A5009716340- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Endoplasmic Reticulum Stress and Disease
- Peptidase Inhibition and Analysis
- Autophagy in Disease and Therapy
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Advanced Proteomics Techniques and Applications
- Viral Infectious Diseases and Gene Expression in Insects
- RNA and protein synthesis mechanisms
- Pancreatitis Pathology and Treatment
- Cancer, Hypoxia, and Metabolism
- Gastrointestinal disorders and treatments
- Cancer-related Molecular Pathways
- Cancer Research and Treatments
- Pancreatic and Hepatic Oncology Research
California Institute of Technology
2016-2021
The University of Texas Southwestern Medical Center
2021
Deggendorf Institute of Technology
2014
Highlights•UBE2R E2s preferentially target CUL2-based CRL2 substrates•CRL2-dependent PROTAC efficiency correlates with UBE2R-family E2 levels in cells•Cryo-EM reveals a UBE2R2-CRL2 interface that underlies geometric substrate selection•A dedicated poly-ubiquitin chain extending is reprogrammed to prime substratesSummaryCullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought be...
The COP9-Signalosome (CSN) regulates cullin–RING ubiquitin ligase (CRL) activity and assembly by cleaving Nedd8 from cullins. Free CSN is autoinhibited, it remains unclear how becomes activated. We combine structural kinetic analyses to identify mechanisms that contribute activation deconjugation. Both neddylated substrate undergo large conformational changes upon binding, with important roles played the N-terminal domains of Csn2 Csn4 RING domain Rbx1 in enabling formation a high affinity,...
The cullin-RING ligases (CRLs) form the major family of E3 ubiquitin ligases. prototypic CRLs in yeast, called SCF enzymes, employ a single E2 enzyme, Cdc34, to build poly-ubiquitin chains required for degradation. In contrast, six different human and enzyme activities, including Cdc34 orthologs UBE2R1 UBE2R2, appear mediate SCF-catalyzed substrate polyubiquitylation vitro. combinatorial interplay these enzymes raises questions about genetic buffering SCFs cells challenges dogma that E3s...
The cullin-4-based RING-type (CRL4) family of E3 ubiquitin ligases functions together with dedicated substrate receptors. Out the ˜29 CRL4 receptors reported, DDB1- and CUL4-associated factor 1 (DCAF1) is essential for cellular survival growth, its deregulation has been implicated in tumorigenesis. We carried out biochemical structural studies to examine structure mechanism CRL4DCAF1 ligase. In 8.4 Å cryo-EM map , four CUL4-RBX1-DDB1-DCAF1 protomers are organized into two dimeric...
Through catalyzing the ubiquitination of key regulatory proteins, cullin-RING ubiquitin ligases (CRLs) play essential biological roles and their activities are controlled by multiple mechanisms including neddylation, conjugation NEDD8 to cullins. Upon a CRL, such as CUL1-based CRL1, undergoes conformational changes that accelerate substrate ubiquitination. Given structural diversity across subfamilies CRLs substrates, what extent neddylation modulates activity individual remains be...
Abstract The COP9-Signalosome (CSN) regulates cullin–RING ubiquitin ligase (CRL) activity and assembly by cleaving Nedd8 from cullins. Free CSN is autoinhibited, it remains unclear how becomes activated. We combine structural kinetic analyses to identify mechanisms that contribute activation deconjugation. Both neddylated substrate undergo large conformational changes upon binding, with important roles played the N-terminal domains of Csn2 Csn4 RING domain Rbx1 in enabling formation a high...