Paving the way to targeting HECT ubiquitin ligases
The ubiquitin-proteasome system (UPS) is responsible for regulated proteolytic degradation in eukaryotes and as such plays a key role in most cellular pathways. Modification of proteins by ubiquitin also has important non-degradative functions in processes such as protein trafficking, autophagy, DNA repair and transcription. Deregulation of protein ubiquitination has been implicated in a wide range of human diseases that include cancer, neurodegenerative and immunological disorders, muscle wasting, viral infection, diabetes and inflammation, and targeting components of UPS offers a powerful means to develop new therapies.
Ubiquitin E3 ligases are enzymes that catalyse the final step in the ubiquitination cascade in which ubiquitin is attached to the target protein. Targeting these enzymes has been predicted to have similar potential to targeting protein kinases and considerable effort is being devoted to this area. As all of the steps in the ubiquitin-transfer reaction are driven by protein-protein interactions (PPIs) the most effective and selective way of targeting E3 ligases is by inhibiting these PPIs.
The HECT E3s offer great potential both in terms of therapeutic index and the range of strategies available to modulate their activity, and here is little doubt that in the near future we will see the development of drugs targeting this class of molecules.