Phosphorylation of tau protein by purified p34cdc28 and a related protein kinase from neurofilaments.
It has been suggested that hyperphosphorylation of the tau protein in neurofibrillary tangles may be relevant to the etiology of Alzheimer's disease and that at least one of the hyperphosphorylated sites lies within a consensus sequence for the p34cdc2/cdc28 family of kinases. We describe a new method for large-scale purification of p34cdc28 kinase from Saccharomyces cerevisiae and show that the purified enzyme can phosphorylate bovine and human tau. Phosphorylation was greatly enhanced by the addition of basic and acidic substrate modulators. The effect of the substrate modulators differed both with the structures of the substrates and the modulators. Similar results were obtained with a kinase that could be purified from neurofilaments by p13suc1 affinity chromatography, a hallmark of p34cdc2/cdc28-type kinases. These results are consistent with the hypothesis that a kinase of this type is involved in tau phosphorylation in vivo and open the possibility that hyperphosphorylation in Alzheimer's disease may be controlled by substrate modulators.
Mawal-Dewan
M
M
Section of Biochemistry and Molecular and Cell Biology, Cornell University, Ithaca, New York 14853.
Sen
P C
PC
Abdel-Ghany
M
M
Shalloway
D
D
Racker
E
E
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D017489:CDC28 Protein Kinase, S cerevisiae; D002417:Cattle; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007382:Intermediate Filaments / Q000201:enzymology*; D007700:Kinetics; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011107:Polylysine / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013110:Sphingosine / Q000494:pharmacology; D013116:Spinal Cord / Q000201:enzymology; D016875:tau Proteins / Q000378:metabolism*
D010455:Peptides; D011134:Polysaccharides; D016875:tau Proteins; D011107:Polylysine; C015462:polyarginine; D006493:Heparin; D011494:Protein Kinases; D016203:CDC2 Protein Kinase; D017489:CDC28 Protein Kinase, S cerevisiae; D013110:Sphingosine