Synthesis and conformational properties of phosphopeptides related to the human tau protein

Du, J.; Li, Yanmei; Ma, Qing-Feng; Wei, Qiang; Zhao, Yufen; Abe, Hiroshi; Kanazawa, Kenji; Qin, Xurong; Aoyagi, Ryousuke; Ishizuka, Yoshihiro; Nemoto, Tadashi; Nakanishi, Hiroshi

doi:10.1016/j.regpep.2005.03.003

Cited by 19 publications

(15 citation statements)

References 36 publications

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“…In phosphorylated peptide pR4, a hydrogen bond between the nearby amide proton and the phosphate group appears to be the driving force behind the structural changes that occur upon phosphorylation of Ser356. In addition, the NMR spectra in water suggested the presence, except for the major conformer, of one or more minor conformations for the R4 peptide, as evidenced by the appearance of additional resonances of lower intensity than those in the major conformer [21]. However, only one major conformation was observed in phosphopeptide pR4.…”

Section: Resultsmentioning

confidence: 99%

Phosphorylation modulates the local conformation and self‐aggregation ability of a peptide from the fourth tau microtubule‐binding repeat

Zhou

et al. 2007

The FEBS Journal

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Phosphorylation of tau protein modulates both its physiological role and its aggregation into paired helical fragments, as observed in Alzheimer's diseased neurons. It is of fundamental importance to study paired helical fragment formation and its modulation by phosphorylation. This study focused on the fourth microtubule‐binding repeat of tau, encompassing an abnormal phosphorylation site, Ser356. The aggregation propensities of this repeat peptide and its corresponding phosphorylated form were investigated using turbidity, thioflavin T fluorescence and electron microscopy. There is evidence for a conformational change in the fourth microtubule‐binding repeat of tau peptide upon phosphorylation, as well as changes in aggregation activity. Although both tau peptides have the ability to aggregate, this is weaker in the phosphorylated peptide. This study reveals that both tau peptides are capable of self‐aggregation and that phosphorylation at Ser356 can modulate this process.

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Section: Resultsmentioning

confidence: 99%

Phosphorylation modulates the local conformation and self‐aggregation ability of a peptide from the fourth tau microtubule‐binding repeat

Zhou

et al. 2007

The FEBS Journal

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“…Hyperphosphorylation at Ser396/404 promotes self assembly of Tau to form aggregates of Tau [39]. Moreover, in vitro studies using Tau peptides showed that phosphorylation of Tau at Ser262 and Ser356 modified both the negative charge and the local conformation near the phosphorylation sites, reducing the affinity of the peptides to bind to MTs [42]. Therefore, our finding of very high levels of p-Ser262 in the brain stem may explain the increased levels of soluble α-tubulin seen in this brain region.…”

Section: Discussionmentioning

confidence: 99%

Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease

et al. 2011

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Backgroundα-synuclein [α-Syn]-mediated activation of GSK-3β leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the α-Syn overexpressing mouse.ResultsHigh levels of α-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of α-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p-Ser202 and p-Ser262. p-GSK-3β levels were not elevated in any of the brain regions, although total GSK-3β was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem.ConclusionOur combined data suggest that in this animal model of PD, tauopathy, along with microtubule destabilization, exists primarily in the brain stem and striatum, which are also the two major brain regions known to express high levels of α-Syn and undergo the highest levels of degeneration in human PD. Thus, tauopathy in PD may have a very restricted pattern of distribution.

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“…For example, the phosphorylation of Ser 63 in Op18/stathmin disrupts the central helix and suppresses its binding to tubulin (Steinmetz et al 2001). Phosphorylation modifies both the negative charge and the local conformation near the phosphorylation sites in Tau protein (Du et al 2005). These structural changes suggest that phosphorylation may act as a conformational switch in the binding domain of MAPs.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Microtubule‐associated Protein SB401 from Solanum berthaultii Regulates Its Effect on Microtubules

Liu

Jin

Zhu

et al. 2009

JIPB

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We reported previously that the protein SB401 from Solanum berthaultii binds to and bundles both microtubules and F-actin. In the current study, we investigated the regulation of SB401 activity by its phosphorylation. Our experimental results showed that the phosphorylation of SB401 by casein kinase II (CKII) downregulates the activities of SB401, namely the bundling of microtubules and enhancement of the polymerization of tubulin. However, phosphorylation of SB401 had no observable effect on its bundling of F-actin. Further investigation using extract of potato pollen indicated that a CKII-like kinase may exist in potato pollen. Antibodies against CKII alpha recognized specifically a major band from the pollen extract and the pollen extract was able to phosphorylate the SB401 protein in vitro. The CKII-like kinase showed a similar ability to downregulate the bundling of microtubules. Our experiments demonstrated that phosphorylation plays an important role in the regulation of SB401 activity. We propose that this phosphorylation may regulate the effects of SB401 on microtubules and the actin cytoskeleton. Microtubule-associated proteins (MAPs) have been increasingly identified from plant cells and play important roles in various functions of microtubules (MTs) (Gardiner et al. 2001;Whittington et al. 2001;Hussey et al. 2002;Webb et al. 2002;Sedbrook et al. 2004;Fu et al. 2005;Wang et al. 2007;Huang et al. 2007). The regulation of MAP activities may be an effective way for the MT cytoskeleton to respond to signal transduction and to alter its functions.It has been reported that the activities of MAPs are regulated by phosphorylation. For example, phosphorylation and dephosphorylation of AtMAP65-1 occurs during the cell cycle, and the phosphorylation reduces the binding and bundling of AtMAP65-1 to MTs (Smertenko et al. 2006). The mitogenactivated protein kinase (MAPK) cascade of tobacco plants is also involved in the phosphorylation of tobacco NtMAP65-1a (Sasabe et al. 2006). Similarly, NRK1/NTF6 phosphorylates the threonine residue at position 579 of NtMAP65-1a and downregulates its MT-bundling activity. This phosphorylation of NtMAP65-1a enhances the destabilization and turnover of MTs at the equator of the phragmoplast and thereby facilitates expansion of the phragmoplast.The protein SB401 was first identified from the cDNA library of in vitro-germinated pollen from the diploid potato species Solanum berthaultii (Liu et al. 1997). Recently, we reported that SB401 binds to MTs and causes their bundling in vitro. In addition, SB401 binds to and bundles actin filaments. Hence, SB401 may function as a link between actin and the MT cytoskeleton ). Nevertheless, our experiment showed that SB401 binds preferentially to MTs (Huang et al. 2007). The mechanism of regulation of the binding of SB401 to MTs or F-actin is unknown.In the study reported herein, we obtained experimental results that showed that phosphorylation by casein kinase II (CKII) 236 Journal of Integrative Plant Biology Vol. 51 No. 3 2009 ...

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Synthesis and conformational properties of phosphopeptides related to the human tau protein

Cited by 19 publications

References 36 publications

Phosphorylation modulates the local conformation and self‐aggregation ability of a peptide from the fourth tau microtubule‐binding repeat

Phosphorylation modulates the local conformation and self‐aggregation ability of a peptide from the fourth tau microtubule‐binding repeat

Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease

Phosphorylation of Microtubule‐associated Protein SB401 from Solanum berthaultii Regulates Its Effect on Microtubules

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