Hierarchical Phosphorylation of Recombinant Tau by the Paired‐Helical Filament‐Associated Protein Kinase Is Dependent on Cyclic AMP‐Dependent Protein Kinase

Hierarchical Phosphorylation of Recombinant Tau by the Paired‐Helical Filament‐Associated... Abstract : Immunoaffinity‐purified paired helical filaments (PHFs) from Alzheimer's disease (AD) brain homogenates contain an associated protein kinase activity that is able to induce the phosphorylation of PHF proteins on addition of exogenous MgCl2 and ATP. PHF kinase activity is shown to be present in immunoaffinity‐purified PHFs from both sporadic and familial AD, Down's syndrome, and Pick's disease but not from normal brain homogenates. Although initial studies failed to show that the kinase was able to induce the phosphorylation of tau, additional studies presented in this article show that only cyclic AMP‐dependent protein kinase‐pretreated recombinant tau is a substrate for the PHF kinase activity. Deletional mutagenesis, phosphopeptide mapping, and site‐directed mutagenesis have identified the PHF kinase phosphorylation sites as amino acids Thr361 and Ser412 in htau40. In addition, the cyclic AMP‐dependent protein kinase phosphorylation sites that direct the PHF kinase have been mapped to amino acids Ser356 and Ser409 in htau40. Additional data demonstrate that these hierarchical phosphorylations in the extreme C terminus of tau allow for the incorporation of recombinant tau into exogenously added AD‐derived PHFs, providing evidence that certain unique phosphorylations of tau may play a role in the pathogenesis of neurofibrillary pathology in AD. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurochemistry Wiley

Hierarchical Phosphorylation of Recombinant Tau by the Paired‐Helical Filament‐Associated Protein Kinase Is Dependent on Cyclic AMP‐Dependent Protein Kinase

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Publisher
Wiley
Copyright
© International Society for Neurochemistry
ISSN
0022-3042
eISSN
1471-4159
D.O.I.
10.1046/j.1471-4159.1999.0720214.x
Publisher site
See Article on Publisher Site

Abstract

Abstract : Immunoaffinity‐purified paired helical filaments (PHFs) from Alzheimer's disease (AD) brain homogenates contain an associated protein kinase activity that is able to induce the phosphorylation of PHF proteins on addition of exogenous MgCl2 and ATP. PHF kinase activity is shown to be present in immunoaffinity‐purified PHFs from both sporadic and familial AD, Down's syndrome, and Pick's disease but not from normal brain homogenates. Although initial studies failed to show that the kinase was able to induce the phosphorylation of tau, additional studies presented in this article show that only cyclic AMP‐dependent protein kinase‐pretreated recombinant tau is a substrate for the PHF kinase activity. Deletional mutagenesis, phosphopeptide mapping, and site‐directed mutagenesis have identified the PHF kinase phosphorylation sites as amino acids Thr361 and Ser412 in htau40. In addition, the cyclic AMP‐dependent protein kinase phosphorylation sites that direct the PHF kinase have been mapped to amino acids Ser356 and Ser409 in htau40. Additional data demonstrate that these hierarchical phosphorylations in the extreme C terminus of tau allow for the incorporation of recombinant tau into exogenously added AD‐derived PHFs, providing evidence that certain unique phosphorylations of tau may play a role in the pathogenesis of neurofibrillary pathology in AD.

Journal

Journal of NeurochemistryWiley

Published: Jan 1, 1999

Keywords: ; ; ; ;

References

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