CRBN (cereblon) is the substrate-recognition subunit of a CRL4 cullin-RING E3 ubiquitin ligase, the DCX/CRL4(CRBN) complex composed of DDB1, CUL4A or CUL4B, RBX1 and CRBN. Through an N-terminal Lon-protease-like domain it binds the adaptor DDB1, and through a C-terminal thalidomide-binding (CULT) domain that coordinates a structural Zn2+ ion it recruits substrate proteins for ubiquitination and subsequent proteasomal degradation. Endogenous substrates include MEIS2, glutamine synthetase (GLUL) and ILF2, and the complex is required for normal limb outgrowth and FGF8 expression in vertebrates. CRBN also regulates neuronal large-conductance Ca2+-activated potassium (BK) channels via interaction with KCNT1, contributing to presynaptic glutamate release, memory and learning; loss-of-function variants cause autosomal recessive intellectual developmental disorder. The CULT domain is the direct molecular target of thalidomide, lenalidomide and pomalidomide (IMiDs) and of newer molecular-glue and PROTAC degraders, which act as molecular glues that reprogram CRBN substrate specificity to recruit neosubstrates such as IKZF1, IKZF3, SALL4, CK1alpha and GSPT1 for degradation. CRBN is expressed widely and most highly in brain, and localizes to cytoplasm, nucleus and peripheral membranes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: CRBN is found in the nucleus as well as the cytoplasm by direct immunolocalization, consistent with this phylogenetic transfer. Reason: Nuclear localization is supported by direct experimental evidence (PMID:20223979, IDA) and is consistent with the substrate-receptor role; the IBA transfer to nucleus is reasonable. It is a localization rather than the core molecular function. Supporting Evidence: PMID:20223979 CRBN is a thalidomide-binding protein that forms an E3 ubiquitin ligase complex with DDB1 and Cul4A; subcellular localization studies place it in the nucleus and cytoplasm. |
| GO:0030177 positive regulation of Wnt signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CRBN promotes Wnt-induced, IMiD-independent degradation of CK1alpha (a negative regulator of Wnt), and is required for physiological Wnt signaling with conserved Wnt phenotypes in zebrafish and Drosophila. Reason: This regulatory role is experimentally supported (PMID:34489457) and conserved, so the phylogenetic transfer is justified, but it is a downstream physiological consequence of the E3-ligase activity rather than CRBN's core substrate-receptor function. Supporting Evidence: PMID:34489457 CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: As the substrate receptor of CRL4(CRBN), CRBN targets substrates for ubiquitination and proteasomal degradation; this is a core biological process for the gene. Reason: Directly supported by experimental evidence (PMID:20223979 IMP; PMID:26131937 showing cullin/proteasome-dependent substrate degradation) and a central function. Supporting Evidence: PMID:26131937 The lenalidomide-dependent decrease in CK1alpha protein level was abrogated by treatment with the proteasome inhibitor MG132 and the NEDD8-activating enzyme inhibitor MLN4924, which interferes with the activity of cullin-RING E3 ubiquitin ligases, implicating proteasome- and cullin-dependent degradation of CK1alpha. |
| GO:0060173 limb development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The CRBN-containing CRL4 complex is required for normal limb outgrowth and FGF8 expression in zebrafish and chicks; thalidomide inhibition of this activity underlies its teratogenic limb defects. Reason: This developmental phenotype is supported (PMID:20223979) and explains thalidomide teratogenicity, but it is a tissue/developmental consequence of the core E3-ligase function rather than the molecular function itself. Supporting Evidence: PMID:20223979 CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. |
| GO:0031464 Cul4A-RING E3 ubiquitin ligase complex | IBA GO_REF:0000033 | ACCEPT | Summary: CRBN is the substrate-receptor component of the CUL4A-RBX1-DDB1-CRBN (CRL4) E3 ubiquitin ligase complex. Reason: Core, well-established complex membership supported by direct experimental and structural evidence (PMID:20223979 IDA, PMID:25108355). Supporting Evidence: PMID:20223979 CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localization, transferred from UniProt subcellular location; corroborated by direct immunolocalization (PMID:20223979). Reason: Redundant with the experimentally supported IDA nucleus annotation; localization, not core function. Supporting Evidence: PMID:20223979 Subcellular localization analysis showed CRBN in the nucleus and cytoplasm. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Cytoplasmic localization, transferred from UniProt subcellular location; corroborated by direct immunolocalization (PMID:20223979). Reason: Redundant with the experimentally supported IDA cytoplasm annotation; localization, not core function. Supporting Evidence: PMID:20223979 Subcellular localization analysis showed CRBN in the nucleus and cytoplasm. |
