TY - JOUR T1 - Spatiotemporal Modulations in Heterotypic Condensates of Prion and α-Synuclein Control Phase Transitions and Amyloid Conversion JF - bioRxiv DO - 10.1101/2021.09.05.459019 SP - 2021.09.05.459019 AU - Aishwarya Agarwal AU - Lisha Arora AU - Sandeep K. Rai AU - Anamika Avni AU - Samrat Mukhopadhyay Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/09/06/2021.09.05.459019.abstract N2 - Biomolecular condensates formed via liquid-liquid phase separation (LLPS) of proteins and nucleic acids are thought to govern critical cellular functions. These multicomponent assemblies provide dynamic hubs for competitive homotypic and heterotypic interactions. Here, we demonstrate that the complex coacervation between the prion protein (PrP) and α-synuclein (α-Syn) within a narrow stoichiometry regime results in the formation of highly dynamic liquid droplets. Domain-specific electrostatic interactions between the positively charged intrinsically disordered N-terminal segment of PrP and the negatively charged C-terminal domain of α-Syn drive the formation of these highly tunable, reversible, thermo-responsive condensates. Picosecond time-resolved measurements revealed the existence of relatively ordered electrostatic nanoclusters that are stable on the nanosecond timescale and can undergo breaking-and-making on a much slower timescale giving rise to the liquid-like behavior on the second timescale and mesoscopic length-scale. The addition of RNA to these preformed coacervates yields multiphasic, anisotropic, vesicle-like, hollow condensates. LLPS promotes liquid-to-solid maturation of α-Syn-PrP condensates resulting in the rapid conversion into heterotypic amyloids. Our results suggest that synergistic interactions between PrP and α-Syn in liquid condensates can offer mechanistic underpinnings of their physiological role and overlapping neuropathological features.Competing Interest StatementThe authors have declared no competing interest. ER -