cereblon | E3 ubiquitin ligase components | IUPHAR/BPS Guide to PHARMACOLOGY

Top ▲

cereblon

target has curated data in GtoImmuPdb

Target id: 3086

Nomenclature: cereblon

Family: E3 ubiquitin ligase components

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 442 3p26.2 CRBN cereblon
Mouse - 445 Ch 6, 49.24 cM; 6 E1 Crbn cereblon
Rat - 445 4q41 Crbn cereblon
Gene and Protein Information Comments
Transcript variants encoding different protein isoforms have been identified for the human and mouse CRBN genes.
Previous and Unofficial Names
mental retardation, non-syndromic, autosomal recessive, 2A | MRT2A
Database Links
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
thalidomide Hs Binding 8.1 pKd 12
pKd 8.1 (Kd 8.5x10-9 M) [12]
Description: Determined in a BiaCore assay using immobilised thalidomide and recombinant cereblon protein.
compound 7f [PMID: 31251063] N/A Binding 7.7 pKi 8-9
pKi 7.7 (Ki 2x10-8 M) [8-9]
Description: Ki determined using the single-domain bacterial CRBN homologue from Magnetospirillum gryphiswaldense (MsCI4) in a FRET assay.
dBRD9 Hs Binding 7.5 pIC50 18
pIC50 7.5 (IC50 3.13x10-8 M) [18]
Description: AlphaScreen competitive ligand binding assay using the CRBN-DDB1 complex.
avadomide Hs Binding 7.3 pIC50 5,7
pIC50 7.3 (IC50 5.4x10-8 M) [5,7]
Description: Inhibition of LPS-induced IL-1β production by human peripheral blood mononuclear cells.
iberdomide Hs Binding 7.2 pIC50 15
pIC50 7.2 (IC50 6x10-8 M) [15]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by CC-220.
dTAG-13 Hs Binding 7.2 pIC50 16
pIC50 7.2 (IC50 6.42x10-8 M) [16]
pomalidomide Hs Binding 5.9 pIC50 15
pIC50 5.9 (IC50 1.2x10-6 M) [15]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by pomalidomide.
lenalidomide Hs Binding 5.8 pIC50 15
pIC50 5.8 (IC50 1.5x10-6 M) [15]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by lenalidomide.
Immunopharmacology Comments
Cereblon is a direct molecular target for the immunomodulatory and antiproliferative activities of thalidomide and its analogues (e.g lenalidomide and pomalidomide) [1-2,12,14]. Mechanistically, this class of drugs has been shown to enhance recruitment of the Ikaros (IKZF1) and Aiolos (IKZF3) transcription factors (Ikaros and Aiolos are transcriptional repressors of IL-2 expression) to the cereblon/CUL4 E3 ubiquitin ligase complex, which increases proteasomal degradation of Ikaros and Aiolos and elevates IL-2 expression and activation of T cells, to bring about their immunomodulatory and antiproliferative effects [6,13].
Immuno Process Associations
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0016567 protein ubiquitination IMP
Biologically Significant Variant Comments
Loss-of-function mutations in cereblon have been identified in patients with autosomal recessive nonsyndromal mental retardation [10-11,19].
General Comments
Cereblon is a substrate adaptor module of E3 ubiquitin ligase. It has no inherent enzymatic activity, but rather controls the substrate specificity of E3-mediated protein ubiquitin modifications. Cereblon forms an E3 complex with damaged DNA binding protein 1 (DDB1), Cullin 4 (CUL4) and regulator of cullins 1 (ROC1), abbreviated here as CRL4CRBN. Under normal conditions CRL4CRBN recognises endogenous substrates including glutamine synthetase [17], MEIS2 [4], and amyloid precursor protein [3]. Exogenous drugs that bind to cereblon are able to allosterically modify CRL4CRBN substrate specificity. In particular the immunomodulatory thalidomide family drugs are know to alter E3 substrate selectivity. Binding of thalidomide to cereblon mediates this drug's teratogenicity, via disruption of fibroblast growth factor 8 expression and limb bud outgrowth [12]. The derivatives lenalidomide and pomalidomide also bind (human) cereblon [2]. All of these drugs contain a glutarimide moiety that is accommodated in a hydrophobic binding pocket on the surface of the C-terminal domain of cereblon. Thalidomide type drugs are not teratogenic in mouse or rat .

Evidence points to a role for cereblon in the assembly and neuronal surface expression of large-conductance Ca2+-activated potassium channels (KCa1.1; KCNMA1) in regions of the brain that are associated with memory and learning [10-11].

