The ubiquitin-proteasome system. The conserved 76-amino-acid polypeptide ubiquitin (Ub) is activated in an ATP-dependent reaction by an E1 ubiquitin-activating enzyme and transferred to an E2 ubiquitin-conjugating enzyme. An E3 ubiquitin ligase binds both the substrate protein and a ubiquitin-charged E2 enzyme for ubiquitin transfer, resulting in the mono-, multi- (not shown) or polyubiquitination of the substrate. The mode of ubiquitination determines whether the substrate protein is degraded by the 26S proteasome or altered in a non-proteolytic manner. See Boxes 1 and 2 for additional information.