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

This paper summarizes our recent studies on microtubule-associated protein tau and its pathological state resembling that of the paired helical filaments of Alzheimer's disease. The Alzheimer-like state of tau protein can be identified and analyzed in terms of certain phosphorylation sites and phosphorylation-dependent antibody epitopes. It can be induced by protein kinases which tend to phosphorylate serine or threonine residues followed by a proline; this includes mitogen-activated protein kinase (MAPK) and glycogen-synthase kinase 3 (GSK-3). Both of these are tightly associated with microtubules as well as with paired helical filaments. Structurally, tau appears as a rod-like molecule; it tends to self-associate into dimers whose monomers are antiparallel. Constructs of truncated tau made up of antiparallel dimers of the microtubule binding domain can be assembled into paired helical filaments in vitro.
Ann N Y Acad Sci 1993 Sep 24
PMID:Microtubule-associated protein tau, paired helical filaments, and phosphorylation. 769 33

The formation of neurofibrillary tangles (NFTs) and paired-helical filaments (PHFs) in Alzheimer's disease (AD) reflects a major disorganization of the cytoskeleton. The role of the neuronal membrane skeleton in the development of these abnormalities has not previously been investigated. In this study, we used 9 antibodies raised against the erythrocyte membrane skeleton protein 4.1 (P4.1) for immunocytochemical and immunoblot analyses to investigate whether or not the brain homologues of this protein were constituents of NFTs or PHFs. Our results show that 7 of the 9 monospecific antibodies against the human and pig erythrocyte P4.1 stained NFTs in the prefrontal cortex and hippocampus of AD brains. The P4.1 antibodies used here did not cross-react with tau protein isolated from AD brain, and preabsorption of these antibodies with tau protein did not cause loss of NFT staining. In age-matched control brains, these P4.1 antibodies stained neuronal cell bodies or nuclei. Six of the antibodies also stained isolated NFTs but the SDS-insoluble NFTs were immunostained only by two of the P4.1 antibodies. By using inositol hexaphosphate affinity chromatography and immunoblot analysis, we identified a 68-kDa protein as the most likely brain analogue of P4.1. When SDS-extracted proteins from the isolated NFTs were immunoblotted, a 50-kDa band was immunostained. The 68-kDa and 50-kDa proteins were not stained by tau protein and neurofilament subunit NF-H antibodies, that strongly stained NFTs. We conclude that brain protein 4.1 isoform(s) are constituents of NFTs in AD.
Brain Res 1994 Sep 05
PMID:Evidence for the association of protein 4.1 immunoreactive forms with neurofibrillary tangles in Alzheimer's disease brains. 780 27

We have studied the conformation of tau protein and Alzheimer paired helical filaments (PHF) by several spectroscopic, scattering, and imaging methods revealing the overall shape and the conformation of the polypeptide backbone. Tau protein behaves in solution as if it were denatured; no evidence for compact folding was detected. The protein is highly extended, there is no defined radius of gyration, and the scattering is best described by that of a random ("Gaussian") polymer. CD and Fourier transform infrared spectroscopy show only a minimal content of ordered secondary structure (alpha-helix or beta-sheet). Similarly, PHFs from Alzheimer brain tissue show no detectable secondary structure by x-ray diffraction or spectroscopy. It is thus unlikely that the aggregation of tau into Alzheimer PHFs is based on interactions between strands of beta-sheets (a model currently favored for other disease-related polymers such as beta-amyloid fibers of Alzheimer's disease).
J Biol Chem 1994 Sep 30
PMID:Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. 792 85

A68, or PHF-tau, is an abnormally phosphorylated form of the microtubule-associated protein tau, which is a primary protein constituent of paired helical filaments (PHFs) and, ultimately, of Alzheimer's disease-associated neurofibrillary tangles (NFTs). Previously, we have shown that in heat-shocked neuronal PC12 cells, tau is hyperphosphorylated and transformed to an A68-like state as determined by immunologic and biochemical criteria. In the present study, we investigated the role of heat shock protein of 72 kDa (hsp72) in the protection of tau against hyperphosphorylation during heat shock. Neuronal PC12 cells were exposed either directly to a heat shock (45 degrees C for 30 min) or to a conditioning heat stress (43 degrees C for 90 min followed by a 4 hr recovery at 37 degrees C) followed by the heat shock. Hsp72 was maximally induced immediately after heat shock in conditioned (acquired thermotolerant, ATT) cells, while unconditioned (nonacquired thermotolerant, non-ATT) cells required 9 hr of recovery to exhibit maximal hsp72 induction. The differential time course of hsp72 induction during recovery of ATT and non-ATT cells correlated with the presence of normal tau. Immediately after the heat shock, when hsps were maximally induced, ATT cells exhibited the normal form of tau. With longer recovery times, the levels of hsp72 were reduced and tau was hyperphosphorylated. A similar correlation was observed in non-ATT cells. In the presence of L-azetidyl 2-carboxylic acid, ATT cells synthesized nonfunctional hsp72, as exhibited by the inability of the cells to recover from the effects of heat shock.(ABSTRACT TRUNCATED AT 250 WORDS)
J Neurosci 1994 Sep
PMID:Heat shock proteins protect against stress-related phosphorylation of tau in neuronal PC12 cells that have acquired thermotolerance. 808 63

