Figure 1.

The ubiquitin-conjugating system in HERC E3 ligases: (A) Ubiquitin (Ub) is conjugated to a target substrate via a cascade that comprises an E1 activating enzyme, an E2 conjugating enzyme, and an E3 ligase enzyme. The HERC proteins belong to the HECT family of E3 ligases, which form a thioester bond with Ub via a conserved cysteine residue. Once formed, Ub is transferred to the substrate’s lysine residue (see text for details). Ub-like proteins, such as ISG15, are also covalently attached to the substrate protein via an E1/E2/E3 cascade; (B) structural features of large and small HERC proteins are also shown. HERC5 and HERC6 may also function as ISG15 E3 ligases.