Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease.
Protein phosphatase (PP) 5 is highly expressed in the mammalian brain, but few physiological substrates have yet been identified. Here, we investigated the kinetics of dephosphoryation of phospho-tau by PP5 and found that PP5 had a K(m) of 8-13 microm toward tau, which is similar to that of PP2A, the major known tau phosphatase. This K(m) value is within the range of intraneuronal tau concentration in human brain, suggesting that tau could be a physiological substrate of both PP5 and PP2A. PP5 dephosphorylated tau at all 12 Alzheimer's disease (AD)-associated abnormal phosphorylation sites studied, with different efficiency toward each site. Thr(205), Thr(212), and Ser(409) of tau were the most favorable sites; Ser(199), Ser(202), Ser(214), Ser(396), and Ser(404) were less favorable sites; and Ser(262) was the poorest site for PP5. Overexpression of PP5 in PC12 cells resulted in dephosphorylation of tau at multiple phosphorylation sites. The activity but not the protein level of PP5 was found to be decreased by approximately 20% in AD neocortex. These results suggest that tau is probably a physiological substrate of PP5 and that the abnormal hyperphosphorylation of tau in AD might result in part from the decreased PP5 activity in the diseased brains.
Liu
Fei
F
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA. feiliu63@hotmail.com
Iqbal
Khalid
K
Grundke-Iqbal
Inge
I
Rossie
Sandra
S
Gong
Cheng-Xin
CX
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002384:Catalysis; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007700:Kinetics; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
D009687:Nuclear Proteins; D011994:Recombinant Proteins; D016875:tau Proteins; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5