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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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi323 – 3231ZincCombined sources
Metal bindingi326 – 3261ZincCombined sources
Metal bindingi391 – 3911ZincCombined sources
Metal bindingi394 – 3941ZincCombined sources

GO - Molecular functioni

  1. ATP-dependent peptidase activity Source: InterPro
  2. metal ion binding Source: UniProtKB-KW

GO - Biological processi

  1. negative regulation of ion transmembrane transport Source: Ensembl
  2. negative regulation of protein homooligomerization Source: Ensembl
  3. positive regulation of protein homodimerization activity Source: Ensembl
  4. proteasome-mediated ubiquitin-dependent protein catabolic process Source: UniProtKB
  5. protein ubiquitination Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

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
ProteomesiUP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:30185. CRBN.

Subcellular locationi

Cytoplasm 1 Publication. Nucleus 1 Publication. Membrane By similarity; Peripheral membrane protein By similarity

GO - Cellular componenti

  1. Cul4A-RING E3 ubiquitin ligase complex Source: UniProtKB
  2. cytoplasm Source: UniProtKB
  3. membrane Source: UniProtKB-SubCell
  4. nucleolus Source: HPA
  5. 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)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi384 – 3841Y → A: Abolishes thalidomide-binding without affecting DCX protein ligase complex activity; when associated with A-386. 1 Publication
Mutagenesisi386 – 3861W → 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 Publications

Keywords - Diseasei

Mental retardation

Organism-specific databases

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

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 442442Protein cereblonPRO_0000076160Add
BLAST

Post-translational modificationi

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

Keywords - PTMi

Ubl conjugation

Proteomic databases

MaxQBiQ96SW2.
PaxDbiQ96SW2.
PRIDEiQ96SW2.

PTM databases

PhosphoSiteiQ96SW2.

Expressioni

Tissue specificityi

Widely expressed. Highly expressed in brain.2 Publications

Gene expression databases

BgeeiQ96SW2.
CleanExiHS_CRBN.
ExpressionAtlasiQ96SW2. baseline and differential.
GenevestigatoriQ96SW2.

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

Protein-protein interaction databases

BioGridi119360. 19 interactions.
DIPiDIP-53521N.
IntActiQ96SW2. 8 interactions.
MINTiMINT-4537481.
STRINGi9606.ENSP00000231948.

Structurei

Secondary structure

1
442
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Turni51 – 533Combined sources
Helixi54 – 563Combined sources
Helixi58 – 603Combined sources
Beta strandi78 – 836Combined sources
Beta strandi96 – 1016Combined sources
Helixi104 – 11310Combined sources
Turni114 – 1174Combined sources
Beta strandi119 – 1257Combined sources
Beta strandi133 – 14917Combined sources
Beta strandi152 – 17120Combined sources
Beta strandi178 – 1847Combined sources
Turni195 – 1973Combined sources
Helixi200 – 2056Combined sources
Helixi222 – 23110Combined sources
Helixi233 – 2375Combined sources
Helixi242 – 2465Combined sources
Helixi250 – 26213Combined sources
Helixi277 – 28711Combined sources
Helixi292 – 3009Combined sources
Helixi304 – 31714Combined sources
Beta strandi320 – 3234Combined sources
Turni324 – 3263Combined sources
Beta strandi330 – 3334Combined sources
Helixi334 – 3363Combined sources
Beta strandi344 – 3507Combined sources
Beta strandi356 – 3638Combined sources
Beta strandi367 – 3759Combined sources
Beta strandi384 – 3918Combined sources
Turni392 – 3943Combined sources
Beta strandi397 – 40610Combined sources
Beta strandi412 – 4187Combined sources
Helixi419 – 4213Combined sources
Beta strandi422 – 4254Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4M91X-ray1.10B229-240[»]
4TZ4X-ray3.01C48-428[»]
ProteinModelPortaliQ96SW2.
SMRiQ96SW2. Positions 48-428.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini80 – 317238LonAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni339 – 442104Thalidomide binding domain1 PublicationAdd
BLAST
Regioni378 – 3869Thalidomide bindingCombined sources1 Publication

Domaini

The thalidomide binding 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 Lon domain.Curated

Phylogenomic databases

eggNOGiNOG313031.
GeneTreeiENSGT00390000016404.
HOGENOMiHOG000067866.
HOVERGENiHBG054571.
InParanoidiQ96SW2.
KOiK11793.
OMAiSWEDQCS.
PhylomeDBiQ96SW2.
TreeFamiTF106115.

Family and domain databases

InterProiIPR003111. Pept_S16_N.
IPR015947. PUA-like_domain.
[Graphical view]
PfamiPF02190. LON. 1 hit.
[Graphical view]
SMARTiSM00464. LON. 1 hit.
[Graphical view]
SUPFAMiSSF88697. SSF88697. 2 hits.

