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arXiv · 2506.22424

Mesoscale properties of protein clusters determine the size and nature of liquid-liquid phase separation (LLPS)

Gonen Golani·Manas Seal·Mrityunjoy Kar·Anthony A. Hyman·Daniella Goldfarb·Samuel Safran
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Abstract

The observation of Liquid-Liquid Phase Separation (LLPS) in biological cells has dramatically shifted the paradigm that soluble proteins are uniformly dispersed in the cytoplasm or nucleoplasm. The LLPS region is preceded by a one-phase solution, where recent experiments have identified clusters in an aqueous solution with 102-103 proteins. Here, we theoretically consider a core-shell model with mesoscale core, surface, and bending properties of the cluster shell and contrast two experimental paradigms for the measured cluster size distributions of the Cytoplasmic Polyadenylation Element Binding-4 (CPEB4) and Fused in Sarcoma (FUS) proteins. The fits to the theoretical model and earlier electron paramagnetic resonance (EPR) experiments suggest that the same protein may exhibit hydrophilic, hydrophobic, and amphiphilic conformations, which act to stabilize the clusters. We find that CPEB4 clusters are much more stable compared to FUS clusters, which are less energetically favorable. This suggests that in CPEB4, LLPS consists of large-scale aggregates of clusters, while for FUS, clusters coalesce to form micron-scale LLPS domains.

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Gonen Golani, Manas Seal, Mrityunjoy Kar, Anthony A. Hyman, Daniella Goldfarb, Samuel Safran. 2025-06-27. Mesoscale properties of protein clusters determine the size and nature of liquid-liquid phase separation (LLPS). https://doi.org/10.1038/s42005-025-02134-w

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