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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Protein Knockouts in Living Eukaryotes Using deGradFP and Green Fluorescent Protein Fusion Targets
TL;DR: DeGradFP as mentioned in this paper is an easy-to-implement protein knockout method applicable in any eukaryotic genetic system, which can be used to counteract maternal effects in embryos and causes early and fast onset loss-of-function phenotypes of maternally contributed proteins.
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Small molecule-mediated protein knockdown as a new approach to drug discovery
TL;DR: Some of the recent advances in the design of small molecule chemical inducers of protein degradation are surveyed and the potential challenges that will need to be overcome in order to allow clinical evaluation are surveyed.
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Substrate selection by the proteasome through initiation regions
TL;DR: How the proteasome selects initiation sites within its substrates is reviewed and how the initiation step affects physiological processes is discussed.
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The therapeutic potential of PROTACs.
TL;DR: The modular composition of PROTACs affords both opportunities and challenges in securing robust intellectual property, and it is envisioned that requirements for novelty are likely to evolve as this area matures.
Patent
Targeted protein degradation to attenuate adoptive t-cell therapy associated adverse inflammatory responses
James E. Bradner,Justin M. Roberts,Behnam Nabet,Georg E. Winter,Andrew J. K. Phillips,Timothy P. Heffernan,Dennis L. Buckley +6 more
TL;DR: In this paper, the authors present compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, such as cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.
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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