Protein liquid-liquid phase separation (LLPS)

Protein liquid-liquid phase separation (LLPS) is a fundamental biophysical process by which proteins and nucleic acids self-assemble into dense, membrane-less droplets known as biomolecular condensates (Shin & Brangwynne, 2017). These condensates, including the nucleolus and stress granules, serve as specialized microenvironments that concentrate specific molecules to facilitate biological reactions such as RNA metabolism and signal transduction (Banani et al., 2017). Dysregulation of LLPS is increasingly linked to the pathogenesis of neurodegenerative diseases, where liquid droplets transition into irreversible, toxic solid-like aggregates, as seen with proteins like TDP-43 and Tau (Alberti & Hyman, 2021). In oncology, LLPS can drive the activity of oncogenic transcription factors and signaling hubs, making it an attractive therapeutic target (Boija et al., 2018). Current drug discovery efforts focus on "condensate modulators" (c-mods) designed to dissolve pathological aggregates or restore healthy condensate dynamics (Dewpoint Therapeutics, 2023). These small molecules can target the multivalent interactions or the intrinsically disordered regions (IDRs) that drive phase separation (Wheeler et al., 2016). However, a significant challenge remains in achieving selectivity to avoid disrupting essential physiological condensates required for normal cellular function (Alberti & Dormann, 2019). Despite these challenges, the modulation of LLPS represents a novel paradigm in drug discovery for previously "undruggable" targets (Hyman et al., 2014).

Other names

Biomolecular condensationLiquid-liquid demixingCoacervationMembraneless organelle formation

Condensate dissolution, phase transition inhibition, and partitioning modulation.