ArticleACS chemical neuroscience2023
Phosphorylation of Tau R2 Repeat Destabilizes Its Binding to Microtubules: A Molecular Dynamics Simulation Study.
Article in ACS chemical neuroscience, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Septin crosstalk with microtubules and actin is regulated by a GSK3-dependent phosphoswitch.bioRxiv : the preprint server for biology · 2026Article
- Molecular Modeling of the Pathogenetic Mechanisms of Neuropsychiatric Disorders.International journal of molecular sciences · 2026Review
- Post-translational modifications as a regulatory code for tau function in health and disease.Frontiers in dementia · 2026Review
- Tau protein in Parkinson's disease: advances in phosphoproteomics and molecular dynamics simulations.Frontiers in aging neuroscience · 2026Review
- Recent molecular insights and biosensor-based diagnostic technologies for hyperphosphorylated Tau in Alzheimer's disease.Alzheimer's research & therapy · 2025Review
- Tau-Mitochondria Interactions in Neurodegeneration: Mechanisms and Therapeutic Potential.Cellular and molecular neurobiology · 2025Review
- Aberrant S293 Phosphorylation Drives Oligomerization of Tau Repeat R2: Insights from Molecular Dynamics Simulations.ACS chemical neuroscience · 2025Article
- Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency.Nature communications · 2025Article
- Disrupting Amyloid Filaments of Tau by Means of Electric Fields.The journal of physical chemistry. B · 2025Article
- Tauopathies: Calmodulin Regulates Tau Hyperphosphorylation and Its Transformation into Disease-Specific Aggregates.Biomolecules · 2025Review
- Bezafibrate treatment rescues neurodevelopmental and neurodegenerative defects in 3D cortical organoid model of MAPT frontotemporal dementia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in vitro.The Biochemical journal · 2025Article
- Effects of All-Atom and Coarse-Grained Molecular Mechanics Force Fields on Amyloid Peptide Assembly: The Case of a Tau K18 Monomer.Journal of chemical information and modeling · 2024Article
- Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution.Journal of chemical information and modeling · 2024Article
- Unveiling the multifaceted pathogenesis and therapeutic drugs of Alzheimer's disease: A comprehensive review.Heliyon · 2024Review
- Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer's Disease: A Narrative Review.Biomedicines · 2024Review
- Modulation of Tau Pathology in Alzheimer's Disease by Dietary Bioactive Compounds.International journal of molecular sciences · 2024Review
- Review
- Aggregation, Transmission, and Toxicity of the Microtubule-Associated Protein Tau: A Complex Comprehension.International journal of molecular sciences · 2023Review
- Article
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Authors and funding
4 authors at 2 institutions in 1 country.
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Abstract
Phosphorylation, the most popular post-translational modification of tau protein, plays an important role in regulating tau physiological functions. However, aberrant phosphorylation attenuates the binding affinity of tau to a microtubule (MT), resulting in MT destabilization followed by accumulation of neurofibrillary tangles in the brain. There are in total 85 potential phosphorylation sites in a full-length tau protein, and about half of them are abnormal as they occur in tau of Alzheimer's disease (AD) brain only. In this work, we investigated the impact of abnormal Ser289, Ser293, and Ser289/Ser293 phosphorylation on tau R2-MT binding and the conformation of tau R2 using molecular dynamics simulation. We found that the phosphorylation significantly affected R2-MT interaction and reduced the binding affinity of tau R2 peptides to MTs. Free energy decomposition analysis suggested that the post-translational modified residues themselves made a significant contribution to destabilize tau repeat R2-MT binding. Therefore, the phosphorylation may attenuate the binding affinity of tau to MTs. Additionally, the phosphorylation also enhanced helix-coil transition of monomeric R2 peptides, which may result in the acceleration of tau aggregation. Since these phosphorylated sites have not been examined in previous experimental studies, our finding through all-atom molecular dynamics simulations and free energy analysis can inspire experimental scientists to investigate the impact of the phosphorylation on MT binding and aggregation of full-length tau and the pathological roles of the phosphorylation at those sites in AD development through in vitro/in vivo assays.
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