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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tau proteins are microtubule-associated proteins that promote microtubule polymerization in vitro and in vivo. They are a family of neuronal proteins with apparent molecular weights in the range 50,000-68,000 determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Recently, a new member of this family has been described and its cDNA has been cloned. It has an apparent molecular weight of 116,000 and has been called high-molecular-weight tau (HMW tau). All the tau proteins are encoded by a single gene, which undergoes complex alternative splicing. In the present study, we have cloned into the baculovirus a cDNA fully encoding HMW tau as well as a truncated cDNA encoding a protein beginning 13 amino acids in front of the tau microtubule-binding domain. HMW tau-recombinant-virus-infected Sf9 cells overexpressed HMW tau, which induced the polymerization of microtubules and the formation of long cellular processes similar to those induced by low-molecular-weight tau (LMW tau) overexpression. Process cross sections revealed a larger spacing (approximately 35 nm) between microtubules when induced by HMW tau than when induced by LMW tau (approximately 20 nm). The truncated construct also induces processes, where microtubules were packed far more closely together (approximately 10 nm). Although branching did not occur in processes induced by intact tau S, 10% of the processes induced by the truncated tau protein branched.
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PMID:tau Regulation of microtubule-microtubule spacing and bundling. 796 49

Previously, we identified protein kinase FA/glycogen synthase kinase-3 (GSK-3) as a microtubule-associated protein tau kinase that can incorporate 4 mol of phosphates into 1 mol of tau protein and cause its electrophoretic mobility shift in sodium dodecyl sulfate gels, a unique property characteristic of paired helical filament-associated pathological tau (PHF-tau) in Alzheimer's disease brains. In this report, we identified TPPKS(p)PSAAK and SPVVSGDTS(p)PR as two phosphorylation site sequences phosphorylated by kinase FA/GSK-3 in tau using peptide sequence analysis and sequential manual Edman degradation for radiosequencing. When mapping with human brain tau sequence, we further identified Ser235-Pro and Ser404-Pro as the two major phosphorylation sites according to the numbering of the longest tau isoform. Ser235 and Ser404 have been reported as two of the major abnormal phosphorylation sites in PHF-tau. Taken together, the results provide initial evidence that protein kinase FA/GSK-3 may represent one of the Ser-Pro motif-directed tau kinases involved in the abnormal phosphorylation of pathological PHF-tau in Alzheimer's disease brain.
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PMID:Protein kinase FA/GSK-3 phosphorylates tau on Ser235-Pro and Ser404-Pro that are abnormally phosphorylated in Alzheimer's disease brain. 822 90

Rat and human fetal brain tau were probed with a panel of monoclonal antibodies (tau-1, AT8, 8D8, RT97, SMI31, SMI34) that distinguish between paired helical filament (PHF)-tau of Alzheimer's disease and normal adult brain tau. These antibodies discriminate between normal and PHF-tau because their epitopes are phosphorylated in PHF-tau. Although only one molecular isoform of tau was shown to be expressed in fetal brain, two fetal tau species could be distinguished on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and the slower migrating species was recognized by all of the PHF-tau-specific antibodies. Moreover, this immunoreactivity was shown to be phosphorylation dependent. Our observations suggest that the abnormal phosphorylation of tau in Alzheimer's disease may be the result of reactivation of pathways governing the phosphorylation of tau in the developing brain.
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PMID:Developmental changes in tau phosphorylation: fetal tau is transiently phosphorylated in a manner similar to paired helical filament-tau characteristic of Alzheimer's disease. 824 63

