Fused in sarcoma undergoes cold denaturation: Implications on phase separation

The mediation of fused in sarcoma (FUS) protein liquid-liquid phase separation (LLPS) is generally attributed to the low-complexity and disordered domains, while the role of its folded domains remains unknown. In this work we questioned the role of the folded domains on the full-length (FL) FUS LLPS and studied the influence of several metabolites, ions and overall conditions on the LLPS process using turbidity assays, differential interference contrast microscopy and nuclear magnetic resonance spectroscopy. We demonstrate that FL FUS LLPS is highly responsive to the surrounding conditions, and that overall intrinsic disorder is crucial for LLPS. To promote such disorder, we reveal that the FUS RNA-recognition domain (RRM) and the zinc-finger motif (ZnF) undergo cold denaturation above 0ºC, at a temperature that is determined by the conformational stability of the ZnF domain. We hypothesize that, in cold shock conditions, cold denaturation might provide a pathway that exposes additional residues to promote FUS self-assembly. Such findings mark the first evidence that FUS globular domains may have an active role in stress granule formation in cold stress.

Liquid–Liquid Phase Separation and Its Mechanistic Role in Pathological Protein Aggregation - ScienceDirect

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Liquid–Liquid Phase Separation and Its Mechanistic Role in Pathological Protein Aggregation - ScienceDirect

Nucleation and dissolution mechanism underlying amyotrophic lateral sclerosis/frontotemporal lobar dementia-linked fused in sarcoma condensates - ScienceDirect

Frontiers Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease

Cold Denaturation of the HIV-1 Protease Monomer

Cold Denaturation of the HIV-1 Protease Monomer

PDF] Fused in Sarcoma: Properties, Self-Assembly and Correlation with Neurodegenerative Diseases

Cold Denaturation of the HIV-1 Protease Monomer

Biomolecules, Free Full-Text

Macromolecular condensation buffers intracellular water potential

Liquid–Liquid Phase Separation and Its Mechanistic Role in Pathological Protein Aggregation - ScienceDirect

The phase separation-dependent FUS interactome reveals nuclear and cytoplasmic function of liquid-liquid phase separation