A5027427166- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Glycosylation and Glycoproteins Research
- Endoplasmic Reticulum Stress and Disease
- Protein Structure and Dynamics
- Biochemical Acid Research Studies
- Machine Learning in Bioinformatics
- Amino Acid Enzymes and Metabolism
- Genetics and Neurodevelopmental Disorders
- 14-3-3 protein interactions
- Cancer-related gene regulation
- Enzyme Structure and Function
- Cancer, Hypoxia, and Metabolism
- Acute Lymphoblastic Leukemia research
- ATP Synthase and ATPases Research
- Enzyme Production and Characterization
- Histone Deacetylase Inhibitors Research
- Chemical Reactions and Isotopes
- Genomics and Phylogenetic Studies
- Bacterial Genetics and Biotechnology
- Chronic Lymphocytic Leukemia Research
- Carbohydrate Chemistry and Synthesis
University of Nevada, Las Vegas
2013-2024
Max Planck Institute of Biochemistry
2024
Howard Hughes Medical Institute
2000-2012
California Institute of Technology
2006-2012
University of California, Los Angeles
2000-2003
Hammersmith Hospital
2000
Abstract E3 ligases are typically classified by hallmark domains such as RING and RBR, which thought to specify unique catalytic mechanisms of ubiquitin transfer recruited substrates 1,2 . However, rather than functioning individually, many neddylated cullin–RING (CRLs) RBR-type in the ARIH family—which together account for nearly half all humans—form E3–E3 super-assemblies 3–7 Here, studying CRLs SKP1–CUL1–F-box (SCF) family, we show how SCF ARIH1 (an ligase) co-evolved ubiquitylate diverse...
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...
Ikaros is a sequence-specific DNA-binding protein that essential for lymphocyte development. Little known about the molecular function of Ikaros, although recent results have led to hypothesis it recruits genes destined heritable inactivation foci containing pericentromeric heterochromatin. To gain further insight into functions we examined mechanism by which targeted centromeric foci. Efficient targeting was observed upon ectopic expression in 3T3 fibroblasts, demonstrating...
The GXXXG motif is a frequently occurring sequence of residues that known to favor helix−helix interactions in membrane proteins. Here we show the also prevalent soluble proteins whose structures have been determined. Some 152 from nonredundant PDB set contain at least one α-helix with motif, 41 ± 9% more than expected if glycine were uniformly distributed those α-helices. More 50% GXXXG-containing α-helices participate interactions. In fact, 26 are structurally similar interaction...
Abstract E3 ubiquitin ligases, in collaboration with E2 ubiquitin-conjugating enzymes, modify proteins poly-ubiquitin chains. Cullin-RING ligase (CRL) E3s use Cdc34/UBE2R-family E2s to build Lys48-linked chains control an enormous swath of eukaryotic biology. Yet the molecular mechanisms underlying this exceptional linkage specificity and millisecond kinetics poly-ubiquitylation remain unclear. Here we obtain cryogenic-electron microscopy (cryo-EM) structures that provide pertinent insight...
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...
Ubiquitylation is catalyzed by coordinated actions of E3 and E2 enzymes. Molecular principles governing many important E3-E2 partnerships remain unknown, including those for RING-family GID/CTLH ubiquitin ligases their dedicated E2, Ubc8/UBE2H (yeast/human nomenclature). GID/CTLH-Ubc8/UBE2H-mediated ubiquitylation regulates biological processes ranging from yeast metabolic signaling to human development. Here, cryoelectron microscopy (cryo-EM), biochemistry, cell biology reveal this...
Protein ubiquitylation typically involves isopeptide bond formation between the C-terminus of ubiquitin to side-chain amino group on Lys residues. However, several ligases (E3s) have recently been identified that ubiquitylate proteins non-Lys For instance, HOIL-1 belongs RING-in-between RING (RBR) class E3s and has an established role in Ser ubiquitylation. Given homology ARIH1, RBR E3 functions with large superfamily cullin-RING (CRLs), a biochemical investigation was undertaken, showing...
Protein misfolding is a recurring phenomenon that cells must manage; otherwise misfolded proteins can aggregate and become toxic should they persist. To counter this burden, have evolved protein quality control (PQC) mechanisms manage proteins. Two classes of systems function in PQC are chaperones aid folding ubiquitin-protein ligases ubiquitinate for proteasomal degradation. How degradative interact coordinate their respective functions not yet fully understood. Previous studies degradation...
Ubiquitylation of proteins can be a signal for variety cellular processes beyond the classical role in proteolysis. The different signaling functions ubiquitylation are thought to rely on ubiquitin-binding domains (UBDs). Several distinct UBD families known, but their not understood detail, and mechanisms interpretation transmission ubiquitin signals remain discovered. One interesting example complexity is Saccharomyces cerevisiae transcription factor Met4, which regulated by single...
Together with ubiquitin ligases (E3), ubiquitin-conjugating enzymes (E2) are charged the essential task of synthesizing chains onto protein substrates. Some 75% known E2s in human proteome contain unique insertions their primary sequences, yet it is largely unclear what effect these impart on ubiquitination reaction. Cdc34 an important E2 prominent roles cell cycle regulation and signal transduction. The amino acid sequence contains insertion distal to active site that absent most other E2s,...