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Ubiquitin (Ub)/proteasome-regulated proteolysis is a key mechanism for regulating many cellular and organismal processes. Conjugation of Ub to substrate proteins requires three enzymes: the Ub-activating enzyme (E1), a Ub-conjugating enzyme (E2), and a Ub ligase (E3). E1 activates Ub through the formation of a thiol-ester bond between the C-terminus of Ub and the active site cysteine (Cys). The activated Ub is then trans-esterified to a conserved Cys of an E2. The E3 ligase interacts with both E2 and the substrate and facilitates polyubiquitylation of the substrate. 1 There are two distinct types of E3 ligases: the enzymatic HECT (homologous to E6-AP C-terminus) domain E3s and the adaptor E3s. HECT domain E3s form a thioester with Ub, which can then be transferred directly to the substrate. The adaptor E3s, containing a RING, SP-RING finger, variant RING/PHD