E2 ubiquitin-conjugating enzymes play a central role in the ubiquitination cascade, shuttling ubiquitin from an E1 ubiquitin-activating enzyme to an E3 ligase-substrate complex. The E2 enzyme holds ubiquitin in its activated form via formation of a thioester bond between the carboxy terminus of ubiquitin and the E2 enzyme’s active site cysteine.
E2 enzymes can be divided into canonical and noncanonical enzymes. Canonical E2 enzymes include UBC9, UBC12, UBC2F, UBCH8, UBE2Z, which carry SUMOs, NEDD8, ISG15, and FAT10 as thioester adducts, respectively. Noncanonical E2 enzymes comprise ATG3, ATG12, and UFC1, which carry ATG8, ATG12, and UFM1 as thioester adducts, respectively.
Despite the large number of E2 enzymes, they share significant similarity at the level of both sequence and structure. All E2 enzymes share a conserved “core” ubiquitin conjugating domain of about 150 amino acid residues, and many E2 enzymes possess additional N- and/or C-terminal protein sequences that can govern intracellular localization, confer regulatory properties, or provide specificity for interactions with particular E3 ligases.