Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation

The intracellular levels of many proteins are regulated by ubiquitin-depend ent proteolysis, One of the best-characterized enzymes that catalyzes the a ttachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cull in-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds th e angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting c himeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF, O ne domain of Protac-1 contains the I kappaB alpha phosphopeptide that is re cognized by the F-box protein beta -TRCP, whereas the other domain is compo sed of ovalicin. We show that MetAP-2 can be tethered to SCFbeta -TRCP, ubi quitinated, and degraded in a Protac-1-dependent manner. In the future, thi s approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.