The Cross-Border Biotech Blog

Biotechnology, Health and Business in Canada, the United States and Worldwide

Friday Science Review: January 8, 2013

John HolyoakeUbiquitin-specific proteases (USPs) are implicated in many diseases and yet only a few weak inhibitors of their function have been available. A report in Science from a collaboration led by the Siddhu lab at the Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto describes the development of a molecular strategy to inhibit these important enzymes.

The conjugation of ubiquitin to proteins is one of the most common post-translational modifications of proteins. Labeling of these proteins by ubiquitin often functions to target the protein for destruction by the proteasome or to alter the proteins’ sub-cellular localization and activities. The labeling process is itself complex involving the sequential action of enzymes (E1, E2 and E3) and can result in the addition of a single ubiquitin or multiple ubiquitins either as a chain (polyubiquitination) or at multiple sites on the target protein (multiubiquitination). Removal of ubiquitin can rescue a protein from destruction or restore its activity and is carried out by deubiquitination enzymes, of which the ubiquitin-specific proteases (USPs) are the largest class. Members of this class are implicated in multiple disease processes, including cancer and neurodegeneration, making them an attractive area of study, but one that has been hampered by the lack of high affinity inhibitors.

USPs share a conserved ubiquitin binding site structure, albeit with low affinity for ubiquitin, therefore the research led by the Siddhu lab used the strategy of phage-display-based screening of ubiquitin mutants that had increased binding affinity for specific USPs. Using this approach several specific USP inhibiting mutants were created and the researchers were able to build upon this success by expanding the concept to inhibit other deubiquitinating enzyme classes and components of the ubiquitin labelling system – the E2 and E3 enzymes. In vivo activity of this system means the door is open to carry out detailed dissections of the ubiquitin system, along with using the system to validate drug targets, to create screening assays and ultimately to guide the generation of ubiquitin-system target specific inhibitors.

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