Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published July 17, 2001 | Published
Journal Article Open

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-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 kappaB 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 SCFbeta -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.

Additional Information

© 2001 National Academy of Sciences. Communicated by Alexander Varshavsky, California Institute of Technology, Pasadena, CA, May 10, 2001 (received for review March 29, 2001). Published online before print July 3, 2001, 10.1073/pnas.141230798 We thank the members of the Deshaies lab for their helpful suggestions and Zhen-Quiang Pan for providing reagents and valuable input on the reconstitution of SCFb-TRCP activity. This work was supported by the University of California Los Angeles Jonsson Comprehensive Cancer Center, CapCURE (K.M.S., R.J.D., and C.M.C.), the Gates Grubstake Fund (R.J.D.), and the Howard Hughes Medical Institute (R.J.D.). K.M.S. is a Scholar of the Leukemia and Lymphoma Society of America. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Attached Files

Published - SAKpnas01.pdf


Files (1.4 MB)
Name Size Download all
1.4 MB Preview Download

Additional details

August 21, 2023
October 13, 2023