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Review
. 2016 Nov 15;473(22):4083-4101.
doi: 10.1042/BCJ20160719.

Systematic approaches to identify E3 ligase substrates

Mary Iconomou  1   2 , Darren N Saunders  3
Affiliations
Review

Systematic approaches to identify E3 ligase substrates

Mary Iconomou et al. Biochem J. .

Abstract

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.

Keywords: cancer; functional genomics; neurodegeneration; proteomics; proteostasis; ubiquitin.

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Figures

Figure 1.
Figure 1.. Challenges in the identification of E3 ligase substrates.
1. The dynamic nature of protein ubiquitylation. 2. Weak and/or transient interactions between ligase and substrate. 3. Significant degrees of redundancy and multiplicity. 4. Rapid destruction of many ubiquitylated proteins.
Figure 2.
Figure 2.. Diversity of systematic approaches available to identify E3 ligase substrates.
See this image and copyright information in PMC

References

    1. Chau V., Tobias J.W., Bachmair A., Marriott D., Ecker D.J., Gonda D.K. et al. (1989) A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243, 1576–1583 PMID: - PubMed
    1. Haglund K., Sigismund S., Polo S., Szymkiewicz I., Di Fiore P.P., Dikic I. et al. (2003) Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat. Cell. Biol. 5, 461–466 doi:10.1038/ncb983 - DOI - PubMed
    1. Hicke L. and Riezman H. (1996) Ubiquitination of a yeast plasma membrane receptor signals its ligand-stimulated endocytosis. Cell 84, 277–287 doi:10.1016/S0092-8674(00)80982-4 - DOI - PubMed
    1. Staub O., Gautschi I., Ishikawa T., Breitschopf K., Ciechanover A., Schild L. et al. (1997) Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J. 16, 6325–6336 doi:10.1093/emboj/16.21.6325 - DOI - PMC - PubMed
    1. Koepp D.M., Harper J.W. and Elledge S.J. (1999) How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell 97, 431–434 doi:http://dx.doi.org/10.1016/S0092-8674(00)80753-9 - DOI - PubMed