11LU

Structure of a tau(297-407)-4D filament grown in potassium citrate buffer for 4 days (polymorph 1)

Summary for 11LU

• Entry DOI: 10.2210/pdb11lu/pdb
• EMDB information: 75820
• Descriptor: Microtubule-associated protein tau (1 entity in total)
• Functional Keywords: tau, filament, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 10
• Total formula weight: 120125.79

Authors

Yan, N.L.,Powell, W.C.,Tse, E.,Melo, A.A.,Southworth, D.R.,Gestwicki, J.E. (deposition date: 2026-03-03, release date: 2026-11-11)

Primary citation

Powell, W.C.,Yan, N.,Tse, E.,Melo, A.A.,Vasquez, J.A.,Southworth, D.R.,Gestwicki, J.E.
Cofactor-Free Tau Filaments Are Dynamic and Undergo Structural Evolution Driven by Thermodynamic Control.
J.Am.Chem.Soc., 148:35386-35398, 2026

PubMed Abstract: Tau filaments are a hallmark of neurodegenerative tauopathies, such as Alzheimer's disease (AD). Structural studies have revealed that patient-derived tau fibrils adopt distinct folds in different tauopathies; however, it is unclear what forces guide this process. To explore this question, we investigated the assembly of a tau fragment containing four disease-associated phospho-mimetics (termed Tau(297-407)-4D) in vitro. Under cofactor-free and quiescent conditions, Tau(297-407)-4D forms fibrils with a core structure that partially resembles the AD fold after about 7 days. Strikingly, we noticed that this filament behaves as a hydrogel and evolves into two new polymorphs as it ages over the next 35 days. Thus, tau fibrils formed under cofactor-free conditions are dynamic, exhibiting substantial nonequilibrium behavior. To probe what types of perturbations might stabilize these structures, we applied mechanical agitation, which drove the filaments toward thermodynamic equilibrium in a mechanism consistent with Ostwald ripening into solid-phase, micrometer-sized particles. Likewise, the addition of polyanionic cofactors to preformed Tau(297-407)-4D fibrils significantly stabilized them, as judged by solubility equilibria and chemical denaturation experiments. A subset of the polyanions also remodeled the fibril structure and tuned the extent of fibril-fibril interactions (i.e., "clumping"). We conclude that environmental factors, such as mechanical stress and/or polyanions, play an important role in promoting the thermodynamic stability of otherwise dynamic tau fibrils. We speculate that, in patients, such factors might contribute to the maturation of disease-specific conformers.

PubMed: 42677560
DOI: 10.1021/jacs.6c04928

Experimental method

ELECTRON MICROSCOPY (3.3 Å)