Fig. 1: Ubiquitin-proteasome system.

Multiple ongoing steps are required for the target protein’s ubiquitin breakdown. Ubiquitin is first activated by E1 enzymes when ATP (adenosine triphosphate) supplies a specific amount of energy. Ubiquitin activase E1 then sends the active ubiquitin molecules to E2 enzymes, and ubiquitin ligase E3 binds E2-binding ubiquitin to the target protein. The substrate protein’s ubiquitin molecule is extended by the E4 ubiquitin chain extension factor, and the tagged protein’s amino acid tail then forms a short ubiquitin molecular chain. Finally, the ubiquitin-tagged substrate protein is selectively recognized by the 26 S proteasome. The binding of 20 s catalytic core particles to 19 s regulatory complex, which binds the substrate protein tagged by ubiquitin chain and transfers the protein substrate to 20 s catalytic core under the energy of ATP, results in the formation of the structure of the 26 S proteasome. The substrate protein is degraded into small oligopeptides of less than 25 amino acids at the proteolytic β subunit of 20 s center, which will eventually be degraded into amino acids by protease in the cytoplasm. Ubiquitin molecules are recovered into the cytoplasmic pool. The deubiquitinating enzymes (DUBs) family hydrolyzes ubiquitin molecules from substrate proteins that include ubiquitin chains by hydrolyzing the ester, peptide, or isopeptide linkages at the carboxyl terminus of ubiquitin, and this process inversely controls protein deterioration. Ubiquitin molecules are also recycled into the cytoplasmic pool to exert their functions.