Activation of the free α-carboxyl group of ubiquitin by E1 ubiquitin-activating enzyme is an obligatory step in all processes dependent on ubiquitin ligation. E1 enzymes play three critical functions in initiating ubiquitin conjugation cascades. First, the E1 enzyme selects the correct ubiquitin for the pathway, associating noncovalently with the ubiquitin in the presence of ATP. Second, the E1 enzyme activates the ubiquitin C-terminus. Third, the E1 enzyme coordinates the ubiquitin with the correct pathway, by transferring the ubiquitin to its cognate E2 ubiquitin-conjugating enzymes.
E1 enzymes can be monomeric (UBA1, UBA6, UBA7), heterodimeric (UBA2/SAE1, UBA3/APPBP1), or homodimeric (UBA4, ATG7, and likely UBA5). The monomeric E1 enzymes are for ubiquitin, FAT10 and ISG15, whereas the homodimeric E1 enzymes of about 110 kDa are for NEDD8 and SUMO family members. Among them, SUMO-1, SUMO-2, SUMO-3, and SUMO-4 are activated by a common E1, the heterodimeric SUMO activating enzyme 1 (SAE1)-UBA2 complex.