activity of CDK5 and increases the phosphorylation of Ser(202)/Thr(205). Considering the fact that phosphorylation of Ser(202)/Thr(205) antagonizes the tau-mediated nucleation of tubulin, p25-CDK5 may play a pivotal role in neuronal cell death in Alzheimer's disease. |
| Databáze: | OpenAIRE |
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