Charge-driven remodelling of monomeric Tau determines its phase behaviour
Tau transitions from a functional microtubule-stabilising monomer into pathological aggregates in tauopathies. However, the molecular mechanism by which soluble Tau transitions into insoluble aggregates remains poorly understood. Here, we show that modulation of Tau internal charge-charge interactions by pH and ionic strength is sufficient to remodel its monomeric conformational ensemble and…
Tau, a protein crucial for stabilising microtubules, transforms into pathological aggregates in tauopathies. However, the underlying mechanism of this transformation from soluble Tau to insoluble aggregates is still not fully understood. In this study, researchers demonstrate that altering Tau's internal charge-charge interactions through pH and ionic strength can change its monomeric conformation and determine its self-assembly pathway.
Exposing the expanded, random coil-like 2N4R Tau to long-term incubation at low ionic strength and near its isoelectric point resulted in a stable, compact molten globule-like monomer. While both expanded and compacted conformations remain disordered, they display significant differences in local solvent accessibility and dynamics.
The researchers found that compaction is stabilized by weak interactions that modify the solvent accessibility of the microtubule-binding repeat region and its surrounding sequences. These conformational changes alter Tau's phase behaviour, suppressing liquid-liquid phase separation and amyloid fibril formation. The findings reveal that charge-driven remodelling of Tau's conformational ensemble directly influences its phase behaviour, offering a mechanistic understanding of the molecular events behind tauopathies.
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