Synergistic control mechanism for abnormal site phosphorylation of Alzheimer's diseased brain tau by kinase FA/GSK-3 alpha.
When a synthetic peptide fragment (VAVVRTPPKSPSSAK) which corresponds to amino acid residues 226-240 from brain microtubule-associated protein tau was used as a testing substrate, we found that protein kinase FA/GSK-3 alpha was almost inactive towards this substrate. In sharp contrast, when Ser-10 of this peptide was replaced by a phosphoserine, the phosphopeptide fragment (VAVVRTPPKS(p)PSSAK) became an excellent substrate for kinase FA/GSK-3 alpha. Sequential manual Edman degradation together with phosphoamino acid analysis and protein sequencing further revealed that Thr-6 of the peptide fragment which corresponds to an important abnormal phosphorylation site Thr-231 in Alzheimer's diseased brain tau was the only site that was greatly phosphorylated, demonstrating that a pre-phosphorylation becomes a prerequisite and is essential for promoting phosphorylation of Thr-231. Taken together, the results provide initial evidence that kinase FA/GSK-3 alpha mediates a synergistic phosphorylation control mechanism involved in the abnormal site phosphorylation of Alzheimer's diseased brain tau.
Yang
S D
SD
Institute of Biomedical Science, National Tsing Hua University, Hsinchu, Taiwan, ROC.
Yu
J S
JS
Liu
W K
WK
Yen
S H
SH
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D007700:Kinetics; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism*; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D010769:Phosphothreonine / Q000032:analysis; D019000:Phosphotyrosine; D013379:Substrate Specificity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D016875:tau Proteins / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D010446:Peptide Fragments; D010748:Phosphopeptides; D016875:tau Proteins; D010769:Phosphothreonine; D010768:Phosphoserine; D019000:Phosphotyrosine; D014443:Tyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3