The ubiquitin proteasome system. (A) ATP-dependent activation of ubiquitin (ubi) by an E1 enzyme followed by ubi conjugation (E2) results in a high-energy E2-ubi thiol ester intermediate. The protein substrate binds via a defined recognition motif to a specific E3 ubi ligase – multiple repetition of this cycle provokes the synthesis of a poly-ubi chain to the protein substrate, ready for the degradation by the proteasome. For deeper insight, refer to . (B) Two-dimensional diagram of the 26S and hybrid proteasome complex. Schematic presentation of the multi-enzyme complex including the 19S regulatory particle (RP) containing lid and base, the 20S core particle with the barrel-like structure of α7β7β7β7 and the proteasome activator complex PA28. 26S proteasome, 19S RP + 20S core; hybrid proteasome, 19S RP + 20S core + PA28. DUB, de-ubiquitinating enzyme; PPi, pyrophosphate; Rpn, non-ATPase subunit of 19S RP; Rpt, AAA-ATPase subunit of 19S RP.