E3 Ligases

Protein ubiquitination is a refined post-translational modification ubiquitous in all eukaryotes that is required for many cellular processes, including protein degradation by the proteasome, cell cycle progression, transcriptional regulation, DNA repair and signal transduction. Ubiquitination is catalyzed by ubiquitin-activating (E1), ubiquitin-conjugating (E2) and ubiquitin ligase (E3) enzymes. E3s mediate the transfer of ubiquitin from an E2 enzyme to specific substrate proteins at the end of a three-enzyme cascade. E3s are the most heterogeneous class of enzymes in the ubiquitination pathway, as they mediate substrate specificity. They can be classified into two groups: 1) the single-subunit group, including several subfamilies based upon their mechanisms of action and the presence of specific domains: HECT (Homology to E6-AP C Terminus), RING (Really Interesting New Gene) and U-box type E3s; 2) the multi-subunit group, Cullin-RING box1-Ligases (CRLs), are further divided into four subfamilies: SCF (S phase kinase-associated protein 1–Cullin 1–F-box), BTB (Bric-a-brac–Tramtrack–Broad complex), DDB (DNA Damage-Binding domain-containing) and APC (anaphase-promoting complex). To date, >650 E3 ubiquitin ligases have been described in humans.