The ubiquitin-proteasome proteolytic system.

Ubiquitin is activated by the ubiquitin-activating enzyme, E1 (1) followed by its transfer to a ubiquitin-carrier protein (ubiquitin-conjugating enzyme, UBC), E2 (2). E2 transfers the activated ubiquitin moieties to the protein substrate that is bound specifically to a unique ubiquitin ligase E3. The transfer is either direct [(3) in the case of RING finger ligases] or via an additional thiol-ester intermediate on the ligase [(4, 4a) in case of HECT domain ligases]. Successive conjugation of ubiquitin moieties to one another generates a polyubiquitin chain that serves as the binding (5) and degradation signal for the downstream 26S proteasome. The substrate is degraded to short peptides (6), and free and reusable ubiquitin is released by de-