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Protein

Protein cereblon

Gene

CRBN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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

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

Complete GO annotation...

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000113851-MONOMER.
SIGNORiQ96SW2.
UniPathwayiUPA00143.

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

HGNCiHGNC:30185. CRBN.

Subcellular locationi

GO - Cellular componenti

  • Cul4A-RING E3 ubiquitin ligase complex Source: UniProtKB
  • cytoplasm Source: UniProtKB
  • membrane Source: UniProtKB-SubCell
  • nucleolus Source: HPA
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Mental retardation, autosomal recessive 2A (MRT2A)1 Publication
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

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

Mental retardation

Organism-specific databases

DisGeNETi51185.
MalaCardsiCRBN.
MIMi607417. phenotype.
OpenTargetsiENSG00000113851.
Orphaneti88616. Autosomal recessive non-syndromic intellectual disability.
1620. Distal monosomy 3p.
PharmGKBiPA134926851.

Chemistry databases

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.

PTM databases

iPTMnetiQ96SW2.
PhosphoSitePlusiQ96SW2.

Expressioni

Tissue specificityi

Widely expressed. Highly expressed in brain.2 Publications

Gene expression databases

BgeeiENSG00000113851.
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

WithEntry#Exp.IntActNotes
PAK7Q8TB933EBI-2510250,EBI-741896
RBPMSQ930623EBI-2510250,EBI-740322

Protein-protein interaction databases

BioGridi119360. 35 interactors.
DIPiDIP-53521N.
IntActiQ96SW2. 14 interactors.
MINTiMINT-4537481.
STRINGi9606.ENSP00000231948.

Structurei

Secondary structure

1442
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni51 – 53Combined sources3
Helixi54 – 56Combined sources3
Helixi58 – 60Combined sources3
Beta strandi78 – 83Combined sources6
Beta strandi96 – 101Combined sources6
Helixi104 – 115Combined sources12
Beta strandi119 – 127Combined sources9
Turni128 – 131Combined sources4
Beta strandi132 – 149Combined sources18
Beta strandi152 – 172Combined sources21
Beta strandi178 – 184Combined sources7
Helixi195 – 197Combined sources3
Helixi200 – 205Combined sources6
Helixi220 – 231Combined sources12
Helixi233 – 237Combined sources5
Beta strandi238 – 240Combined sources3
Helixi242 – 246Combined sources5
Helixi250 – 262Combined sources13
Helixi269 – 272Combined sources4
Helixi277 – 286Combined sources10
Helixi292 – 299Combined sources8
Helixi304 – 317Combined sources14
Beta strandi320 – 323Combined sources4
Turni324 – 326Combined sources3
Beta strandi330 – 333Combined sources4
Helixi334 – 336Combined sources3
Beta strandi344 – 350Combined sources7
Beta strandi356 – 363Combined sources8
Beta strandi367 – 375Combined sources9
Beta strandi384 – 391Combined sources8
Turni392 – 394Combined sources3
Beta strandi397 – 406Combined sources10
Beta strandi410 – 418Combined sources9
Helixi419 – 421Combined sources3
Beta strandi422 – 425Combined sources4
Beta strandi427 – 429Combined sources3

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[»]
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
Contains 1 CULT domain.PROSITE-ProRule annotation
Contains 1 Lon N-terminal domain.PROSITE-ProRule annotation

Phylogenomic databases

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

Family and domain databases

InterProiIPR003111. LON_substr-bd_dom.
IPR015947. PUA-like_domain.
IPR004910. Yippee/Mis18/Cereblon.
[Graphical view]
PfamiPF02190. LON_substr_bdg. 1 hit.
PF03226. Yippee-Mis18. 1 hit.
[Graphical view]
SMARTiSM00464. LON. 1 hit.
[Graphical view]
SUPFAMiSSF88697. SSF88697. 2 hits.
PROSITEiPS51788. CULT. 1 hit.
PS51787. LON_N. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

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

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

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

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[»]
ProteinModelPortaliQ96SW2.
SMRiQ96SW2.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119360. 35 interactors.
DIPiDIP-53521N.
IntActiQ96SW2. 14 interactors.
MINTiMINT-4537481.
STRINGi9606.ENSP00000231948.

Chemistry databases

DrugBankiDB00480. Lenalidomide.
DB08910. Pomalidomide.
DB01041. Thalidomide.

PTM databases

iPTMnetiQ96SW2.
PhosphoSitePlusiQ96SW2.

Polymorphism and mutation databases

BioMutaiCRBN.
DMDMi73918916.

Proteomic databases

EPDiQ96SW2.
MaxQBiQ96SW2.
PaxDbiQ96SW2.
PeptideAtlasiQ96SW2.
PRIDEiQ96SW2.

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.
GeneCardsiCRBN.
HGNCiHGNC:30185. CRBN.
HPAiHPA045910.
MalaCardsiCRBN.
MIMi607417. phenotype.
609262. gene.
neXtProtiNX_Q96SW2.
OpenTargetsiENSG00000113851.
Orphaneti88616. Autosomal recessive non-syndromic intellectual disability.
1620. Distal monosomy 3p.
PharmGKBiPA134926851.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

UniPathwayiUPA00143.
BioCyciZFISH:ENSG00000113851-MONOMER.
SIGNORiQ96SW2.

Miscellaneous databases

ChiTaRSiCRBN. human.
GeneWikiiCereblon.
GenomeRNAii51185.
PROiQ96SW2.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000113851.
CleanExiHS_CRBN.
ExpressionAtlasiQ96SW2. baseline and differential.
GenevisibleiQ96SW2. HS.

Family and domain databases

InterProiIPR003111. LON_substr-bd_dom.
IPR015947. PUA-like_domain.
IPR004910. Yippee/Mis18/Cereblon.
[Graphical view]
PfamiPF02190. LON_substr_bdg. 1 hit.
PF03226. Yippee-Mis18. 1 hit.
[Graphical view]
SMARTiSM00464. LON. 1 hit.
[Graphical view]
SUPFAMiSSF88697. SSF88697. 2 hits.
PROSITEiPS51788. CULT. 1 hit.
PS51787. LON_N. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCRBN_HUMAN
AccessioniPrimary (citable) accession number: Q96SW2
Secondary accession number(s): B2R6H4
, C9IZA9, C9JAH6, Q6AI62, Q6NVZ0, Q9UHW4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: December 1, 2001
Last modified: November 2, 2016
This is version 131 of the entry and version 1 of the sequence. [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

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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.