Brain proline-directed protein kinase phosphorylates tau on sites that are abnormally phosphorylated in tau associated with Alzheimer's paired helical filaments.
Brain proline-directed protein kinase (BPDK), which contains a catalytic subunit homologous to and displaying site-specific phosphorylation similar to p34cdc2 kinase (Lew, J., Winkfein, R. J., Paudel, H. K., and Wang, J. H. (1992) J. Biol. Chem. 267, 25922-25926), has been examined for possible involvement in tau phosphorylation. Immunoblot analyses using peptide antibodies specific for BPDK have revealed the presence of the kinase in bovine brain microtubules purified extensively by repeated polymerization and depolymerization cycles. When the microtubule proteins are separated into the tubulin and microtubule-associated protein fractions, BPDK is found exclusively in the latter fraction. BPDK phosphorylates both tau and MAP2, the former protein being phosphorylated to a stoichiometry of 3.8 mol of phosphate/mol of tau. Analysis of the phosphopeptides isolated from the tryptic digest of the phosphorylated bovine tau has revealed seven phosphorylation sites. Based on the sequence alignment between bovine and human tau proteins, these sites correspond to Ser-195, Ser-202, Thr-205, Thr-231, Ser-235, Ser-396, and Ser-404 of human tau. Mass spectrometric analysis of the tau protein isolated from Alzheimer's paired helical filaments (PHFs) has determined three abnormal phosphorylation sites and two phosphopeptides containing a total of five abnormal phosphates (Hasegawa, M., Morishima-Kawashima, M., Takio, K., Suzuki, M., Titani, K., and Ihara, Y. (1992) J. Biol. Chem. 267, 17047-17054). Two of the sites in tau phosphorylated by BPDK, Thr-231 and Ser-235, are among the abnormal phosphorylation sites, and the other sites phosphorylated by BPDK are within phosphopeptides from PHF-tau. These results suggest that BPDK may be one of the kinases responsible for the abnormal phosphorylation-associated PHF-tau.
Paudel
H K
HK
Department of Medical Biochemistry, Faculty of Medicine, University of Calgary, Alberta, Canada.
Lew
J
J
Ali
Z
Z
Wang
J H
JH
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002417:Cattle; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000737:chemistry; D010769:Phosphothreonine / Q000737:chemistry; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; D016875:tau Proteins; D010769:Phosphothreonine; D010768:Phosphoserine; D038461:Proline-Directed Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases