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)

Extensive in vitro phosphorylation of a purified preparation of control human brain tau consistently produces four rather than, as previously believed, three tau species on SDS-PAGE. The species thus generated are shifted on SDS-PAGE to positions that match those of PHF-tau isolated from Alzheimer's disease brain. A mixture of recombinant human tau isoforms phosphorylated by GSK-3 beta gave similar results to those obtained with control human brain tau. In vitro phosphorylation of the individual recombinant isoforms by GSK-3 beta showed that the four bands of PHF-tau are likely to consist of isoforms 3R,0 alone; 4R,0 with 3R,29; 4R,29 with 3R,58 and 4R,58 alone.
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PMID:PHF-tau from Alzheimer's brain comprises four species on SDS-PAGE which can be mimicked by in vitro phosphorylation of human brain tau by glycogen synthase kinase-3 beta. 805 May 97

To determine which proteins were associated with and intrinsic to the marginal band (MB) of microtubules (MTs), we studied protein components of MBs isolated from nucleated erythrocytes by differential detergent solubilization of the membrane skeleton (MS). MBs isolated from dogfish erythrocytes contained major proteins in the tubulin M(r) range. A high molecular weight protein of approximately 290 kD that bound antibody to syncolin and to heat-stable brain MAPs was present in the whole cytoskeleton. However, most of it was solubilized by the MB isolation medium, together with the MS. Dogfish erythrocyte cytoskeletons and isolated MBs were examined with polyclonal and monoclonal antibodies against mammalian brain tau and chicken erythrocyte tau. As shown by immunofluorescence and immunoblotting, these antibodies bound to proteins in the 50 to 67 kD range, located along the length of isolated MBs. Two-dimensional SDS-PAGE revealed isolated MB proteins of pI approximately 6.8 in the same molecular weight range, as well as alpha- and beta-tubulin with pI approximately 5.4. Subtilisin or high-salt treatment of isolated MBs resulted in unbundling of MTs, indicating involvement of MAPs. MBs isolated from chicken erythrocyte cytoskeletons also contained tau as shown by anti-mammalian brain tau immunofluorescence. Both chicken and dogfish isolated MBs also bound phalloidin, but the binding was usually discontinuous and, for any given MB, matched the pattern of anti-syncolin binding. Both syncolin and F-actin were part of the MS remnant remaining after MT disassembly, supporting their assignment to a specialized MS region at the MB/MS interface. In contrast, tau protein appears to be intrinsic to the MB, where it may have an MT stabilizing and bundling function.
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PMID:Localization of tau and other proteins of isolated marginal bands. 806 41

Phosphorylation is an indispensable process for energy and signal transduction in biological systems. AlCl3 at 10 nM to 10 microM range activated in-vitro [gamma-32P]ATP phosphorylation of the brain (tau) tau protein in both normal human or E. coli expressed tau forms; in the presence of the kinases P34, PKP, and PKC. However, higher concentrations of ALCl3 inhibited the tau phosphorylation with P34, PKP, and PKC to a maximum at 1 mM level. AlCl3 at 100 microM to 500 microM range induced non-enzymatic phosphorylation of tau with gamma-ATP, gamma-GTP, and alpha-GTP. AlCl3 activated histone phosphorylation by P34 in a similar pattern. The hyperphosphorylation of tau by Al3+ was accompanied by molecular shift and mobility retardation in SDS-PAGE. This may demonstrate the mechanism of the longterm neurological effect of Al3+ in human brain leading to the formation of the neurofibrillary tangles related to Alzheimer's disease.
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PMID:Aluminum interaction with human brain tau protein phosphorylation by various kinases. 827 Jul 65

