A5009081376- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Autophagy in Disease and Therapy
- Click Chemistry and Applications
- Biochemical and Molecular Research
- Genetics and Neurodevelopmental Disorders
- Carbohydrate Chemistry and Synthesis
- RNA modifications and cancer
Leiden University Medical Center
2020-2023
Leiden University
2022
Oncode Institute
2020-2022
Abstract The ubiquitin-proteasome axis has been extensively explored at a system-wide level, but the impact of deubiquitinating enzymes (DUBs) on ubiquitinome remains largely unknown. Here, we compare contributions proteasome and DUBs global ubiquitinome, using UbiSite technology, inhibitors mass spectrometry. We uncover large dynamic ubiquitin signalling networks with substrates sites preferentially regulated by or proteasome, highlighting role in degradation-independent ubiquitination....
Ubiquitin (Ub) chain formation by homologous to E6AP C-terminus (HECT)-family E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We used chemistry and cryo-electron microscopy (cryo-EM) visualize stable mimics of intermediates along K48-linked Ub human E3, UBR5. The data reveal a ≈ 620 kDa UBR5 dimer as functional unit, comprising scaffold with flexibly tethered Ub-associated (UBA) domains, elaborately arranged HECT domains. Chains are forged UBA domain...
ABSTRACT Ubiquitin chain formation by HECT catalytic domain-containing E3 ligases regulates vast biology, yet the structural mechanisms remain unknown. We employed chemistry and cryo-EM to visualize stable mimics of intermediates along K48-linked ubiquitin human E3, UBR5. The data reveal a ≈620 kDa UBR5 dimer as functional unit, comprising scaffold with flexibly-tethered ubiquitin-binding UBA domains, elaborately arranged domains. Chains are forged domain capturing an acceptor ubiquitin, its...
Protein post-translational modification with ubiquitin (Ub) is a versatile signal regulating almost all aspects of cell biology, and an increasing range diseases associated impaired Ub modification. In this light, the system offers attractive, yet underexplored route to development novel targeted treatments. A promising strategy for small molecule intervention posed by final components enzymatic ubiquitination cascade, E3 ligases, as they determine specificity protein pathway. Here, we...
Abstract Protein post‐translational modification with ubiquitin (Ub) is a versatile signal regulating almost all aspects of cell biology, and an increasing range diseases associated impaired Ub modification. In this light, the system offers attractive, yet underexplored route to development novel targeted treatments. A promising strategy for small molecule intervention posed by final components enzymatic ubiquitination cascade, E3 ligases, as they determine specificity protein pathway. Here,...