University of Dundee

Mechanisms of substrate recognition by Deubiquitinases

Ubiquitin signalling, which involves the posttranslational modification of proteins with ubiquitin, regulates almost every facet of eukaryotic biology. It is therefore very important that ubiquitylation is tightly regulated. Deubiquitinating enzymes (DUBs) control ubiquitin signalling by removing ubiquitin thus regulating several important cellular pathways. Deregulated DUB activity is implicated in several human diseases ranging from inflammation and cancer to neurodegeneration, and are being increasingly explored as therapeutic strategies in several diseases. Developing inhibitors and modulators of DUBs is therefore an area of intense research. Despite their importance, we have a poor understanding of how DUBs recognize substrate and the mechanisms by which their activity is regulated. We have recently discovered five new DUBs – the MINDY DUBs and ZUFSP/ZUP1 [1,2] and our exciting unpublished results suggest important cellular roles for these DUBs. Being newly discovered enzymes, there is a need to characterize the molecular mechanisms regulating these DUBs. The aim of this project is to structurally characterize these DUBs on their own and in complex with substrate. This project will also explore the mechanisms by which DUB activity and function are modulated. This research will not only address important fundamental questions about how DUBs recognize substrate and how their activity is regulated, but also provide crucial insights that will be key to developing drugs to inhibit DUBs.

References:

[1] Abdul Rehman et al. Mol Cell 2016

[2] Kwasna et al. Mol Cell 2018

At the MRC PPU, as well as the possibility of a PhD in one particular lab, we offer the possibility of two 4.5-month rotations in labs of their choice. A range of other projects from MRC PPU scientists are advertised on this website. Rotations provide valuable experience and help with deciding on the choice of PhD project and research group.

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