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Protein

Protein cereblon

Gene

CRBN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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. Normal degradation of key regulatory proteins is required for normal limb outgrowth and expression of the fibroblast growth factor FGF8. May play a role in memory and learning by regulating the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1. Binding of pomalidomide and other thalidomide-related drugs changes the substrate specificity of the human protein, leading to decreased degradation of MEIS2 and other target proteins and increased degradation of MYC, IRF4, IKZF1 and IKZF3.Curated5 Publications

Miscellaneous

Thalidomide was widely prescribed to pregnant women in the late 1950s as a sedative and as treatment against morning sickness. Thalidomide was found to be teratogenic, causing multiple birth defects. Recently, thalidomide use has increased for the treatment of multiple myeloma and erythema nodosum leprosum, a painful complication of leprosy. Thalidomide binding leads to a change in substrate specificity of the human DCX (DDB1-CUL4-X-box) E3 protein ligase complex, and this is probably the underlying cause of the teratogenic activity of thalidomide, possibly due to abnormal regulation of the BMP and FGF8 signaling pathways (PubMed:20223979). The thalidomide-induced change in substrate specificity leads to increased degradation of MYC, IRF4, IKZF1 and IKZF3, and this is probably the reason for the anti-proliferative and immunomodulatory effects of thalidomide and related drugs (PubMed:25108355). Thalidomide is also teratogenic in chicken and zebrafish, but not in mice.2 Publications

Caution

Although it contains a Lon N-terminal domain also found in proteases of the peptidase S16 family, it does not contain the ATP-binding and catalytic domains, suggesting that it has no protease activity.Curated

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.1 Publication1 Publication
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi323ZincCombined sources1 Publication1
Metal bindingi326ZincCombined sources1 Publication1
Metal bindingi391ZincCombined sources1 Publication1
Metal bindingi394ZincCombined sources1 Publication1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processUbl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

SIGNORiQ96SW2
UniPathwayi
UPA00143

Names & Taxonomyi

Protein namesi
Recommended name:
Protein cereblon
Gene namesi
Name:CRBN
ORF Names:AD-006
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000113851.13
HGNCiHGNC:30185 CRBN
MIMi609262 gene
neXtProtiNX_Q96SW2

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Mental retardation, autosomal recessive 2A (MRT2A)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs. MRT2A patients display mild mental retardation with a standard IQ ranged from 50 to 70. IQ scores are lower in males than females. Developmental milestones are mildly delayed. There are no dysmorphic or autistic features.
See also OMIM:607417
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_079409391C → R in MRT2A. 1 PublicationCorresponds to variant dbSNP:rs797045036EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi384Y → A: Abolishes thalidomide-binding without affecting DCX protein ligase complex activity; when associated with A-386. 1 Publication1
Mutagenesisi386W → A: Abolishes thalidomide-binding without affecting DCX protein ligase complex activity; when associated with A-384. Abolishes pomalidomide-induced change in substrate specificity and abolishes pomalidomide-induced decrease in cell viability that is brought about by increased degradation of MYC, IRF4 and IKZF3. 2 Publications1

Keywords - Diseasei

Disease mutation, Mental retardation

Organism-specific databases

DisGeNETi51185
MalaCardsiCRBN
MIMi607417 phenotype
OpenTargetsiENSG00000113851
Orphaneti88616 Autosomal recessive non-syndromic intellectual disability
PharmGKBiPA134926851

Chemistry databases

ChEMBLiCHEMBL3763008
DrugBankiDB00480 Lenalidomide
DB08910 Pomalidomide
DB01041 Thalidomide

Polymorphism and mutation databases

BioMutaiCRBN
DMDMi73918916

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000761601 – 442Protein cereblonAdd BLAST442

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei25PhosphoserineCombined sources1

Post-translational modificationi

Ubiquitinated, ubiquitination is mediated by its own DCX protein ligase complex.2 Publications

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ96SW2
MaxQBiQ96SW2
PaxDbiQ96SW2
PeptideAtlasiQ96SW2
PRIDEiQ96SW2
ProteomicsDBi78157
78158 [Q96SW2-2]

PTM databases

iPTMnetiQ96SW2
PhosphoSitePlusiQ96SW2

Expressioni

Tissue specificityi

Widely expressed. Highly expressed in brain.2 Publications

Gene expression databases

BgeeiENSG00000113851 Expressed in 225 organ(s), highest expression level in corpus callosum
CleanExiHS_CRBN
ExpressionAtlasiQ96SW2 baseline and differential
GenevisibleiQ96SW2 HS

Organism-specific databases

HPAiHPA045910

Interactioni

Subunit structurei

Interacts with KCNT1 (By similarity). Component of a DCX (DDB1-CUL4-X-box) protein ligase complex, at least composed of CRBN, CUL4A, DDB1 and RBX1. Interacts directly with DDB1 (PubMed:25043012, PubMed:25108355). Interacts (in pomalidomide-bound form) with IKZF1 and IKZF3 (PubMed:24328678).By similarity4 Publications

