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Last update 08 May 2025

UBE2L3

Last update 08 May 2025

Basic Info

Synonyms

E2 ubiquitin-conjugating enzyme L3, L-UBC, UBCE7

+ [7]

Introduction

Ubiquitin-conjugating enzyme E2 that specifically acts with HECT-type and RBR family E3 ubiquitin-protein ligases. Does not function with most RING-containing E3 ubiquitin-protein ligases because it lacks intrinsic E3-independent reactivity with lysine; in contrast, it has activity with the RBR family E3 enzymes, such as PRKN, RNF31 and ARIH1, that function like RING-HECT hybrids. Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Mediates ubiquitination by the CUL9-RBX1 complex (PubMed:38605244). In vitro catalyzes 'Lys-11'-linked polyubiquitination. Involved in the selective degradation of short-lived and abnormal proteins. Down-regulated during the S-phase it is involved in progression through the cell cycle. Regulates nuclear hormone receptors transcriptional activity. May play a role in myelopoiesis.

Drugs associated with UBE2L3

HG-1344

Target

UBE2L3

Mechanism

UBE2L3 modulators

Active Org.-

Originator Org.

Human Genome Sciences, Inc.

Active Indication-

Inactive Indication

Neoplasms [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with UBE2L3

100 Translational Medicine associated with UBE2L3

0 Patents (Medical) associated with UBE2L3

255

Literatures (Medical) associated with UBE2L3

01 Mar 2025·Structure

Structure of E6AP in complex with HPV16-E6 and p53 reveals a novel ordered domain important for E3 ligase activation

Article

Author: Gabel, Clinton A ; Pol, Scott Vande ; Chang, Leifu ; Iyer, Shalini ; Das, Chittaranjan ; Tegenfeldt, Natalia ; Davisson, V Jo ; DeMarco, Andrew G ; Hall, Mark C ; Kenny, Sebastian

High-risk human papillomavirus E6 oncoprotein is a model system for the recognition and degradation of cellular p53 tumor suppressor protein. There remains a gap in the understanding of the ubiquitin transfer reaction, including placement of the E6AP catalytic HECT domain of the ligase concerning the p53 substrate and how E6 itself is protected from ubiquitination. We determined the cryoelectron microscopy (cryo-EM) structure of the E6AP/E6/p53 complex, related the structure to in vivo modeling of the tri-molecular complex, and identified structural interactions associated with activation of the ubiquitin ligase function. The structure reveals that the N-terminal ordered domain (NOD) in E6AP has a terminal alpha helix that mediates the interaction of the NOD with the HECT domain of E6AP and protects the HPV-E6 protein from ubiquitination. In addition, this NOD helix is required for E6AP ligase function by contributing to the affinity of the E6-E6AP association, modulating E6 substrate recognition, while displacing UbcH7.

05 Feb 2025·ACS Chemical Neuroscience

Computational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant

Article

Author: Cinviz, Zeynep Nur ; Sensoy, Ozge

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It impairs the control of movement and balance. Parkin mutations worsen the symptoms in sporadic cases and cause the early onset of the disease. Therefore, recent efforts have focused on the rescue of defective parkin by engineered proteins or small-molecule activators to enhance parkin activation. These attempts require holistic understanding of the multistep activation mechanism and molecular effects of disease-associated mutations. Hereby, we provided a comprehensive analysis of the activation mechanism of parkin and a clinically relevant mutant, parkin^S167N, using molecular dynamics simulations based on the following crystal structures: (1) parkin, (2) parkin/pUb (phosphorylated Ubiquitin), (3) pparkin/pUb, and (4) pparkin/pUb/UbcH7-Ub. Each of these represents an individual step in the activation process. We showed that the mutation impacted the dynamics of not only the RING0 domain, where it is localized, but also the RING2, Ubl, and IBR domains. We identified residues participating in the allosteric interaction network involved in parkin activation. Some of them are mutated in PD-associated parkin variants. The RING0 domain provides a binding interface with various proteins, so understanding problems associated with the mutation paves the way to the discovery of effective engineered proteins or small molecules that activate mutant parkin.

01 Feb 2025·Recent Patents on Anti-Cancer Drug Discovery

UBE2L3 Suppresses Oxidative Stress-regulated Necroptosis to Accelerate Osteosarcoma Progression

Article

Author: Gao, Hongwei ; Hui, Wenpeng ; Zhao, Xiwu ; Xing, Deguo ; Gong, Mingzhi ; Xiong, Zhenggang ; Shan, Guoqiang

Background:Osteosarcoma is a highly invasive bone marrow stromal tumor with limited treatment options. Oxidative stress plays a crucial role in the development and progression of tumors, but the underlying regulatory mechanisms are not fully understood. Recent studies have revealed the significant involvement of UBE2L3 in oxidative stress, but its specific role in osteosarcoma remains poorly investigated.Objective:This study aimed to explore the molecular mechanisms by which UBE2L3 promotes oxidative stress-regulated necroptosis to accelerate the progression of osteosarcoma using in vitro cell experiments.Methods:Human osteoblast hFOB1.19 cells and various human osteosarcoma cell lines (MG-63, U2OS, SJSA-1, HOS, and 143B) were cultured in vitro. Plasmids silencing UBE2L3 and negative control plasmids were transfected into U2OS and HOS cells. The cells were divided into the following groups: U2OS cell group, HOS cell group, si-NC-U2OS cell group, si-UBE2L3-U2OS cell group, si-NC-HOS cell group, and si-UBE2L3-HOS cell group. Cell viability and proliferation capacity were measured using the Tunnel method and clonogenic assay. Cell migration and invasion abilities were assessed by Transwell and scratch assays. Cell apoptosis was analyzed by flow cytometry, and ROS levels were detected using immunofluorescence. The oxidative stress levels in various cell groups and the expression changes of necroptosis-related proteins were assessed by PCR and WB. Through these experiments, we aim to evaluate the impact of oxidative stress on necroptosis and uncover the specific mechanisms by which targeted regulation of oxidative stress promotes tumor cell necroptosis as a potential therapeutic strategy for osteosarcoma.Results:The mRNA expression levels of UBE2L3 in human osteosarcoma cell lines were significantly higher than those in human osteoblast hFOB1.19 cells (p <0.01). UBE2L3 expression was significantly decreased in U2OS and HOS cells transfected with si-UBE2L3, indicating the successful construction of stable cell lines with depleted UBE2L3. Tunnel assay results showed a significant increase in the number of red fluorescent-labeled cells in si-UBE2L3 groups compared to si-NC groups in both cell lines, suggesting a pronounced inhibition of cell viability. Transwell assay demonstrated a significant reduction in invasion and migration capabilities of si-UBE2L3 groups in osteosarcoma cells. The clonogenic assay revealed significant suppression of proliferation and clonogenic ability in both U2OS and HOS cells upon UBE2L3 knockdown. Flow cytometry confirmed that UBE2L3 knockdown significantly enhanced apoptosis in U2OS and HOS cells. Immunofluorescence results showed that UBE2L3 silencing promoted oxidative stress levels in osteosarcoma cells and facilitated tumor cell death. WB analysis indicated a significant increase in phosphorylation levels of necroptosis-related proteins, RIP1, RIP3, and MLKL, in both osteosarcoma cell lines after UBE2L3 knockdown. In addition, the expression of necrosis-associated proteins was inhibited by the addition of the antioxidant N-acetylcysteine (NAC).Conclusion:UBE2L3 is upregulated in osteosarcoma cells, and silencing of UBE2L3 promotes oxidative stress in these cells, leading to enhanced necroptosis and delayed progression of osteosarcoma.

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UBE2L3

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