Phosphorylation at Ser289 Enhances the Oligomerization of Tau Repeat R2

Abstract

In tauopathies such as Alzheimer's disease (AD), aberrant phosphorylation causes the dissociation of tau proteins from microtubules. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments and insoluble neurofibrillary tangles (NFTs). NFTs is a hallmark of AD, while oligomers are found to be the most toxic form of the tau aggregates. Therefore, understanding tau oligomerization with regard to abnormal phosphorylation is important for the therapeutic development of AD. In this study, we investigated the impact of phosphorylated Ser289, one of the 40 aberrant phosphorylation sites of full-length tau proteins, on monomeric and dimeric structures of tau repeat R2 peptides. We carried out intensive replica exchange molecular dynamics simulation with a total simulation time of up to 0.1 ms. Our result showed that the phosphorylation significantly affected the structures of both the monomer and the dimer. For the monomer, the phosphorylation enhanced ordered−disordered structural transition and intramolecular interaction, leading to more compactness of the phosphorylated R2 compared to the wild-type one. As to the dimer, the phosphorylation increased intermolecular interaction and β-sheet formation, which can accelerate the oligomerization of R2 peptides. This result suggests that the phosphorylation at Ser289 is likely to promote tau aggregation. We also observed a phosphorylated Ser289-Na + -phosphorylated Ser289 bridge in the phosphorylated R2 dimer, suggesting an important role of cation ions in tau aggregation. Our findings suggest that phosphorylation at Ser289 should be taken into account in the inhibitor screening of tau oligomerization.

Molecular Insights into the Differential Effects of Acetylation on the Aggregation of Tau Microtubule-Binding Repeats

“…By performing 500 ns REMD simulation with the Charmm36m force field, Man et al investigated the effect of phosphorylated Ser289 on dimeric structures of tau R2 peptides and reported that the βsheet probability of the R2 dimer was 14.17% and phosphorylation increased the β-sheet content to 16.89%. 59 This different result of β-sheet probability of the R2 dimer may be due to the different force fields used in our and Man et al's works. The probability of the β-strand length of the R2 dimer in two systems is shown in Figure 3c.…”

“…It is noted that PHF6* ( 275 VQIINK 280 ) is one of the fibril-nucleating core motifs of tau and plays a vital role in tau aggregation; , thus, the enhanced β-sheet probability in this region is supposed to promote tau dimerization. By performing 500 ns REMD simulation with the Charmm36m force field, Man et al investigated the effect of phosphorylated Ser289 on dimeric structures of tau R2 peptides and reported that the β-sheet probability of the R2 dimer was 14.17% and phosphorylation increased the β-sheet content to 16.89% . This different result of β-sheet probability of the R2 dimer may be due to the different force fields used in our and Man et al’s works.…”

“…The high β-sheet regions of R2 and R3 dimers are in good agreement with those of full-length tau identified by NMR spectroscopy. 58 Previous REMD simulations on R2 59 and R3 dimers 60 revealed that high probability of β-structure is mainly distributed in the Nterminal and C-terminal residues of R2 and three regions (Q307−K311, V318−C322, and G326−K331) of R3. R2 dimer has a high probability to form β-strands with lengths of 3 and 4, with probabilities of 6.73 and 6.0%, respectively.…”

nP-collabs: Investigating counterion mediated bridges in the multiply phosphorylated tau-R2 repeat

“…Intermolecular 2P-collabs were also observed by Man et al when modeling a system comprising two monophosphorylated (pSer289) tau-R2 fragments with the C36 FF. 69 A pS289-Na + -pS289 bridge was present in 16% of the MD trajectory, and this result raises the question of whether nP-collabs could be a possible pathway to aggregation by bridging monomers. Generally speaking, all these recognized and unrecognized sightings of nP-collabs make a strong case for the importance of bulk ions in MD simulations, and we therefore urge the computational community to reconsider their relevance and keep track of them in the future.…”

Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer’s Disease: A Narrative Review

“…Tau, as a 'tubulin-associated unit' and a protein constituting over 80% of MT-associated proteins, primarily plays a physiological role in bundling and stabilizing axonal MTs through tubulin polymerization, a process that is disrupted by phosphorylation [63][64][65]. Additionally, phosphorylation, particularly by GSK-3β, results in reduced tau transport along the axon due to diminished interaction with kinesin [64,66].…”