Binary interactionsi

Protein-protein interaction databases

BioGridi119360, 132 interactors
DIPiDIP-53521N
IntActiQ96SW2, 28 interactors
MINTiQ96SW2
STRINGi9606.ENSP00000231948

Chemistry databases

BindingDBiQ96SW2

Structurei

Secondary structure

1442
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ96SW2
SMRiQ96SW2
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini81 – 317Lon N-terminalPROSITE-ProRule annotationAdd BLAST237
Domaini318 – 426CULTPROSITE-ProRule annotationAdd BLAST109

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni378 – 386Thalidomide bindingCombined sources1 Publication9

Domaini

The CULT domain binds thalidomide and related drugs, such as pomalidomide and lenalidomide. Drug binding leads to a change in substrate specificity of the human DCX (DDB1-CUL4-X-box) E3 protein ligase complex, while no such change is observed in rodents.1 Publication

Sequence similaritiesi

Belongs to the CRBN family.Curated

Phylogenomic databases

eggNOGiKOG1400 Eukaryota
ENOG410XQGE LUCA
GeneTreeiENSGT00390000016404
HOGENOMiHOG000067866
HOVERGENiHBG054571
InParanoidiQ96SW2
KOiK11793
OMAiKRQLHEW
OrthoDBiEOG091G0EBG
PhylomeDBiQ96SW2
TreeFamiTF106115

Family and domain databases

CDDicd15777 CRBN_C_like, 1 hit
InterProiView protein in InterPro
IPR034750 CULT
IPR003111 Lon_substr-bd
IPR015947 PUA-like_sf
IPR004910 Yippee/Mis18/Cereblon
PfamiView protein in Pfam
PF02190 LON_substr_bdg, 1 hit
PF03226 Yippee-Mis18, 1 hit
SMARTiView protein in SMART
SM00464 LON, 1 hit
SUPFAMiSSF88697 SSF88697, 1 hit
PROSITEiView protein in PROSITE
PS51788 CULT, 1 hit
PS51787 LON_N, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: Q96SW2-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD
60 70 80 90 100
TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMMI LIPGQTLPLQ
110 120 130 140 150
LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF
160 170 180 190 200
GIEIVKVKAI GRQRFKVLEL RTQSDGIQQA KVQILPECVL PSTMSAVQLE
210 220 230 240 250
SLNKCQIFPS KPVSREDQCS YKWWQKYQKR KFHCANLTSW PRWLYSLYDA
260 270 280 290 300
ETLMDRIKKQ LREWDENLKD DSLPSNPIDF SYRVAACLPI DDVLRIQLLK
310 320 330 340 350
IGSAIQRLRC ELDIMNKCTS LCCKQCQETE ITTKNEIFSL SLCGPMAAYV
360 370 380 390 400
NPHGYVHETL TVYKACNLNL IGRPSTEHSW FPGYAWTVAQ CKICASHIGW
410 420 430 440
KFTATKKDMS PQKFWGLTRS ALLPTIPDTE DEISPDKVIL CL
Length:442
Mass (Da):50,546
Last modified:December 1, 2001 - v1
Checksum:i90DF77D98A8BEAA8
GO
Isoform 2 (identifier: Q96SW2-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     23-23: Missing.

Note: No experimental confirmation available.
Show »
Length:441
Mass (Da):50,475
Checksum:i28B44733BBB461C1
GO

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
J3QT87J3QT87_HUMAN
Protein cereblon
CRBN
394Annotation score:
J3QT51J3QT51_HUMAN
Protein cereblon
CRBN
228Annotation score:
A0A1W2PPJ5A0A1W2PPJ5_HUMAN
Protein cereblon
CRBN
490Annotation score:
A0A0D9SF49A0A0D9SF49_HUMAN
Protein cereblon
CRBN
21Annotation score:

Sequence cautioni

The sequence AAF17211 differs from that shown. Reason: Frameshift at positions 347, 397 and 401.Curated
The sequence BAG35471 differs from that shown. Reason: Frameshift at position 347.Curated
The sequence BAG35471 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti229K → R in AAH67811 (PubMed:16641997).Curated1
Sequence conflicti237L → P in BAG35471 (PubMed:14702039).Curated1
Sequence conflicti292D → G in BAG35471 (PubMed:14702039).Curated1
Sequence conflicti330E → G in BAG35471 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_079409391C → R in MRT2A. 1 PublicationCorresponds to variant dbSNP:rs797045036EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_01520923Missing in isoform 2. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK027507 mRNA Translation: BAB55162.1
AK312577 mRNA Translation: BAG35471.1 Sequence problems.
AC024060 Genomic DNA No translation available.
BC017419 mRNA Translation: AAH17419.1
BC067811 mRNA Translation: AAH67811.1
AF117230 mRNA Translation: AAF17211.1 Frameshift.
CR627060 mRNA Translation: CAH10361.1
CCDSiCCDS2562.1 [Q96SW2-1]
CCDS54547.1 [Q96SW2-2]
RefSeqiNP_001166953.1, NM_001173482.1 [Q96SW2-2]
NP_057386.2, NM_016302.3 [Q96SW2-1]
UniGeneiHs.18925

