ID CRBN_HUMAN Reviewed; 442 AA. AC Q96SW2; B2R6H4; C9IZA9; C9JAH6; Q6AI62; Q6NVZ0; Q9UHW4; DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 187. DE RecName: Full=Protein cereblon; GN Name=CRBN; ORFNames=AD-006; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Brain, and Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 3-442. RC TISSUE=Adrenal gland; RX PubMed=10931946; DOI=10.1073/pnas.160270997; RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J., RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., RA Chen M.-D., Chen J.-L.; RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis RT and full-length cDNA cloning."; RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 64-250. RC TISSUE=Fetal kidney; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [6] RP INVOLVEMENT IN MRT2, AND TISSUE SPECIFICITY. RX PubMed=15557513; DOI=10.1212/01.wnl.0000146196.01316.a2; RA Higgins J.J., Pucilowska J., Lombardi R.Q., Rooney J.P.; RT "A mutation in a novel ATP-dependent Lon protease gene in a kindred with RT mild mental retardation."; RL Neurology 63:1927-1931(2004). RN [7] RP TISSUE SPECIFICITY. RX PubMed=17380424; DOI=10.1007/s11033-007-9077-3; RA Xin W., Xiaohua N., Peilin C., Xin C., Yaqiong S., Qihan W.; RT "Primary function analysis of human mental retardation related gene CRBN."; RL Mol. Biol. Rep. 35:251-256(2008). RN [8] RP FUNCTION. RX PubMed=18414909; DOI=10.1007/s10048-008-0128-2; RA Higgins J.J., Hao J., Kosofsky B.E., Rajadhyaksha A.M.; RT "Dysregulation of large-conductance Ca2+-activated K+ channel expression in RT nonsyndromal mental retardation due to a cereblon p.R419X mutation."; RL Neurogenetics 9:219-223(2008). RN [9] RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY, RP IDENTIFICATION IN A DCX COMPLEX WITH DDB1; RBX1 AND CUL4A, RP THALIDOMIDE-BINDING, UBIQUITINATION, AND MUTAGENESIS OF TYR-384 AND RP TRP-386. 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). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-25, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [11] RP FUNCTION, AND MISCELLANEOUS. RX PubMed=24328678; DOI=10.1111/bjh.12708; RA Gandhi A.K., Kang J., Havens C.G., Conklin T., Ning Y., Wu L., Ito T., RA Ando H., Waldman M.F., Thakurta A., Klippel A., Handa H., Daniel T.O., RA Schafer P.H., Chopra R.; RT "Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells RT by inducing degradation of T cell repressors Ikaros and Aiolos via RT modulation of the E3 ubiquitin ligase complex CRL4(CRBN.)."; RL Br. J. Haematol. 164:811-821(2014). RN [12] RP FUNCTION, INTERACTION WITH DDB1, AND UBIQUITINATION. RX PubMed=25043012; DOI=10.1038/nature13527; RA Fischer E.S., Bohm K., Lydeard J.R., Yang H., Stadler M.B., Cavadini S., RA Nagel J., Serluca F., Acker V., Lingaraju G.M., Tichkule R.B., RA Schebesta M., Forrester W.C., Schirle M., Hassiepen U., Ottl J., Hild M., RA Beckwith R.E., Harper J.W., Jenkins J.L., Thoma N.H.; RT "Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with RT thalidomide."; RL Nature 512:49-53(2014). RN [13] RP FUNCTION. RX PubMed=26990986; DOI=10.1016/j.molcel.2016.02.032; RA Nguyen T.V., Lee J.E., Sweredoski M.J., Yang S.J., Jeon S.J., RA Harrison J.S., Yim J.H., Lee S.G., Handa H., Kuhlman B., Jeong J.S., RA Reitsma J.M., Park C.S., Hess S., Deshaies R.J.; RT "Glutamine