Issue 44, 2019

Development of a DUB-selective fluorogenic substrate

Abstract

Ubiquitination is a post-translational modification that is involved in a plethora of cellular processes. Target proteins can be specifically modified with a single ubiquitin (Ub) molecule or with complex chains. In recent years, research has focused on deubiquitinating enzymes (DUBs) as potential therapeutic candidates in various diseases. USP16 is an emerging target due to its involvement in mitosis and stem cell self-renewal. Generally, activity-based probes (ABPs) used to study DUBs are based on the ubiquitin scaffold, thus lacking target selectivity. To overcome this issue, we designed a Ub-based activity probe bearing specific mutations to achieve selectivity for USP16, by combining structural modelling and analysis and mutational calculation predictions. We develop a fluorogenic substrate, the first of its kind, that is processed exclusively by USP16, which allows us to monitor USP16 activity in complex samples.

Graphical abstract: Development of a DUB-selective fluorogenic substrate

Supplementary files

Article information

Article type
Edge Article
Submitted
07 May 2019
Accepted
28 Sep 2019
First published
30 Sep 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2019,10, 10290-10296

Development of a DUB-selective fluorogenic substrate

L. Gjonaj, A. Sapmaz, D. Flierman, G. M. C. Janssen, P. A. van Veelen and H. Ovaa, Chem. Sci., 2019, 10, 10290 DOI: 10.1039/C9SC02226K

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