Correction: HECT E3 ubiquitin ligases – emerging insights into their biological roles and disease relevance

Intersection of Redox Chemistry and Ubiquitylation: Post-Translational Modifications Required for Maintaining Cellular Homeostasis and Neuroprotection

“…The ubiquitin-proteasome system (UPS) is a highly regulated mechanism for protein degradation that regulates many biological processes to maintain cellular homeostasis [60]. A protein is targeted for degradation upon ubiquitylation, where the small 8.6 kDa protein, ubiquitin, is covalently attached to the target protein through an isopeptide bond [61].…”

“…The E2/E3 combination ultimately determines the specific site of attachment of ubiquitin on the target protein and the lysine linkage between ubiquitin molecules within the polyubiquitin chain that is built [61][62][63][64]. The process is initiated when ubiquitin and E1 undergo an ATP-dependent reaction in which a thioester bond is formed between the Cterminus of ubiquitin and the catalytic cysteine on the E1 (E1~ubiquitin) [60]. The activated ubiquitin is then transferred through a transthiolation reaction to a cysteine residue on an E2 enzyme (E2~ubiquitin) [64].…”

“…An E3 ligase then facilitates or directly catalyzes the transfer of ubiquitin from the E2~ubiquitin complex to a lysine residue of the substrate to form a stable isopeptide bond between the C-terminus of ubiquitin and the epsilon-amine of the lysine residue on the substrate [64,65]. The type of mechanism used to attach ubiquitin onto a target protein is dependent on the type of E3 ligase-Really Interesting New Gene (RING), Homologous to E6-AP Carboxyl Terminus (HECT), or RING-Between-RING (RBR) [60]. A RING E3 ubiquitin ligase acts as a scaffold to mediate the transfer of ubiquitin from the E2~ubiquitin complex directly to a lysine residue on the substrate [61].…”

“…A RING E3 ubiquitin ligase acts as a scaffold to mediate the transfer of ubiquitin from the E2~ubiquitin complex directly to a lysine residue on the substrate [61]. In contrast, a HECT E3 ubiquitin ligase removes ubiquitin from E2~ubiquitin to form an E3~ubiquitin thioester intermediate, which then catalyzes the ubiquitin transfer on to the substrate [60]. A RBR E3 ubiquitin ligase recruits an E2~ubiquitin complex through its RING1 domain, like a RING E3 ligase, but instead of coordinating the transfer of ubiquitin from E2~ubiquitin directly to a substrate, the ubiquitin is transferred to a conserved catalytic cysteine in the RING2 domain (also known as "required for catalysis" (Rcat)) prior to discharge on to a substrate, analogous to the HECT E3 ubiquitin ligase mechanism [66].…”

An E3 ligase guide to the galaxy of small-molecule-induced protein degradation

“…The assembly of such ubiquitin polymers is initiated by E1 ubiquitin activating enzymes (Jin et al, 2007), which transfer ubiquitin to the active-site cysteine in 40 E2 ubiquitin-conjugating enzymes (Ye and Rapé , 2009). E2 enzymes can then charge a Cys residue in E3 ligases of the HECT (homologous to E6-AP C terminus), RBR (RING-in between-RING), and RCR (RING Cys relay) families, thereby enabling these enzymes to ubiquitylate a target (Pao et al, 2018;Walden and Rittinger, 2018;Wang et al, 2020b) (Figure 1A). Alternatively, E2s can be activated by E3 ligases with signature RING (really interesting new gene) domains to transfer ubiquitin from their own active site to the substrate (Baek et al, 2020b;Deshaies and Joazeiro, 2009) (Figure 1B).…”