triggers acetylation-dependent degradation of glutamine RT synthetase via the thalidomide receptor cereblon."; RL Mol. Cell 61:809-820(2016). RN [14] RP FUNCTION, AND MUTAGENESIS OF 419-ARG--LEU-442. RX PubMed=29530986; DOI=10.1523/jneurosci.2081-17.2018; RA Choi T.Y., Lee S.H., Kim Y.J., Bae J.R., Lee K.M., Jo Y., Kim S.J., RA Lee A.R., Choi S., Choi L.M., Bang S., Song M.R., Chung J., Lee K.J., RA Kim S.H., Park C.S., Choi S.Y.; RT "Cereblon Maintains Synaptic and Cognitive Function by Regulating BK RT Channel."; RL J. Neurosci. 38:3571-3583(2018). RN [15] RP FUNCTION, AND INTERACTION WITH ILF2. RX PubMed=33009960; DOI=10.1007/s10930-020-09918-9; RA Lian Q., Gao Y., Li Q., He X., Jiang X., Pu Z., Xu G.; RT "Cereblon Promotes the Ubiquitination and Proteasomal Degradation of RT Interleukin Enhancer-Binding Factor 2."; RL Protein J. 39:411-421(2020). RN [16] RP X-RAY CRYSTALLOGRAPHY (3.01 ANGSTROMS) OF 48-428 IN COMPLEX WITH DDB1; RP S-LENALIDOMIDE AND ZINC, FUNCTION, INTERACTION WITH DDB1, DOMAIN, RP MUTAGENESIS OF TRP-386, AND MISCELLANEOUS. RX PubMed=25108355; DOI=10.1038/nsmb.2874; RA Chamberlain P.P., Lopez-Girona A., Miller K., Carmel G., Pagarigan B., RA Chie-Leon B., Rychak E., Corral L.G., Ren Y.J., Wang M., Riley M., RA Delker S.L., Ito T., Ando H., Mori T., Hirano Y., Handa H., Hakoshima T., RA Daniel T.O., Cathers B.E.; RT "Structure of the human cereblon-DDB1-lenalidomide complex reveals basis RT for responsiveness to thalidomide analogs."; RL Nat. Struct. Mol. Biol. 21:803-809(2014). RN [17] RP INVOLVEMENT IN MRT2, AND VARIANT MRT2 ARG-391. RX PubMed=28143899; DOI=10.1136/jmedgenet-2016-104117; RA Sheereen A., Alaamery M., Bawazeer S., Al Yafee Y., Massadeh S., Eyaid W.; RT "A missense mutation in the CRBN gene that segregates with intellectual RT disability and self-mutilating behaviour in a consanguineous Saudi RT family."; RL J. Med. Genet. 54:236-240(2017). RN [18] RP FUNCTION, AND INTERACTION WITH TRAF6 AND ECSIT. RX PubMed=31620128; DOI=10.3389/fimmu.2019.02203; RA Kim M.J., Min Y., Shim J.H., Chun E., Lee K.Y.; RT "CRBN Is a Negative Regulator of Bactericidal Activity and Autophagy RT Activation Through Inhibiting the Ubiquitination of ECSIT and BECN1."; RL Front. Immunol. 10:2203-2203(2019). 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, ILF2 or GLUL CC (PubMed:26990986, PubMed:33009960). Normal degradation of key CC regulatory proteins is required for normal limb outgrowth and CC expression of the fibroblast growth factor FGF8 (PubMed:20223979, CC PubMed:24328678, PubMed:25043012, PubMed:25108355). Maintains CC presynaptic glutamate release and consequently cognitive functions, CC such as memory and learning, by negatively regulating large-conductance CC calcium-activated potassium (BK) channels in excitatory neurons CC (PubMed:18414909, PubMed:29530986). Likely to function by regulating CC the assembly and neuronal surface expression of BK channels via its CC interaction with KCNT1 (PubMed:18414909). May also be involved in CC regulating anxiety-like behaviors via a BK channel-independent CC mechanism (By similarity). Plays a negative role in TLR4 signaling by CC interacting with TRAF6 and ECSIT, leading to inhibition of ECSIT CC ubiquitination, an important step of the signaling (PubMed:31620128). CC {ECO:0000250|UniProtKB:Q8C7D2, ECO:0000269|PubMed:18414909, CC ECO:0000269|PubMed:20223979, ECO:0000269|PubMed:24328678, CC ECO:0000269|PubMed:25043012, ECO:0000269|PubMed:25108355, CC ECO:0000269|PubMed:29530986, ECO:0000269|PubMed:31620128}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC {ECO:0000269|PubMed:20223979, ECO:0000305|PubMed:25108355}. CC -!