An intrinsically disordered pathological prion variant Y145Stop converts into self-seeding amyloids via liquid–liquid phase separation

TLDR

Liquid–liquid phase separation of flexible proteins and nucleic acids enables precise cellular control, yet these condensates can irreversibly transition into solid aggregates that underlie fatal human diseases. The Y145Stop prion truncation spontaneously forms liquid droplets that mature into self‑seeding amyloids, a behavior absent in full‑length protein and implicating domain interactions in modulating phase behavior.

Abstract

Significance Biology has evolved to achieve precise spatiotemporal control of crucial cellular functions through liquid–liquid phase separation of highly flexible proteins and nucleic acids into membraneless organelles. However, these liquid-like intracellular condensates can undergo irreversible phase transitions into solid-like aggregates associated with deadly human diseases. Here, we show that a pathological truncation variant of the prion protein comprising the N-terminal unstructured domain spontaneously phase-separates into liquid droplets under physiological conditions. These liquid-like condensates gradually mature into solid-like self-replicable amyloids reminiscent of toxic misfolded proteinaceous aggregates involved in transmissible prion diseases. This aberrant phase-transition propensity is suppressed in the full-length protein, which may indicate an evolutionarily conserved role of an intriguing relationship between different domains in modulating the protein phase behavior.