Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The microtubule array in neuronal cells undergoes extensive growth, dynamics and rearrangements during neurite outgrowth. While little is known about how these changes are regulated, microtubule-associated proteins (MAPs) including tau protein are likely to perform an important role. Tau is one of the MAPs in mammalian brain. When isolated it is usually a mixture of several isoforms containing between 341 and 441 residues that arise from alternative splicing. Tau can be phosphorylated by several protein kinases. Phosphorylation at certain sites results in major structural and functional changes, as seen by changes in electrophoretic mobility, interaction with microtubules, molecular length and elasticity. Here we show that the sites of phosphorylation by four kinases (PKA, PKC, CK and CaMK) all lie in the C-terminal microtubule-binding half of tau, but only the phosphorylation by CaM kinase shows the pronounced shift in electrophoretic mobility characteristic for tau from Alzheimer neurofibrillary tangles. By using a combination of limited proteolysis, protein sequencing and protein engineering we show that a single phosphorylation site is responsible for this shift, located at Ser 405 in the C-terminal tail of the protein outside the region of internal repeats. Phosphorylation at this site not only reduces the electrophoretic mobility of tau, it also makes the protein long and stiff, as shown earlier. The site is likely to be phosphorylated in tau from Alzheimer neurofibrillary tangles.
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PMID:Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. 212 43

In aged human brain and particularly in Alzheimer's disease brain, paired helical filaments (PHFs) accumulate in the neuronal cell. Recently, it has been found that the highly phosphorylated tau protein, one of the microtubule-associated proteins (MAPs), is a component of PHF. The authors attempted to clarify the mechanism underlying the accumulation of PHF from the following two aspects; 1) What is the mechanism of phosphorylation of tau protein? 2) Is the highly phosphorylated tau protein capable of forming PHFs? From rat or bovine microtubule proteins we partially purified and characterized a novel protein kinase that specifically phosphorylated tau and MAP2 among many proteins in the brain extract, and which formed a PHF epitope on the phosphorylated human tau. This enzyme was one of the protein serine/threonine kinases and was independent of known second messengers. The phosphorylation of tau by this enzyme was stimulated by tubulin under the condition of microtubule formation, suggesting that the phosphorylation of tau could occur concomitantly with microtubule formation in the brain. Since this kinase was usually bound to tau but not directly to tubulin, the enzyme was associated with microtubules through tau. From these properties related to tau, this kinase is designated as tau protein kinase. The tau that been phosphorylated with this kinase using [gamma-32P]ATP as a phosphate donor, was digested by endoprotinase Lys-C to produce three labeled fragments, K1, K2 and K3. These three fragments were sequenced and the phosphorylation sites on tau by this kinase were identified. The K2 fragment overlapped with the tau-1 site known to be one of the phosphorylation site in PHF. This result strengthens the possibility that tau protein phosphorylated by tau protein kinase is incorporated into PHF. Tubulin binding sites on tau were located between K1 and K3 fragments, while K2 fragment was located in the neighboring to N-terminus of K1. No phosphorylated sites were found on the tubulin-binding domain of tau, leading us to the idea that the interaction of tau with tubulin could induce conformational changes on tau making it accessible to effects of the kinase. We detected -SP- as a sequence common to three major phosphorylation sites on K1, K2 and K3 fragments. Neurofilament-specific kinase and growth-associated histone H1 kinase are known to recognize the consensus sequence including -SP-. These enzymes exhibit certain properties similar to tau protein kinase and seem to play a crucial role in the regulation of neurite outgrowth or cell growth, through the phosphorylation of a specific substrate, neurofilaments or histone H1, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Phosphorylation of tau protein]. 212 Apr 90

Abnormal protein phosphorylation has been identified in Alzheimer's disease (AD) for several proteins including a Mr 60,000 protein, a Mr 86,000 protein and a microtubule-associated protein tau. The Mr 86,000 protein is phosphorylated by protein kinase C, whereas protein kinases responsible for other aberrant phosphorylation reactions are not known. In addition to protein kinase C, another kinase, casein kinase II (CK-II), has now been shown to be aberrant in AD. The spermine-dependent CK-II activity is reduced by 84% in AD and the amount of CK-II as determined by its immunoreactivity on a Western blot is reduced by 63%. Furthermore, the distribution of CK-II in AD is altered. Although the neuronal cell body reacts well with CK-II antisera in the normal cortex, the non-tangle-bearing neurons in the AD cortex showed a 15-30% decrease in anti-CK-II immunoreactivity. The neurofibrillary tangles, on the other hand, stain very strongly with rabbit anti-CK-II and indicates that CK-II may be involved in the pathology of AD. The study of CK-II immunoreactivity for dementing diseases other than AD revealed a similar reduction, suggesting the CK-II involvement in the common process of neurodegeneration.
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PMID:Aberrant casein kinase II in Alzheimer's disease. 233 67