Aluminum has been detected in Alzheimer neurofibrillary tangles, but the significance of its presence is unknown. The principal component of tangles is the paired helical filament (PHF), comprised of tau protein. We investigated whether aluminum could induce tau protein to form filaments or aggregate. When 10 microM bovine tau or non-phosphorylated recombinant human tau was combined with 400 microM or more aluminum, tau protein appeared to aggregate, observed as a dose-dependent decrease in electrophoretic mobility on SDS-PAGE. Tau appeared as a smear above the region of the expected tau bands and, at higher aluminum doses, failed to enter the gel. A tau fragment encompassing the microtubule binding domains did not show decreased mobility in the presence of aluminum, but did form aggregates that failed to electrophorese. However no fibrillar structures were observed in the aluminum-treated tau samples when observed by electron microscopy. The effect of aluminum on tau mobility was reversed by incubating with 1 mM deferoxamine. In contrast, the morphology of PHF fibrils was unaffected by deferoxamine treatment and the characteristic abnormal mobility of PHF-tau was not reduced by deferoxamine. This suggests that aluminum is not, by itself, a significant factor in maintaining the assembly of PHF-tau as fibrils or in its abnormal mobility on SDS gels. Aluminum treatment of 3T3 fibroblasts transfected with human tau resulted in toxicity, but did not change tau expression levels or induce tau aggregation. In conclusion, aluminum appears to induce isolated tau protein to aggregate in a phosphate-independent way, without the formation of fibrils.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aggregation of tau protein by aluminum. 831 73

Bovine brain tau protein was tagged with the fluorescent dye 5 (and 6)-carboxyx-rhodamine-succinimidyl ester and the functional properties of the fluorescent analog were tested in vitro by kinetic measurement and SDS gel electrophoresis. X-rhodamine tau was competent to bind to microtubules and promote microtubule assembly in vitro. Labeled tau was further characterized by microinjection of cultured Chinese hamster ovary (CHO) cells to study its intracellular distribution and potential new functions. X-rhodamine tau incorporated rapidly into centrosomes within seconds after microinjection. It distinctly labeled the microtubule network as early as 5 to 10 minutes following miroinjection. In addition, X-rhodamine tau was transported into the nucleus and labeled the nucleolus specifically. Double labeling of the injected cells with DiC6(3) indicated that in some cases, fluorescent tau may associate with the endoplasmic reticulum. The concentrations of injected X-rhodamine tau ranged from 1.7 to 5.0 mg/ml, yet distinct bundling of microtubules was not observed. Studies of nocodazole effects on the microtubules established that X-rhodamine tau stabilized microtubules against depolymerization conditions. We conclude that this fluorescent analog of tau is associated with microtubules, the nucleolus, and other microtubule-related structures in living cells, and is competent to stabilize microtubules against microtubule depolymerizing drug treatment. This approach provides a useful model system for the study of modified tau in neurodegenerative disease.
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PMID:Characterization of fluorescently derivatized bovine tau protein and its localization and functions in cultured Chinese hamster ovary cells. 832 32

Tau protein kinase II purified from a bovine brain tau protein fraction (Ishiguro, K., Takamatsu, M., Tomizawa, K., Omori, A., Takahashi, M., Arioka, M., Uchida, T., and Imahori, K. (1992) J. Biol. Chem. 267, 10897-10901) was shown to have a similar substrate specificity to cdc2 kinase in that both phosphorylate neurofilament (NF) proteins. Tau protein kinase II recognized the dephosphorylated form of the heavy subunit of NF (NF-H) as a predominant substrate. The substrate was phosphorylated to the same extent with tau protein kinase II as with cdc2 kinase. Upon phosphorylation, the electrophoretic mobility of the NF-H on SDS-polyacrylamide gel electrophoresis changed to the position of the phosphorylated form. A synthetic peptide containing a KSPXK sequence was by far a better substrate for tau protein kinase II than that containing a KSPXX sequence, as was also observed with cdc2 kinase. NF-H lost its microtubule-associating ability upon phosphorylation with tau protein kinase II as well as with cdc2 kinase. Although anti-PSTAIR antibody (PSTAIR is an amino acid sequence commonly found in cdc2 and several cdc2-related kinases) failed to react with tau protein kinase II, tau protein kinase II bound to p13suc1-Sepharose beads (p13suc1 is a yeast protein known to bind to cdc2 kinase).
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PMID:Tau protein kinase II has a similar characteristic to cdc2 kinase for phosphorylating neurofilament proteins. 832 81

