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bioRxiv · 10.64898/2026.01.21.700558

Liquid-liquid phase separation of tau regulates client binding via a conformational relay

Osterholz, H.·Chen, G.·Freudenberger, J.·Lama, D.·Landreh, M.·Leppert, A.
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Abstract

Intrinsically disordered proteins (IDPs) achieve functional specificity through dynamic, multivalent interactions that are often reorganized during liquid-liquid phase separation (LLPS). How LLPS reshapes IDP conformational landscapes and binding preferences remains poorly understood. Here, we combine native ion mobility mass spectrometry, mass photometry, fluorescence microscopy, and computational modeling to dissect how conditions that promote LLPS of the intrinsically disordered human tau protein regulate its interactions with tubulin and the neuronal anti-amyloid chaperone domain BRICHOS from Bri2. We show that electrostatically driven compaction and transient oligomerization of tau during LLPS promote BRICHOS binding to a specific Tau segment. Within tau condensates, BRICHOS can compete with tubulin for tau interactions by blocking its adjacent binding site, thereby modulating LLPS-dependent microtubule assembly. Using a generalizable experimental strategy, we provide a proof of concept for detecting conformational selectivity in a dynamic condensate.

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Osterholz, H., Chen, G., Freudenberger, J., Lama, D., Landreh, M., Leppert, A.. 2026-01-23. Liquid-liquid phase separation of tau regulates client binding via a conformational relay. https://doi.org/10.64898/2026.01.21.700558

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