Phosphorylation of the neurofilament proteins of high and medium relative molecular mass, as well as of the Alzheimer's tau protein, is thought to be catalysed by a protein kinase with Cdc2-like substrate specificity. We have purified a novel Cdc2-like kinase from bovine brain capable of phosphorylating both the neurofilament proteins and tau. The purified enzyme is a heterodimer of cyclin-dependent kinase 5 (Cdk5) and a novel regulatory subunit, p25 (ref. 8). When overexpressed and purified from Escherichia coli, p25 can activate Cdk5 in vitro. Unlike Cdk5, which is ubiquitously expressed in human tissue, the p25 transcript is expressed only in brain. A full-length complementary DNA clone showed that p25 is a truncated form of a larger protein precursor, p35, which seems to be the predominant form of the protein in crude brain extract. Cdk5/p35 is the first example of a Cdc2-like kinase with neuronal function.
Nature 1994 Sep 29
PMID:A brain-specific activator of cyclin-dependent kinase 5. 809 Feb 22

Paired helical filaments, a constituent of neurofibrillary tangles in Alzheimer's disease, consist primarily of the microtubule-associated protein tau. However, the process by which the detergent-insoluble filaments of the neurofibrillary tangles are formed from soluble tau remains unknown. Here, we present a potential mechanism for the abnormal aggregation of tau in Alzheimer's disease: the covalent cross-linking of tau by the enzyme transglutaminase. Macromolecular complexes of tau, formed in the presence of transglutaminase, were found to be insoluble in ionic detergent, beta-mercaptoethanol, guanidine-HCl, and urea and, furthermore, demonstrated an increased immunoreactivity with the monoclonal antibody Alz-50. Electron microscopic studies revealed that tau cross-linked by transglutaminase has a defined filamentous structure. These results indicate that transglutaminase, the activity of which has been shown to increase during programmed cell death, may play a role in the formation of pathology associated with Alzheimer's disease.
J Neurochem 1993 Sep
PMID:Transglutaminase catalyzes the formation of sodium dodecyl sulfate-insoluble, Alz-50-reactive polymers of tau. 810 81

tau in paired helical filaments (PHF-tau) and fetal tau share several phosphorylated epitopes, as revealed by several phosphorylation-dependent PHF monoclonals. We have asked whether there is any difference between the two molecules in tubulin assembly-promoting activity and found that PHF-tau is almost assembly incompetent, whereas fetal tau is low in this activity but still assembly competent. This indicates that despite substantial similarities in immunoreactivities, PHF-tau and fetal tau are quite distinct from each other in function.
J Neurochem 1993 Sep
PMID:Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. 836 Jun 83

Much indirect evidence suggests that the interconnections of actin microfilaments with the microtubule system are mediated by microtubule-associated proteins (MAPs). In this study we provide new data to support the interaction of a specific tubulin-binding domain on tau with actin in vitro. In actin polymerization assays, the synthetic peptide VRSKIGSTENLKHQPGGG, corresponding to the first repetitive sequence of tau protein, increased turbidity at 320 nm in a dose-dependent fashion. A salient feature of the tau peptide-induced assembly process is the formation of a large amount of actin filament bundles, as revealed by electron microscopic analysis. An increase in the tau peptide concentration resulted in a proportional increase in the bundling of actin filaments. It is interesting that a gradual decrease of pH within the range 7.6-4.7 resulted in a higher effect of tau peptide in promoting bundles of actin filaments. A similar pH-dependent effect was observed for tau protein-induced bundling. An analysis of the mechanisms that operate in the peptide induction of actin filament bundles suggests the involvement of electrostatic forces, because the neutralization of epsilon-aminolysyl residues by selective carbamoylation resulted in a complete loss of the peptide induction of actin bundles. The data suggest that a tau repetitive sequence (also found in MAP-2 and MAP-4) containing a common tubulin binding motif may constitute a functional domain on tau for the dynamics of the interconnections between actin filaments and microtubules.
J Neurochem 1993 Sep
PMID:A tau fragment containing a repetitive sequence induces bundling of actin filaments. 836 Jun 95

The microtubule-associated protein tau is found primarily in neuronal tissues and is highly enriched in the axon. It promotes microtubule assembly in vitro and stabilizes microtubules in cells. To study how tau protein might be involved in the unique features of axonal microtubules, we have analyzed the effect of E. coli-synthesized tau protein using an in vitro centrosome-mediated microtubule regrowth assay over a wide range of tau/tubulin ratios. We report that microtubule assembly promoted by tau protein exhibits characteristic changes dependent on the tau/tubulin ratio. Above a threshold level, nucleation of new microtubules is favored over growth of existing ones. tau isoform variation does not change this phase transition in microtubule assembly. We discuss how tau might participate in the elaboration of axonal morphology based on our results and present evidence that the phase transition from microtubule growth to nucleation is critical for axonal development.
J Neurochem 1993 Sep
PMID:The balance between tau protein's microtubule growth and nucleation activities: implications for the formation of axonal microtubules. 836 Jun 96

Synthetic peptide representing the site Ser-41 in vimentin, Leu-Gly-Ser41-Ala42-Leu-Arg44-Arg-Arg-NH2, and its analogs in which Ala-42 was replaced by various amino acids were tested as substrates for cdc2 kinase. Among them, the analog containing sarcosine as well as proline was an excellent substrate. The result suggests that the N-substituted structure of proline immediately following the site is important for cdc2 kinase phosphorylation. Replacement of Ala-42 by polar amino acids, especially lysine, had negative effects on peptide phosphorylation. The peptides in this study were also assayed with another type of proline-directed protein kinase, tau protein kinase II. The substrate specificity differed essentially from that of cdc2 kinase.
Biochem Biophys Res Commun 1993 Sep 15
PMID:Phosphorylation of synthetic vimentin peptides by cdc2 kinase. 837 19


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