Structure, Function, and Evolution of E3 Ligases and Targets

The majority of targeted protein degradation in the cell is performed by the ubiquitin (Ub)/26S proteasome pathway, which is highly conserved in all eukaryotic species. In this pathway, target proteins are covalently linked to the 76 amino acid Ub protein by the sequential action of three enzymes (the E1 activating enzyme, the E2 conjugating enzyme, and the E3 ubiquitin-ligase). E3 Ub-ligases recognize structural motifs in the target, bind the substrate protein, and catalyze the formation of an amide isopeptide linkage between Gly₇₆ in the C-terminus of the Ub molecule (brought to the E3 by the E2) and the ε-amino group of a lysine residue in the target protein. By selecting the target proteins, the E3-ligases serve as the primary regulators of ubiquitylation. The most common outcome of ubiquitin pathway action is the formation of polyubiquitin chains on the target protein, resulting from the addition of Ub molecules to the polymer by linkage through the Ub Lys₄₈ ε-amino group. Polyubiquitylation of this sort leads to degradation of the target protein by the 26S proteasome. In eukaryotes, selective degradation of regulatory proteins to modulate activity is a feature of many signaling pathways in the cell. Besides degradation, there are other possible effects of Ub attachment, such as alteration of the activity or localization of the target protein. These outcomes are triggered not by polyubiquitylation via Lys₄₈, but monoubiquitylation, or oligo- and polyubiquitylation via attachment to alternative Ub lysines.
E3 Ub-ligases group into four main types: the RING (really-interesting new gene) family, the U-box family, the HECT (homologous to the E6AP carboxyl terminus) family, and the RBR (RING-in-between-RING) family. The RING family is by far the largest class, and is divide into multiple subfamilies, including the monomeric/dimeric/heterodimeric RINGs, the anaphase-promoting complex/cyclosome (APC/C), and the Cullin-RING ligases. Higher eukaryotes encode large numbers of E3s in their genomes, and this is particularly so in plants. Arabidopsis thaliana, for instance, has >1,400 loci encoding potential E3s or E3 subunits. While there has been significant effort to elucidate the targets and functions of individual E3s in plants, to date the targets of the majority have yet to be determined. In addition, there is still much that we don’t understand about the nature and regulation of E3-ligase/target interactions and about the co-evolution of E3s and their targets.

This Research Topic welcomes Original Research, Reviews, Mini Reviews, and Opinion articles providing new insights into structure, function, and evolution of E3 ligases and targets. Topics can include:
• Identification of new E3 targets in plants
• Characterization of the structure of E3/target complexes
• Identification of mechanisms that regulate E3/target interactions
• Studies exploring the evolution of E3 Ub-ligases and their targets