| GO:0016020 membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: CRBN is annotated as a peripheral membrane protein (by similarity), consistent with its interaction with membrane ion channels such as KCNT1/BK channels. Reason: The very general "membrane" term reflects a peripheral membrane association (by similarity, UniProt) related to its channel-regulatory role; retained as a non-core location but uninformative as to function. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Membrane; Peripheral membrane protein. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a high-throughput binary interactome map (HuRI), reporting interactions with RBPMS and PAK5. Reason: GO:0005515 protein binding is uninformative and these high-throughput interactors (RBPMS, PAK5) have no established functional relationship to CRBN's E3-ligase role; per curation guidance bare protein binding should not be retained as informative. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:26131937 Lenalidomide induces ubiquitination and degradation of CK1Ξ± ... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation derived from the lenalidomide study; the interactors are DDB1 (complex partner) and CK1alpha (a strictly IMiD-induced neosubstrate). Reason: The underlying interactions are biologically meaningful (DDB1 defines complex membership; CK1alpha is a lenalidomide-induced neosubstrate), but the generic protein binding term is uninformative; the meaningful content is captured by the CRL4 complex-membership and ubiquitination/catabolism annotations and proposed substrate-adaptor MF. Supporting Evidence: PMID:26131937 Lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1alpha) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)). |
| GO:0005515 protein binding | IPI PMID:26909574 Structural basis of lenalidomide-induced CK1Ξ± degradation by... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation from the structural study of the DDB1-CRBN-lenalidomide-CK1alpha complex; interactors are DDB1 and the IMiD-dependent neosubstrate CK1alpha. Reason: CK1alpha binding to CRL4(CRBN) is strictly IMiD-dependent (a drug-induced neosubstrate), and DDB1 binding is captured by complex membership; the generic protein binding term itself is uninformative. Supporting Evidence: PMID:26909574 We show that CK1alpha binding to CRL4(CRBN) is strictly dependent on the presence of an IMiD. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a large-scale interaction-perturbation screen, reporting an interaction with PAK5. Reason: Uninformative generic term from a high-throughput screen with no established functional link to CRBN biology. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a binary human interactome reference map (HuRI), reporting an interaction with MISP. Reason: Uninformative generic term from a high-throughput map with no established functional relationship to CRBN. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Bare protein binding from a neurodegenerative-disease interactome screen, reporting interactions with PMP22, KLF11 and COL26A1. Reason: Uninformative generic term from a high-throughput screen with no established functional link to CRBN's E3-ligase function. Supporting Evidence: PMID:32814053 Interactome mapping providing a network of neurodegenerative-disease proteins, reporting CRBN interactions including with PMP22, KLF11 and COL26A1. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation from the OpenCell endogenous-tagging study, reporting interaction with DDB1. Reason: The DDB1 interaction is biologically central (it defines CRBN's incorporation into CRL4), but the generic protein binding term is uninformative; complex membership is already captured by the Cul4-RING complex annotations. Supporting Evidence: PMID:35271311 OpenCell: Endogenous tagging for the cartography of human cellular organization. |
| GO:0031333 negative regulation of protein-containing complex assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred by orthology from rat Crbn (Q56AP7), reflecting CRBN's regulation of BK channel assembly/surface expression via KCNT1. Reason: The underlying biology (CRBN regulating ion-channel complex assembly) is supported in rodent models, but this is a peripheral neuronal role transferred by orthology, not the core E3-ligase function. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1. |
| GO:0031334 positive regulation of protein-containing complex assembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Transferred by orthology from rat Crbn (Q56AP7); reflects CRBN's role in BK channel assembly/surface expression. Reason: As with the negative-regulation counterpart, this is an ortholog-transferred peripheral neuronal role rather than the core E3 function; retained as non-core. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1. |