- SUBUNIT: Interacts with KCNT1 (By similarity). Component of a DCX CC (DDB1-CUL4-X-box) protein ligase complex, at least composed of CRBN, CC CUL4A, DDB1 and RBX1. Interacts directly with DDB1 (PubMed:25043012, CC PubMed:25108355). Interacts (in pomalidomide-bound form) with IKZF1 and CC IKZF3 (PubMed:24328678). Interacts with ILF2 (PubMed:33009960). CC Interacts with TRAF6 and ECSIT (PubMed:31620128). CC {ECO:0000250|UniProtKB:Q56AP7, ECO:0000269|PubMed:20223979, CC ECO:0000269|PubMed:24328678, ECO:0000269|PubMed:25043012, CC ECO:0000269|PubMed:25108355, ECO:0000269|PubMed:31620128, CC ECO:0000269|PubMed:33009960}. CC -!- INTERACTION: CC Q96SW2; Q96A83-2: COL26A1; NbExp=3; IntAct=EBI-2510250, EBI-21553822; CC Q96SW2; P48729: CSNK1A1; NbExp=3; IntAct=EBI-2510250, EBI-1383726; CC Q96SW2; Q16531: DDB1; NbExp=4; IntAct=EBI-2510250, EBI-350322; CC Q96SW2; O14901: KLF11; NbExp=3; IntAct=EBI-2510250, EBI-948266; CC Q96SW2; Q8IVT2: MISP; NbExp=3; IntAct=EBI-2510250, EBI-2555085; CC Q96SW2; Q9P286: PAK5; NbExp=4; IntAct=EBI-2510250, EBI-741896; CC Q96SW2; A0A6Q8PF08: PMP22; NbExp=3; IntAct=EBI-2510250, EBI-50433196; CC Q96SW2; Q93062: RBPMS; NbExp=3; IntAct=EBI-2510250, EBI-740322; CC Q96SW2-2; Q16531: DDB1; NbExp=7; IntAct=EBI-10693561, EBI-350322; CC Q96SW2-2; Q13422-7: IKZF1; NbExp=2; IntAct=EBI-10693561, EBI-11522367; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:20223979}. Nucleus CC {ECO:0000269|PubMed:20223979}. Membrane {ECO:0000250}; Peripheral CC membrane protein {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q96SW2-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96SW2-2; Sequence=VSP_015209; CC -!- TISSUE SPECIFICITY: Widely expressed. Highly expressed in brain. CC {ECO:0000269|PubMed:15557513, ECO:0000269|PubMed:17380424}. CC -!- DOMAIN: The CULT domain binds thalidomide and related drugs, such as CC pomalidomide and lenalidomide. Drug binding leads to a change in CC substrate specificity of the human DCX (DDB1-CUL4-X-box) E3 protein CC ligase complex, while no such change is observed in rodents. CC {ECO:0000269|PubMed:25108355}. CC -!- PTM: Ubiquitinated, ubiquitination is mediated by its own DCX protein CC ligase complex. {ECO:0000269|PubMed:20223979, CC ECO:0000269|PubMed:25043012}. CC -!- DISEASE: Intellectual developmental disorder, autosomal recessive 2 CC (MRT2) [MIM:607417]: A disorder characterized by significantly below CC average general intellectual functioning associated with impairments in CC adaptive behavior and manifested during the developmental period. MRT2 CC patients display mild intellectual disability with a standard IQ ranged CC from 50 to 70. IQ scores are lower in males than females. Developmental CC milestones are mildly delayed. There are no dysmorphic or autistic CC features. {ECO:0000269|PubMed:15557513, ECO:0000269|PubMed:28143899}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- MISCELLANEOUS: Thalidomide was widely prescribed to pregnant women in