id: Q96SW2
gene_symbol: CRBN
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: Q96SW2-1
- name: '2'
  id: Q96SW2-2
  sequence_note: VSP_015209
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: CRBN is found in the nucleus as well as the cytoplasm by direct immunolocalization,
      consistent with this phylogenetic transfer.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: 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.
      full_text_unavailable: true
      reference_section_type: ABSTRACT
- term:
    id: GO:0030177
    label: positive regulation of Wnt signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:34489457
      supporting_text: CRBN is required for physiological Wnt signaling, as modulation
        of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes.
      reference_section_type: ABSTRACT
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Directly supported by experimental evidence (PMID:20223979 IMP; PMID:26131937
      showing cullin/proteasome-dependent substrate degradation) and a central function.
    supported_by:
    - reference_id: PMID:26131937
      supporting_text: 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.
      reference_section_type: RESULTS
- term:
    id: GO:0060173
    label: limb development
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: 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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: CRBN is the substrate-receptor component of the CUL4A-RBX1-DDB1-CRBN
      (CRL4) E3 ubiquitin ligase complex.
    action: ACCEPT
    reason: Core, well-established complex membership supported by direct experimental
      and structural evidence (PMID:20223979 IDA, PMID:25108355).
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: CRBN forms an E3 ubiquitin ligase complex with damaged DNA
        binding protein 1 (DDB1) and Cul4A.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization, transferred from UniProt subcellular location;
      corroborated by direct immunolocalization (PMID:20223979).
    action: ACCEPT
    reason: Redundant with the experimentally supported IDA nucleus annotation; localization,
      not core function.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: Subcellular localization analysis showed CRBN in the nucleus
        and cytoplasm.
      full_text_unavailable: true
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, transferred from UniProt subcellular location;
      corroborated by direct immunolocalization (PMID:20223979).
    action: ACCEPT
    reason: Redundant with the experimentally supported IDA cytoplasm annotation;
      localization, not core function.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: Subcellular localization analysis showed CRBN in the nucleus
        and cytoplasm.
      full_text_unavailable: true
      reference_section_type: ABSTRACT
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: CRBN is annotated as a peripheral membrane protein (by similarity), consistent
      with its interaction with membrane ion channels such as KCNT1/BK channels.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Membrane; Peripheral
        membrane protein.'
      reference_section_type: OTHER
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Bare protein binding from a high-throughput binary interactome map (HuRI),
      reporting interactions with RBPMS and PAK5.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: >-
        A proteome-scale map of the human interactome network.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26131937
  qualifier: enables
  review:
    summary: Protein-binding annotation derived from the lenalidomide study; the interactors
      are DDB1 (complex partner) and CK1alpha (a strictly IMiD-induced neosubstrate).
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:26131937
      supporting_text: Lenalidomide induces the ubiquitination of casein kinase 1A1
        (CK1alpha) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)).
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26909574
  qualifier: enables
  review:
    summary: Protein-binding annotation from the structural study of the DDB1-CRBN-lenalidomide-CK1alpha
      complex; interactors are DDB1 and the IMiD-dependent neosubstrate CK1alpha.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:26909574
      supporting_text: We show that CK1alpha binding to CRL4(CRBN) is strictly dependent
        on the presence of an IMiD.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  qualifier: enables
  review:
    summary: Bare protein binding from a large-scale interaction-perturbation screen,
      reporting an interaction with PAK5.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term from a high-throughput screen with no established
      functional link to CRBN biology.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: >-
        Extensive disruption of protein interactions by genetic variants across the allele
        frequency spectrum in human populations.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare protein binding from a binary human interactome reference map (HuRI),
      reporting an interaction with MISP.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term from a high-throughput map with no established
      functional relationship to CRBN.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: >-
        A reference map of the human binary protein interactome.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare protein binding from a neurodegenerative-disease interactome screen,
      reporting interactions with PMP22, KLF11 and COL26A1.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic term from a high-throughput screen with no established
      functional link to CRBN's E3-ligase function.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome mapping providing a network of neurodegenerative-disease
        proteins, reporting CRBN interactions including with PMP22, KLF11 and COL26A1.
      full_text_unavailable: true
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: Protein-binding annotation from the OpenCell endogenous-tagging study,
      reporting interaction with DDB1.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: >-
        OpenCell: Endogenous tagging for the cartography of human cellular organization.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031333
    label: negative regulation of protein-containing complex assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Transferred by orthology from rat Crbn (Q56AP7), reflecting CRBN's regulation
      of BK channel assembly/surface expression via KCNT1.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: Likely to function by regulating the assembly and neuronal
        surface expression of BK channels via its interaction with KCNT1.
      reference_section_type: OTHER
- term:
    id: GO:0031334
    label: positive regulation of protein-containing complex assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Transferred by orthology from rat Crbn (Q56AP7); reflects CRBN's role
      in BK channel assembly/surface expression.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: Likely to function by regulating the assembly and neuronal
        surface expression of BK channels via its interaction with KCNT1.
      reference_section_type: OTHER
- term:
    id: GO:0034766
    label: negative regulation of monoatomic ion transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: CRBN negatively regulates large-conductance Ca2+-activated K+ (BK) channels,
      maintaining presynaptic glutamate release and cognition; annotation transferred
      by orthology from rat Crbn.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: 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.
      reference_section_type: OTHER
- term:
    id: GO:0035641
    label: locomotory exploration behavior
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Behavioral term transferred by orthology from mouse Crbn (Q8C7D2).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: May also be involved in regulating anxiety-like behaviors via
        a BK channel-independent mechanism (By similarity).
