cereblon | E3 ubiquitin ligase components | IUPHAR Guide to IMMUNOPHARMACOLOGY

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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 5
pKd 8.1 (Kd 8.5x10-9 M) [5]
Description: Determined in a BiaCore assay using immobilised thalidomide and recombinant cereblon protein.
iberdomide Hs Binding 7.2 pIC50 8
pIC50 7.2 (IC50 6x10-8 M) [8]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by CC-220.
pomalidomide Hs Binding 5.9 pIC50 8
pIC50 5.9 (IC50 1.2x10-6 M) [8]
Description: Measuring displacement of a Cy5-conjugated cereblon modulating compound from the binding pocket of CRBN by pomalidomide.
lenalidomide Hs Binding 5.8 pIC50 8
pIC50 5.8 (IC50 1.5x10-6 M) [8]
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) [1,5,7]. 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 proteosomal degradation of Ikaros and Aiolos and elevates IL-2 expression and activation of T cells, to bring about their immunomodulatory and antiproliferative effects [2,6].
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 [3-4,9].
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). Binding of thalidomide to cereblon mediates this drug's teratogenicity, via disruption of fibroblast growth factor 8 expression and limb bud outgrowth [5]. Thalidomide type drugs are not teratogenic in mouse or rat. The thalidomide-related immunomodulatory agents lenalidomide and pomalidomide also bind (human) cereblon [1]. 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.

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 [3-4].

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

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1. 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]

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

How to cite this page

E3 ubiquitin ligase components: cereblon. Last modified on 13/06/2019. Accessed on 22/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3086.