A strategy for modulation of enzymes in the ubiquitin system.
Andreas Ernst,George V. Avvakumov,Jiefei Tong,Yihui Fan,Yanling Zhao,Philipp Alberts,Avinash Persaud,John R. Walker,Ana-Mirela Neculai,Dante Neculai,Andrew Vorobyov,Pankaj Garg,Linda G. Beatty,Pak-Kei Chan,Yu Chi Juang,Marie-Claude Landry,Christina Yeh,Christina Yeh,Elton Zeqiraj,Konstantina Karamboulas,Abdellah Allali-Hassani,Masoud Vedadi,Mike Tyers,Mike Tyers,Jason Moffat,Frank Sicheri,Frank Sicheri,Laurence Pelletier,Laurence Pelletier,Daniel Durocher,Daniel Durocher,Brian Raught,Daniela Rotin,Jianhua Yang,Michael Moran,Sirano Dhe-Paganon,Sirano Dhe-Paganon,Sachdev S. Sidhu +37 more
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TLDR
This work used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography to report a method to target the myriad enzymes that govern ubiquitination of protein substrates.Abstract:
The ubiquitin system regulates virtually all aspects of cellular function. We report a method to target the myriad enzymes that govern ubiquitination of protein substrates. We used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography. We extended the selection strategy to the ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes and found that ubiquitin variants can also enhance enzyme activity. Last, we showed that ubiquitin variants can bind selectively to ubiquitin-binding domains. Ubiquitin variants exhibit selective function in cells and thus enable orthogonal modulation of specific enzymatic steps in the ubiquitin system.read more
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Proteomic Analysis of the Epidermal Growth Factor Receptor (EGFR) Interactome and Post-translational Modifications Associated with Receptor Endocytosis in Response to EGF and Stress
TL;DR: Mass spectrometry was applied to comprehensively analyze the phosphorylation, ubiquitination, and protein-protein interactions of wild type and endocytosis-defective EGFR variants before and after internalization in response to EGF ligand and stress, providing new insight into spatial, temporal, and mechanistic aspects of EGFR regulation.
Journal ArticleDOI
Advances in Discovering Deubiquitinating Enzyme (DUB) Inhibitors
TL;DR: Recent successes in solving DUB-ligand co-structures and the development of rigorously characterized potent and selective inhibitors are highlighted and it is posited that these advances in pharmacological targeting of DUBs establish the enzyme family as targetable and provide a framework for other Dubs programs.
Journal ArticleDOI
DUBs, the regulation of cell identity and disease.
Johanna Heideker,Ingrid E. Wertz +1 more
TL;DR: New insights into DUB activity regulation and their links to disease are discussed, focusing on the role of DUBs as regulators of cell identity and differentiation, and their potential as emerging drug targets are discussed.
Journal ArticleDOI
Activity-based probes for the ubiquitin conjugation-deconjugation machinery: new chemistries, new tools, and new insights.
TL;DR: How features of the probe (cysteine‐reactive group, recognition element, and reporter tag) affect reactivity and suitability for certain experimental applications are discussed.
Journal ArticleDOI
The role of ubiquitin-specific peptidases in cancer progression.
TL;DR: Most of the recent studies on the roles of USPs in cancer progression are collected and organized and the development of USP inhibitors for cancer therapy in the future is discussed.
References
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TL;DR: A description is given of Phaser-2.1: software for phasing macromolecular crystal structures by molecular replacement and single-wavelength anomalous dispersion phasing.
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