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Mechanisms, biology and inhibitors of deubiquitinating enzymes

Abstract

The addition of ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers to proteins serves to modulate function and is a key step in protein degradation, epigenetic modification and intracellular localization. Deubiquitinating enzymes and Ubl-specific proteases, the proteins responsible for the removal of Ub and Ubls, act as an additional level of control over the ubiquitin-proteasome system. Their conservation and widespread occurrence in eukaryotes, prokaryotes and viruses shows that these proteases constitute an essential class of enzymes. Here, we discuss how chemical tools, including activity-based probes and suicide inhibitors, have enabled (i) discovery of deubiquitinating enzymes, (ii) their functional profiling, crystallographic characterization and mechanistic classification and (iii) development of molecules for therapeutic purposes.

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Figure 1: Ub/Ubl modifiers have a comparable fold and are activated and conjugated similarly.
Figure 2: ABPP approach for identifying DUBs.
Figure 3: Topological comparison of the M48USP structure to other DUBs.
Figure 4: Cladogram representation of proteases forming covalent adducts with Ub-based probes.
Figure 5: Small-molecule inhibitors of DUBs.
Figure 6: Ligation of an auxiliary-containing peptide with a C-terminally truncated Ub-thioester to achieve isopeptide-linked DUB substrates.

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Acknowledgements

We thank T. DiCesare (Whitehead Institute Bioinformatics & Research Computing Group) for help with the figures. K.R.L. is a US National Institutes of Health postdoctoral fellow (F32 AI63854). C.S. is supported by a European Molecular Biology Organization long-term fellowship (187-2005).

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Love, K., Catic, A., Schlieker, C. et al. Mechanisms, biology and inhibitors of deubiquitinating enzymes. Nat Chem Biol 3, 697–705 (2007). https://doi.org/10.1038/nchembio.2007.43

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