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MeSH Disease

Human Phenotype

There are no HP terms in the subcorpus


Transmission

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Seroprevalence

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    Engineered unnatural ubiquitin for optimal detection of deubiquitinating enzymes

    Authors: Wioletta Rut; Mikolaj Zmudzinski; Scott J. Snipas; Miklos Bekes; Tony T. Huang; Marcin Drag

    doi:10.1101/2020.01.30.926881 Date: 2020-01-31 Source: bioRxiv

    Deubiquitinating enzymes (DUBs) are responsible for removing ubiquitin (Ub) from its protein conjugates. DUBs have been implicated as attractive therapeutic targets in the treatment of viral diseases MESHD, neurodegenerative disorders MESHD and cancer MESHD. The lack of selective chemical tools for the exploration of these enzymes significantly impairs the determination of their roles in both normal and pathological states. Commercially available fluorogenic substrates are based on the C-terminal Ub motif or contain Ub coupled to a fluorophore (Z-LRGG-AMC, Ub-AMC); therefore, these substrates suffer from lack of selectivity. By using a hybrid combinatorial substrate library (HyCoSuL) and a defined P2 library containing a wide variety of nonproteinogenic amino acids, we established a full substrate specificity profile for two DUBs--MERS PLpro and human UCH-L3. Based on these results, we designed and synthesized Ub-based substrates and activity-based probes (ABPs) containing selected unnatural amino acids located in the C-terminal Ub motif. Biochemical analysis and cell-based experiments confirmed the activity and selectivity of engineered Ub-based substrates and probes. Using this approach, we propose that for any protease that recognizes Ub and Ub-like substrates, a highly active and selective unnatural substrate or probe can be engineered.

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MeSH Disease
Human Phenotype
Transmission
Seroprevalence


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