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.
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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
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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.
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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
The emerging complexity of protein ubiquitination
TL;DR: The present review focuses on the emerging complexity of the ubiquitin system, and reviews what is known about individual chain types, and highlights recent advances that explain how the ubiqu itin system achieves its intrinsic specificity.
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A Dynamic Role of HAUSP in the p53-Mdm2 Pathway
TL;DR: This study provides an example of an ubiquitin ligase (MDM2) that is directly regulated by a deubiquitinase (HAUSP) and also reveals a dynamic role of HAUSP in the p53-Mdm2 pathway.
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SuperPose: a simple server for sophisticated structural superposition.
TL;DR: The SuperPose web server rapidly and robustly calculates both pairwise and multiple protein structure superpositions using a modified quaternion eigenvalue approach and yields results that are intuitively more in agreement with known biological or structural data.
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Crystal Structure of a UBP-Family Deubiquitinating Enzyme in Isolation and in Complex with Ubiquitin Aldehyde
Min Hu,Pingwei Li,Muyang Li,Wenyu Li,Tingting Yao,Jia-Wei Wu,Wei Gu,Robert E. Cohen,Yigong Shi +8 more
TL;DR: In this paper, the crystal structures of the 40 kDa catalytic core domain of HAUSP in isolation and in complex with ubiquitin aldehyde were reported, showing that the UBP deubiquitinating enzymes exhibit a conserved three-domain architecture, comprising Fingers, Palm and Thumb.
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Ubiquitin-binding domains
TL;DR: The covalent modification of proteins by ubiquitination is a major regulatory mechanism of protein degradation and quality control, endocytosis, vesicular trafficking, cell-cycle control, stress response, DNA repair, growth-factor signalling, transcription, gene silencing and other areas of biology.