Activity‐Based Probes Developed by Applying a Sequential Dehydroalanine Formation Strategy to Expressed Proteins Reveal a Potential α‐Globin‐Modulating Deubiquitinase. Issue 20 (14th April 2018)

• Record Type: Journal Article
• Authors: Meledin, Roman; Mali, Sachitanand M.; Kleifeld, Oded; Brik, Ashraf
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 20(2018)
• Page Start: 5645
• Page End: 5649
• Publication Date: 2018-04-14
• Subjects: activity-based probes -- chemical proteomics -- dehydroalanine -- protein modifications -- ubiquitin; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201800032
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: We report a general and novel semisynthetic strategy for the preparation of ubiquitinated protein‐activity‐based probes on the basis of sequential dehydroalanine formation on expressed proteins. We applied this approach to construct a physiologically and therapeutically relevant ubiquitinated α‐globin probe, which was used for the enrichment and proteomic identification of α‐globin‐modulating deubiquitinases. We found USP15 as a potential deubiquitinase for the modulation of α‐globin, an excess of which aggravates β‐thalassemia symptoms. This development opens new opportunities for activity‐based‐probe design to shed light on the important aspects underlying ubiquitination and deubiquitination in health and disease. Abstract : It takes two to tango : A strategy based on sequential dehydroalanine formation was used to construct an α‐globin–ubiquitin probe, which enabled the identification of a potential, previously unknown α‐globin‐modulating deubiquitinase (DUB; see scheme). This approach opens new opportunities for activity‐based probe design to shed light on the processes of ubiquitination and deubiquitination in health and disease.