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Proc Natl Acad Sci U S A
2001 Jul 17;9815:8554-9. doi: 10.1073/pnas.141230798.
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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
.
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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.
Belshaw,
Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins.
1996, Pubmed
Belshaw,
Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins.
1996,
Pubmed
Borchardt,
Small molecule-dependent genetic selection in stochastic nanodroplets as a means of detecting protein-ligand interactions on a large scale.
1997,
Pubmed
Ciechanover,
Ubiquitin-mediated proteolysis: biological regulation via destruction.
2000,
Pubmed
Deshaies,
SCF and Cullin/Ring H2-based ubiquitin ligases.
1999,
Pubmed
Griffith,
Methionine aminopeptidase (type 2) is the common target for angiogenesis inhibitors AGM-1470 and ovalicin.
1997,
Pubmed
Karin,
Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.
2000,
Pubmed
Li,
Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases.
1995,
Pubmed
Lyapina,
Human CUL1 forms an evolutionarily conserved ubiquitin ligase complex (SCF) with SKP1 and an F-box protein.
1998,
Pubmed
Margottin,
A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif.
1998,
Pubmed
Meng,
Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity.
1999,
Pubmed
Mercurio,
IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation.
1997,
Pubmed
Murray,
Cell cycle extracts.
1991,
Pubmed
Nagahara,
Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration.
1998,
Pubmed
Schubert,
CD4 glycoprotein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteasomes and the ubiquitin-conjugating pathway.
1998,
Pubmed
Sin,
The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase, MetAP-2.
1997,
Pubmed
Winston,
A family of mammalian F-box proteins.
1999,
Pubmed
Yaron,
Inhibition of NF-kappa-B cellular function via specific targeting of the I-kappa-B-ubiquitin ligase.
1997,
Pubmed
Yaron,
Identification of the receptor component of the IkappaBalpha-ubiquitin ligase.
1998,
Pubmed
Yeh,
The antiangiogenic agent TNP-470 requires p53 and p21CIP/WAF for endothelial cell growth arrest.
2000,
Pubmed
You,
A miniaturized arrayed assay format for detecting small molecule-protein interactions in cells.
1997,
Pubmed
Zhou,
Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins.
2000,
Pubmed