The product of the Saccharomyces cerevisiae MCK1 gene is a protein kinase that phosphorylates poly (Glu,Tyr) in vitro and is itself phosphorylated at both tyrosine and serine in vivo. To characterize the substrate specificity of Mck1, the enzyme was purified to apparent homogeneity from the soluble fraction of yeast cell extracts by ammonium sulfate precipitation, followed by ion exchange chromatography (Q- and S-Sepharose), dye-ligand affinity chromatography (Orange A-agarose), adsorption chromatography (hydroxylapatite), and ion exchange fast protein liquid chromatography (Mono-S). In the absence of an exogenous substrate, purified Mck1 was able to autophosphorylate on tyrosine and serine. A catalytically inactive mutant (K68R in conserved kinase domain II) expressed in an mck1 delta strain did not contain detectable phosphotyrosine, confirming that the tyrosine phosphorylation observed in vivo is due to autophosphorylation, but did contain phosphoserine, suggesting that Mck1 is a target for other cellular protein kinases. Purified Mck1 phosphorylated a variety of proteins in heat-inactivated yeast extracts, primarily on serine (and threonine). The purified enzyme also used a number of mammalian proteins as phosphoacceptors, including myelin basic protein (MBP), microtubule-associated protein 2 (MAP-2), and tau protein. All of these substrates were phosphorylated on either serine or threonine (or both). Mck1 isolated from yeast extracts by immunoprecipitation with an anti-Mck1 antibody directed against its C terminus also phosphorylated MBP at serine. In the same immune complex kinase assay, the K68R mutant did not detectably phosphorylate MBP, indicating that the serine-specific phosphotransferase activity of Mck1 is intrinsic and not due to contamination by an associated kinase. These findings demonstrate that Mck1 is a member of a novel class of protein kinases that displays the ability to phosphorylate all three hydroxyamino acids in proteins.
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PMID:Yeast MCK1 protein kinase autophosphorylates at tyrosine and serine but phosphorylates exogenous substrates at serine and threonine. 840 52

Hyperphosphorylated forms of the microtubule-associated protein tau are components of the paired helical filaments (PHFs) seen in patients with Alzheimer's disease. Slices of human lateral temporal cortex were obtained from tissues removed incidental to resections for intractable hippocampal epilepsy. Tau phosphorylation in temporal lobe slices was determined using mobility shifts after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunodetection with the monoclonal antibodies Alz-50, 5E2, and Tau-1. The results indicate that tau phosphorylation was altered in a dose-dependent manner by the phosphatase inhibitor okadaic acid, but not by N-methyl-D-aspartate, quisqualate, or kainate. The slowest mobility forms of tau, termed "PHF-like tau," produced by okadaic acid treatment were dephosphorylated by purified protein phosphatase 2B (calcineurin). Formation of PHF-like tau peptides was blocked by KN-62, 1[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, an inhibitor of Ca2+/calmodulin-dependent protein kinase II. The protein kinase inhibitor staurosporine also prevented formation of PHF-like tau. These data suggest that phosphorylation of tau is regulated by Ca(2+)-dependent protein kinases and okadaic acid-sensitive protein phosphatases, alterations of which may be implicated in the pathogenesis of Alzheimer's disease.
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PMID:Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices. 849 35

Neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute not only one of the defining neuropathological features of Alzheimer disease but also are present in a number of other neurodegenerative diseases with dementia. Here we describe a novel autosomal dominant disease named familial "multiple system tauopathy with presenile dementia," which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells. There are no detectable deposits of beta-amyloid. The tau deposits are in the form of twisted filaments that differ in diameter and periodicity from the paired helical filaments of Alzheimer disease. They are stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexists with heparan sulfate in affected nerve and glial cells. Tau protein extracted from filaments of familial multiple system tauopathy with presenile dementia shows a minor 72-kDa band and two major bands of 64 and 68 kDa that contain mainly hyperphosphorylated four-repeat tau isoforms of 383 and 412 amino acids.
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PMID:Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. 910 14

1. Cultured human SH-SY5Y adrenergic neuroblastoma cells were used to examine the action of morphine sulfate on microtubular tau protein. 2. After 48 hr treatment morphine sulfate (200 microM) reduced tau protein in the cytoplasmic (supernatant) fraction of undifferentiated cells, and in the cytoplasmic as well as membrane (pellet) fractions of differentiated cells. 3. A 71% increase (P < 0.05) in total protein in the membrane (pellet) fraction of undifferentiated cells and a 188% increase (P < 0.01) in that of differentiated cells accompanied the decrease in tau protein. 4. A 51% reduction (P < 0.01) in the number of undifferentiated (but not differentiated) cells was seen after this drug (200 microM).
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PMID:Changes in microtubular tau protein after morphine in a cultured human neuroblastoma cell line. 934 40

