Publications by authors named "Jin-Tang Du"

10 Publications

  • Page 1 of 1

O-GlcNAcylation modulates the self-aggregation ability of the fourth microtubule-binding repeat of tau.

Biochem Biophys Res Commun 2008 Oct 29;375(1):59-62. Epub 2008 Jul 29.

Department of Chemistry, Beihua University, Jilin 132013, PR China.

In Alzheimer's disease (AD), tau protein is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs). It was discovered recently that tau is also O-GlcNAcylated in human brains. And O-GlcNAcylation may regulate phosphorylation of tau in a site-specific manner. In this work, we focused on the fourth microtubule-binding repeat (R4) of tau, which has an O-GlcNAcylation site-Ser356. The aggregation behavior of this repeat and its O-GlcNAcylated form was investigated by turbidity, precipitation assay and electron microscopy. In addition, conformations of these two peptides were analyzed with circular dichroism (CD). Our results revealed that O-GlcNAcylation at Ser356 could greatly slow down the aggregation speed of R4 peptide. This modulation of O-GlcNAcylation on tau aggregation implies a new perspective of tau pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2008.07.101DOI Listing
October 2008

Copper (II) modulates in vitro aggregation of a tau peptide.

Peptides 2007 Nov 31;28(11):2229-34. Epub 2007 Aug 31.

Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.

Copper (II) has been implicated in the pathology of Alzheimer's disease (AD) for the impaired homeostatic mechanism found in the brains of AD patients. Here we studied the binding properties of Cu(II) with the first microtubule-binding repeat, encompassing residues 256-273 of the human tau441 sequence. Additionally, the effect of Cu(II) on the assembly of this repeat was also investigated. Our results indicate that Cu(II) can bind to this repeat with His(268) involved and has an inhibiting effect on the in vitro aggregation of this repeat. This work provides new insight into the role of Cu(II) in Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.peptides.2007.08.022DOI Listing
November 2007

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

FEBS J 2007 Oct 24;274(19):5012-20. Epub 2007 Aug 24.

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing, China.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1742-4658.2007.06018.xDOI Listing
October 2007

Alternative O-GlcNAcylation/O-phosphorylation of Ser16 induce different conformational disturbances to the N terminus of murine estrogen receptor beta.

Chem Biol 2006 Sep;13(9):937-44

Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China.

Serine and threonine residues in many proteins can be modified by either phosphorylation or GlcNAcylation. To investigate the mechanism of O-GlcNAc and O-phosphate's reciprocal roles in modulating the degradation and activity of murine estrogen receptor beta (mER-beta), the conformational changes induced by O-GlcNAcylation and O-phosphorylation of Ser(16) in 17-mer model peptides corresponding to the N-terminal intrinsically disordered (ID) region of mER-beta were studied by NMR techniques, circular dichroism (CD), and molecular dynamics simulations. Our results suggest that O-phosphorylation discourages the turn formation in the S(15)STG(18) fragment. In contrast, O-GlcNAcylation promotes turn formation in this region. Thus, we postulate that the different changes of the local structure in the N-terminal S(15)STG(18) fragment of mER-beta caused by O-phosphate or O-GlcNAc modification might lead to the disturbances to the dynamic ensembles of the ID region of mER-beta, which is related to its modulatory activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chembiol.2006.06.017DOI Listing
September 2006

The self-assembly ability of the first microtubule-binding repeat from tau and its modulation by phosphorylation.

Biochem Biophys Res Commun 2006 Sep 28;348(2):637-42. Epub 2006 Jul 28.

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.

Aggregation of abnormally phosphorylated tau in the form of tangs of paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease (AD) and other tauopathies. It is of fundamental importance to study the mechanism of PHF formation and its modulation by phosphorylation. In this work, we have focused on the first microtubule-binding repeat of tau encompassing an abnormal phosphorylation site Ser262. The assembly propensities of this repeat and its corresponding phosphorylated form were investigated by turbidity and electron microscopy. Additionally, conformation of the two peptides is also analyzed through circular dichroism (CD) and NMR spectroscopy. Our results reveal that both of them are capable of self-assembly and phosphorylation at Ser262 could speed up the process of assembly. A possible mechanism of PHF formation is proposed and enhancing effect of phosphorylation on assembly provides an explanation to its toxicity in Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2006.07.099DOI Listing
September 2006

Characterization of copper binding to the peptide amyloid-beta(1-16) associated with Alzheimer's disease.

Biopolymers 2006 Sep;83(1):20-31

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, 100084 Beijing, China.

Amyloid-beta peptide (Abeta) is the principal constituent of plaques associated with Alzheimer's disease (AD) and is thought to be responsible for the neurotoxicity associated with the disease. Copper binding to Abeta has been hypothesized to play an important role in the neruotoxicity of Abeta and free radical damage, and Cu2+ chelators represent a possible therapy for AD. However, many properties of copper binding to Abeta have not been elucidated clearly, and the location of copper binding sites on Abeta is also in controversy. Here we have used a range of spectroscopic techniques to characterize the coordination of Cu2+ to Abeta(1-16) in solution. Electrospray ionization mass spectrometry shows that copper binds to Abeta(1-16) at pH 6.0 and 7.0. The mode of copper binding is highly pH dependent. Circular dichroism results indicate that copper chelation causes a structural transition of Abeta(1-16). UV-visible absorption spectra suggest that three nitrogen donor ligands and one oxygen donor ligand (3N1O) in Abeta(1-16) may form a type II square-planar coordination geometry with Cu2+. By means of fluorescence spectroscopy, competition studies with glycine and L-histidine show that copper binds to Abeta(1-16) with an affinity of Ka approximately 10(7) M(-1) at pH 7.8. Besides His6, His13, and His14, Tyr10 is also involved in the coordination of Abeta(1-16) with Cu2+, which is supported by 1H NMR and UV-visible absorption spectra. Evidence for the link between Cu2+ and AD is growing, and this work has made a significant contribution to understanding the mode of copper binding to Abeta(1-16) in solution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bip.20523DOI Listing
September 2006

Novel acetylation-aided migrating rearrangement of uridine-diphosphate-N-acetylglucosamine in electrospray ionization multistage tandem mass spectrometry.

