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[Experimental & Molecular Medicine]Glutathionylation on RNA-binding proteins: a regulator of liquid‒liquid phase separation in the pathogenesis of amyotrophic lateral sclerosis, 55, pages735–744 (2023), Hyun-Jun Choi, Ji Young Lee & Kiyoung Kim
Fig. 1: Protein phase transition and driving force.
a The liquid-like protein condensates formed through liquid‒liquid phase separation (LLPS) are highly dynamic and constantly exchange with the surrounding environment. With time and changes in the surrounding environment, the solidification of liquid-like condensates to hydrogels and amyloid fibrils occurs via liquid‒solid phase transition (LSPT). b Various types of multivalent interactions that promote the initiation and maintenance of LLPS include RNA-binding domains, oligomerization domains, motif-binding domains, helix-helix interactions, β-zippers, π–π interactions, cation‒anion interactions, dipole‒dipole interactions, and cation–π interactions.
Fig. 2: Glutathionylation of the cysteine residue of FUS in the zinc-finger (ZnF) domain promotes aberrant liquid‒liquid phase separation (LLPS). In the FUS-associated ALS disease model, glutathionylation of the FUS ZnF domain led to decreased FUS solubility by promoting phase separation and the formation of pathological aggregates. Glutathione S-transferase omega inhibits the phase separation of FUS via deglutathionylation to prevent the formation of pathological aggregates.
Fig. 3: Effects of various posttranslational modifications (PTMs) on the phase separation of ALS-associated RNA-binding proteins (RBPs).
PTMs can positively or negatively regulate LLPS in ALS-associated RBPs. Phosphorylation, methylation, citrullination, and ubiquitination of ALS-associated RBPs inhibit LLPS, whereas acetylation, poly(ADP-ribosyl)lation, and glutathionylation promote LLPS.