Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The E3 ubiquitin ligase adaptor cereblon targets the C-terminal cyclic imide degron

ABSTRACT: Global quantitative proteomics of cells treated with the immunomodulatory drug pomalidomide or dipeptide degrons; global quantitative proteomics of cells treated with heterobifunctional degraders embedded with thalidomide or cyclic imide degrons; gloabl quantitative proteomics of red blood cells to search for the presence of C-terminal cyclic imide modifications on hemoglobin.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Erythrocyte, B Cell, Cell Suspension Culture, Cell Culture

DISEASE(S): Multiple Myeloma

SUBMITTER: Christina Woo

LAB HEAD: Christina Woo

PROVIDER: PXD025413 | Pride | 2022-07-28

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Publications

The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron.

Ichikawa Saki S Flaxman Hope A HA Xu Wenqing W Vallavoju Nandini N Lloyd Hannah C HC Wang Binyou B Shen Dacheng D Pratt Matthew R MR Woo Christina M CM

Nature 20221019 7933

The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide1, therapeutic agents used in the treatment of haematopoietic malignancies2-4 and as ligands for targeted protein degradation5-7. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifi ...[more]

PMID: 36261529

Similar Datasets

The E3 ubiquitin ligase adaptor cereblon targets the C-terminal cyclic imide degron

Project description:The E3 ligase factor cereblon (CRBN) is a target of thalidomide and lenalidomide, which are therapeutic agents used in the treatment of hematopoietic malignancies and as ligands for targeted protein degradation. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN is unknown. Here, we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are degrons for CRBN. Dipeptides bearing the cyclic imide degron are substitutes for thalidomide when embedded within bifunctional small molecule degraders. Installation of the degron to the C-terminus of proteins induces CRBN-dependent ubiquitylation and degradation in vitro and in cells. C-Terminal cyclic imides are previously underappreciated post-translational modifications found throughout the human proteome that are endogenously recognized and removed by CRBN. The discovery of the cyclic imide degron defines a novel regulatory process controlled by these modifications, which may impact the development of therapeutic agents that engage CRBN.

2022-07-28 | PXD034248 | Pride

Global proteomics in MM.1S treated with pomalidomide or dipeptides

Project description:Global proteomics of Multiple Myeloma cell line MM.1S treated with pomalidomide or cyclic imide dipeptides for 10 h. The samples were labeled with TMT-16pro.

2022-07-28 | PXD025336 | Pride

The E3 ubiquitin ligase adaptor cereblon targets the C-terminal cyclic imide degron

Project description:We identify cyclic imides, previously overlooked post-translation modifications, across different tissues (red blood cells and bovine lens) and human-derived cell lines and found that these modifications are globally regulated by cereblon.

2022-07-28 | PXD030091 | Pride

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling]

Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included 15 samples from multiple myeloma cell lines.

2011-09-30 | E-GEOD-31421 | biostudies-arrayexpress

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH]

2011-09-30 | E-GEOD-31451 | biostudies-arrayexpress

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH]

2011-10-01 | GSE31451 | GEO

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling]

2011-10-01 | GSE31421 | GEO

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide

Project description:This SuperSeries is composed of the following subset Series: GSE31421: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling] GSE31451: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH] Refer to individual Series

2011-09-30 | E-GEOD-31452 | biostudies-arrayexpress

Elucidation of E3 Ubiquitin Ligase Specificity Through Proteome-wide Internal Degron Mapping

Project description:The ubiquitin-proteasome system plays critical roles in biology by regulating protein degradation. Despite their importance, precise recognition specificity is known for few of the 600 E3s. Here we establish a two-pronged strategy for identifying and mapping critical residues of internal degrons on a genome scale in HEK-293T cells. We employ Global Protein Stability profiling combined with machine learning to identify 15,800 peptides likely to contain sequence-dependent degrons. We combine this with scanning mutagenesis to define critical residues for over 5,000 predicted degrons. Focusing on Cullin-RING ligase degrons, we generated mutational fingerprints for 219 degrons and developed DegronID, a computational algorithm enabling the clustering of degron peptides with similar motifs. CRISPR analysis enabled the discovery of E3-degron pairs of which we uncover 16 pairs that revealed extensive degron variability and structural determinants. We provide the visualization of this data on the public DegronID Data Browser as a resource for future exploration.

2023-09-21 | GSE240610 | GEO

Redirecting the neo-substrate specificity of Cereblon-targeting PROTACs to Helios

Project description:Immunomodulatory imide drugs (IMiDs), such as thalidomide and its analogues, are some of the most commonly utilized E3 ligase ligands for the development of proteolysis targeting chimeras (PROTACs). While the canonical neo-substrates of IMiDs (i.e., Ikaros and Aiolos) are often considered to be unwanted off-targets of PROTACs, maintaining the degradation of these neo-substrates also provides the opportunity to synergistically degrade multiple proteins with a single compound. Here, we report the development of ALV-07-082-03, a CDK4/CDK6/Helios triple degrader that consists of palbociclib, an FDA-approved CDK4/6 inhibitor, conjugated to DKY709, a novel IMiD-based Helios degrader. Pharmacological co-degradation of CDK4/6 and Helios resulted in potent suppression of downstream signaling and proliferation in cancer cells, as well as enhanced de-repression of IL-2 secretion. Thus, not only do we demonstrate the possibility of rationally re-directing the neo-substrate specificity of PROTACs by incorporating alternative molecular glue molecules as E3 ligase ligands, but our findings also suggest that co-targeting CDK4/6 and Helios may have synergistic effects.

2022-09-07 | PXD036170 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data