CC the late 1950s as a sedative and as treatment against morning sickness. CC Thalidomide was found to be teratogenic, causing multiple birth CC defects. More recently, thalidomide use has increased for the treatment CC of multiple myeloma and erythema nodosum leprosum, a painful CC complication of leprosy. Binding of pomalidomide and other thalidomide- CC related drugs leads to a change in substrate specificity of the human CC DCX (DDB1-CUL4-X-box) E3 protein ligase complex, and this is probably CC the underlying cause of the teratogenic activity of thalidomide, CC possibly due to abnormal regulation of the BMP and FGF8 signaling CC pathways (PubMed:20223979). The thalidomide-induced change in substrate CC specificity leads to decreased degradation of MEIS2 and other target CC proteins and increased degradation of MYC, IRF4, IKZF1 and IKZF3, and CC this is probably the reason for the anti-proliferative and CC immunomodulatory effects of thalidomide and related drugs CC (PubMed:25108355). Thalidomide is also teratogenic in chicken and CC zebrafish, but not in mice. {ECO:0000305|PubMed:20223979, CC ECO:0000305|PubMed:25108355}. CC -!- SIMILARITY: Belongs to the CRBN family. {ECO:0000305}. CC -!- CAUTION: Although it contains a Lon N-terminal domain also found in CC proteases of the peptidase S16 family, it does not contain the ATP- CC binding and catalytic domains, suggesting that it has no protease CC activity. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF17211.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=BAG35471.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAG35471.1; Type=Frameshift; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=A short story - Issue 117 of CC May 2010; CC URL="https://www.proteinspotlight.org/back_issues/117"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK027507; BAB55162.1; -; mRNA. DR EMBL; AK312577; BAG35471.1; ALT_SEQ; mRNA. DR EMBL; AC024060; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC017419; AAH17419.1; -; mRNA. DR EMBL; BC067811; AAH67811.1; -; mRNA. DR EMBL; AF117230; AAF17211.1; ALT_FRAME; mRNA. DR EMBL; CR627060; CAH10361.1; -; mRNA. DR CCDS; CCDS2562.1; -. [Q96SW2-1] DR CCDS; CCDS54547.1; -. [Q96SW2-2] DR RefSeq; NP_001166953.1; NM_001173482.1. [Q96SW2-2] DR RefSeq; NP_057386.2; NM_016302.3. [Q96SW2-1] DR PDB; 4M91; X-ray; 1.10 A; B=229-240. DR PDB; 4TZ4; X-ray; 3.01 A; C=48-428. DR PDB; 5FQD; X-ray; 2.45 A; B/E=41-442. DR PDB; 5HXB; X-ray; 3.60 A; C/Z=40-442. DR PDB; 5V3O; X-ray; 3.20 A; C=40-442. DR PDB; 6BN7; X-ray; 3.50 A; B=1-442. DR PDB; 6BN8; X-ray; 3.99 A; B=1-442. DR PDB; 6BN9; X-ray; 4.38 A; B=1-442. DR PDB; 6BNB; X-ray; 6.34 A; B=1-442. DR PDB; 6BOY; X-ray; 3.33 A; B=1-442. DR PDB; 6H0F; X-ray; 3.25 A; B/E/H/K=41-442. DR PDB; 6H0G; X-ray; 4.25 A; B/E=41-397. DR PDB; 6UML; X-ray; 3.58 A; C=40-442. DR PDB; 6XK9; X-ray; 3.64 A; C/Z=40-442. DR PDB; 7BQU; X-ray; 1.90 A; A=318-426. DR PDB; 7BQV; X-ray; 1.80 A; A=318-426. DR PDB; 7LPS; X-ray; 3.78 A; B/E/H/K=47-436. DR PDB; 7U8F; X-ray; 3.15 A; A/D=40-442. DR PDB; 8CVP; EM; 3.40 A; B=1-442. DR PDB; 8D7U; EM; 3.10 A; B=1-442. DR PDB; 8D7V; EM; 3.20 A; B=1-442. DR PDB; 8D7W; EM; 3.10 A; B=1-442. DR PDB; 8D7X; EM; 3.40 A; B=1-442. DR PDB; 8D7Y; EM; 3.40 A; B=1-442. DR PDB; 8D7Z; EM; 3.10 A; B=1-442. DR PDB; 8D80; EM; 3.60 