HUWE1, a HECT E3 ligase, is critical for processes like protein degradation and tumor development. Contrary to previous findings which suggested minimal non-covalent interactions between the HUWE1 HECT domain and ubiquitin, we identified a non-covalent interaction between the HUWE1 HECT N-lobe and ubiquitin using NMR spectroscopy, revealing a conserved ubiquitin-binding mode shared across HECT E3 ligases. Molecular dynamics simulations not only confirmed the stability of this interaction but also uncovered conformational changes in key residues, which likely influence binding affinity. Additionally, we highlighted the roles of both conserved and unique residues in ubiquitin binding. These findings advance our understanding of the interactions between the HUWE1 HECT domain and ubiquitin, and highlight potential targets for therapeutic intervention in the ubiquitin-proteasome pathway.
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The E3 ligase HUWE1 interacts with ubiquitin non-covalently via key residues in the HECT domain.
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Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, China.
HUWE1, a HECT E3 ligase, is critical for processes like protein degradation and tumor development. Contrary to previous findings which suggested minimal non-covalent interactions between the HUWE1 HECT domain and ubiquitin, we identified a non-covalent interaction between the HUWE1 HECT N-lobe and ubiquitin using NMR spectroscopy, revealing a conserved ubiquitin-binding mode shared across HECT E3 ligases. Molecular dynamics simulations not only confirmed the stability of this interaction but also uncovered conformational changes in key residues, which likely influence binding affinity.
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Aging is a gradual and irreversible physiological process that significantly increases the risks of developing a variety of pathologies, including neurodegenerative, cardiovascular, metabolic, musculoskeletal, and immune system diseases. Mitochondria are the energy-producing organelles, and their proper functioning is crucial for overall cellular health. Over time, mitochondrial function declines causing an increased release of harmful reactive oxygen species (ROS) and DNA, which leads to oxidative stress, inflammation and cellular damage, common features associated with various age-related pathologies.
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Article Synopsis
- The study investigates how SARS-CoV-2's ORF9b protein suppresses the immune response by inhibiting type I and III interferon (IFN) production and is subsequently degraded through a process called ubiquitination.
- Researchers identified 14 E3 ubiquitin ligases that bind to ORF9b, with three specific ligases (HUWE1, UBR4, and UBR5) shown to trigger the degradation of ORF9b via polyubiquitination, thus restoring IFN responses and reducing the virus's replication.
- The findings highlight the potential of targeting these E3 ligases for new antiviral therapies, as they play a crucial role in enhancing the host's antiviral defenses against SARS-CoV-
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