J Mass Spectrom 2006 Feb;41(2):208-15

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.

Uridine 5'-diphospho-N-acetylglucosamine (UDP-GlcNAc) is the final product of hexosamine biosynthetic pathway (HSP) and the donor substrate for the modification of nucleocytoplasmic proteins at serine and threonine residues with N-acetylglucosamine (GlcNAc) catalyzed by O-GlcNAc transferase (OGT). Many analogs of UDP-GlcNAc were designed to interfere with the process of protein O-glycosylation by blocking OGT. A novel rearrangement reaction was observed in which phosphate-N-acetylglucosamine moiety migrated to 3' terminus of ribose in ESI-MS(n) of UDP-GlcNAc. Results from tandem mass spectrometry, control experiments and calculation showed that the phosphate-N-acetylglucosamine migration might undergo a pentacoordinate phosphoric intermediate. Furthermore, the acetylation of glucosamine in UDP-GlcNAc was essential in the migration process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jms.979DOI Listing
February 2006

Low-barrier hydrogen bond between phosphate and the amide group in phosphopeptide.

J Am Chem Soc 2005 Nov;127(47):16350-1

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.

As the conversion between the monoionic (1) and diionic (2) form of the phosphate occurs, the phosphorylated peptides or proteins can not only cause the formation of a hydrogen bond between the phosphate group and the amide group but also change the strength of the hydrogen bond to form low-barrier hydrogen bonds (LBHBs). This reversible protonation of the phosphate group, which changes both the electrostatic properties of the phosphate group and the strength of the hydrogen bond, provides a possible mechanism in regulating protein function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja054568pDOI Listing
November 2005

Binding of copper (II) ion to an Alzheimer's tau peptide as revealed by MALDI-TOF MS, CD, and NMR.

Biopolymers 2005 Oct;79(2):74-85

Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, 100084 Beijing, China.

The tau protein plays an important role in some neurodegenerative diseases including Alzheimer's disease (AD). Neurofibrillary tangles (NFTs), a biological marker for AD, are aggregates of bundles of paired helical filaments (PHFs). In general, the alpha-sheet structure favors aberrant protein aggregates. However, some reports have shown that the alpha-helix structure is capable of triggering the formation of aberrant tau protein aggregates and PHFs have a high alpha-helix content. In addition, the third repeat fragment in the four-repeat microtubule-binding domain of the tau protein (residues 306-336: VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQ, according to the longest tau protein) adopts a helical structure in trifluoroethanol (TFE) and may be a self-assembly model in the tau protein. In the human brain, there is a very small quantity of copper, which performs an important function. In our study, by means of matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS), circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopy, the binding properties of copper (II) ion to the R3 peptide derived from the third repeat fragment (residues 318-335: VTSKCGSLGNIHHKPGGG) have been investigated. The results show that copper ions bind to the R3 peptide. CD spectra, ultraviolet (UV)-visible absorption spectra, and MALDI-TOF MS show pH dependence and stoichiometry of Cu2+ binding. Furthermore, CD spectra and NMR spectroscopy elucidate the copper binding sites located in the R3 peptide. Finally, CD spectra reveal that the R3 peptide adopts a mixture structure of random structures, alpha-helices, and beta-turns in aqueous solutions at physiological pH. At pH 7.5, the addition of 0.25 mol eq of Cu2+ induces the conformational change from the mixture mentioned above to a monomeric helical structure, and a beta-sheet structure forms in the presence of 1 mol eq of Cu2+. As alpha-helix and beta-sheet structures are responsible for the formation of PHFs, it is hypothesized that Cu2+ is an inducer of self-assembly of the R3 peptide and makes the R3 peptide form a structure like PHF. Hence, it is postulated that Cu2+ plays an important role in the aggregation of the R3 peptide and tau protein and that copper (II) binding may be another possible involvement in AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bip.20335DOI Listing
October 2005

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

Regul Pept 2005 Aug;130(1-2):48-56

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.

In the brains of Alzheimer's disease patients, the tau protein dissociates from the axonal microtubule and abnormally aggregates to form a paired helical filament (PHF). One of the priorities in Alzheimer research is to determine the effects of abnormal phosphorylation on the local structure. A series of peptides corresponding to isolated regions of tau protein have been successfully synthesized using Fmoc-based chemistry and their conformations were determined by 1H NMR spectroscopy and circular dichroism (CD) spectroscopy. Immunodominant peptides corresponding to tau-(256-273), tau-(350-367) and two phosphorylated derivatives in which a single Ser was phosphorylated at positions 262 and 356, respectively, were the main focus of the study. A direct alteration of the local structure after phosphorylation constitutes a new strategy through which control of biological activity can be enforced. In our study on Ser262 in R1 peptide and Ser356 in R4 peptide, phosphorylation modifies both the negative charge and the local conformation nearby the phosphorylation sites. Together, these structural changes indicate that phosphorylation may act as a conformational switch in the binding domain of tau protein to alter specificity and affinity of binding to microtubule, particularly in response to the abnormal phosphorylation events associated with Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.regpep.2005.03.003DOI Listing
August 2005
-->