Proline-directed and Non-proline-directed Phosphorylation of PHF-tau

Morishima-Kawashima, Maho; Hasegawa, Masato; Takio, Koji; Suzuki, Masami; Yoshida, Hirotaka; Titani, Koiti; Ihara, Yasuo

doi:10.1074/jbc.270.2.823

Cited by 552 publications

(471 citation statements)

References 71 publications

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“…It has been reported that PHF-tau is highly phosphorylated in the tau 1 portion [26] and carboxy-terminal portion [27]. Recently 19 phosphorylation sites in PHF-tau have been identified, 10 of them are proline-directed sites, the remainder are non-proline sites [28], Among the non-proline-directed phosphorylation sites there are Ser-208 and Ser-210, which have -SR-motif and are located in K2 fragment/tau 1 portion. TTK phosphorylates K2 fragment as shown in Table 3A and Fig.…”

Section: Discussionmentioning

confidence: 99%

A novel tau‐tubulin kinase from bovine brain

et al. 1995

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During purification oftau protein kinase I and II from the bovine brain extract, a new tau protein kinase was detected and purified with phosphocellulose, gel filtration, S-Sepharose and AF-Heparin column chromatography. The molecular mass of the enzyme was determined to be 32 kDa by gel filtration and activity staining on SDS-PAGE. The enzyme is a Ser/Thr protein kinase phosphorylating tau, l~-tubulin, MAP2 and ~-casein. Employing many synthetic peptides, the recognition site of this enzyme appears to be -SR-. The enzyme requires no second messenger and is inhibited with high concentration of heparin, but not by inhibitors of CKI. These results indicate that this enzyme, tau-tubulin kinase is novel and distinct from TPKI, II and CKI, II.

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Section: Discussionmentioning

confidence: 99%

A novel tau‐tubulin kinase from bovine brain

et al. 1995

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“…In the AD brain, 19 phosphorylation sites have been identified in paired helical filament (PHF) tau throughout its 441 amino acids. 7,8 In vitro experiments have demonstrated that tau is a substrate for many kinases, including cyclic adenosine 5′-monophosphate (cAMP) dependent protein kinase, 9 calcium/ calmodulin-dependent protein kinase, 10 protein kinase C, 11 casein kinase, 12 mitogen-activated protein kinase, 13 microtubule affinityregulating kinase, 14 glycogen synthase kinase, 15 and cyclindependent kinase 5, cdk5. [16][17][18][19] Among these kinases, cdk5-a serine-threonine protein kinase, as well as its cyclin-related activator molecules p35, p39, p25, and p29 20 -has been demonstrated to phosphorylate tau at sites implicated in AD pathology.…”

Section: Introductionmentioning

confidence: 99%

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

et al. 2004

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A high-throughput assay for tau phosphorylation by cdk5/p25 is described. Full-length recombinant tau was used as a substrate in the presence of saturating adenosine triphosphate (ATP). Using PHF-1, an antibody directed specifically against 2 tau phosphorylation epitopes (serine 396 and serine 404), an enzyme-linked immunosorbent assay (ELISA)-based colorimetric assay was formatted in 384-well plates. The assay was validated by measuring kinetic parameters for cdk5/p25 catalysis and known inhibitors. Rate constants for the site-specific phosphorylations at the PHF-1 epitopes were determined and suggested preferential phosphorylation at these sites. The performance of this assay in a high-throughput format was demonstrated and used to identify inhibitors of tau phosphorylation at specific epitopes phosphorylated by cdk5/p25. (Journal of Biomolecular Screening 2004:122-131)

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“…The biochemical processes that cause soluble tau to aggregate into filaments are not clear. However, some posttranslational modifications, such as hyperphosphorylation (Iqbal et al, 1989;Lee et al, 1991;Morishima-Kawashima et al, 1995), glycation (Ledesma et al, 1994(Ledesma et al, , 1995, and glycosylation (Wang et al, 1996), have been detected in PHF-tau. The role of these modifications of tau in the formation of PHFs has not been well established so far.…”

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confidence: 99%

Characterization of In Vitro Glycation Sites of Tau

Nacharaju

Yen

1997

Journal of Neurochemistry

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Tau is a microtubule-associated protein that loses microtubule binding activity and aggregates into paired helical filaments (PHFs) in Alzheimer's disease. Nonenzymic glycation is one of the posttranslational modifications detected in PHF-tau, but not in normal tau. PHF-tau has reduced ability to bind to microtubules. To determine whether glycation of tau occurs in its microtubule binding domains, we have characterized in vitro glycation sites of the longest isoform of tau, which has four microtubule binding domains (Tau-4). The identified glycation sites are 132, 150, 163, 174, 225, 234, 259, 280, 281, 347, 353, and 369. We have also studied glycation of another isoform of tau, which has only three microtubule binding domains (Tau-3). This isoform is modified by glucose 15-20% more slowly than Tau-4. However, the glycation sites appear to be the same in both isoforms, except for Lys-280 and 281; these are located in the second microtubule binding domain, which is missing in Tau-3. Lys-150, 163, and 174 are located within or proximal to the sequence of tau that is involved in the microtubule nucleation activity, and 280, 281, 347, 353, and 369 are located in the microtubule binding domains. Glycation at these sites can affect the functional properties of tau, and advanced glycation at these sites might lead to the formation of insoluble aggregates similar to the ones seen in Alzheimer's disease.

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Proline-directed and Non-proline-directed Phosphorylation of PHF-tau

Cited by 552 publications

References 71 publications

A novel tau‐tubulin kinase from bovine brain

A novel tau‐tubulin kinase from bovine brain

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

Characterization of In Vitro Glycation Sites of Tau

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