Dephosphorylation of Tau by Protein Phosphatase 5

Abstract

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 M 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. Tau protein is a major microtubule-associated protein in neurons. The known biological function of tau protein is to stimulate and stabilize microtubule formation from tubulin subunits. In human brain, there are six tau isoforms generated by alternative mRNA splicing from a single gene (1, 2). Tau is a phosphoprotein that normally contains 2-3 phosphates/molecule, but it is abnormally hyperphosphorylated with a stoichiometry of 9 -10 moles of phosphate per mole of protein in Alzheimer's disease (AD) 1 brain (3, 4). To date, more than 30 phosphorylation sites have been identified in AD hyperphosphorylated tau, some of which are not phosphorylated in normal tau (for review, see Refs. 5 and 6). The abnormally hyperphosphorylated tau is the major component of paired helical filaments (PHFs) (7-10), which form neurofibrillary tangles, a histopathological hallmark brain lesion of AD and several other tauopathies.The hyperphosphorylation of tau appears to be responsible for the loss of its biological function, gain of its toxicity, and aggregation into PHFs (11-16). However, the molecular mechanism by which tau becomes abnormally hyperphosphorylated in AD brain is not yet well understood. Theoretically, the abnormal hyperphosphorylation of tau could be the result of up-regulation of tau kinases or down-regulation of tau phosphatases. Several studies have shown that three major protein phosphatases (PPs), PP1, PP2A, and PP2B, dephosphorylate tau in vitro (17-23). Among these, PP2A appears to be the major phosphatase that regulates tau phosphorylation in the brain (23-28). The activity of PP2A was found to be decreased in AD brain (29 -33). Nevertheless, PP2A does not dephosphorylate all the phosphorylation sites of tau, and down-regulation of PP2A in animal brain could not produce PHFs (26,28). These studies suggest that in addition to PP2A, other phosphatases or factors might also participate in the regulation of tau phosphorylation.PP5 is a 58-KDa phosphoseryl/phosphothreonyl protein phosphatase. It is ubiquitously expressed in all types of mammalian tissue, with a relatively high level in the brain (34,35). PP5 contains a C-terminal catalytic domain structurally related to the PP1/PP2A/PP2B family and an N-terminal regulatory domain consisting of three tetratricopeptide repeats (TPRs) that usually mediate protein-protein interaction. It has been demonstrated that PP5 interacts with mul...

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