Note: Cereblon is included in the Enzymes section of the Guide To PHARMACOLOGY as it is part of the E3 compex. We fully acknowledge that the protein has no intrinsic catalytic activity.

References

Show »

1. Asatsuma-Okumura T, Ito T, Handa H. (2019) Molecular mechanisms of cereblon-based drugs. Pharmacol. Ther., 202: 132-139. [PMID:31202702]

2. Chamberlain PP, Lopez-Girona A, Miller K, Carmel G, Pagarigan B, Chie-Leon B, Rychak E, Corral LG, Ren YJ, Wang M et al.. (2014) Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol., 21 (9): 803-9. [PMID:25108355]

3. Del Prete D, Rice RC, Rajadhyaksha AM, D'Adamio L. (2016) Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration. J. Biol. Chem., 291 (33): 17209-27. [PMID:27325702]

4. Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM et al.. (2014) Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature, 512 (7512): 49-53. [PMID:25043012]

5. Gandhi A, Dimartino J, Chopra R. (2014) Methods for the treatment of locally advanced breast cancer. Patent number: WO2014039960A1. Assignee: Celgene Corporation. Priority date: 10/09/2012. Publication date: 13/03/2014.

6. Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, Ito T, Ando H, Waldman MF, Thakurta A et al.. (2014) Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br. J. Haematol., 164 (6): 811-21. [PMID:24328678]

7. Hagner PR, Man HW, Fontanillo C, Wang M, Couto S, Breider M, Bjorklund C, Havens CG, Lu G, Rychak E et al.. (2015) CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood, 126 (6): 779-89. [PMID:26002965]

8. Hartmann MD, Boichenko I, Coles M, Zanini F, Lupas AN, Hernandez Alvarez B. (2014) Thalidomide mimics uridine binding to an aromatic cage in cereblon. J. Struct. Biol., 188 (3): 225-32. [PMID:25448889]

9. Heim C, Pliatsika D, Mousavizadeh F, Bär K, Hernandez Alvarez B, Giannis A, Hartmann MD. (2019) De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives. J. Med. Chem., 62 (14): 6615-6629. [PMID:31251063]

10. Higgins JJ, Hao J, Kosofsky BE, Rajadhyaksha AM. (2008) Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics, 9 (3): 219-23. [PMID:18414909]

11. Higgins JJ, Pucilowska J, Lombardi RQ, Rooney JP. (2004) A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology, 63 (10): 1927-31. [PMID:15557513]

12. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. (2010) Identification of a primary target of thalidomide teratogenicity. Science, 327 (5971): 1345-50. [PMID:20223979]

13. Ito T, Handa H. (2016) Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs. Int. J. Hematol., 104 (3): 293-9. [PMID:27460676]

14. Lopez-Girona A, Mendy D, Ito T, Miller K, Gandhi AK, Kang J, Karasawa S, Carmel G, Jackson P, Abbasian M et al.. (2012) Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia, 26 (11): 2326-35. [PMID:22552008]

15. Matyskiela ME, Zhang W, Man HW, Muller G, Khambatta G, Baculi F, Hickman M, LeBrun L, Pagarigan B, Carmel G et al.. (2018) A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos. J. Med. Chem., 61 (2): 535-542. [PMID:28425720]

16. Nabet B, Roberts JM, Buckley DL, Paulk J, Dastjerdi S, Yang A, Leggett AL, Erb MA, Lawlor MA, Souza A et al.. (2018) The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol., 14 (5): 431-441. [PMID:29581585]

17. Nguyen TV, Lee JE, Sweredoski MJ, Yang SJ, Jeon SJ, Harrison JS, Yim JH, Lee SG, Handa H, Kuhlman B et al.. (2016) Glutamine Triggers Acetylation-Dependent Degradation of Glutamine Synthetase via the Thalidomide Receptor Cereblon. Mol. Cell, 61 (6): 809-20. [PMID:26990986]

18. Remillard D, Buckley DL, Paulk J, Brien GL, Sonnett M, Seo HS, Dastjerdi S, Wühr M, Dhe-Paganon S, Armstrong SA et al.. (2017) Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands. Angew. Chem. Int. Ed. Engl., 56 (21): 5738-5743. [PMID:28418626]

19. Sheereen A, Alaamery M, Bawazeer S, Al Yafee Y, Massadeh S, Eyaid W. (2017) A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family. J. Med. Genet., 54 (4): 236-240. [PMID:28143899]

Contributors

Show »

How to cite this page

Select citation format: