Charge-driven remodelling of monomeric Tau determines its phase behaviour
- 1Department of Chemistry, University of Cambridge
Abstract
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 direct its subsequent self-assembly pathway. By subjecting the expanded random coil-like 2N4R Tau to prolonged incubation at low ionic strength and near its isoelectric point, we generated a long-lived compact molten globule-like monomer. Although both expanded and compacted conformations remain disordered, they differ markedly in their local solvent accessibility and dynamics. We show that monomer compaction is stabilised by weak interactions that remodel the solvent accessibility of the microtubule-binding repeat region and its flanking sequences. Consequently, these conformational changes alter Tau phase behaviour, inhibiting liquid-liquid phase separation and amyloid fibril formation. Our findings demonstrate that charge-driven remodelling of the Tau conformational ensemble determines its phase behaviour and provide a mechanistic insight into the molecular events underlying tauopathies.
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BibTeX
@misc{oktaviandie2026chargedriven,
title = {{Charge-driven remodelling of monomeric Tau determines its phase behaviour}},
author = {Y. Oktaviandie and Z. Han and K. Stott and T. P. J. Knowles},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.752903},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.752903v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Charge-driven remodelling of monomeric Tau determines its phase behaviour
AU - Y. Oktaviandie
AU - Z. Han
AU - K. Stott
AU - T. P. J. Knowles
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.752903
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.752903v1
AB - 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 direct its subsequent self-assembly pathway. By subjecting the expanded random coil-like 2N4R Tau to prolonged incubation at low ionic strength and near its isoelectric point, we generated a long-lived compact molten globule-like monomer. Although both expanded and compacted conformations remain disordered, they differ markedly in their local solvent accessibility and dynamics. We show that monomer compaction is stabilised by weak interactions that remodel the solvent accessibility of the microtubule-binding repeat region and its flanking sequences. Consequently, these conformational changes alter Tau phase behaviour, inhibiting liquid-liquid phase separation and amyloid fibril formation. Our findings demonstrate that charge-driven remodelling of the Tau conformational ensemble determines its phase behaviour and provide a mechanistic insight into the molecular events underlying tauopathies.
ER -