CRBN_DANRE
ID CRBN_DANRE Reviewed; 431 AA.
AC Q68EH9;
DT 20-APR-2010, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 91.
DE RecName: Full=Protein cereblon;
DE Short=zcrbn;
GN Name=crbn; ORFNames=zgc:92404;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (AUG-2004) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP FUNCTION, THALIDOMIDE-BINDING, DISRUPTION PHENOTYPE, MUTAGENESIS OF TYR-374
RP AND TRP-376, AND TISSUE SPECIFICITY.
RX PubMed=20223979; DOI=10.1126/science.1177319;
RA Ito T., Ando H., Suzuki T., Ogura T., Hotta K., Imamura Y., Yamaguchi Y.,
RA Handa H.;
RT "Identification of a primary target of thalidomide teratogenicity.";
RL Science 327:1345-1350(2010).
CC -!- FUNCTION: Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3
CC protein ligase complex that mediates the ubiquitination and subsequent
CC proteasomal degradation of target proteins, such as MEIS2 (Probable).
CC Normal degradation of key regulatory proteins is required for normal
CC limb outgrowth and expression of the fibroblast growth factor FGF8
CC (PubMed:20223979). Maintains presynaptic glutamate release and
CC consequently cognitive functions, such as memory and learning, by
CC negatively regulating large-conductance calcium-activated potassium
CC (BK) channels in excitatory neurons. Likely to function by regulating
CC the assembly and neuronal surface expression of BK channels via its
CC interaction with KCNT1 (By similarity). May also be involved in
CC regulating anxiety-like behaviors via a BK channel-independent
CC mechanism (By similarity). {ECO:0000250|UniProtKB:Q8C7D2,
CC ECO:0000250|UniProtKB:Q96SW2, ECO:0000269|PubMed:20223979,
CC ECO:0000305}.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC {ECO:0000269|PubMed:20223979}.
CC -!- SUBUNIT: Component of a DCX (DDB1-CUL4-X-box) protein ligase complex.
CC {ECO:0000250|UniProtKB:Q96SW2, ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q96SW2}. Nucleus
CC {ECO:0000250|UniProtKB:Q96SW2}.
CC -!- TISSUE SPECIFICITY: Highly expressed in brain, head, vasculature otic
CC vesicles and developing pectoral fins. {ECO:0000269|PubMed:20223979}.
CC -!- DISRUPTION PHENOTYPE: Specific defects in fin and otic vesicle
CC development. {ECO:0000269|PubMed:20223979}.
CC -!- MISCELLANEOUS: Thalidomide is teratogenic in human, chicken and
CC zebrafish, but not in mice. Binding of thalidomide and related drugs
CC changes the substrate specificity of the human DCX (DDB1-CUL4-X-box) E3
CC protein ligase complex, leading to decreased degradation of endogenous
CC target proteins and increased degradation of other proteins that are
CC not normal substrates. This is probably the underlying cause of the
CC teratogenic activity of thalidomide, possibly due to abnormal
CC regulation of the BMP and FGF8 signaling pathways.
CC {ECO:0000305|PubMed:20223979}.
CC -!- SIMILARITY: Belongs to the CRBN family. {ECO:0000305}.
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DR EMBL; BC080253; AAH80253.1; -; mRNA.
DR RefSeq; NP_001003996.1; NM_001003996.1.
DR AlphaFoldDB; Q68EH9; -.
DR SMR; Q68EH9; -.
DR BioGRID; 92546; 1.
DR STRING; 7955.ENSDARP00000062723; -.
DR PaxDb; Q68EH9; -.
DR GeneID; 445491; -.
DR KEGG; dre:445491; -.
DR CTD; 51185; -.
DR ZFIN; ZDB-GENE-040822-43; crbn.
DR eggNOG; KOG1400; Eukaryota.
DR InParanoid; Q68EH9; -.
DR OrthoDB; 1069900at2759; -.
DR PhylomeDB; Q68EH9; -.
DR UniPathway; UPA00143; -.
DR PRO; PR:Q68EH9; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Unplaced.