| GO:0034766 negative regulation of monoatomic ion transmembrane transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CRBN negatively regulates large-conductance Ca2+-activated K+ (BK) channels, maintaining presynaptic glutamate release and cognition; annotation transferred by orthology from rat Crbn. Reason: Supported by rodent functional studies (PMID:29530986; UniProt FUNCTION) and explains MRT2-related cognitive phenotypes, but is a distinct neuronal role separate from the core E3-ligase function. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt Maintains presynaptic glutamate release and consequently cognitive functions, such as memory and learning, by negatively regulating large-conductance calcium-activated potassium (BK) channels in excitatory neurons. |
| GO:0035641 locomotory exploration behavior | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Behavioral term transferred by orthology from mouse Crbn (Q8C7D2). Reason: Reflects organism-level behavioral phenotypes of rodent Crbn (consistent with CRBN's neuronal/BK-channel role) but is far removed from the molecular function and rests only on ortholog transfer. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt May also be involved in regulating anxiety-like behaviors via a BK channel-independent mechanism (By similarity). |
| GO:0044325 transmembrane transporter binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Reflects CRBN's interaction with the KCNT1 channel and the BK channel, transferred by orthology from rat Crbn. Reason: A more informative MF than bare protein binding (channel binding underlies CRBN's neuronal role) and supported by interaction data, but peripheral to the core substrate-receptor function and based on ortholog transfer. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt Likely to function by regulating the assembly and neuronal surface expression of BK channels via its interaction with KCNT1. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perinuclear cytoplasmic localization transferred by orthology from rat Crbn. Reason: A plausible sub-cytoplasmic localization consistent with the experimentally supported cytoplasm annotation, but based only on ortholog transfer and not core function. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Membrane; Peripheral membrane protein. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: As the substrate receptor of CRL4(CRBN), CRBN mediates ubiquitination of target proteins; this UniPathway-mapped term is a core process. Reason: Directly supported by experimental evidence (PMID:20223979 IMP) and central to CRBN function. Supporting Evidence: PMID:20223979 CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. |
| GO:0031464 Cul4A-RING E3 ubiquitin ligase complex | NAS PMID:25108355 Structure of the human Cereblon-DDB1-lenalidomide complex re... | ACCEPT | Summary: CRBN is a component of the CUL4A variant CRL4-CRBN E3 ubiquitin ligase complex (ComplexPortal CPX-2759). Reason: Core complex membership; structurally and biochemically established (PMID:25108355 Cul4-Rbx1-DDB1-Cereblon complex). Redundant with the IDA annotation to the same term. Supporting Evidence: PMID:25108355 The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is the target of thalidomide, lenalidomide and pomalidomide. |
| GO:0031465 Cul4B-RING E3 ubiquitin ligase complex | NAS PMID:25108355 Structure of the human Cereblon-DDB1-lenalidomide complex re... | ACCEPT | Summary: CRBN is also a component of the CUL4B variant CRL4-CRBN E3 ubiquitin ligase complex (ComplexPortal CPX-2762). Reason: CRBN can assemble with either CUL4A or CUL4B; the CUL4B-variant complex is documented in ComplexPortal and is a valid core complex membership. Supporting Evidence: file:human/CRBN/CRBN-uniprot.txt ComplexPortal; CPX-2762; CRL4-CRBN E3 ubiquitin ligase complex, CUL4B variant. |
| GO:0030177 positive regulation of Wnt signaling pathway | IMP PMID:34489457 The E3 ubiquitin ligase component, Cereblon, is an evolution... | KEEP AS NON CORE | Summary: CRBN mediates Wnt-induced, IMiD-independent degradation of CK1alpha (a negative regulator of Wnt) and is required for physiological Wnt signaling. Reason: Experimentally supported (PMID:34489457) and conserved, but a downstream physiological consequence of the E3-ligase activity rather than CRBN's core molecular function. Supporting Evidence: PMID:34489457 Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9681169 | ACCEPT | Summary: Cytosolic localization from Reactome (CRBN binds IMiDs), consistent with the experimentally supported cytoplasm annotation. Reason: Consistent with direct cytoplasmic localization data; a localization rather than core function. Supporting Evidence: PMID:20223979 Subcellular localization analysis showed CRBN in the nucleus and cytoplasm. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IMP PMID:20223979 Identification of a primary target of thalidomide teratogeni... | ACCEPT | Summary: CRBN, as the substrate receptor of CRL4(CRBN), directs substrates for ubiquitin-dependent proteasomal degradation; a core process. Reason: Directly supported by experimental evidence; central to CRBN function. Supporting Evidence: PMID:20223979 CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. |
