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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

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			Action	DRS
	201202L_SAM07773_WX102_CF_.msf	Msf
	201202L_SAM07773_WX102_CF_1.raw	Raw
	201202L_SAM07773_WX102_CF_10.raw	Raw
	201202L_SAM07773_WX102_CF_11.raw	Raw
	201202L_SAM07773_WX102_CF_12.raw	Raw

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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

Continuous evolution of compact protein degradation tags regulated by selective cereblon molecular glues

Project description:Small molecule-triggered protein degradation tags (degrons) are powerful tools for biology, biotechnology, and therapeutics development. Commonly used degrons, however, are large protein domains (typically >100 amino acids) that cannot be easily or cleanly installed in endogenous protein-coding genes in most cell types. Although some zinc-finger (ZF) degrons are theoretically small enough for facile endogenous tagging, all are triggered by small molecules with substantial off-target effects, precluding their use as highly specific modulators of endogenous protein levels. We developed a phage-assisted continuous evolution platform for molecular glues (MG-PACE) and applied it to evolve ZF degrons that engage cereblon (CRBN) only in the presence of orthogonal thalidomide derivatives. MG-PACE evolved a 36-amino acid ZF degron (SD40) that binds CRBN with high affinity in the presence of PT-179, a thalidomide derivative with no detected neosubstrate activity. The evolved degron is small enough to be efficiently inserted into targeted genomic sites in human cells using prime editing. Human proteins tagged with the evolved degron are rapidly and potently degraded by the otherwise-inert PT-179. To overcome the inactivity of IMiD-based degrons in rodents, we separately used MG-PACE to evolve ZF degrons that engage mouse CRBN, enabling induced target protein degradation in mouse cells. High-resolution cryo-electron microscopy structures of SD40 in complex with CRBN/DDB1 bound to PT-179 or pomalidomide reveal mechanistic insights into the evolution and molecular basis of SD40’s activity and specificity. Collectively, our efforts establish a system for the rapid evolution of molecular glue complexes with novel specificities and compact ZF tags that overcome shortcomings associated with existing degrons.

2024-08-09 | PXD044940 | Pride

Continuous evolution of compact protein degradation tags regulated by selective cereblon molecular glues

2024-08-09 | PXD047593 | Pride

Continuous evolution of compact protein degradation tags regulated by selective cereblon molecular glues

2024-08-09 | PXD047665 | 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

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

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

2011-10-01 | GSE31451 | GEO

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]

2011-10-01 | GSE31421 | GEO