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
Citations
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Haven't got a glue: Protein surface variation for the design of molecular glue degraders.
Zuzanna Kozicka,Nicolas H. Thomä +1 more
TL;DR: In this article, a review of strategies by which E3 ubiquitin ligases can be reprogrammed by monovalent degraders, with a focus on molecular glues hijacking cullin-RING ubiquity ligases.
Journal ArticleDOI
Targeted Degradation of KRAS by an Engineered Ubiquitin Ligase Suppresses Pancreatic Cancer Cell Growth In Vitro and In Vivo
TL;DR: An engineered E3 ubiquitin ligase (RC-U) was generated to target the KRAS oncoprotein for ubiquitination and degradation and resulted in reduced cell proliferation in vitro and in vivo.
Journal ArticleDOI
Chemoselective Synthesis of Lenalidomide-Based PROTAC Library Using Alkylation Reaction.
TL;DR: An organic base-promoted chemoselective alkylation of lenalidomide with different halides was developed and successfully applied to BET PROTAC, which not only degraded BET protein but also effectively inhibited cancer cell proliferation.
Patent
Small-molecule hydrophobic tagging of fusion proteins and induced degradation of same
TL;DR: In this paper, it was shown that adding a hydrophobic moiety to the surface of a protein can mimic the partially denatured state of the protein, thus engaging the cellular quality control machinery to induce its proteasomal degradation.
Journal ArticleDOI
Design of a PROTAC that antagonizes and destroys the cancer-forming X-protein of the hepatitis B virus.
TL;DR: The design of a novel PROTAC (proteolysis targeting chimeric molecule) capable of simultaneously inducing the degradation of the X-protein, and antagonizing its function is described, and warrants investigation in a preclinical study for its ability to prevent or treat HBV infection and/or the development of HCC.
References
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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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