Binding between the microtubule-associated tau protein and S100b protein was demonstrated by affinity chromatography and cross-linking experiments and was manifested in the effect of S100b on tau protein phosphorylation by protein kinase II. All three expressions of the binding showed that S100b discriminates among the four species of tau, revealing for the first time that the different kinds of tau may differ functionally. Noncovalent interaction between tau and S100b depended on the presence of Ca2+ or Zn2+ and resulted in total inhibition of tau phosphorylation by protein kinase II. In the absence of reducing agent, covalent binding studies between Cys84 beta in the carboxyl-terminal region of the S100b-beta subunit and tau proteins confirmed interactions between the two proteins. It is suggested that the homologous calcium-binding domain that characterizes the carboxyl terminus of S100 and the tubulin subunit may be responsible for the common interaction of both proteins with tau proteins. The physicochemical relationship between S100 subunits and p11, the subunit of a substrate for tyrosine kinase, and their similarity in interaction with protein kinase substrates are discussed.
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PMID:Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II. 283 19

Calcium/calmodulin (CaM)-dependent protein kinases isolated from bovine and rat brains phosphorylate the microtubule-associated tau protein in the mode that shifts the mobility of tau in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (mode I). This mode of tau phosphorylation is the one that occurs abnormally in Alzheimer's lesions. Purified tau protein in solution can be phosphorylated by the Ca2+/CaM kinases maximally to about 50% of the total tau protein. Incorporation of one phosphate group per mol of tau is sufficient to shift the protein to a slower migrating electrophoretic band. Additional phosphate incorporation into the shifted tau proteins can occur depending on protein kinase concentration. In the presence of phosphatidylserine, tau proteins were phosphorylated to an extent of 100% at a tau: phosphatidylserine ratio of 20. Phosphatidylethanolamine also stimulated tau phosphorylation by Ca2+/CaM kinase and phosphatidylinositol was found to be a potent inhibitor of tau protein phosphorylation. The direct observation that tau proteins interact with phospholipids such as phosphatidylethanolamine and phosphatidylinositol, resulting in a smearing of the protein band on sodium dodecyl sulfate-gel electrophoresis, supports the possibility that tau protein may interact with phospholipid membranes in vivo and that tau protein phosphorylation could be modulated by the phospholipid composition of the membranes with which tau interacts.
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PMID:Phosphorylation of tau proteins to a state like that in Alzheimer's brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. 312 1

Bovine brain tau protein (tau) consists of four closely related phosphoproteins named tau 1, tau 2, tau 3 and tau 4, that range in size from 55 to 68 kDa (as determined by gel electrophoresis). Here we report an improved large-scale purification method for tau protein and the separation of the four individual tau protein species. The separation of the individual tau protein was accomplished by two chromatographic techniques: hydroxyapatite chromatography allowed the separation of two pairs of tau protein (tau 1 and tau 3) and (tau 2 and tau 4); fast protein liquid chromatography on a Mono Q column at basic pH achieved the resolution of the individual tau protein species in each pair derived from hydroxyapatite columns. Chromatography on the Mono Q column revealed that tau protein possesses previously unrecognized, highly reactive sulfhydryl groups that may oxidize to form intermolecular disulfide bridges. The isolation of individual species of tau in substantial quantities permitted an improved amino acid analysis that demonstrated the occurrence of cysteine and tryptophan in the protein. The availability of individual tau protein species greatly simplified the analysis for mode II phosphorylation of tau, which was found to be catalyzed by the calcium/phospholipid-dependent protein kinase C. The mode II phosphorylation of tau by protein kinase C was not associated with a mobility shift for tau protein in SDS-polyacrylamide gel electrophoresis, in contrast to mode I phosphorylation of tau by the Ca2+/calmodulin-dependent kinase, which produces a substantial shift in mobility.
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PMID:Separation of the different microtubule-associated tau protein species from bovine brain and their mode II phosphorylation by Ca2+/phospholipid-dependent protein kinase C. 312 2