DR GO; GO:0031464; C:Cul4A-RING E3 ubiquitin ligase complex; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0000151; C:ubiquitin ligase complex; IDA:ZFIN.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0008283; P:cell population proliferation; IMP:ZFIN.
DR GO; GO:0035118; P:embryonic pectoral fin morphogenesis; IMP:ZFIN.
DR GO; GO:0033333; P:fin development; IMP:UniProtKB.
DR GO; GO:0060173; P:limb development; IMP:UniProtKB.
DR GO; GO:0071599; P:otic vesicle development; IMP:UniProtKB.
DR GO; GO:0071600; P:otic vesicle morphogenesis; IMP:ZFIN.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; ISS:UniProtKB.
DR CDD; cd15777; CRBN_C_like; 1.
DR Gene3D; 2.30.130.40; -; 1.
DR InterPro; IPR034750; CULT.
DR InterPro; IPR003111; Lon_prtase_N.
DR InterPro; IPR046336; Lon_prtase_N_sf.
DR InterPro; IPR015947; PUA-like_sf.
DR InterPro; IPR004910; Yippee/Mis18/Cereblon.
DR Pfam; PF02190; LON_substr_bdg; 1.
DR Pfam; PF03226; Yippee-Mis18; 1.
DR SMART; SM00464; LON; 1.
DR SUPFAM; SSF88697; SSF88697; 1.
DR PROSITE; PS51788; CULT; 1.
DR PROSITE; PS51787; LON_N; 1.
PE 1: Evidence at protein level;
KW Cytoplasm; Metal-binding; Nucleus; Reference proteome;
KW Ubl conjugation pathway; Zinc.
FT CHAIN 1..431
FT /note="Protein cereblon"
FT /id="PRO_0000393877"
FT DOMAIN 69..307
FT /note="Lon N-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01123"
FT DOMAIN 308..416
FT /note="CULT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01124"
FT REGION 1..36
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 9..25
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 313
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96SW2"
FT BINDING 316
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96SW2"
FT BINDING 368
FT /ligand="(S)-thalidomide"
FT /ligand_id="ChEBI:CHEBI:61918"
FT /evidence="ECO:0000250|UniProtKB:Q96SW2"
FT BINDING 370
FT /ligand="(S)-thalidomide"
FT /ligand_id="ChEBI:CHEBI:61918"
FT /evidence="ECO:0000250|UniProtKB:Q96SW2"
FT BINDING 376
FT /ligand="(S)-thalidomide"
FT /ligand_id="ChEBI:CHEBI:61918"
FT /evidence="ECO:0000250|UniProtKB:Q96SW2"
FT BINDING 381
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96SW2"
FT BINDING 384
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:Q96SW2"
FT MUTAGEN 374
FT /note="Y->A: Abolishes thalidomide-binding; when associated
FT with A-376."
FT /evidence="ECO:0000269|PubMed:20223979"
FT MUTAGEN 376
FT /note="W->A: Abolishes thalidomide-binding; when associated
FT with A-374."
FT /evidence="ECO:0000269|PubMed:20223979"
SQ SEQUENCE 431 AA; 49095 MW; 0B490311E861FEC3 CRC64;
MGNQLQLLPE NEEEEEDDME TEDRDGEDVE KPSIINFDTS LPTSHAYLGS DMEEFHGRTL
HDEDSVQNLP VLPHVALILI PGQTLPLQLF RPQEVSMFRN LVSQDRTFAV LAHSPDPSGT
ETKAEFGTTA EIYAFREEQE YGIETVKIKA VGRQRFRVHD IRTQADGIRQ AKVQILPERI
LPDPLCALQF LPRLHTHSPQ TKHTQTTPPQ KRCSQNYRQK KLHCASMTSW PPWVYSLYDS
KTLMSRVKKQ LHEWDENLKD ESLPTNPTDF SYRVAACLPI DDALRLQLLK IGSAIQRLRC
ELDIMDRCTS LCCKQCQDTE ITSKNEIFSL SLYGPMAAYV NPHGYVHETL TVYKASNLNL
IGRPSTLHSW FPGYAWTIAQ CRTCSSHMGW KFSAVKKDLS PPRFWGLTRS ALLPTIPQGE
EGVEGSRLLC L
