Scaffold-client behavior and structural organization in multicomponent protein condensates as revealed by studying tau/TDP-43 droplets

Liquid-liquid phase separation (LLPS) is known to modulate pathological aggregation of proteins implicated in neurodegenerative diseases, such as tau and TDP-43. While LLPS mechanisms of individual proteins are well characterized, much less is known about phase behavior of multicomponent protein systems. Here, we investigated the LLPS behavior of mixtures of tau and TDP-43 low complexity domain (LCD), two proteins known to co-aggregate in Alzheimer’s disease. We found that, depending on the concentration, each protein can function either as a scaffold (driving condensate formation) or as a client (passively recruited into condensates formed by the other). Notably, scaffold-client roles can be modulated by selectively inhibiting the interactions driving LLPS: electrostatic for tau, and hydrophobic for TDP-43 LCD. A striking feature of this system is the formation of a tau “halo” around TDP-43 LCD droplets, which coarse-grained simulations reveal to arise from tau’s amphiphilic organization at condensate interfaces. Together, these findings provide molecular-level insights into the general principles governing the assembly and organization of multicomponent protein condensates. Liquid-liquid phase separation (LLPS) is known to modulate the pathological aggregation of proteins implicated in neurodegenerative diseases, such as tau and TDP-43, but the phase behavior of the tau/TDP-43 multicomponent system remains underexplored. Here, the authors show that, depending on protein concentration and the strength of LLPS-driving interactions, tau and TDP-43 low complexity domain (LCD) can function either as scaffolds — driving condensate formation — or as clients — being passively recruited into condensates formed by the other.