A; B=1-442. DR PDB; 8D81; EM; 3.90 A; B=1-442. DR PDB; 8DEY; X-ray; 3.70 A; A/D=70-442. DR PDB; 8G66; X-ray; 3.45 A; B/E=41-442. DR PDB; 8OIZ; X-ray; 2.50 A; B=40-442. DR PDB; 8OJH; X-ray; 2.72 A; B=40-442. DR PDB; 8RQ1; X-ray; 3.11 A; A=41-187, A=249-426. DR PDB; 8RQ8; X-ray; 2.19 A; A=41-187, A=249-426. DR PDB; 8RQ9; X-ray; 2.91 A; A/C=41-187, A/C=249-426. DR PDB; 8RQA; X-ray; 2.50 A; A=41-187, A=249-426. DR PDB; 8RQC; X-ray; 2.15 A; A/D=41-187, A/D=249-426. DR PDB; 8TNP; EM; 3.30 A; B=1-442. DR PDB; 8TNQ; EM; 2.41 A; B=1-442. DR PDB; 8TNR; EM; 2.50 A; B=1-442. DR PDB; 8TZX; X-ray; 3.15 A; A/D=70-442. DR PDB; 8U15; X-ray; 2.95 A; A/D=70-442. DR PDB; 8U16; X-ray; 2.90 A; A/D=70-442. DR PDB; 8U17; X-ray; 3.10 A; A/D=70-442. DR PDB; 8UH6; EM; 3.30 A; B=1-442. DR PDB; 9CUO; X-ray; 1.60 A; A/B/C/D/E/F=319-427. DR PDB; 9D0W; EM; 2.95 A; B=40-442. DR PDB; 9D0X; EM; 2.84 A; B=40-442. DR PDB; 9DJT; X-ray; 2.95 A; A/D=70-442. DR PDB; 9DJX; X-ray; 3.35 A; A/D=70-442. DR PDB; 9DOM; X-ray; 1.69 A; A/C/E/G=319-426. DR PDB; 9DQD; EM; 3.00 A; A=1-442. DR PDB; 9FJX; X-ray; 2.00 A; B=40-442. DR PDB; 9GAO; X-ray; 1.95 A; A/C=41-187, A/C=249-426. DR PDB; 9ODR; X-ray; 2.42 A; A/B/C/D=319-426. DR PDB; 9ODS; X-ray; 2.61 A; A/B/C/D=319-426. DR PDBsum; 4M91; -. DR PDBsum; 4TZ4; -. DR PDBsum; 5FQD; -. DR PDBsum; 5HXB; -. DR PDBsum; 5V3O; -. DR PDBsum; 6BN7; -. DR PDBsum; 6BN8; -. DR PDBsum; 6BN9; -. DR PDBsum; 6BNB; -. DR PDBsum; 6BOY; -. DR PDBsum; 6H0F; -. DR PDBsum; 6H0G; -. DR PDBsum; 6UML; -. DR PDBsum; 6XK9; -. DR PDBsum; 7BQU; -. DR PDBsum; 7BQV; -. DR PDBsum; 7LPS; -. DR PDBsum; 7U8F; -. DR PDBsum; 8CVP; -. DR PDBsum; 8D7U; -. DR PDBsum; 8D7V; -. DR PDBsum; 8D7W; -. DR PDBsum; 8D7X; -. DR PDBsum; 8D7Y; -. DR PDBsum; 8D7Z; -. DR PDBsum; 8D80; -. DR PDBsum; 8D81; -. DR PDBsum; 8DEY; -. DR PDBsum; 8G66; -. DR PDBsum; 8OIZ; -. DR PDBsum; 8OJH; -. DR PDBsum; 8RQ1; -. DR PDBsum; 8RQ8; -. DR PDBsum; 8RQ9; -. DR PDBsum; 8RQA; -. DR PDBsum; 8RQC; -. DR PDBsum; 8TNP; -. DR PDBsum; 8TNQ; -. DR PDBsum; 8TNR; -. DR PDBsum; 8TZX; -. DR PDBsum; 8U15; -. DR PDBsum; 8U16; -. DR PDBsum; 8U17; -. DR PDBsum; 8UH6; -. DR PDBsum; 9CUO; -. DR PDBsum; 9D0W; -. DR PDBsum; 9D0X; -. DR PDBsum; 9DJT; -. DR PDBsum; 9DJX; -. DR PDBsum; 9DOM; -. DR PDBsum; 9DQD; -. DR PDBsum; 9FJX; -. DR PDBsum; 9GAO; -. DR PDBsum; 9ODR; -. DR PDBsum; 9ODS; -. DR AlphaFoldDB; Q96SW2; -. DR EMDB; EMD-27012; -. DR EMDB; EMD-27234; -. DR EMDB; EMD-27235; -. DR EMDB; EMD-27236; -. DR EMDB; EMD-27237; -. DR EMDB; EMD-27238; -. DR EMDB; EMD-27239; -. DR EMDB; EMD-27240; -. DR EMDB; EMD-27241; -. DR EMDB; EMD-27242; -. DR EMDB; EMD-41423; -. DR EMDB; EMD-41424; -. DR EMDB; EMD-41425; -. DR EMDB; EMD-41777; -. DR EMDB; EMD-41778; -. DR EMDB; EMD-41779; -. DR EMDB; EMD-42247; -. DR EMDB; EMD-46464; -. DR EMDB; EMD-46465; -. DR EMDB; EMD-47111; -. DR EMDB; EMD-47268; -. DR EMDB; EMD-47269; -. DR EMDB; EMD-51881; -. DR EMDB; EMD-72209; -. DR EMDB; EMD-72215; -. DR SMR; Q96SW2; -. DR BioGRID; 119360; 201. DR ComplexPortal; CPX-2759; CRL4-CRBN E3 ubiquitin ligase complex, CUL4A variant. DR ComplexPortal; CPX-2762; CRL4-CRBN E3 ubiquitin ligase complex, CUL4B variant. DR CORUM; Q96SW2; -. DR DIP; DIP-53521N; -. DR FunCoup; Q96SW2; 4077. DR IntAct; Q96SW2; 45. DR MINT; Q96SW2; -. DR STRING; 9606.ENSP00000231948; -. DR