A68, the primary protein constituent of Alzheimer's disease-associated neurofibrillary tangles, is an abnormally phosphorylated form of the microtubule-associated protein tau. We find that A68 is formed in neuronal PC12 cells when the cells are subjected to a heat shock (45 degrees C for 30 min). A68 was identified by immunoprecipitation with two different anti-tau antibodies (tau-2 and Alz50). Upon separation by SDS-polyacrylamide gel electrophoresis, the tau immunoprecipitates from heat-shocked cells exhibited an additional polypeptide of reduced electrophoretic mobility (approximately 68 kDa) when compared to control cells. A68 was formed with heat shock in the presence of cycloheximide, suggesting that its production occurred by post-translational modification of existing polypeptides. The tau/A68 polypeptides were identified as phosphoproteins by incorporation of 32P into the immunoprecipitates. The phosphorylation of tau to form A68 was reversed with recovery of the intact cells from the heat shock. Finally, immunoprecipitation of lysates from heat-shocked cells with antibodies to heat shock protein (hsp) 72/73 resulted in co-precipitation of tau with hsp 72, which indicates a stable complex formation between these two proteins. On the other hand, A68 remained unassociated with hsp during the heat shock. These results suggest that tau is reversibly phosphorylated to form A68 in neuronal PC12 cells under conditions of stress.
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PMID:Reversible phosphorylation of tau to form A68 in heat-shocked neuronal PC12 cells. 836 38

Using a novel PCR approach, we have cloned a cDNA encoding the entire high molecular weight tau molecule from rat dorsal root ganglia. The resulting 2080 bp cDNA differs from low molecular weight rat brain tau by the insertion of a novel 762 bp region (exon 4a) between exons 4 and 5. This cDNA clone is identical in sequence with a high molecular weight tau (HMW) cDNA from rat PC12 tumor cells and is closely related to a HMW tau cDNA from mouse N115 tumor cells. In vitro transcription/translation produces a protein that migrates on SDS-PAGE with the same apparent molecular weight as HMW tau purified from rat sciatic nerve. The HMW tau protein is generated from an 8 kb mRNA, which can be detected by northern blots in peripheral ganglia, but not in brain. A more sensitive assay using PCR and Southern blot analysis demonstrates the presence of exon 4a in spinal cord and in retina. In combination with immunohistochemical studies of spinal cord, these data suggest that HMW tau, though primarily in the peripheral nervous system, is also expressed in limited areas of the central nervous system, although its presence cannot be detected in the cerebral cortices.
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PMID:Expression of high molecular weight tau in the central and peripheral nervous systems. 840

We have fractionated tau isoforms by elution at increasing pH values using iron-chelated affinity chromatography, which discriminates between isoforms phosphorylated to different extents. Microtubule-associated tau elutes from the column at a pH gradient narrower than that of total brain tau. Neither under-phosphorylated nor highly phosphorylated isoforms are found in the microtubule-associated tau protein preparation. This indicates that phosphorylation at certain sites is needed for tau binding to microtubules, whereas phosphorylation at some other sites may prevent the association. The self-association ability of the different tau isoforms has also been analyzed. Tau isoforms containing three tubulin binding motifs form covalently bound dimers more efficiently than tau isoforms containing four motifs. This dimer-forming ability is notably diminished in the presence of a reducing agent, as determined by SDS-polyacrylamide gel electrophoresis, thus suggesting the involvement of cysteine residues. Additionally, tau forms larger aggregates, as detected by gel permeation chromatography, which are solubilized by SDS and cannot, therefore, be observed by SDS-polyacrylamide gel electrophoresis. These tau aggregates are observed even in the presence of reducing agents. These results support the idea that other regions in the tau molecule, besides the Cys-containing tubulin binding region, also contribute to tau self-association. Tau dimerization and aggregation may be prior steps to the formation of paired helical filaments.
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PMID:Differences in microtubule binding and self-association abilities of bovine brain tau isoforms. 846 18

Incubation of purified recombinant human tau protein with aluminum salts at concentrations > or = 100 microM induces aggregation of tau that prevents its entry into SDS-polyacrylamide gels and filtration through nylon membranes. This effect is noncovalent and can be reversed by addition of EDTA. However, when incubated along with ATP, GTP, or CTP, aluminum catalyzes a covalent linkage that results in incorporation of the alpha- and gamma-phosphates into the tau protein (phospho-incorporation). The sensitivity to phosphatases and partial hydrolysis and the labeling observed with ATP containing radioisotopes at different positions suggest a novel reaction in which the entire triphosphate moiety is transferred from ATP and linked to tau via an O-linkage to the alpha-phosphate. The aggregation and triphosphorylation phenomena were not catalyzed by divalent or quadrivalent cations, but similar effects were observed with some other trivalent cations. They occurred at aluminum concentrations similar to those found in human brains with Alzheimer's disease, suggesting the possibility that related reactions may have physiological significance in vivo.
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PMID:Aluminum-induced nonenzymatic phospho-incorporation into human tau and other proteins. 850 22


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