Abstract

Deubiquitylating enzymes (DUBs) remove ubiquitin (Ub) from various cellular proteins and render eukaryotic ubiquitylation a dynamic process. The misregulation of protein ubiquitylation is associated with many human diseases, and there is an urgent need to identify specific DUBs associated with therapeutically relevant targets of Ub. We report the development of two facile selenocysteine-based strategies to generate the DUB probe dehydroalanine (Dha). Optimized oxidative or alkylative elimination of Se yielded Dha at the C-terminus of Ub. The high utility of alkylative elimination, which is compatible with multiple thiols in Ub targets, was demonstrated by generating a probe derived from the Ub ligase tripartite motif protein 25 (TRIM-25). Successful capture of the TRIM-25-associated DUB, ubiquitin-specific protease 15, demonstrated the versatility of our chemical strategy for identifying target-specific DUBs.

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