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 AAF17211.1 differs from that shown. Reason: Frameshift at positions 347, 397 and 401. Curated
The sequence BAG35471.1 differs from that shown. Reason: Frameshift at position 347. Curated
The sequence BAG35471.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti229 – 2291K → R in AAH67811 (PubMed:16641997).Curated
Sequence conflicti237 – 2371L → P in BAG35471 (PubMed:14702039).Curated
Sequence conflicti292 – 2921D → G in BAG35471 (PubMed:14702039).Curated
Sequence conflicti330 – 3301E → G in BAG35471 (PubMed:14702039).Curated

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei23 – 231Missing in isoform 2. 1 PublicationVSP_015209

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.3. human. [Q96SW2-1]
uc003bpr.3. human. [Q96SW2-2]

Polymorphism databases

DMDMi73918916.

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
EntryMethodResolution (Å)ChainPositionsPDBsum
4M91X-ray1.10B229-240[»]
4TZ4X-ray3.01C48-428[»]
ProteinModelPortaliQ96SW2.
SMRiQ96SW2. Positions 48-428.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi119360. 19 interactions.
DIPiDIP-53521N.
IntActiQ96SW2. 8 interactions.
MINTiMINT-4537481.
STRINGi9606.ENSP00000231948.

Chemistry

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

PTM databases

PhosphoSiteiQ96SW2.

Polymorphism databases

DMDMi73918916.

Proteomic databases

MaxQBiQ96SW2.
PaxDbiQ96SW2.
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.3. human. [Q96SW2-1]
uc003bpr.3. human. [Q96SW2-2]

Organism-specific databases

CTDi51185.
GeneCardsiGC03M003166.
HGNCiHGNC:30185. CRBN.
HPAiHPA045910.
MIMi607417. phenotype.
609262. gene.
neXtProtiNX_Q96SW2.
Orphaneti88616. Autosomal recessive non-syndromic intellectual disability.
1620. Distal monosomy 3p.
PharmGKBiPA134926851.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiNOG313031.
GeneTreeiENSGT00390000016404.
HOGENOMiHOG000067866.
HOVERGENiHBG054571.
InParanoidiQ96SW2.
KOiK11793.
OMAiSWEDQCS.
PhylomeDBiQ96SW2.
TreeFamiTF106115.

Enzyme and pathway databases

UniPathwayiUPA00143.

Miscellaneous databases

ChiTaRSiCRBN. human.
GeneWikiiCereblon.
GenomeRNAii51185.
NextBioi54159.
PROiQ96SW2.
SOURCEiSearch...

Gene expression databases

BgeeiQ96SW2.
CleanExiHS_CRBN.
ExpressionAtlasiQ96SW2. baseline and differential.
GenevestigatoriQ96SW2.

Family and domain databases

InterProiIPR003111. Pept_S16_N.
IPR015947. PUA-like_domain.
[Graphical view]
PfamiPF02190. LON. 1 hit.
[Graphical view]
SMARTiSM00464. LON. 1 hit.
[Graphical view]
SUPFAMiSSF88697. SSF88697. 2 hits.
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
    Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
    , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
    Nat. Genet. 36:40-45(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
    Tissue: Brain.
  2. "The DNA sequence, annotation and analysis of human chromosome 3."
    Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J.
    , Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.
    Nature 440:1194-1198(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
    Tissue: Brain and Lung.
  4. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-442.
    Tissue: Adrenal gland.
  5. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 64-250.
    Tissue: Fetal kidney.
  6. "A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation."
    Higgins J.J., Pucilowska J., Lombardi R.Q., Rooney J.P.
    Neurology 63:1927-1931(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: INVOLVEMENT IN MRT2A, TISSUE SPECIFICITY.
  7. "Primary function analysis of human mental retardation related gene CRBN."
    Xin W., Xiaohua N., Peilin C., Xin C., Yaqiong S., Qihan W.
    Mol. Biol. Rep. 35:251-256(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY.
  8. "Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation."
    Higgins J.J., Hao J., Kosofsky B.E., Rajadhyaksha A.M.
    Neurogenetics 9:219-223(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  9. "Identification of a primary target of thalidomide teratogenicity."
    Ito T., Ando H., Suzuki T., Ogura T., Hotta K., Imamura Y., Yamaguchi Y., Handa H.
    Science 327:1345-1350(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY, IDENTIFICATION IN A DCX COMPLEX WITH DDB1; RBX1 AND CUL4A, THALIDOMIDE-BINDING, UBIQUITINATION, MUTAGENESIS OF TYR-384 AND TRP-386.
  10. "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.)."
    Gandhi A.K., Kang J., Havens C.G., Conklin T., Ning Y., Wu L., Ito T., Ando H., Waldman M.F., Thakurta A., Klippel A., Handa H., Daniel T.O., Schafer P.H., Chopra R.
    Br. J. Haematol. 164:811-821(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, MISCELLANEOUS.
  11. Cited for: FUNCTION, INTERACTION WITH DDB1, UBIQUITINATION.
  12. Cited for: X-RAY CRYSTALLOGRAPHY (3.01 ANGSTROMS) OF 48-428 IN COMPLEX WITH DDB1; S-LENALIDOMIDE AND ZINC, FUNCTION, INTERACTION WITH DDB1, DOMAIN, MUTAGENESIS OF TRP-386, MISCELLANEOUS.

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: March 4, 2015
This is version 113 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 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

External Data

Dasty 3

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 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.