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

Proceedings of the National Academy of Sciences of the United States of America - Tập 98 Số 15 - Trang 8554-8559 - 2001
Kathleen M. Sakamoto1, Kyung B. Kim1, Akiko Kumagai1, Frank Mercurio1, Craig M. Crews1, Raymond J. Deshaies1
1Department of Pediatrics and Pathology, Mattel Children's Hospital at University of California Los Angeles, University of California Los Angeles School of Medicine, Gwynn Hazen Cherry Memorial Laboratories, and Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095-1752; Division of Biology, and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520; and Signal...

Tóm tắt

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 IκBα phosphopeptide that is recognized by the F-box protein β-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF β -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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 98 Số 15

8554-8559

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