Protein cereblon

Function

Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2, ILF2 or GLUL. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. Maintains presynaptic glutamate release and consequently cognitive functions, such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons. Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1. May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism (By similarity). Plays a negative role in TLR4 signaling by interacting with TRAF6 and ECSIT, leading to inhibition of ECSIT ubiquitination, an important step of the signaling.

Classification

Family (Pfam)

PF02190 LON_substr_bdg, PF03226 Yippee-Mis18

InterPro

CULT, Lon_prtase_N, Lon_prtase_N_sf, PUA-like_sf, Yippee/Mis18/Cereblon

Functional cluster

Zinc-Finger & Ubiquitination Proteins

Experimental structures · PDB · 65

• 4M91 X-ray 1.10A
• 4TZ4 X-ray 3.01A
• 5FQD X-ray 2.45A
• 5HXB X-ray 3.60A
• 5V3O X-ray 3.20A
• 6BN7 X-ray 3.50A
• 6BN8 X-ray 3.99A
• 6BN9 X-ray 4.38A
• 6BNB X-ray 6.34A
• 6BOY X-ray 3.33A
• 6H0F X-ray 3.25A
• 6H0G X-ray 4.25A
• … and 53 more

A predicted model is available from AlphaFold.

Gene Ontology · 16

• GO:0031464 Cul4A-RING E3 ubiquitin ligase complex
• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0016020 membrane
• GO:0005634 nucleus
• GO:0048471 perinuclear region of cytoplasm
• GO:0046872 metal ion binding
• GO:0044325 transmembrane transporter binding
• GO:0060173 limb development
• GO:0035641 locomotory exploration behavior
• GO:0034766 negative regulation of monoatomic ion transmembrane transport
• GO:0031333 negative regulation of protein-containing complex assembly
• GO:0031334 positive regulation of protein-containing complex assembly
• GO:0030177 positive regulation of Wnt signaling pathway
• GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
• GO:0016567 protein ubiquitination

Disease associations

• intellectual disability, autosomal recessive 2 MONDO:0011828

Drugs targeting this protein · 5

• IBERDOMIDE modulator
• POMALIDOMIDE inhibitor
• THALIDOMIDE inhibitor
• LENALIDOMIDE HYDROCHLORIDE MONOHYDRATE modulator
• LENALIDOMIDE inhibitor

Related proteins · sequence + function similarity

• Protein cereblon 0.99
• Protein cereblon 0.99
• Protein cereblon 0.99
• Protein cereblon 0.99
• Protein cereblon 0.95
• Protein cereblon 0.92
• Protein cereblon 0.90
• Protein cereblon 0.56
• Protein cereblon 0.53
• Protein cereblon 0.52
• Protein cereblon 0.51
• Protein cereblon 0.50

Co-cited proteins · studied together in the literature

• Protein cereblon 2 shared papers
• Protein cereblon 2 shared papers
• Protein cereblon 1 shared papers
• Protein cereblon 1 shared papers
• DNA damage-binding protein 1 1 shared papers
• Interleukin enhancer-binding factor 2 1 shared papers
• Glutamine synthetase 1 shared papers
• Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial 1 shared papers
• DNA damage-binding protein 1 2 shared papers
• TNF receptor-associated factor 6 1 shared papers
• Histone acetyltransferase p300 1 shared papers

Literature · 18 cited papers

• Cereblon Promotes the Ubiquitination and Proteasomal Degradation of Interleukin Enhancer-Binding Factor 2. Protein J. · 2020
• CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1. Front. Immunol. · 2019
• Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel. J. Neurosci. · 2018
• A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family. J. Med. Genet. · 2017
• Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Mol. Cell · 2016
• Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol. · 2014
• Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature · 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. · 2014
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• Identification of a primary target of thalidomide teratogenicity. Science · 2010
• Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation. Neurogenetics · 2008
• The full-ORF clone resource of the German cDNA consortium. BMC Genomics · 2007
• … and 6 more in the literature graph