Ubiquitin-protein ligase (E3 ubiquitin ligase) (E3 ligase)

Ubiquitin-protein ligases, commonly known as E3 ligases, are a large family of enzymes that play a critical role in the ubiquitin-proteasome system (UPS) by providing substrate specificity for protein ubiquitination (Zheng & Shabek, 2017). They facilitate the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to a specific target protein, typically marking it for degradation by the 26S proteasome (Bulatov & Ciulli, 2015). With over 600 members in the human genome, E3 ligases regulate diverse cellular processes, including cell cycle progression, DNA repair, and signal transduction (Nalepa et al., 2006). Dysregulation of these enzymes is linked to various pathologies, such as cancer, where they may inappropriately degrade tumor suppressors or stabilize oncoproteins (Sakamoto, 2010). In drug discovery, E3 ligases are targeted using small-molecule inhibitors or hijacked by bifunctional molecules like Proteolysis Targeting Chimeras (PROTACs) and molecular glues to induce the degradation of otherwise undruggable proteins (Sun et al., 2019). This targeted protein degradation approach has revolutionized the therapeutic potential of the UPS, particularly in oncology and immunology (Cromm & Crews, 2017). Notable examples include the recruitment of Cereblon (CRBN) or Von Hippel-Lindau (VHL) ligases to degrade specific disease-relevant proteins (Bondeson et al., 2015). The specificity of E3 ligases makes them ideal candidates for precision medicine, allowing for the selective modulation of protein levels within the cell (Deshaies, 2015).

Other names

E3 ubiquitin-protein ligaseUbiquitin ligaseE3 enzymeUbiquitin-protein ligase

E3 ubiquitin ligases catalyze the transfer of ubiquitin to a lysine residue on a target substrate, often forming a polyubiquitin chain that signals for degradation by the 26S proteasome (Zheng & Shabek, 2017). Therapeutic strategies involve either inhibiting the ligase to prevent the degradation of beneficial proteins (e.g., MDM2 inhibitors to stabilize p53) or utilizing molecular glues and Proteolysis Targeting Chimeras (PROTACs) to recruit an E3 ligase to a specific pathogenic protein for its targeted destruction (Sun et al., 2019).