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
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.
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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
Amino-terminal dimerization, NRDP1-rhodanese interaction, and inhibited catalytic domain conformation of the ubiquitin-specific protease 8 (USP8)
George V. Avvakumov,George V. Avvakumov,John R. Walker,Sheng Xue,Sheng Xue,P.J. Finerty,Farrell MacKenzie,E.M. Newman,E.M. Newman,Sirano Dhe-Paganon,Sirano Dhe-Paganon +10 more
TL;DR: In this paper, the first high-resolution crystal structures of USP8 were reported and discussed their implications for USP-8 function, including coiled-coil, rhodanese, and catalytic domains.
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The Isopeptidase USP2a Protects Human Prostate Cancer from Apoptosis
Carmen Priolo,Dan Tang,Mohan Brahamandan,Barbara Benassi,Ewa Sicinska,Shuji Ogino,Antonella Farsetti,Alessandro Porrello,Stephen P. Finn,Johann Zimmermann,Phillip G. Febbo,Massinio Loda +11 more
TL;DR: It is shown that when USP2a is overexpressed in nontransformed cells, it exhibits oncogenic behavior both in vitro and in vivo and prevents apoptosis induced by chemotherapeutic agents, and thus represents a therapeutic target in prostate cancer.
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Deubiquitinase USP37 Is Activated by CDK2 to Antagonize APCCDH1 and Promote S Phase Entry
XiaoDong Huang,Matthew K. Summers,Victoria Pham,Jennie R. Lill,Jinfeng Liu,Gwanghee Lee,Donald S. Kirkpatrick,Peter K. Jackson,Guowei Fang,Vishva M. Dixit +9 more
TL;DR: It is shown that the deubiquitinase USP37 binds CDH1 and removes degradative polyubiqu itin from cyclin A, which is critical for the G1/S transition and accumulates even when APC(CDH1) is active.
Journal ArticleDOI
USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1
TL;DR: Usp4 knockout mice are viable and developmentally normal, but showed enhanced apoptosis in thymus and spleen in response to ionizing radiation, consistent with upregulated levels and activity of p53 in the absence of USP4.
Journal ArticleDOI
Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays
Avinash Persaud,Philipp Alberts,Eva Amsen,Xuejian Xiong,James D. Wasmuth,Zachary Saadon,Christopher Fladd,John Parkinson,Daniela Rotin +8 more
TL;DR: The feasibility of identifying substrates and deciphering substrate specificity of mammalian E3 ligases is demonstrated and Nedd4‐1 knockdown or knockout in cells led to sustained signalling via some of its substrate Tyr kinases (e.g. FGFR), suggesting Nedd 4‐1 suppresses their signalling.