- UBE2E (Ubiquitin-conjugating enzyme E2 E family) refers to a subgroup of E2 ubiquitin-conjugating enzymes that includes UBE2E1, UBE2E2, and UBE2E3.
- These enzymes share significant structural and functional similarities but also display some unique regulatory features. Like other E2 enzymes, UBE2E family members transfer ubiquitin from the E1 ubiquitin-activating enzyme to substrates in conjunction with an E3 ligase. What makes this family distinctive is its N-terminal extension, which is absent in many other E2 enzymes. This extension influences both their enzymatic activity and subcellular localization, allowing them to function as versatile regulators of ubiquitination.
- The UBE2E enzymes are capable of catalyzing both monoubiquitination and polyubiquitination, depending on the E3 ligase partners and substrate context. Monoubiquitination often alters protein localization, activity, or interactions, while polyubiquitination typically regulates protein turnover or signaling. For example, UBE2E enzymes have been implicated in the ubiquitination of transcription factors, DNA repair proteins, and regulators of cellular stress responses. Through these activities, the UBE2E family influences fundamental processes such as transcriptional regulation, DNA damage response, apoptosis, and cell cycle progression.
- A notable feature of the UBE2E family is their involvement in nuclear processes. UBE2E enzymes are frequently localized to the nucleus, where they participate in chromatin-associated events and gene expression control. They also play roles in genomic stability, as their activity has been linked to DNA repair pathways, ensuring cells can recover from genotoxic stress. UBE2E3, in particular, has been studied for its interaction with specific transcriptional regulators and tumor suppressors, suggesting that the family acts at the interface of protein turnover and gene expression.
- Clinically, dysregulation of UBE2E enzymes has been associated with cancer and neurodegeneration. Overexpression of UBE2E family members has been observed in certain cancers, where it may promote tumor progression by degrading growth-suppressing proteins or altering signaling pathways. Conversely, deficiencies or mutations in these enzymes may impair normal protein quality control, leading to accumulation of damaged proteins and increased susceptibility to stress, which has implications for neurodegenerative conditions. Their nuclear roles also suggest potential links to diseases involving DNA repair defects and genomic instability.
- Structurally, all UBE2E proteins contain the conserved ubiquitin-conjugating (UBC) catalytic domain, with an active-site cysteine that forms the thioester bond with ubiquitin. The N-terminal extension unique to this family acts as a regulatory region, influencing enzyme activity and interactions with E3 ligases. This structural configuration allows UBE2E enzymes to fine-tune ubiquitination outcomes depending on cellular conditions and partner proteins.
- In summary, the UBE2E family (UBE2E1, UBE2E2, UBE2E3) is a subgroup of E2 enzymes distinguished by an N-terminal extension and their preference for nuclear functions. They regulate diverse processes, from transcription and DNA repair to apoptosis and stress response, through both monoubiquitination and polyubiquitination. Their dysregulation contributes to cancer progression, genomic instability, and neurodegeneration. Given their dual regulatory and degradative roles, UBE2E enzymes represent important nodes in the ubiquitin network and are of increasing interest as potential therapeutic targets.
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