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

Zhou, Lian-Xiu; Zeng, Zhiyang; Du, J.; Zhao, Yufen; Li, Yanmei

doi:10.1016/j.bbrc.2006.07.099

Cited by 22 publications

(15 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3A), Z-average-size of the DR1-p231 aggregation increased from 200 nm to 600 nm at 30 h and was kept at about 700 nm during 50-100 h (Fig. Similar data was reported for the phosphorylation at Ser262 [37], suggesting that phosphorylation commonly enhanced aggregation of the R1 peptide. Similar data was reported for the phosphorylation at Ser262 [37], suggesting that phosphorylation commonly enhanced aggregation of the R1 peptide.…”

Section: Resultssupporting

confidence: 77%

“…1A) in order to elucidate the relationship between the cis/trans isomeric state at the bond and the aggregation propensity of the peptide. Although the isolated R1 region (R1 peptide) was reported to be less aggregation-prone [24,25,37], our peptide formed large aggregation with 863.9 AE 46.1 nm of hydrodynamic diameter after 11 days' incubation ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 71%

See 1 more Smart Citation

The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

et al. 2018

View full text Add to dashboard Cite

In Alzheimer's, the disease-related protein Tau is hyperphosphorylated and aggregates into neurofibrillary tangles (NFT). The cis isomer of the phosphorylated Thr231-Pro232 has been proposed as a precursor of aggregation ('Cistauosis'), but this aggregation scheme is not yet completely accepted. Here, we synthesized peptides comprising a phosphorylated region including Thr231-Pro232 and an aggregation-core region R1 to investigate isomer-specific-aggregation of Tau. The phosphorylated peptide formed amyloid-like aggregation. This aggregation was observed even in the presence of the catalytic domain of the peptidyl-prolyl-isomerase Pin1, which preferentially converts the cis isomer to the trans isomer, but decreased drastically in the presence of the WW domain of Pin1 selectively binding to the trans isomer. These results indicate that the trans isomer is aggregation-prone and that the WW domain of Pin1 effectively inhibits its aggregation.

show abstract

Section: Resultssupporting

confidence: 77%

Section: Resultsmentioning

confidence: 71%

The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Hyperphosphorylation of tau in the MTBD by microtubule affinity regulating kinase (MARK)/PAR1 or other kinases gives rise to a destabilized MT network and concomitant self-assembly of the increased concentration of unbound tau [13], [15], [16]. This self-assembled tau is purported to serve as a seed for further assembly of redistributed tau into PHFs along neurites (neuropil threads) and in the somatodendritic domain (neurofibrillary tangles) [1], [2], [54], [55].…”

Section: Discussionmentioning

confidence: 99%

“…In AD, tau is hyperphosphorylated, the MT network is destabilized and tau self-assembles into paired helical filaments (PHFs) that form the NFT and neuropil thread structures. Over 20 phosphorylation sites have been characterized for tau, two of these are located in the MTBD at two ‘KXGS’ amino acid motifs corresponding to residues S262 and S356 [11]–[13]. Phosphorylation of these KXGS motifs is one of the earliest markers of AD pathology, readily detectable in neuropil threads with the monoclonal antibody 12E8 that recognizes these conserved motifs in both tau as well as in other MAPs [14].…”

Section: Introductionmentioning

confidence: 99%

Rapid Changes in Phospho-MAP/Tau Epitopes during Neuronal Stress: Cofilin-Actin Rods Primarily Recruit Microtubule Binding Domain Epitopes

et al. 2011

View full text Add to dashboard Cite

Abnormal mitochondrial function is a widely reported contributor to neurodegenerative disease including Alzheimer's disease (AD), however, a mechanistic link between mitochondrial dysfunction and the initiation of neuropathology remains elusive. In AD, one of the earliest hallmark pathologies is neuropil threads comprising accumulated hyperphosphorylated microtubule-associated protein (MAP) tau in neurites. Rod-like aggregates of actin and its associated protein cofilin (AC rods) also occur in AD. Using a series of antibodies - AT270, AT8, AT100, S214, AT180, 12E8, S396, S404 and S422 - raised against different phosphoepitopes on tau, we characterize the pattern of expression and re-distribution in neurites of these phosphoepitope labels during mitochondrial inhibition. Employing chick primary neuron cultures, we demonstrate that epitopes recognized by the monoclonal antibody 12E8, are the only species rapidly recruited into AC rods. These results were recapitulated with the actin depolymerizing drug Latrunculin B, which induces AC rods and a concomitant increase in the 12E8 signal measured on Western blot. This suggests that AC rods may be one way in which MAP redistribution and phosphorylation is influenced in neurons during mitochondrial stress and potentially in the early pathogenesis of AD.

show abstract

“…Tau can self-assemble when phosphorylated with a combination of isolated kinases (23), and the biological activity of Tau (microtubulebinding, disruption, and self-assembly) can be differentially regulated by different kinases (24). Studying the self-assembly properties of the first microtubule-binding domain of Tau, Zhou et al (25) showed by turbidity, electron microscopy, circular dichroism (CD), and NMR spectroscopy that phosphorylation at Ser 262 could accelerate Tau assembly into filaments. The discovery of mutations in the Tau gene, which cosegregate with the disease in FTDP-17, provided unequivocal evidence that Tau abnormalities alone are enough to cause neurodegenerative disease (26 -28).…”

mentioning

confidence: 99%

Phosphorylation of Tau at Thr212, Thr231, and Ser262 Combined Causes Neurodegeneration

Alonso

Clerico

et al. 2010

Journal of Biological Chemistry

197

153

View full text Add to dashboard Cite

Abnormal hyperphosphorylation of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and related diseases called tauopathies. As yet, the exact mechanism by which this pathology causes neurodegeneration is not understood. The present study provides direct evidence that Tau abnormal hyperphosphorylation causes its aggregation, breakdown of the microtubule network, and cell death and identifies phosphorylation sites involved in neurotoxicity. We generated pseudophosphorylated Tau proteins by mutating Ser/Thr to Glu and, as controls, to Ala. These mutations involved one, two, or three pathological phosphorylation sites by site-directed mutagenesis using as backbones the wild type or FTDP-17 mutant R406W Tau. Pseudophosphorylated and corresponding control Tau proteins were expressed transiently in PC12 and CHO cells. We found that a single phosphorylation site alone had little influence on the biological activity of Tau, except Thr 212 , which, upon mutation to Glu in the R406W background, induced Tau aggregation in cells, suggesting phosphorylation at this site along with a modification on the C-terminal of the protein facilitates self-assembly of Tau. The expression of R406W Tau pseudophosphorylated at Thr 212 , Thr 231 , and Ser 262 triggered caspase-3 activation in as much as 85% of the transfected cells, whereas the corresponding value for wild type pseudophosphorylated Tau was 30%. Cells transfected with pseudophosphorylated Tau became TUNEL-positive.

show abstract

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

Cited by 22 publications

References 32 publications

The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

The trans isomer of Tau peptide is prone to aggregate, and the WW domain of Pin1 drastically decreases its aggregation

Rapid Changes in Phospho-MAP/Tau Epitopes during Neuronal Stress: Cofilin-Actin Rods Primarily Recruit Microtubule Binding Domain Epitopes

Phosphorylation of Tau at Thr212, Thr231, and Ser262 Combined Causes Neurodegeneration

Contact Info

Product

Resources

About