title: Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
abstract: 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.
authors: Department of Pediatrics and Pathology, Mattel Children's Hospital at University of California Los Angeles, 90095-1752, USA. kms@ucla.edu
authors: K M
authors: KM
authors: Sakamoto
authors: K B
authors: KB
authors: Kim
authors: A
authors: A
authors: Kumagai
authors: F
authors: F
authors: Mercurio
authors: C M
authors: CM
authors: Crews
authors: R J
authors: RJ
authors: Deshaies
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D002457:Cell Extracts; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D008666:Metalloendopeptidases / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D010063:Ovum / Q000378:metabolism; D010453:Peptide Synthases / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases; D014452:Ubiquitins / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D002457:Cell Extracts; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D011993:Recombinant Fusion Proteins; D014452:Ubiquitins; D000072000:NF-KappaB Inhibitor alpha; D044843:SKP Cullin F-Box Protein Ligases; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D010453:Peptide Synthases