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Protein kinase FA/glycogen synthase kinase-3 alpha after heparin potentiation phosphorylates tau on sites abnormally phosphorylated in Alzheimer's disease brain.
Yang, S D; Yu, J S; Shiah, S G; Huang, J J.
Afiliación
  • Yang SD; Institute of Biomedical Sciences, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.
J Neurochem ; 63(4): 1416-25, 1994 Oct.
Article en En | MEDLINE | ID: mdl-7931292
Previously, we identified protein kinase FA/glycogen synthase kinase-3 alpha (GSK-3 alpha) as a brain microtubule-associated tau kinase that phosphorylates Ser235 and Ser404 of tau and causes its electrophoretic mobility shift in gels, a unique property characteristic of paired helical filament-associated pathological tau (PHF-tau) in Alzheimer's disease brains. In this study, we found that the activity of kinase FA/GSK-3 alpha towards phosphorylation of brain tau could be stimulated approximately fourfold by heparin. The phosphorylation molar ratio was increased simultaneously up to 9 mol of phosphates/mol of tau, resulting in a reduced mobility of tau with an apparent molecular mass shift to approximately 68 kDa in sodium dodecyl sulfate gels, which is very similar to that observed in Alzheimer-tau. Tryptic digestion of 32P-labelled tau, followed by HPLC and two-dimensional separation on TLC cellulose plates, revealed eight major phosphopeptides. Phosphoamino acid analysis together with sequential manual Edman degradation and protein sequence analysis further revealed that, in addition to Ser235 and Ser404, heparin generated Thr212, Thr231, Ser262, Ser324, and Ser356, the five extra phosphorylation sites in tau. As Ser235, Ser262, Ser324, Ser356, and Ser404 (particularly the site of Ser262) have been identified as five of the most potent sites in tau responsible for reducing microtubule binding possibly involved in neuronal degeneration, and Thr231, Ser235, Ser262, and Ser404 are four of the most well documented sites abnormally phosphorylated in Alzheimer-tau, the results provide initial evidence that protein kinase FA/GSK-3 alpha after heparin potentiation may represent one of the most potent systems possibly involved in the abnormal phosphorylation of PHF-tau in Alzheimer's disease brains.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Heparina / Proteínas tau / Proteínas Quinasas Dependientes de Calcio-Calmodulina / Enfermedad de Alzheimer Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Neurochem Año: 1994 Tipo del documento: Article Pais de publicación: Reino Unido
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Heparina / Proteínas tau / Proteínas Quinasas Dependientes de Calcio-Calmodulina / Enfermedad de Alzheimer Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: J Neurochem Año: 1994 Tipo del documento: Article Pais de publicación: Reino Unido