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) quench ubiquitin signalling by removing ubiquitin, and are being increasingly explored as therapeutic strategies in several diseases ranging from inflammation and cancer to neurodegeneration. 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 We have recently discovered five new DUBs and our exciting unpublished results suggest important roles for these DUBs.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 is modulated. Addressing these questions 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.
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