UbiquitinConjugating

Ubiquitin-conjugating enzymes, commonly referred to as E2 enzymes, form a key component of the ubiquitin–proteasome system. They catalyze the transfer of ubiquitin from the ubiquitin-activating enzyme (E1) to substrate proteins, often with the help of a ubiquitin ligase (E3). E2s typically work in cooperation with E3s to confer substrate specificity and determine the type of ubiquitin modification.

Mechanism and architecture: E2 enzymes carry a catalytic cysteine residue that forms a thioester bond with the C-terminal glycine of ubiquitin, generating Ub–E2 thioester. The E2 then participates in ubiquitin transfer either directly to substrate or to an E3-bound substrate, depending on the ligase and context. The same E2 can participate in monoubiquitination or polyubiquitin chain elongation, and certain E2s bias chain linkages (for example Lys48-linked for proteasomal degradation, Lys63-linked for signaling) in conjunction with specific E3s.

Distribution and examples: In humans, dozens of UBE2 family members exist, sharing a conserved UBC (ubiquitin-conjugating) domain but differing in regulatory regions and partner interactions. Notable examples include the UBE2D family (UBC4/5), which partners with many E3 ligases; UBE2N (UBC13) in complex with UBE2V1/UBE2V2 to assemble Lys63-linked chains; UBE2G2 involved in ER-associated degradation; and Cdc34 (UBE2R1) that collaborates with SCF E3 ligases in cell cycle control. Other E2s contribute to chain elongation or proofreading.

Clinical and research relevance: Aberrations in E2 function have been linked to cancer, neurodegenerative diseases, and immune disorders. Because E2 enzymes shape the ubiquitin landscape, they are targets of interest for drugs modulating protein degradation and signaling pathways.