9DME

Type 3 KD-mxyl filament of miniature tau macrocycle derived from 4R tauopathic fold

Summary for 9DME

• Entry DOI: 10.2210/pdb9dme/pdb
• EMDB information: 47002
• Descriptor: Microtubule-associated protein tau, 1,3-dimethylbenzene (2 entities in total)
• Functional Keywords: tauopathies, neurodegenerative disorders, seed-competent miniature tau macrocycle, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 15
• Total formula weight: 35202.18

Authors

Xu, X.,Angera, J.I.,Rajewski, H.B.,Jiang, W.,Del Valle, R.J. (deposition date: 2024-09-13, release date: 2025-04-23, Last modification date: 2025-11-05)

Primary citation

Angera, I.J.,Xu, X.,Rajewski, B.H.,Hallinan, G.I.,Zhang, X.,Ghetti, B.,Vidal, R.,Jiang, W.,Del Valle, J.R.
Macrocyclic beta-arch peptides that mimic the structure and function of disease-associated tau folds.
Nat.Chem., 17:865-874, 2025

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-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.

PubMed: 40307419
DOI: 10.1038/s41557-025-01805-z

Experimental method

ELECTRON MICROSCOPY (3.2 Å)