Decoupling Phase Separation and Fibrillization Preserves Activity of Biomolecular Condensates.

ABSTRACT: Age-dependent transition of metastable, liquid-like protein condensates to amyloid fibrils is an emergent phenomenon of numerous neurodegeneration-linked protein systems. A key question is whether the thermodynamic forces underlying reversible phase separation and maturation to irreversible amyloids are distinct and separable. Here, we address this question using an engineered version of the microtubule-associated protein Tau, which forms biochemically active condensates. Liquid-like Tau condensates exhibit rapid aging to amyloid fibrils under quiescent, cofactor-free conditions. Tau condensate interface promotes fibril nucleation, impairing their activity to recruit tubulin and catalyze microtubule assembly. Remarkably, a small molecule metabolite, L-arginine, selectively impedes condensa

SUBMITTER: Mahendran TS 

PROVIDER: S-EPMC11957012 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature