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7050530 
Journal Article 
Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation 
Sakamoto, KM; Kim, KB; Kumagai, A; Mercurio, F; Crews, CM; Deshaies, RJ; , 
2001 
Proceedings of the National Academy of Sciences of the United States of America 
NATL ACAD SCIENCES 
WASHINGTON 
8554-8559 
English 
11438690 
WOS:000169967000064 
The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-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 the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the I kappa B alpha phosphopeptide that is recognized by the F-box protein beta-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF(beta-TRCP), ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.