Low-complexity domains in phase-separated droplets suppress the amyloid formation of yeast prion Sup35

Intracellular droplets are formed through liquid-liquid phase separation, mediated by proteins containing low-complexity domains (LCDs) that enable multivalent and transient interactions with other molecules. A certain class of LCDs is prone to aggregation, and in vitro experiments have shown that amyloid-like aggregates can form from droplets of various proteins with LCDs. This phenomenon is thought to underlie diseases associated with protein aggregation. Elucidating the mechanism of amyloid-like aggregate formation from droplets and identifying ways to regulate this process could contribute to significant advances in drug discovery and treatment of these diseases. In this study, we demonstrated that LCDs coexisting within droplets suppress amyloid formation using yeast prion protein Sup35 from various yeast species as a model. Notably, high sequence homology between coexisting proteins is not required as long as a common interaction mechanism is utilized for droplet formation, implying that other LCDs within cells could modulate the amyloid formation.