Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.
Kathleen M. Sakamoto,Kyung Bo Kim,Akiko Kumagai,Frank Mercurio,Craig M. Crews,Raymond J. Deshaies +5 more
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TLDR
It is shown that MetAP-2 can be tethered to SCFβ-TRCP, ubiquitinated, and degraded in a Protac-1-dependent manner, which may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.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 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 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.read more
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References
More filters
Journal ArticleDOI
Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity.
Michael Karin,Yinon Ben-Neriah +1 more
TL;DR: Recent progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1.
Journal ArticleDOI
IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation
Frank Mercurio,Hengyi Zhu,Brion W. Murray,Andrej Shevchenko,Brydon L. Bennett,Jian Wu Li,David B. Young,Miguel Barbosa,Matthias Mann,Anthony M. Manning,Anjana Rao +10 more
TL;DR: In this article, a large multiprotein complex, the IkappaB kinase (IKK) signalsome, was purified from HeLa cells and found to contain a cytokine-inducible IKK kinase activity that phosphorylates IappaB-alpha and IKK-beta.
Journal ArticleDOI
SCF and Cullin/RING H2-Based Ubiquitin Ligases
TL;DR: This review is focused on a conserved ubiquitin ligase complex known as SCF that plays a key role in marking a variety of regulatory proteins for destruction by the 26S proteasome.
Journal ArticleDOI
Transduction of full-length TAT fusion proteins into mammalian cells:TAT-p27Kip1 induces cell migration
Hikaru Nagahara,Adamina Vocero-Akbani,Eric L. Snyder,Alan L. Ho,Dawn G. Latham,Natalie A. Lissy,Michelle Becker-Hapak,Sergei A. Ezhevsky,Steven F. Dowdy +8 more
TL;DR: Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27 Kip1 induces cell migration and promotes cell migration in mice.
Journal ArticleDOI
Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity
TL;DR: In this article, the authors used biotinylated-epoxomicin as a molecular probe and showed that it covalently binds to the LMP7, X, MECL1, and Z catalytic subunits of the proteasome.
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