Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly

Abstract

Protein ubiquitylation is essential for the maintenance of cellular homeostasis. E3 ubiquitin ligases are key components of the enzymatic machinery catalyzing the attachment of ubiquitin to substrate proteins. Consequently, enzymatic dysfunction has been associated with medical conditions including cancer, diabetes, and cardiovascular and neurodegenerative disorders. To safeguard substrate selection and ubiquitylation, the activity of E3 ligases is tightly regulated by post-translational modifications including phosphorylation, sumoylation, and ubiquitylation, as well as binding of alternative adaptor molecules and cofactors. Recent structural studies identified homotypic and heterotypic interactions between E3 ligases, adding another layer of control for rapid adaptation to changing environmental and physiological conditions. Here, we discuss the regulation of E3 ligase activity by combinatorial oligomerization and summarize examples of associated ubiquitylation pathways and mechanisms.

Keywords: C. elegans; CHIP; E3 ligase; HECT; RING; chaperone; proteostasis; ubiquitin.

Figure 1.. Different types of E3 ligase regulation and assembly.

E3 ligase A is inactive (red) as an oligomer and converted into an active monomer (green) upon post-translational modification or binding to adaptor molecules, indicated with orange, yellow, black, and violet circles, representing phosphate (P), sumo, ubiquitin (Ub), and adaptor molecules, respectively. Conversely, E3 ligase B is inactive as a monomer and activated upon dimerization. Heterotypic interaction of inactive E3 ligase C and active E3 ligase D results in the formation of a multimeric E3 ligase complex, which is able to target oligomeric substrates for ubiquitylation. Upon substrate degradation, the remaining, active ligase D undergoes auto-ubiquitylation and turnover. The different substrates are indicated in other shapes.