The Ubiquitin Proteasome System (UPS)
Protein targeting by ubiquitin (Ub) requires sequential action of three enzymes: Ub is activated by a specific activating enzyme (E1) to yield a Ub-E1-thiolester. Activated Ub is transferred to a carrier protein (E2), and then transferred to a ligase (E3) and linked by an isopeptide bond to the substrate protein. PROTAC molecules capture ligases and intended substrate proteins thereby effecting ubiquitination directly. After linkage of Ub to the substrate, a polyUb chain is usually formed. Ubiquitylated proteins can be deubiquitylated by specific isopeptidases or recognized and processed by the 26S proteasome. Proteasomes contain Ub isopeptidase [deconjugating] activity that allows Ub recycling.