Regulation of E3 ubiquitin ligases by homotypic and heterotypic assembly.

Vishnu Balaji,Thorsten Hoppe

doi:10.12688/f1000research.21253.1

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.

Highlights

The covalent attachment of ubiquitin to substrate proteins is essential for the maintenance of organismal homeostasis by regulating diverse cellular signaling processes and protein quality control[1]
Depending on the mechanism by which ubiquitin is transferred from the E2 enzyme to the substrate, E3 ligases are classified into Really Interesting New Gene (RING) finger domain, Homologous to E6-associated protein C Terminus (HECT) domain, or RING Between RING (RBR) domain-containing ubiquitin ligases[3]
While RING E3s facilitate the direct transfer of ubiquitin from E2~ubiquitin intermediates to the target protein, HECT and RBR E3s contain an active-site cysteine that forms a thioester with ubiquitin before transferring it to the substrate[3,4,5]

Summary

Introduction

The covalent attachment of ubiquitin to substrate proteins is essential for the maintenance of organismal homeostasis by regulating diverse cellular signaling processes and protein quality control[1]. The activity and abundance of E3 ligases are defined by both post-translational modifications and binding of cofactors and/or adaptor molecules[12,13,14] Besides these well-known control mechanisms, recent structural work identified an additional layer of regulation provided by homotypic and heterotypic combination of E3 ligases into oligomeric ubiquitylation complexes[4,5,15,16]. The HECT ligase E6AP is active in its trimeric form whereas monomerization inhibits its catalytic function, which is triggered by c-Abl kinase-dependent phosphorylation[22,32] This phenomenon is intriguingly different from other HECT ligases, which are inactive as oligomers. The Mdm2–Mdmx heterodimer has the potential to form tetramers, especially to target the putative substrate p53, which is primarily a tetramer[4,45]

15 CHIP U-box

Conclusion