A kinetic model for USP14 regulated substrate degradation in 26S proteasome.

Despite high-resolution structural studies on the USP14-proteasome-substrate complexes, time-resolved cryo-electron microscopy (cryo-EM) results on USP14-regulated allostery of the 26S proteasome are still very limited and a quantitative understanding of substrate degradation dynamics remains elusive. In this study, we propose a mean field model of ordinary differential equations (ODEs) for USP14 regulated substrate degradation in 26S proteasome. The kinetic model incorporates recent cryo-EM findings on the allostery of 26S proteasome and generates results in good agreement with time-resolved experimental observations. The model elucidates that USP14 typically reduces the substrate degradation rate and reveals the functional dependence of this rate on the concentrations of substrate and adenosine triphosphate (ATP). The half-maximal effective concentration (EC50) of the substrate for different ATP concentrations is predicted. When multiple substrates are present, the model suggests that substrates that are easier to insert into the OB-ring and disengage from the proteasome, or less likely to undergo deubiquitination would be more favored to be degraded by the USP14-bound proteasome. The mean field model proposed here quantitatively considers the process of proteasomal substrate degradation from the perspective of chemical kinetics, and provides a quantitative framework to decode the dynamic interplay between USP14 and the proteasome.