| GO:0031464 Cul4A-RING E3 ubiquitin ligase complex | IDA PMID:20223979 Identification of a primary target of thalidomide teratogeni... | ACCEPT | Summary: CRBN was directly shown to form a DCX/CRL4 complex with DDB1, RBX1 and CUL4A. Reason: Core complex membership supported by direct experimental identification of the DCX complex. Supporting Evidence: PMID:20223979 CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A. |
| GO:0005515 protein binding | IPI PMID:20223979 Identification of a primary target of thalidomide teratogeni... | MARK AS OVER ANNOTATED | Summary: Protein-binding annotation capturing the direct CRBN-DDB1 interaction that incorporates CRBN into the CRL4 complex. Reason: The DDB1 interaction is biologically central but the generic protein binding term is uninformative; complex membership is already captured by the Cul4-RING complex annotations, and the adaptor MF is better represented by the proposed substrate-adaptor term. Supporting Evidence: PMID:20223979 CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A. |
| GO:0005634 nucleus | IDA PMID:20223979 Identification of a primary target of thalidomide teratogeni... | ACCEPT | Summary: Direct immunolocalization places CRBN in the nucleus. Reason: Experimentally supported localization (IDA); a location rather than the core function. Supporting Evidence: PMID:20223979 Subcellular localization analysis showed CRBN in the nucleus and cytoplasm. |
| GO:0005737 cytoplasm | IDA PMID:20223979 Identification of a primary target of thalidomide teratogeni... | ACCEPT | Summary: Direct immunolocalization places CRBN in the cytoplasm; CRBN acts in both the nucleus and cytoplasm, consistent with substrate degradation in both compartments. Reason: Experimentally supported localization (IDA); a location rather than the core function. The dual nucleus/cytoplasm distribution is further corroborated by the falcon deep research synthesis. Supporting Evidence: PMID:20223979 Subcellular localization analysis showed CRBN in the nucleus and cytoplasm. file:human/CRBN/CRBN-deep-research-falcon.md Cereblon is localized in both the nucleus and cytoplasm, enabling it to ubiquitinate and degrade substrates in multiple cellular compartments |
| GO:0016567 protein ubiquitination | IMP PMID:20223979 Identification of a primary target of thalidomide teratogeni... | ACCEPT | Summary: CRBN mediates ubiquitination of target proteins as the substrate receptor of CRL4(CRBN); a core process. Reason: Directly supported by experimental evidence (IMP) and central to CRBN function. Supporting Evidence: PMID:20223979 CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:26909574 Structural basis of lenalidomide-induced CK1Ξ± degradation by... | NEW | Summary: CRBN is the substrate receptor/adaptor of the CRL4(CRBN) E3 ubiquitin ligase, recruiting substrates (and drug-induced neosubstrates) for ubiquitination. It has no intrinsic catalytic activity but confers substrate specificity to the complex. Reason: The existing GOA set lacks any molecular function term for CRBN's actual role. GO:1990756 ubiquitin-like ligase-substrate adaptor activity is the precise, well-supported MF and is proposed as a new annotation. The substrate-adaptor (non-catalytic) nature is corroborated by the falcon deep research synthesis. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:26909574 IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase. file:human/CRBN/CRBN-deep-research-falcon.md CRBN does not possess enzymatic activity itself but rather acts as an adapter protein that confers substrate specificity to the ubiquitination machinery |
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Download this section (compressed HTML)Q: Beyond MEIS2, GLUL and ILF2, what is the full endogenous (IMiD-independent) substrate repertoire of human CRL4(CRBN), and which degrons does CRBN recognize natively?
Suggested experts: Handa H, Ebert BL
Q: Is CRBN's regulation of BK/KCNT1 channels mediated by ubiquitination of a channel-associated substrate, or by a non-degradative scaffolding mechanism?
Suggested experts: Choi SY, Park CS
Experiment: Perform global diGly (K-epsilon-GG) ubiquitinome and quantitative proteomics comparing CRBN-knockout and wild-type human cells in the absence of any IMiD, to define drug-independent CRL4(CRBN) substrates.
Hypothesis: CRBN has a defined set of endogenous neosubstrate-independent substrates whose stabilization explains the developmental phenotypes seen on CRBN loss.
Type: ubiquitinome and degradation proteomics
Experiment: Compare BK/KCNT1 channel surface expression and current in neurons expressing wild-type CRBN, a DDB1-binding-deficient mutant, and a ligase-dead CRL4 context, using surface biotinylation and electrophysiology.
Hypothesis: CRBN regulates BK channel surface expression through the CRL4 ubiquitin ligase activity rather than a degradation-independent scaffold function.
Type: electrophysiology and surface-expression assay
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