
FAT10は基質の構造的可塑性を増大させることで、プロテアソーム分解を迅速化する。


coremsg

The proteasome controls levels of most cellular proteins, and its activity is regulated under stress, quiescence, and inflammation. However, factors determining the proteasomal degradation activity remain poorly understood. Proteasome substrates are conjugated with small proteins (tags) like ubiquitin and Fat10 to target them to the proteasome. It is unclear if the structural plasticity of proteasome-targeting tags influences substrate degradation. The tag Fat10 is activated during inflammation, and ambiguously, Fat10 and its substrates undergo rapid proteasomal degradation. We report that the rapid degradation of Fat10 substrates depends on its structural plasticity. While the ubiquitin tag is recycled at the proteasome, Fat10 is degraded with the substrate, and the mechanical unfolding kinetics of Fat10 regulates substrate degradation. Our studies reveal that long-range salt bridges are absent in the Fat10 structure, creating a plastic protein with partially unstructured regions suitable for proteasome engagement. Such a malleable structure also provides low resistance to mechanical unfolding and expedites proteasomal degradation. We also uncovered that the Fat10 plasticity destabilizes substrates significantly and creates partially unstructured regions in the substrate to enhance degradation. NMR-relaxation-derived order parameters and temperature dependence of chemical shifts identify the Fat10-induced partially unstructured regions in the substrate. They correlated excellently to the regions where Fat10 contacts the substrate, suggesting that the tag-substrate collision destabilizes the substrate. These results highlight a strong dependence of proteasomal degradation on the structural plasticity and thermodynamic properties of the proteasome-targeting tag.

### Competing Interest Statement

The authors have declared no competing interest.

Plasticity of the proteasome-targeting signal Fat10 enhances substrate degradation

炎症時に迅速に分解されるプロテアソーム分解シグナルfat10は基質の安定性を変調させて分解を促進する


炎症時に迅速に分解されるプロテアソーム分解シグナルFAT10は基質の安定性を変調させて分解を促進する
