E2 conjugating enzymes: A silent but crucial player in ubiquitin biology

E2 conjugating enzymes serve as the linchpin of the Ubiquitin-Proteasome System (UPS), facilitating ubiquitin (Ub) transfer to substrate proteins and regulating diverse processes critical to cellular homeostasis. The interaction of E2s with E1 activating enzymes and E3 ligases singularly positions them as middlemen of the ubiquitin machinery that guides protein turnover. Structural determinants of E2 enzymes play a pivotal role in these interactions, enabling precise ubiquitin transfer and substrate specificity. Regulation of E2 enzymes is tightly controlled through mechanisms such as post-translational modifications (PTMs), allosteric control, and gene expression modulation. Specific residues that undergo PTMs highlight their impact on E2 function and their role in ubiquitin dynamics. E2 enzymes also cooperate with deubiquitinases (DUBs) to maintain proteostasis. Design of small molecule inhibitors to modulate E2 activity is emerging as promising avenue to restrict ubiquitination as a potential therapeutic intervention. Additionally, E2 enzymes have been implicated in the pathogenesis and progression of neurodegenerative disorders (NDDs), where their dysfunction contributes to disease mechanisms. In summary, examining E2 enzymes from structural and functional perspectives offers potential to advance our understanding of cellular processes and assist in discovery of new therapeutic targets.