Protein ubiquitylation requires sequential action of three enzymes: Ubiquitin (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 both the ligase and the intended substrate protein, thereby effecting ubiquitylation directly. After linkage of Ub to the substrate, a polyUb chain is usually formed, and the tagged protein is degraded by the 26S proteasome. Alternatively, ubiquitylation can lead to lysosomal degradation. Proteasomes contain Ub isopeptidase [deconjugating] activity that allows Ub recycling.
PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.