Q96SW2 (CRBN_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Protein cereblon

Gene names

Name:	CRBN
ORF Names:	AD-006

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	442 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates 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. Ref.8 Ref.9
Pathway	Protein modification; protein ubiquitination.
Subunit structure	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. Ref.9
Subcellular location	Cytoplasm. Nucleus. Membrane; Peripheral membrane protein By similarity Ref.9.
Tissue specificity	Widely expressed. Highly expressed in brain. Ref.6 Ref.7
Post-translational modification	Ubiquitinated, ubiquitination is mediated by its own DCX protein ligase complex. Ref.9
Involvement in disease	Mental retardation, autosomal recessive 2A (MRT2A) [MIM:607417]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptative 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6
Miscellaneous	Specifically binds thalidomide, a drug widely prescribed to pregnant women in the late 1950s. Thalidomide was sold as a sedative but 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 teratogenic activity may be a consequence of CRBN-binding, which inhibits the ubiquitin ligase activity of the DCX (DDB1-CUL4-X-box) protein ligase complex, possibly leading to abnormal regulation of the BMP and FGF8 signaling pathways (Ref.9).
Sequence similarities	Belongs to the CRBN family. Contains 1 Lon domain.
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.
Sequence caution	The sequence AAF17211.1 differs from that shown. Reason: Frameshift at positions 347, 397 and 401. The sequence BAG35471.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence BAG35471.1 differs from that shown. Reason: Frameshift at position 347.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm Membrane Nucleus
Coding sequence diversity	Alternative splicing
Disease	Mental retardation
PTM	Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	negative regulation of ion transmembrane transport Inferred from electronic annotation. Source: Compara negative regulation of protein homooligomerization Inferred from electronic annotation. Source: Compara positive regulation of protein homodimerization activity Inferred from electronic annotation. Source: Compara proteasomal ubiquitin-dependent protein catabolic process Inferred from mutant phenotype Ref.9. Source: UniProtKB protein ubiquitination Inferred from mutant phenotype Ref.9. Source: UniProtKB
Cellular_component	Cul4A-RING ubiquitin ligase complex Inferred from direct assay Ref.9. Source: UniProtKB cytoplasm Inferred from direct assay Ref.9. Source: UniProtKB membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nucleolus Inferred from direct assay. Source: HPA
Molecular_function	ATP-dependent peptidase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q96SW2-1)

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.

Isoform 2 (identifier: Q96SW2-2)

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

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 442	442	Protein cereblon		PRO_0000076160
Regions
	Domain	80 – 317	238	Lon
	Region	339 – 442	104	Thalidomide-binding
Natural variations
	Alternative sequence	23	1	Missing in isoform 2.		VSP_015209
Experimental info
	Mutagenesis	384	1	Y → A: Abolishes thalidomide-binding without affecting DCX protein ligase complex activity; when associated with A-386. Ref.9
	Mutagenesis	386	1	W → A: Abolishes thalidomide-binding without affecting DCX protein ligase complex activity; when associated with A-384. Ref.9
	Sequence conflict	229	1	K → R in AAH67811. Ref.2
	Sequence conflict	237	1	L → P in BAG35471. Ref.1
	Sequence conflict	292	1	D → G in BAG35471. Ref.1
	Sequence conflict	330	1	E → G in BAG35471. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 1, 2001. Version 1. Checksum: 90DF77D98A8BEAA8	FASTA	442	50,546
	10 20 30 40 50 60 MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL 70 80 90 100 110 120 GADMEEFHGR TLHDDDSCQV IPVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF 130 140 150 160 170 180 AVLAYSNVQE REAQFGTTAE IYAYREEQDF GIEIVKVKAI GRQRFKVLEL RTQSDGIQQA 190 200 210 220 230 240 KVQILPECVL PSTMSAVQLE SLNKCQIFPS KPVSREDQCS YKWWQKYQKR KFHCANLTSW 250 260 270 280 290 300 PRWLYSLYDA ETLMDRIKKQ LREWDENLKD DSLPSNPIDF SYRVAACLPI DDVLRIQLLK 310 320 330 340 350 360 IGSAIQRLRC ELDIMNKCTS LCCKQCQETE ITTKNEIFSL SLCGPMAAYV NPHGYVHETL 370 380 390 400 410 420 TVYKACNLNL IGRPSTEHSW FPGYAWTVAQ CKICASHIGW KFTATKKDMS PQKFWGLTRS 430 440 ALLPTIPDTE DEISPDKVIL CL
	Isoform 2 [UniParc]. Checksum: 28B44733BBB461C1	FASTA	441	50,475
	10 20 30 40 50 60 MAGEGDQQDA AHNMGNHLPL LPESEEEDEM EVEDQDSKEA KKPNIINFDT SLPTSHTYLG 70 80 90 100 110 120 ADMEEFHGRT LHDDDSCQVI PVLPQVMMIL IPGQTLPLQL FHPQEVSMVR NLIQKDRTFA 130 140 150 160 170 180 VLAYSNVQER EAQFGTTAEI YAYREEQDFG IEIVKVKAIG RQRFKVLELR TQSDGIQQAK 190 200 210 220 230 240 VQILPECVLP STMSAVQLES LNKCQIFPSK PVSREDQCSY KWWQKYQKRK FHCANLTSWP 250 260 270 280 290 300 RWLYSLYDAE TLMDRIKKQL REWDENLKDD SLPSNPIDFS YRVAACLPID DVLRIQLLKI 310 320 330 340 350 360 GSAIQRLRCE LDIMNKCTSL CCKQCQETEI TTKNEIFSLS LCGPMAAYVN PHGYVHETLT 370 380 390 400 410 420 VYKACNLNLI GRPSTEHSWF PGYAWTVAQC KICASHIGWK FTATKKDMSP QKFWGLTRSA 430 440 LLPTIPDTED EISPDKVILC L