Hyperphosphorylated microtubule-associated protein tau is the major proteinaceous component of the paired helical and straight filaments which constitute a defining neuropathological characteristic of Alzheimer's disease and a number of other neurodegenerative disorders. We have recently shown that full-length recombinant tau assembles into Alzheimer-like filaments upon incubation with heparin. Heparin also promotes phosphorylation of tau by a number of protein kinases, prevents tau from binding to taxol-stabilized microtubules, and produces rapid disassembly of microtubules assembled from tau and tubulin. Here, we have used the above parameters to study the interactions between tau protein and a number of naturally occurring and synthetic glycosaminoglycans. We show that the magnitude of the glycosaminoglycan effects is proportional to their degree of sulfation. Thus, the strongly sulfated glycosaminoglycans dextran sulfate, pentosan polysulfate, and heparin were the most potent, whereas the non-sulfated dextran and hyaluronic acid were without effect. The moderately sulfated glycosaminoglycans heparan sulfate, chondroitin sulfate, and dermatan sulfate had intermediate effects, whereas keratan sulfate had little or no effect. These in vitro interactions between tau protein and sulfated glycosaminoglycans reproduced the known characteristics of paired helical filament-tau from Alzheimer's disease brain. Sulfated glycosaminoglycans are present in nerve cells in Alzheimer's disease brain in the early stages of neurofibrillary degeneration, suggesting that their interactions with tau may constitute a central event in the development of the neuronal pathology of Alzheimer's disease.
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PMID:Alzheimer-like changes in microtubule-associated protein Tau induced by sulfated glycosaminoglycans. Inhibition of microtubule binding, stimulation of phosphorylation, and filament assembly depend on the degree of sulfation. 940 97

Tau-positive inclusions that occur in glial cells are called glial fibrillary tangles or, more simply, glial tangles. These include tuft-shaped astrocytes, thorn-shaped astrocytes, coiled bodies, and argyrophilic threads. The latter two structures occur in oligodendroglia. The tau protein in glial tangles is hyperphosphorylated and has similar immunohistochemical profiles to that in neurofibrillary tangles (NFTs) except that there are no epitopes derived from alternatively spliced exon 2 and 3. In contrast to NFTs, glial tangles rarely show solid filaments. Such NFT-associated molecules as ubiquitin, apolipoprotein E, alpha1-antichymotrypsin, and heparan sulfate are all absent from glial tangles. These characteristics suggest that glial tangles resemble the pre-tangles that occur in neurons and are thought to represent an early stage of NFTs. Tau pathology in neurodegenerative diseases takes heterogenous forms.
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PMID:Glial tau pathology in neurodegenerative diseases: their nature and comparison with neuronal tangles. 956 75

The molecular mechanism of pathological aggregation of microtubule-associated protein tau during neurodegeneration is unclear. In the present study, the in vitro effect of various metal ions on the aggregation of tau was examined using paired helical filament tau (PHF-tau) obtained from corticobasal degeneration (CBD) and Alzheimer's disease (AD) brains as well as normal human tau proteins isolated from fetal and adult brains and a recombinant system. Among the metal ions tested, Ca2+ and Mg2+ effectively induced formation of approximately 340 kD aggregates of PHF-tau but not normal tau proteins as determined by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and immunoblotting. Al3+ and Fe2+ precipitated both PHF-tau and normal tau protein as SDS-insoluble pellets. The other metal ions examined (Cu2+, Zn2+, and Li+) were inactive and caused neither aggregation nor precipitation of any tau protein. Intermixing experiments using PHF-tau and various normal tau preparations showed that the 340-kD aggregates induced by Ca2+ contained PHF-tau but not normal tau regardless whether unmodified (recombinant) or highly phosphorylated (fetal brain) tau proteins were used. The present results suggest that post-translational modifications other than the fetal-type phosphorylation are required for Ca2+- and Mg2+-dependent aggregation of PHF-tau and that the regional elevation of these ions may trigger pathological deposition of PHF-tau in certain neurodegenerative disorders.
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PMID:Ca2+ and Mg2+ selectively induce aggregates of PHF-tau but not normal human tau. 989 Apr 32


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