Building ubiquitin chains: E2 enzymes at work

Abstract

The reversible attachment of ubiquitin chains regulates the activity, localization and/or stability of a myriad of cellular proteins. The formation of ubiquitin chains requires the sequential action of three types of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Humans express at least 38 E2 genes. E2s contain a highly conserved catalytic ubiquitin-conjugating (UBC) domain that interacts with E1s and E3s. Several E2s possess amino- or carboxy-terminal appendices that modulate their interaction with E3s or enable their association with E2 cofactors. E2s are key regulators of ubiquitin chain assembly, and E2s with specific roles in ubiquitin chain initiation or elongation have been described. Some E2s catalyse both initiation and elongation with high specificity and efficiency. E2s can determine the processivity of ubiquitin chain formation. They have evolved distinct strategies to increase the processivity of chain formation, including the recognition of substrate motifs or the preassembly of ubiquitin chains on their active sites. E2s are crucial regulators of ubiquitin chain topology. Most linkage-specific E2s bind to the acceptor ubiquitin in a non-covalent manner to orient a particular Lys residue relative to the E2 active site (charged with the donor ubiquitin).