Figure 1. Simplified scheme of the ubiquitin-proteasome proteolytic pathway. In this pathway, ubiquitinated proteins are recognized and degraded by the 26S proteasome. The steps involved in the breakdown of proteins by this mechanism include 1) activation of ubiquitin by the ubiquitin activating enzyme E1; 2) transfer of ubqiutin to the ubiquitin conjugating enzyme E2; 3) interaction between the substrate protein and the ubiquitin ligase E3; 4) interaction between E2 and E3 resulting in 5) multiubiquitination of the substrate protein; 6) degradation of the ubiquitinated protein by the 26S proteasome; and 7) deubiquitination resulting in the release and reuse of ubiquitin in the pathway. Energy is required for at least two steps in the pathway: activation of ubiquitin by E1 (step 1) and the proteolytic activity in the 26S proteasome (step 6). (From Hershko A. Lessons from the discovery of the ubiquitin system. Trends Biochem Sci 1996; 21:445–449, with permission.)