Liquid phase condensation in cell physiology and disease

Abstract

Phase transitions are ubiquitous in nonliving matter, and recent discoveries have shown that they also play a key role within living cells. Intracellular liquid-liquid phase separation is thought to drive the formation of condensed liquid-like droplets of protein, RNA, and other biomolecules, which form in the absence of a delimiting membrane. Recent studies have elucidated many aspects of the molecular interactions underlying the formation of these remarkable and ubiquitous droplets and the way in which such interactions dictate their material properties, composition, and phase behavior. Here, we review these exciting developments and highlight key remaining challenges, particularly the ability of liquid condensates to both facilitate and respond to biological function and how their metastability may underlie devastating protein aggregation diseases.

Coactivator condensation at super-enhancers links phase separation and gene control

“…As determined by aspect ratio analysis, the MED1-IDR and BRD4-IDR droplets were highly spherical (Fig. S6A), a property expected for liquid-like droplets (1–3). …”

“…A hallmark of liquid-like condensates is internal dynamical reorganization and rapid exchange kinetics (1–3), which can be interrogated by measuring the rate of fluorescence recovery after photobleaching (FRAP). To study the dynamics of BRD4 and MED1 foci in live cells, we performed FRAP experiments on endogenously tagged mEGFP-BRD4 or mEGFP-MED1 cell lines.…”

“…4A) and share features with the IDRs of several proteins known to facilitate condensate formation (2, 3), including high proline and glutamine content (BRD4), high serine content (MED1), and acidic and basic regions (BRD4 and MED1). The purified IDRs of several proteins involved in condensate formation form phase-separated droplets in vitro (36, 37, 42, 43), so we investigated whether the IDRs of BRD4 or MED1 form such droplets in vitro .…”

Environment-transformable sequence–structure relationship: a general mechanism for proteotoxicity

“…In particular, the exaggeration or molecular aging of liquid droplets into aggregation or amyloid fibrils may lie at the heart of a variety of human diseases including ALS (Murakami et al 2015;Patel et al 2015;Shin and Brangwynne 2017). The TDP-43 and FUS prion-like domains appear to remain highly disordered in the liquid droplets (Burke et al 2015;Lim et al 2016a;Conicella et al 2016;Lu et al 2016).…”

mRNA structure determines specificity of a polyQ-driven phase separation

“…These condensates often display liquid-like properties and form through liquid-liquid phase separation (LLPS) (1, 2). The growing list of LLPS-assembled compartments includes the nucleolus, RNA granules, cell signaling hubs, the spindle matrix, chromatin, the synaptonemal complex, and many pathological neuronal granules (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Despite the growing appreciation of the variety of liquid-like assemblies employed in diverse cellular processes, a fundamental unsolved problem is how liquid droplets recruit distinct constituents and retain independent identities, rather than fusing into a singular compartment.…”