BindingDB; Q96SW2; -. DR ChEMBL; CHEMBL3763008; -. DR DrugBank; DB14857; Avadomide. DR DrugBank; DB12101; Iberdomide. DR DrugBank; DB00480; Lenalidomide. DR DrugBank; DB08910; Pomalidomide. DR DrugBank; DB01041; Thalidomide. DR DrugCentral; Q96SW2; -. DR GuidetoPHARMACOLOGY; 3086; -. DR TCDB; 8.A.162.1.1; the cereblon (crbn) family. DR GlyGen; Q96SW2; 1 site, 1 N-linked glycan (1 site). DR iPTMnet; Q96SW2; -. DR PhosphoSitePlus; Q96SW2; -. DR BioMuta; CRBN; -. DR DMDM; 73918916; -. DR jPOST; Q96SW2; -. DR MassIVE; Q96SW2; -. DR PaxDb; 9606-ENSP00000231948; -. DR PeptideAtlas; Q96SW2; -. DR ProteomicsDB; 78157; -. [Q96SW2-1] DR ProteomicsDB; 78158; -. [Q96SW2-2] DR Pumba; Q96SW2; -. DR Antibodypedia; 25089; 150 antibodies from 30 providers. DR DNASU; 51185; -. DR Ensembl; ENST00000231948.9; ENSP00000231948.4; ENSG00000113851.17. [Q96SW2-1] DR Ensembl; ENST00000432408.6; ENSP00000412499.2; ENSG00000113851.17. [Q96SW2-2] DR GeneID; 51185; -. DR KEGG; hsa:51185; -. DR MANE-Select; ENST00000231948.9; ENSP00000231948.4; NM_016302.4; NP_057386.2. DR UCSC; uc003bpq.4; human. [Q96SW2-1] DR AGR; HGNC:30185; -. DR CIViC; 51185; 1 evidence item across 2 molecular profiles. DR ClinPGx; PA134926851; -. DR CTD; 51185; -. DR DisGeNET; 51185; -. DR GeneCards; CRBN; -. DR HGNC; HGNC:30185; CRBN. DR HPA; ENSG00000113851; Low tissue specificity. DR MalaCards; CRBN; -. DR MIM; 607417; phenotype. DR MIM; 609262; gene. DR OpenTargets; ENSG00000113851; -. DR Orphanet; 88616; Autosomal recessive non-syndromic intellectual disability. DR VEuPathDB; HostDB:ENSG00000113851; -. DR eggNOG; KOG1400; Eukaryota. DR GeneTree; ENSGT00390000016404; -. DR HOGENOM; CLU_025648_1_1_1; -. DR InParanoid; Q96SW2; -. DR OMA; SPQYIAR; -. DR OrthoDB; 267517at2759; -. DR PAN-GO; Q96SW2; 2 GO annotations based on evolutionary models. DR PhylomeDB; Q96SW2; -. DR PathwayCommons; Q96SW2; -. DR Reactome; R-HSA-9679191; Potential therapeutics for SARS. DR SignaLink; Q96SW2; -. DR SIGNOR; Q96SW2; -. DR UniPathway; UPA00143; -. DR Agora; ENSG00000113851; -. DR BioGRID-ORCS; 51185; 35 hits in 1204 CRISPR screens. DR ChiTaRS; CRBN; human. DR EvolutionaryTrace; Q96SW2; -. DR GeneWiki; Cereblon; -. DR GenomeRNAi; 51185; -. DR Pharos; Q96SW2; Tclin. DR PRO; PR:Q96SW2; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q96SW2; protein. DR Bgee; ENSG00000113851; Expressed in calcaneal tendon and 202 other cell types or tissues. DR ExpressionAtlas; Q96SW2; baseline and differential. DR GO; GO:0031464; C:Cul4A-RING E3 ubiquitin ligase complex; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0044325; F:transmembrane transporter binding; IEA:Ensembl. DR GO; GO:0060173; P:limb development; IBA:GO_Central. DR GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl. DR GO; GO:0034766; P:negative regulation of monoatomic ion transmembrane transport; IEA:Ensembl. DR GO; GO:0031333; P:negative regulation of protein-containing complex assembly; IEA:Ensembl. DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IEA:Ensembl. DR GO; GO:0030177; P:positive regulation of Wnt signaling pathway; IMP:FlyBase. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:UniProtKB. DR GO; GO:0016567; P:protein ubiquitination; IMP:UniProtKB. DR CDD; cd15777; CRBN_C_like; 1. DR FunFam; 1.20.58.1480:FF:000004; Cereblon, isoform CRA_c; 1. DR FunFam; 2.30.130.40:FF:000002; Cereblon, isoform CRA_c; 1. DR FunFam; 2.170.150.20:FF:000007; Protein cereblon; 1. DR Gene3D; 1.20.58.1480; -; 1. DR Gene3D; 2.30.130.40; LON domain-like; 1. DR Gene3D; 2.170.150.20; Peptide methionine sulfoxide reductase; 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 PANTHER; PTHR14255; CEREBLON; 1. DR PANTHER; PTHR14255:SF4; PROTEIN CEREBLON; 1. DR Pfam; PF02190; LON_substr_bdg; 1. DR Pfam; PF03226; Yippee-Mis18; 1. DR SMART; SM00464; LON; 1. DR SUPFAM; SSF88697; PUA domain-like; 1. DR PROSITE; PS51788; CULT; 1. DR PROSITE; PS51787; LON_N; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant; KW Intellectual disability; Membrane; Metal-binding; Nucleus; Phosphoprotein; KW Proteomics identification; Reference proteome; Ubl conjugation; KW Ubl conjugation pathway; Zinc. FT CHAIN 1..442 FT /note="Protein cereblon" FT /id="PRO_0000076160" FT DOMAIN 81..319 FT /note="Lon N-terminal" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01123" FT DOMAIN 318..426 FT /note="CULT" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01124" FT REGION 1..45 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 24..35 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 323 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:25108355, FT ECO:0007744|PDB:4TZ4" FT BINDING 326 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:25108355, FT ECO:0007744|PDB:4TZ4" FT BINDING 378 FT /ligand="(S)-thalidomide" FT /ligand_id="ChEBI:CHEBI:61918" FT /evidence="ECO:0000269|PubMed:25108355, FT ECO:0007744|PDB:4TZ4" FT BINDING 380 FT /ligand="(S)-thalidomide" FT /ligand_id="ChEBI:CHEBI:61918" FT /evidence="ECO:0000269|PubMed:25108355, FT ECO:0007744|PDB:4TZ4" FT BINDING 386 FT /ligand="(S)-thalidomide" FT /ligand_id="ChEBI:CHEBI:61918" FT /evidence="ECO:0000269|PubMed:25108355, FT ECO:0007744|PDB:4TZ4" FT BINDING 391 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:25108355, FT ECO:0007744|PDB:4TZ4" FT BINDING 394 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /evidence="ECO:0000269|PubMed:25108355, FT ECO:0007744|PDB:4TZ4" FT MOD_RES 25 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VAR_SEQ 23 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_015209" FT VARIANT 391 FT /note="C -> R (in MRT2; dbSNP:rs797045036)" FT /evidence="ECO:0000269|PubMed:28143899" FT /id="VAR_079409" FT MUTAGEN 384 FT /note="Y->A: Abolishes thalidomide-binding without FT affecting DCX protein ligase complex activity; when FT associated with A-386." FT /evidence="ECO:0000269|PubMed:20223979" FT MUTAGEN 386 FT /note="W->A: Abolishes thalidomide-binding without FT affecting DCX protein ligase complex activity; when FT associated with A-384. Abolishes pomalidomide-induced FT change in substrate specificity and abolishes FT pomalidomide-induced decrease in cell viability that is FT brought about by increased degradation of MYC, IRF4 and FT IKZF3." FT /evidence="ECO:0000269|PubMed:20223979, FT ECO:0000269|PubMed:25108355" FT MUTAGEN 419..442 FT /note="Missing: Fails to rescue increased BK channel FT activity and decreased probability of neurotransmission in FT a mouse hippocampal neuron model." FT /evidence="ECO:0000269|PubMed:29530986" FT CONFLICT 229 FT /note="K -> R (in Ref. 2; AAH67811)" FT /evidence="ECO:0000305" FT CONFLICT 237 FT /note="L -> P (in Ref. 1; BAG35471)" FT /evidence="ECO:0000305" FT CONFLICT 292 FT /note="D -> G (in Ref. 1; BAG35471)" FT /evidence="ECO:0000305" FT CONFLICT 330 FT /note="E -> G (in Ref. 1; BAG35471)" FT /evidence="ECO:0000305" FT HELIX 53..56 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 58..60 FT /evidence="ECO:0007829|PDB:9FJX" FT STRAND 78..83 FT /evidence="ECO:0007829|PDB:9FJX" FT STRAND 96..101 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 104..115 FT /evidence="ECO:0007829|PDB:9FJX" FT TURN 116..118 FT /evidence="ECO:0007829|PDB:8RQ1" FT STRAND 119..127 FT /evidence="ECO:0007829|PDB:9FJX" FT TURN 128..131 FT /evidence="ECO:0007829|PDB:9FJX" FT STRAND 132..147 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 149..151 FT /evidence="ECO:0007829|PDB:9FJX" FT STRAND 154..172 FT /evidence="ECO:0007829|PDB:9FJX" FT STRAND 174..176 FT /evidence="ECO:0007829|PDB:8U15" FT STRAND 178..184 FT /evidence="ECO:0007829|PDB:9FJX" FT TURN 193..197 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 200..203 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 204..206 FT /evidence="ECO:0007829|PDB:8TZX" FT STRAND 212..215 FT /evidence="ECO:0007829|PDB:8D7U" FT TURN 218..220 FT /evidence="ECO:0007829|PDB:8TNQ" FT HELIX 221..231 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 233..237 FT /evidence="ECO:0007829|PDB:9FJX" FT STRAND 238..240 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 242..246 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 250..264 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 270..272 FT /evidence="ECO:0007829|PDB:8RQC" FT HELIX 277..285 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 292..300 FT /evidence="ECO:0007829|PDB:9FJX" FT HELIX 304..317 FT /evidence="ECO:0007829|PDB:9FJX" FT STRAND 320..323 FT /evidence="ECO:0007829|PDB:7BQV" FT TURN 324..326 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 330..333 FT /evidence="ECO:0007829|PDB:7BQV" FT HELIX 334..336 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 341..343 FT /evidence="ECO:0007829|PDB:7BQU" FT STRAND 345..350 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 352..354 FT /evidence="ECO:0007829|PDB:8RQA" FT STRAND 356..363 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 367..375 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 384..391 FT /evidence="ECO:0007829|PDB:7BQV" FT TURN 392..394 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 397..406 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 410..418 FT /evidence="ECO:0007829|PDB:7BQV" FT HELIX 419..421 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 422..424 FT /evidence="ECO:0007829|PDB:7BQV" FT STRAND 427..429 FT /evidence="ECO:0007829|PDB:5FQD" FT STRAND 432..434 FT /evidence="ECO:0007829|PDB:6H0F" SQ SEQUENCE 442 AA; 50546 MW; 90DF77D98A8BEAA8 CRC64; MAGEGDQQDA AHNMGNHLPL LPAESEEEDE MEVEDQDSKE AKKPNIINFD TSLPTSHTYL GADMEEFHGR TLHDDDSCQV IPVLPQVMMI LIPGQTLPLQ LFHPQEVSMV RNLIQKDRTF AVLAYSNVQE REAQFGTTAE IYAYREEQDF GIEIVKVKAI GRQRFKVLEL RTQSDGIQQA KVQILPECVL PSTMSAVQLE SLNKCQIFPS KPVSREDQCS YKWWQKYQKR KFHCANLTSW PRWLYSLYDA ETLMDRIKKQ LREWDENLKD DSLPSNPIDF SYRVAACLPI DDVLRIQLLK IGSAIQRLRC ELDIMNKCTS LCCKQCQETE ITTKNEIFSL SLCGPMAAYV NPHGYVHETL TVYKACNLNL IGRPSTEHSW FPGYAWTVAQ CKICASHIGW KFTATKKDMS PQKFWGLTRS ALLPTIPDTE DEISPDKVIL CL //