Phosphorus-31 (31P) NMR is proving to be a powerful analytical method for investigating molecular/metabolic issues in neural tissues. Recent studies have demonstrated high levels of phosphomonoesters and phosphodiesters in mammalian brain, and revealed the influence of brain maturation, development, and aging on these levels. Preliminary studies in Alzheimer's disease have demonstrated elevated levels of phosphomonoesters and phosphodiesters in the areas of Alzheimer's brain which exhibit neuropathological changes. Moreover, phosphomonoester levels were also elevated in areas of Alzheimer's brain that were devoid of neuropathological changes. These findings suggest that the phosphomonoester elevations in Alzheimer's brain antedate changes in cellular morphology and structure. Abnormalities in protein kinase function could potentially explain these findings, as well as the reported hyperphosphorylation of tau protein in Alzheimer's brain. Recent studies from this laboratory suggest that aluminum could also be involved in the changes in phosphomonoesters and phosphodiesters.
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PMID:31P nuclear magnetic resonance (NMR) spectroscopy of brain in aging and Alzheimer's disease. 331 99

Binding of both synthetic poly(A) and naturally occurring poly(A) (+)mRNA as well as DNA to microtubule protein is mediated by microtubule-associated proteins; tubulin itself is not capable of binding these polymers. Bovine brain microtubule protein from immature animals was found to have a significantly lower capacity to bind poly(A) than microtubule protein from old animals. On the other hand, "old" microtubule protein binds DNA more efficiently than "immature" microtubule protein. Microtubule-associated protein 2 [preferred binding site for DNA] and tau proteins [preferred binding site for poly (A)] are specifically phosphorylated by a microtubule-associated, cAMP-dependent protein kinase. It was found that the affinity of microtubule protein for poly(A) is markedly decreased by autophosphorylation of the protein; in the case of DNA, the decrease in affinity was less. Autophosphorylation of "immature" microtubule proteins diminished the binding capacity for poly(A) to a greater extent than do "old" proteins. Scatchard plot analysis revealed that microtubule-protein possesses two different binding sites for poly(A). The corresponding dissociation constants were found to be increased in the phosphorylated system, but phosphorylation does not appear to alter the total number of binding sites. Compared to immature animals, microtubule protein from "old" bovine brains was found to have a reduced number of binding sites for poly(A), whereas the values of the dissociation constants remain unchanged. In contrast to total microtubule protein and homogeneous microtubule-associated protein 2, only one kind of binding site for poly(A) could be detected in homogeneous tau protein. No influence of different RNA or DNA species on microtubule protein-associated cAMP-dependent protein kinase, adenosine triphosphatase and guanosine triphosphatase activities could be detected.
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PMID:Binding of polyribonucleotides and polydeoxyribonucleotides to bovine brain microtubule protein: age-dependent modulation via phosphorylation of high-molecular-weight microtubule-associated proteins and tau proteins. 614 31

The immunoreactivity of cortical and brainstem-type Lewy bodies has been investigates with antibodies to the cyclin-dependent kinase 5 (cdk5), to the extracellular regulated kinase 1 (ERK-1), and to the cdc2p34 kinase and with antibodies specific for phosphorylation epitopes typical of paired helical filament-tau (PHF-tau). Both cortical and brainstem-type Lewy bodies in diffuse Lewy body disease and brainstem-type Lewy bodies in Parkinson's disease were found to be immunoreactive for cdk5 but not for cdc2p34 or ERK-1 or with the PHF-tau antibodies. Double immunolabeling showed that cdk5-positive Lewy bodies were also ubiquitin immunoreactive and that cdk5 antibodies labeled as many Lewy bodies as ubiquitin antibodies in adequately fixed tissue. The cdk5 immunoreactivity of Lewy bodies was abolished by preabsorption of the antibody with a cdk5 peptide. The antibodies to cdk5 labeled a single 33-kd species on Western blots of human brain homogenates, with a similar intensity in control, diffuse Lewy body disease, and Alzheimer's disease, and this cdk5 species was found mainly in the particulate fraction of brain homogenates. This observation suggests that cdk5 might be a protein kinase involved in the phosphorylation of a molecular component of Lewy bodies, for example, neurofilament proteins known to be present in these inclusions.
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PMID:Cortical and brainstem-type Lewy bodies are immunoreactive for the cyclin-dependent kinase 5. 748 9

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.
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PMID:Synergistic control mechanism for abnormal site phosphorylation of Alzheimer's diseased brain tau by kinase FA/GSK-3 alpha. 750 67


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