Fig. 1

Schematic diagram depicting the process of the ubiquitin–proteasome system. First, ubiquitin is activated by E1 with the energy provided by ATP. Subsequently, the activated ubiquitin is transferred to an active cysteine of E2. And then, E3 catalyzes the transfer of ubiquitin from E2 to the substrate with the formation of an isopeptide bond between the carboxy-terminal glycine of ubiquitin and a lysine residue of the target protein. In the case of RING/U-box type E3 ligase, E2 interacts with or does not interact with substrate; whereas in the case of HECT type E3 ligase, ubiquitin is directly transferred to a lysine residue in a substrate protein by E3s. Finally, the ubiquitinated substrate is degraded by the 26S proteasome and ubiquitins are released. Ubiquitins linked to the substrates could also be removed by DUB before the degradation. E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; DUB, deubiquitinating enzyme