{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBE2D2, a member of the UbcH5 family of E2 ubiquitin‐conjugating enzymes, serves a central mechanistic role in catalyzing ubiquitin transfer by partnering with a diverse array of E3 ligases. Structural and biochemical studies have shown that UBE2D2 engages in both covalent and noncovalent interactions with ubiquitin—often adopting a “closed” conformation—to promote efficient ubiquitin transfer in complexes with RING‐ and HECT‐domain ligases. For example, high‐resolution crystallography of complexes involving BIRC7, NEDD4L, c‐Cbl, cIAP1, and MUL1 reveals that UBE2D2 (also known as UbcH5B) provides the active platform for ubiquitin loading and subsequent substrate modification, with specific basic residues and unique binding surfaces dictating the topology and linkage of ubiquitin chains. Such studies further illustrate that even subtle alterations in the E2–E3 interaction surface can switch ubiquitination profiles—from monoubiquitination to polyubiquitination—thereby influencing the fate of key targets including p53, IκBα, and VEGFR2."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its catalytic role, UBE2D2 is pivotal in modulating cellular homeostasis and signaling pathways, with its dysregulation contributing to diverse pathophysiological conditions. Genome‐wide analyses in myelodysplastic syndromes have indicated that point mutations or small deletions affecting the 5q31.2 region—including UBE2D2—are uncommon, suggesting that altered expression rather than genetic inactivation underpins functional defects. Moreover, UBE2D2 contributes to the regulation of receptor turnover, as evidenced by its involvement in dopamine transporter and VEGFR2 trafficking, and it supports DNA repair pathways via homologous recombination. Altered UBE2D2 expression has also been linked to aberrant p53 accumulation in cadmium‐induced renal toxicity. Finally, emerging studies on circular RNA derivatives derived from the UBE2D2 transcript (circUBE2D2) reveal novel roles in promoting tamoxifen resistance in breast cancer and enhancing ovarian cancer progression, thereby underscoring the multifaceted impact of UBE2D2 in both normal physiology and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "G Sebastiaan Winkler, Thomas K Albert, Cyril Dominguez, et al. 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