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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Methods in Enzymology.
TL;DR: This volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of the instrument and its ancillary tools are simply and well presented.
Journal ArticleDOI
Ubiquitin Ligases: Structure, Function, and Regulation
Ning Zheng,Nitzan Shabek +1 more
TL;DR: Current progress in structure-function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms are summarized.
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Ubiquitination in disease pathogenesis and treatment
TL;DR: The role of ubiquitination in the onset and progression of cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infection and muscle dystrophies is described and how current knowledge could be exploited for the development of new clinical therapies is indicated.
Journal ArticleDOI
Sailfish enables alignment-free isoform quantification from RNA-seq reads using lightweight algorithms
TL;DR: Sailfish, a computational method for quantifying the abundance of previously annotated RNA isoforms from RNA-seq data, exemplifies the potential of lightweight algorithms for efficiently processing sequencing reads.
Journal ArticleDOI
Drugging the undruggables: exploring the ubiquitin system for drug development.
XiaoDong Huang,Vishva M. Dixit +1 more
TL;DR: A review of therapeutic intervention nodes in the ubiquitin-proteasome system can be found in this article, where the authors highlight the most promising strategies to target the UPS.
References
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Journal ArticleDOI
Structural basis and specificity of human otubain 1-mediated deubiquitination
Mariola J. Edelmann,Alexander Iphöfer,Masato Akutsu,Mikael Altun,Katalin Di Gleria,Holger B. Kramer,Edda Fiebiger,Sirano Dhe-Paganon,Benedikt M. Kessler +8 more
TL;DR: Analysis of cellular interaction partners of OTUB1 by co-immunoprecipitation and MS/MS (tandem mass spectrometry) experiments demonstrated that FUS and RACK1 are part ofOTUB1-containing complexes, pointing towards a molecular function of this deubiquitinating enzyme in RNA processing and cell adhesion/morphology.
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OTUB1 Co-opts Lys48-Linked Ubiquitin Recognition to Suppress E2 Enzyme Function
Yu Chi Juang,Marie Claude Landry,Mario Sanches,Vinayak Vittal,Charles C.Y. Leung,Derek F. Ceccarelli,Abigail Rachele F. Mateo,Abigail Rachele F. Mateo,Jonathan N. Pruneda,Daniel Y.L. Mao,Daniel Y.L. Mao,Rachel K. Szilard,Stephen Orlicky,Meagan Munro,Peter S. Brzovic,Rachel E. Klevit,Frank Sicheri,Frank Sicheri,Daniel Durocher,Daniel Durocher +19 more
TL;DR: This work elucidate the structural mechanism by which OTUB1 binds E2s to inhibit ubiquitin transfer and co-opts Lys48-linked ubiquitIn chain recognition to suppress ubiquit in conjugation and the DNA damage response.
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Essential Role of Ubiquitin-Specific Protease 8 for Receptor Tyrosine Kinase Stability and Endocytic Trafficking In Vivo
Sandra Niendorf,Alexander Oksche,Agnes Kisser,Jürgen Löhler,Marco Prinz,Hubert Schorle,Stephan M. Feller,Marc Lewitzky,Ivan Horak,Klaus-Peter Knobeloch +9 more
TL;DR: It is shown that lack of UBPy results in embryonic lethality, whereas its conditional inactivation in adults causes fatal liver failure, unveiling a central and nonredundant role in growth regulation, endosomal sorting, and the control of RTKs in vivo.
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Targeting the ubiquitin-proteasome system for cancer therapy
TL;DR: It is conceivable that ‘druggable’ inhibitors of the ubiquitin system will be able to be used to evaluate their effects in animal tumor models in the not‐so‐distant future.
Journal ArticleDOI
Itch: a HECT-type E3 ligase regulating immunity, skin and cancer.
Gerry Melino,Ewen Gallagher,Rami I. Aqeilan,Richard A. Knight,Angelo Peschiaroli,Mario Rossi,Flavia Scialpi,Martina Malatesta,Loredana Zocchi,Gareth J. Browne,Aaron Ciechanover,Francesca Bernassola +11 more
TL;DR: This review aims to bring together a growing body of work exploring Itch-regulated biological processes, and to highlight recent discoveries on the regulatory mechanisms modulating its catalytic activity and substrate recognition capability.