Modeling liquid-liquid phase separation and its impact on proteasomal substrate degradation

Wu, D.; Ouyang, Q.; Wang, H.

doi:10.1101/2025.07.20.665740

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bioRxiv · 10.1101/2025.07.20.665740

Modeling liquid-liquid phase separation and its impact on proteasomal substrate degradation

Wu, D.·Ouyang, Q.·Wang, H.

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Abstract

The proteasome, central to ubiquitin-proteasome mediated degradation, undergoes liquid-liquid phase separation (LLPS) during substrate processing. However, the mechanisms governing proteasomal LLPS and its functional interplay with degradation dynamics remain elusive. Here, we developed a reaction-diffusion model with thermodynamic constraints to quantitatively characterize proteasome-associated LLPS. The model successfully captures experimental LLPS dynamics, revealing a concentration-dependent phase transition boundary influenced by proteasome activity and molecular interactions. Significantly, LLPS was found to have bidirectional (enhancing or suppressing), context-dependent effects on degradation efficiency. This work elucidates regulatory mechanisms and functional roles of LLPS in proteasome-mediated degradation, offering a predictive quantitative model and testable hypotheses for future investigation.

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Wu, D., Ouyang, Q., Wang, H.. 2025-07-23. Modeling liquid-liquid phase separation and its impact on proteasomal substrate degradation. https://doi.org/10.1101/2025.07.20.665740

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