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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Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1.
Mingxing Hu,Weilin Zhou,Yijie Wang,Dongping Yao,Tinghong Ye,Yuqin Yao,Bin Chen,Gong-Ping Liu,Gong-Ping Liu,Xifei Yang,Wei Wang,Yongmei Xie +11 more
TL;DR: The application of PROTAC technology in targeted degradation of IDO1 is reported, leading to the discovery of the first IDO 1 PROTAC degrader 2c, which induced significant and persistent degradation ofIDO1 with maximum degradation (dmax) of 93% in HeLa cells.
Journal ArticleDOI
The ubiquitin–proteasome system at the crossroads of stress-response and ageing pathways: A handle for skin care?
TL;DR: It comes out that the ubiquitin system plays a major role in signal transduction associated with stress and ageing, in skin in particular through the control of retinoid and NF-kappaB pathways.
Journal ArticleDOI
PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network.
Kurt M. Reichermeier,Kurt M. Reichermeier,Ronny Straube,Ronny Straube,Justin M. Reitsma,Michael J. Sweredoski,Christopher M. Rose,Annie Moradian,Willem den Besten,Willem den Besten,Trent Hinkle,Erik Verschueren,Georg Petzold,Nicolas H. Thomä,Ingrid E. Wertz,Raymond J. Deshaies,Raymond J. Deshaies,Donald S. Kirkpatrick +17 more
TL;DR: This work establishes protein interaction kinetics and estimation of stoichiometries (PIKES) analysis, a systematic proteomic profiling platform that integrates cellular engineering, affinity purification, chemical stabilization, and quantitative mass spectrometry to investigate the dynamics of interchangeable multiprotein complexes.
Journal ArticleDOI
Myxobacteria versus sponge-derived alkaloids: the bengamide family identified as potent immune modulating agents by scrutiny of LC-MS/ELSD libraries.
Tyler A. Johnson,Johann Sohn,Yvette M. Vaske,Kimberly N. White,Tanya L. Cohen,Helene C. Vervoort,Karen Tenney,Frederick A. Valeriote,Leonard F. Bjeldanes,Phillip Crews +9 more
TL;DR: The results suggest that the bengamides may serve as therapeutic leads for the treatment of diseases involving inflammation, that their anti-tumor activity can in part be attributed to their ability to serve as immune modulating agents, and that their therapeutic potential against cancer merits further consideration.
Journal ArticleDOI
Proteolysis targeting chimeras (PROTACs) for epigenetics research.
TL;DR: This review will discuss and summarize recent advances in PROTAC discovery with focus on epigenetic targets and proposes a new strategy of chemically induced protein degradation to address these targets.
References
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