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| Title | Macrocyclic β-arch peptides that mimic the structure and function of disease-associated tau folds. |
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| Journal, issue, pages | Nat Chem, Vol. 17, Issue 6, Page 865-874, Year 2025 |
| Publish date | Apr 30, 2025 |
 Authors | Isaac J Angera / Xueyong Xu / Benjamin H Rajewski / Grace I Hallinan / Xiaoqi Zhang / Bernardino Ghetti / Ruben Vidal / Wen Jiang / Juan R Del Valle /  |
| PubMed Abstract | Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion- ...Tauopathies are a class of neurodegenerative disorders that feature tau protein aggregates in the brain. Misfolded tau has the capacity to seed the fibrillization of soluble tau, leading to the prion-like spread of aggregates. Within these filaments, tau protomers always exhibit a cross-β amyloid structure. However, distinct cross-β amyloid folds correlate with specific diseases. An understanding of how these conformations impact seeding activity remains elusive. Identifying the minimal epitopes required for transcellular propagation of tau aggregates represents a key step towards more relevant models of disease progression. Here we implement a diversity-oriented peptide macrocyclization approach towards miniature tau, or 'mini-tau', proteomimetics that can seed the aggregation of tau in engineered cells and primary neurons. Structural elucidation of one such seed-competent macrocycle reveals remarkable conformational congruence with core folds from patient-derived extracts of tau. The ability to impart β-arch form and function through peptide stapling has broad-ranging implications for the minimization and mimicry of pathological tau and other amyloid proteins that drive neurodegeneration. |
 External links | Nat Chem / PubMed:40307419 |
| Methods | EM (helical sym.) |
| Resolution | 3.2 Å |
| Structure data | EMDB-44133, PDB-9b3a: EMDB-47002, PDB-9dme: |
| Chemicals |  ChemComp-NH2:  ChemComp-8VH: |
| Source |
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 Keywords | PROTEIN FIBRIL / tauopathies / neurodegenerative disorders / seed-competent miniature tau macrocycle |
homo sapiens (human)