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Publication Abstract from PubMed

The E2/E3 hybrid enzyme UBE2O plays important roles in key biological events, but its autoubiquitination mechanism remains largely unclear. In this study, we determined the crystal structures of full-length (FL) UBE2O from Trametes pubescens (tp) and its ubiquitin-conjugating (UBC) domain. The dimeric FL-tpUBE2O structure revealed interdomain interactions between the conserved regions (CR1-CR2) and UBC. The dimeric intermolecular and canonical ubiquitin/UBC interactions are mechanistically important for UBE2O functions in catalyzing the formation of free polyubiquitin chains and substrate ubiquitination. Beyond dimerization, autoubiquitination within the CR1-CR2 domain also regulates tpUBE2O activity. Additionally, we show that tpUBE2O catalyzes the formation of all seven types of polyubiquitin chains in vitro. The CR1-CR2/UBC and canonical ubiquitin/UBC interactions are important for the polyubiquitination of AMP-activated protein kinase alpha2 (AMPKalpha2) by human UBE2O (hUBE2O), which leads to tumorigenesis. These structural insights lay the groundwork for understanding UBE2O's mechanisms and developing structure-based therapeutics targeting UBE2O.

Structural insights into the biochemical mechanism of the E2/E3 hybrid enzyme UBE2O.,Huang H, Zhu W, Huang B, Fu Z, Xiong Y, Cao D, Ye Y, Chang Q, Li W, Li L, Zhou H, Niu X, Zhang W Structure. 2025 Feb 6;33(2):274-288.e4. doi: 10.1016/j.str.2024.12.002. Epub 2024 , Dec 30. PMID:39740670^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.