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.

Temperature-Controlled Liquid–Liquid Phase Separation of Disordered Proteins

Temperature-Controlled Liquid–Liquid Phase Separation of Disordered Proteins

Biomolecules, Free Full-Text

A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation: Cell

NMR Experiments for Studies of Dilute and Condensed Protein Phases: Application to the Phase-Separating Protein CAPRIN1

The C-terminal deletion mutant of TDP-43 still binds to UG 12 RNA. A

Promotion of Liquid–Liquid Phase Separation by G-Quadruplex DNA and RNA

PDF) The cold denaturation of IscU highlights structure–function dualism in marginally stable proteins

It's not just a phase: function and characteristics of RNA-binding proteins in phase separation. - Abstract - Europe PMC

Biomolecules, Free Full-Text

Liquid-liquid phase separation: Fundamental physical principles, biological implications, and applications in supramolecular materials engineering - ScienceDirect

Phase separation in Cancer: From the Impacts and Mechanisms to Treatment potentials

Coarse grain model of cold denaturation. a Free energy difference

Cold Denaturation of the HIV-1 Protease Monomer

Thermograms of IscU and of its mutants. a IscU_wt (no Zn²⁺, pale blue);