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.
PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.