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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Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code.
Yanfeng Wang,Feng Wang +1 more
TL;DR: In this paper, the authors summarized the current knowledge on the regulatory effects of post-translational modifications of deubiquitinating enzymes (DUBs), which remove conjugated ubiquitin molecules from target substrates.
Journal ArticleDOI
Annexin-1 regulated by HAUSP is essential for UV-induced damage response.
Park Jj,Lim Kh,Kwang-Hyun Baek +2 more
TL;DR: P proteomic analysis using two-dimensional electrophoresis, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry and nano LC-MS/MS, and immunoprecipitation revealed that ANXA1 binds to HAUSP through itsHAUSP-binding motif (P/AXXS), and the cleavage and damage-responsive functions of ANX a1 upon UV-induced DNA damage may be followed by HAUS
Journal ArticleDOI
Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors.
TL;DR: A comprehensive review of small-molecule ubiquitin-proteasome (UPS) inhibitors can be found in this paper, where the authors highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.
Journal ArticleDOI
Converting a broad matrix metalloproteinase family inhibitor into a specific inhibitor of MMP-9 and MMP-14.
Jason Shirian,Valeria Arkadash,Itay Cohen,Tamila Sapir,Evette S. Radisky,Niv Papo,Julia M. Shifman +6 more
TL;DR: An inhibitor starting from a nonspecific MMP inhibitor, N‐TIMP2, showed 1000‐fold preference for MMP‐9 vs. M MP‐14, which is likely to translate into significant differences under physiological conditions.
Journal ArticleDOI
Understanding molecular mechanisms in cell signaling through natural and artificial sequence variation.
Neel H. Shah,John Kuriyan +1 more
TL;DR: Recent work is discussed that illustrates how the analysis of sequence variation synergizes with protein structure information, to provide new insights into specificity and allosteric regulation of signaling proteins.
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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