Genome annotation databases

EnsembliENST00000231948; ENSP00000231948; ENSG00000113851 [Q96SW2-1]
ENST00000432408; ENSP00000412499; ENSG00000113851 [Q96SW2-2]
GeneIDi51185
KEGGihsa:51185
UCSCiuc003bpq.4 human [Q96SW2-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Web resourcesi

Protein Spotlight

A short story - Issue 117 of May 2010

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK027507 mRNA Translation: BAB55162.1
AK312577 mRNA Translation: BAG35471.1 Sequence problems.
AC024060 Genomic DNA No translation available.
BC017419 mRNA Translation: AAH17419.1
BC067811 mRNA Translation: AAH67811.1
AF117230 mRNA Translation: AAF17211.1 Frameshift.
CR627060 mRNA Translation: CAH10361.1
CCDSiCCDS2562.1 [Q96SW2-1]
CCDS54547.1 [Q96SW2-2]
RefSeqiNP_001166953.1, NM_001173482.1 [Q96SW2-2]
NP_057386.2, NM_016302.3 [Q96SW2-1]
UniGeneiHs.18925

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4M91X-ray1.10B229-240[»]
4TZ4X-ray3.01C48-428[»]
5FQDX-ray2.45B/E41-442[»]
5HXBX-ray3.60C/Z40-442[»]
5V3OX-ray3.20C40-442[»]
6BN7X-ray3.50B1-442[»]
6BN8X-ray3.99B1-442[»]
6BN9X-ray4.38B1-442[»]
6BNBX-ray6.34B1-442[»]
6BOYX-ray3.33B1-442[»]
ProteinModelPortaliQ96SW2
SMRiQ96SW2
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119360, 132 interactors
DIPiDIP-53521N
IntActiQ96SW2, 28 interactors
MINTiQ96SW2
STRINGi9606.ENSP00000231948

Chemistry databases

BindingDBiQ96SW2
ChEMBLiCHEMBL3763008
DrugBankiDB00480 Lenalidomide
DB08910 Pomalidomide
DB01041 Thalidomide

PTM databases

iPTMnetiQ96SW2
PhosphoSitePlusiQ96SW2

Polymorphism and mutation databases

BioMutaiCRBN
DMDMi73918916

Proteomic databases

EPDiQ96SW2
MaxQBiQ96SW2
PaxDbiQ96SW2
PeptideAtlasiQ96SW2
PRIDEiQ96SW2
ProteomicsDBi78157
78158 [Q96SW2-2]

Protocols and materials databases

DNASUi51185
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000231948; ENSP00000231948; ENSG00000113851 [Q96SW2-1]
ENST00000432408; ENSP00000412499; ENSG00000113851 [Q96SW2-2]
GeneIDi51185
KEGGihsa:51185
UCSCiuc003bpq.4 human [Q96SW2-1]

Organism-specific databases

CTDi51185
DisGeNETi51185
EuPathDBiHostDB:ENSG00000113851.13
GeneCardsiCRBN
HGNCiHGNC:30185 CRBN
HPAiHPA045910
MalaCardsiCRBN
MIMi607417 phenotype
609262 gene
neXtProtiNX_Q96SW2
OpenTargetsiENSG00000113851
Orphaneti88616 Autosomal recessive non-syndromic intellectual disability
PharmGKBiPA134926851
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1400 Eukaryota
ENOG410XQGE LUCA
GeneTreeiENSGT00390000016404
HOGENOMiHOG000067866
HOVERGENiHBG054571
InParanoidiQ96SW2
KOiK11793
OMAiKRQLHEW
OrthoDBiEOG091G0EBG
PhylomeDBiQ96SW2
TreeFamiTF106115

Enzyme and pathway databases

UniPathwayi
UPA00143

SIGNORiQ96SW2

Miscellaneous databases

ChiTaRSiCRBN human
GeneWikiiCereblon
GenomeRNAii51185
PROiPR:Q96SW2
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000113851 Expressed in 225 organ(s), highest expression level in corpus callosum
CleanExiHS_CRBN
ExpressionAtlasiQ96SW2 baseline and differential
GenevisibleiQ96SW2 HS

Family and domain databases

CDDicd15777 CRBN_C_like, 1 hit
InterProiView protein in InterPro
IPR034750 CULT
IPR003111 Lon_substr-bd
IPR015947 PUA-like_sf
IPR004910 Yippee/Mis18/Cereblon
PfamiView protein in Pfam
PF02190 LON_substr_bdg, 1 hit
PF03226 Yippee-Mis18, 1 hit
SMARTiView protein in SMART
SM00464 LON, 1 hit
SUPFAMiSSF88697 SSF88697, 1 hit
PROSITEiView protein in PROSITE
PS51788 CULT, 1 hit
PS51787 LON_N, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCRBN_HUMAN
AccessioniPrimary (citable) accession number: Q96SW2
Secondary accession number(s): B2R6H4
, C9IZA9, C9JAH6, Q6AI62, Q6NVZ0, Q9UHW4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: December 1, 2001
Last modified: November 7, 2018
This is version 148 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  7. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  8. Protein Spotlight
    Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries
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