E3 ubiquitin-protein ligase complex (E3 ligase) (E3 ligase)

The E3 ubiquitin-protein ligase complex (E3 ligase) is a multi-subunit or single-protein enzyme system that facilitates the final step of the ubiquitination cascade, conferring substrate specificity to the ubiquitin-proteasome system (UPS) (Deshaies & Joazeiro, 2009). By transferring ubiquitin molecules from an E2 conjugating enzyme to a lysine residue on a target protein, E3 ligases mark substrates for degradation by the 26S proteasome or alter their cellular localization and function (Petroski & Deshaies, 2005). There are hundreds of E3 ligases in the human genome, categorized into families such as RING, HECT, and RBR based on their structural domains and mechanism of action (Zheng & Shabek, 2017). In many diseases, E3 ligases are either overactive, leading to the premature degradation of tumor suppressors, or underactive, allowing the accumulation of toxic proteins (Bulatov & Ciulli, 2015). Therapeutically, E3 ligases like Cereblon (CRBN) and Von Hippel-Lindau (VHL) are hijacked by Proteolysis-Targeting Chimeras (PROTACs) and molecular glues to induce the degradation of specific pathogenic proteins (Bondeson et al., 2015). This approach has revolutionized drug discovery by enabling the targeting of proteins previously considered "undruggable" due to the lack of functional binding pockets (Sakamoto et al., 2001).

Other names

Ubiquitin ligaseE3 ligaseCullin-RING ligase (CRL)SCF complexAnaphase-promoting complex/cyclosome (APC/C)HECT-type E3 ligaseRING-finger E3 ligaseRBR-type E3 ligase

Targeted protein degradation (TPD) via recruitment of E3 ligases to specific substrates using Proteolysis-Targeting Chimeras (PROTACs) or molecular glues; competitive inhibition of E3 ligase-substrate interactions (e.g., MDM2-p53 inhibitors).