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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(2004) [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(2006) [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(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). Tissue: Brain and Lung.
[4]	"Gene expression profiling in the human hypothalamus-pituitary-adrenal axis and full-length cDNA cloning." Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M. , Zhou J., Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L. Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-442. Tissue: Adrenal gland.
[5]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] 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(2004) [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(2008) [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(2008) [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(2010) [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.
+	Additional computationally mapped references.

Web resources

Protein Spotlight

A short story - Issue 117 of May 2010

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00045917. IPI00641620.
RefSeq	NP_001166953.1. NM_001173482.1. NP_057386.2. NM_016302.3.
UniGene	Hs.18925.
3D structure databases
ProteinModelPortal	Q96SW2.
SMR	Q96SW2. Positions 79-185.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q96SW2. 6 interactions.
STRING	9606.ENSP00000231948.
PTM databases
PhosphoSite	Q96SW2.
Polymorphism databases
DMDM	73918916.
Proteomic databases
PaxDb	Q96SW2.
PRIDE	Q96SW2.
Protocols and materials databases
DNASU	51185.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000231948; ENSP00000231948; ENSG00000113851. ENST00000432408; ENSP00000412499; ENSG00000113851.
GeneID	51185.
KEGG	hsa:51185.
UCSC	uc003bpq.3. human. uc003bpr.3. human.
Organism-specific databases
CTD	51185.
GeneCards	GC03M003166.
HGNC	HGNC:30185. CRBN.
HPA	HPA045910.
MIM	607417. phenotype. 609262. gene.
neXtProt	NX_Q96SW2.
Orphanet	88616. Autosomal recessive nonsyndromic intellectual deficit. 1620. Distal monosomy 3p.
PharmGKB	PA134926851.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG313031.
HOGENOM	HOG000067866.
HOVERGEN	HBG054571.
InParanoid	Q96SW2.
KO	K11793.
OMA	IRTQSDG.
OrthoDB	EOG44XJGR.
PhylomeDB	Q96SW2.
Enzyme and pathway databases
UniPathway	UPA00143.
Gene expression databases
ArrayExpress	Q96SW2.
Bgee	Q96SW2.
CleanEx	HS_CRBN.
Genevestigator	Q96SW2.
GermOnline	ENSG00000113851. Homo sapiens.
Family and domain databases
InterPro	IPR003111. Pept_S16_N. IPR015947. PUA-like_domain. [Graphical view]
Pfam	PF02190. LON. 1 hit. [Graphical view]
SMART	SM00464. LON. 1 hit. [Graphical view]
SUPFAM	SSF88697. PUA-like. 1 hit.
ProtoNet	Search...
Other
GenomeRNAi	51185.
NextBio	54159.
SOURCE	Search...

Entry information

Entry name

CRBN_HUMAN

Accession

Primary (citable) accession number: Q96SW2
Secondary accession number(s): B2R6H4 , C9IZA9, C9JAH6, Q6AI62, Q6NVZ0, Q9UHW4

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 30, 2005
Last sequence update:	December 1, 2001
Last modified:	May 1, 2013
This is version 94 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.