Systematic approaches to identify E3 ligase substrates.
Protein ubiquitylation is a widespread post-translational modification, regulating cellular signalling with many outcomes, such as protein degradation, endocytosis, cell cycle progression, DNA repair and transcription. E3 ligases are a critical component of the ubiquitin proteasome system (UPS), determining the substrate specificity of the cascade by the covalent attachment of ubiquitin to substrate proteins. Currently, there are over 600 putative E3 ligases, but many are poorly characterized, particularly with respect to individual protein substrates. Here, we highlight systematic approaches to identify and validate UPS targets and discuss how they are underpinning rapid advances in our understanding of the biochemistry and biology of the UPS. The integration of novel tools, model systems and methods for target identification is driving significant interest in drug development, targeting various aspects of UPS function and advancing the understanding of a diverse range of disease processes.
The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Randwick 2052, Sydney, Australia.
Mary
M
Iconomou
School of Medical Sciences, Faculty of Medicine, University of New South Wales, Randwick 2052, Sydney, Australia.
Darren N
DN
Saunders
D000818:Animals; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D040901:Proteomics / Q000379:methods; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
cancer; functional genomics; neurodegeneration; proteomics; proteostasis; ubiquitin