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Hierarchical Phosphorylation of Recombinant Tau by the Paired‐Helical Filament‐Associated Protein Kinase Is Dependent on Cyclic AMP‐Dependent Protein Kinase
Author(s) -
Jicha Gregory A.,
Donnell Audrey O',
Weaver Charles,
Angeletti Ruth,
Davies Peter
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720214.x
Subject(s) - phosphorylation , protein kinase a , kinase , phosphopeptide , map2k7 , mitogen activated protein kinase kinase , biochemistry , cyclin dependent kinase 2 , recombinant dna , chemistry , mutagenesis , microbiology and biotechnology , biology , mutation , gene
: Immunoaffinity‐purified paired helical filaments (PHFs)from Alzheimer's disease (AD) brain homogenates contain an associated proteinkinase activity that is able to induce the phosphorylation of PHF proteins onaddition of exogenous MgCl 2 and ATP. PHF kinase activity is shownto be present in immunoaffinity‐purified PHFs from both sporadic and familialAD, 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 thephosphorylation of tau, additional studies presented in this article show thatonly cyclic AMP‐dependent protein kinase‐pretreated recombinant tau is asubstrate for the PHF kinase activity. Deletional mutagenesis, phosphopeptidemapping, and site‐directed mutagenesis have identified the PHF kinasephosphorylation sites as amino acids Thr 361 and Ser 412 in htau40. In addition, the cyclic AMP‐dependent protein kinasephosphorylation sites that direct the PHF kinase have been mapped to aminoacids Ser 356 and Ser 409 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.