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

Kathleen M. Sakamoto, Kyung B. Kim, Akiko Kumagai, Frank Mercurio, Craig M. Crews, Raymond J. Deshaies

Research output: Contribution to journalArticlepeer-review

1416 Scopus citations

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 lκBα 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 SCFβ-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.

Original languageEnglish
Pages (from-to)8554-8559
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number15
DOIs
StatePublished - Jul 17 2001

ASJC Scopus subject areas

  • General

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