ArticleProceedings of the National Academy of Sciences of the United States of America2024
Precision proteoform design for 4R tau isoform selective templated aggregation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 13 citations in OpenAlex.
- A water-pinning hotspot drives templated tau aggregation.bioRxiv : the preprint server for biology · 2026Article
- Water-Mediated Phosphoryl Wires Stabilize Pathological Tau Fibrils.Angewandte Chemie (International ed. in English) · 2026Article
- tRNA-derived fragments elevated in Alzheimer's disease promote Tau aggregation.bioRxiv : the preprint server for biology · 2026Article
- Disentangling Intrachain Folding from Interchain Assembly through Multidimensional Visualization.The journal of physical chemistry. B · 2026Article
- Tau profiling of brain extracellular vesicles reveals PHF6 peptide as core for pathological tau seeding in Alzheimer's disease.Journal of biomedical science · 2026Article
- amyloid-predict and LLPS-predict: Predicting phase separation propensities in the intrinsically disordered proteome.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- BAG2 Condensates Couple Proteostasis to CD8bioRxiv : the preprint server for biology · 2026Article
- Electric Double Layer Phenomena Near Surfaces Irreversibly Trigger Assembly of Tau Protein.Journal of the American Chemical Society · 2026Article
- Detection of Mutation-Induced Conformational Changes in an Intrinsically Disordered Protein by Double Quantum Coherence Electron Spin Resonance Methodology.Journal of the American Chemical Society · 2026Article
- From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.Frontiers in neuroscience · 2026Review
- Hydrophobicity in Intrinsically Disordered Protein Force Fields: Implications for Conformational Ensembles and Protein-Protein Interactions.The journal of physical chemistry. B · 2025Article
- Structure-specific Mini-Prion Model for Alzheimer's Disease Tau Fibrils.bioRxiv : the preprint server for biology · 2025Article
- Macrocyclic β-arch peptides that mimic the structure and function of disease-associated tau folds.Nature chemistry · 2025Article
- Water-directed pinning is key to tau prion formation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Geometry based prediction of tau protein sites and motifs associated with misfolding and aggregation.Scientific reports · 2025Article
- The structure of a Tau fragment bound to tubulin prompts new hypotheses on Tau mechanism and oligomerization.PNAS nexus · 2024Article
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Authors and funding
20 authors at 2 institutions in 3 countries.
Funding
Abstract
Prion-like spread of disease-specific tau conformers is a hallmark of all tauopathies. A 19-residue probe peptide containing a P301L mutation and spanning the R2/R3 splice junction of tau folds and stacks into seeding-competent fibrils and induces aggregation of 4R, but not 3R tau. These tau peptide fibrils propagate aggregated intracellular tau over multiple generations, have a high β-sheet content, a colocalized lipid signal, and adopt a well-defined U-shaped fold found in 4R tauopathy brain-derived fibrils. Fully atomistic replica exchange molecular dynamics (MD) simulations were used to compute the free energy landscapes of the conformational ensemble of the peptide monomers. These identified an aggregation-prohibiting β-hairpin structure and an aggregation-competent U-fold unique to 4R tauopathy fibrils. Guided by MD simulations, we identified that the N-terminal-flanking residues to PHF6, which slightly vary between 4R and 3R isoforms, modulate seeding. Strikingly, when a single amino acid switch at position 305 replaced the serine of 4R tau with a lysine from the corresponding position in the first repeat of 3R tau, the seeding induced by the 19-residue peptide was markedly reduced. Conversely, a 4R tau mimic with three repeats, prepared by replacing those amino acids in the first repeat with those amino acids uniquely present in the second repeat, recovered aggregation when exposed to the 19-residue peptide. These peptide fibrils function as partial prions to recruit naive 4R tau-ten times the length of the peptide-and serve as a critical template for 4R tauopathy propagation. These results hint at opportunities for tau isoform-specific therapeutic interventions.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.