      reference_section_type: OTHER
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Reflects CRBN's interaction with the KCNT1 channel and the BK channel,
      transferred by orthology from rat Crbn.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: Likely to function by regulating the assembly and neuronal
        surface expression of BK channels via its interaction with KCNT1.
      reference_section_type: OTHER
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Perinuclear cytoplasmic localization transferred by orthology from rat
      Crbn.
    action: KEEP_AS_NON_CORE
    reason: A plausible sub-cytoplasmic localization consistent with the experimentally
      supported cytoplasm annotation, but based only on ortholog transfer and not
      core function.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Membrane; Peripheral
        membrane protein.'
      reference_section_type: OTHER
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: As the substrate receptor of CRL4(CRBN), CRBN mediates ubiquitination
      of target proteins; this UniPathway-mapped term is a core process.
    action: ACCEPT
    reason: Directly supported by experimental evidence (PMID:20223979 IMP) and central
      to CRBN function.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: >-
        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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:25108355
  qualifier: part_of
  review:
    summary: CRBN is a component of the CUL4A variant CRL4-CRBN E3 ubiquitin ligase
      complex (ComplexPortal CPX-2759).
    action: ACCEPT
    reason: Core complex membership; structurally and biochemically established (PMID:25108355
      Cul4-Rbx1-DDB1-Cereblon complex). Redundant with the IDA annotation to the
      same term.
    supported_by:
    - reference_id: PMID:25108355
      supporting_text: The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase complex is
        the target of thalidomide, lenalidomide and pomalidomide.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031465
    label: Cul4B-RING E3 ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:25108355
  qualifier: part_of
  review:
    summary: CRBN is also a component of the CUL4B variant CRL4-CRBN E3 ubiquitin
      ligase complex (ComplexPortal CPX-2762).
    action: ACCEPT
    reason: CRBN can assemble with either CUL4A or CUL4B; the CUL4B-variant complex
      is documented in ComplexPortal and is a valid core complex membership.
    supported_by:
    - reference_id: file:human/CRBN/CRBN-uniprot.txt
      supporting_text: ComplexPortal; CPX-2762; CRL4-CRBN E3 ubiquitin ligase complex,
        CUL4B variant.
      reference_section_type: OTHER
- term:
    id: GO:0030177
    label: positive regulation of Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:34489457
  qualifier: involved_in
  review:
    summary: CRBN mediates Wnt-induced, IMiD-independent degradation of CK1alpha (a
      negative regulator of Wnt) and is required for physiological Wnt signaling.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported (PMID:34489457) and conserved, but a downstream
      physiological consequence of the E3-ligase activity rather than CRBN's core
      molecular function.
    supported_by:
    - reference_id: PMID:34489457
      supporting_text: >-
        Herein we demonstrate that Wnt, the extracellular ligand of an essential signal
        transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9681169
  qualifier: located_in
  review:
    summary: Cytosolic localization from Reactome (CRBN binds IMiDs), consistent with
      the experimentally supported cytoplasm annotation.
    action: ACCEPT
    reason: Consistent with direct cytoplasmic localization data; a localization rather
      than core function.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: Subcellular localization analysis showed CRBN in the nucleus
        and cytoplasm.
      full_text_unavailable: true
      reference_section_type: ABSTRACT
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:20223979
  qualifier: involved_in
  review:
    summary: CRBN, as the substrate receptor of CRL4(CRBN), directs substrates for
      ubiquitin-dependent proteasomal degradation; a core process.
    action: ACCEPT
    reason: Directly supported by experimental evidence; central to CRBN function.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: >-
        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.
      reference_section_type: ABSTRACT
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:20223979
  qualifier: part_of
  review:
    summary: CRBN was directly shown to form a DCX/CRL4 complex with DDB1, RBX1 and
      CUL4A.
    action: ACCEPT
    reason: Core complex membership supported by direct experimental identification
      of the DCX complex.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: CRBN forms an E3 ubiquitin ligase complex with damaged DNA
        binding protein 1 (DDB1) and Cul4A.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20223979
  qualifier: enables
  review:
    summary: Protein-binding annotation capturing the direct CRBN-DDB1 interaction
      that incorporates CRBN into the CRL4 complex.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: CRBN forms an E3 ubiquitin ligase complex with damaged DNA
        binding protein 1 (DDB1) and Cul4A.
      reference_section_type: ABSTRACT
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:20223979
  qualifier: located_in
  review:
    summary: Direct immunolocalization places CRBN in the nucleus.
    action: ACCEPT
    reason: Experimentally supported localization (IDA); a location rather than the
      core function.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: Subcellular localization analysis showed CRBN in the nucleus
        and cytoplasm.
      full_text_unavailable: true
      reference_section_type: ABSTRACT
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20223979
  qualifier: located_in
  review:
    summary: Direct immunolocalization places CRBN in the cytoplasm; CRBN acts in
      both the nucleus and cytoplasm, consistent with substrate degradation in both
      compartments.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: Subcellular localization analysis showed CRBN in the nucleus
        and cytoplasm.
      full_text_unavailable: true
      reference_section_type: ABSTRACT
    - reference_id: file:human/CRBN/CRBN-deep-research-falcon.md
      supporting_text: Cereblon is localized in both the nucleus and cytoplasm, enabling
        it to ubiquitinate and degrade substrates in multiple cellular compartments
      reference_section_type: OTHER
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IMP
  original_reference_id: PMID:20223979
  qualifier: involved_in
  review:
    summary: CRBN mediates ubiquitination of target proteins as the substrate receptor
      of CRL4(CRBN); a core process.
    action: ACCEPT
    reason: Directly supported by experimental evidence (IMP) and central to CRBN
      function.
    supported_by:
    - reference_id: PMID:20223979
      supporting_text: >-
        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.
      reference_section_type: ABSTRACT
- term:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:26909574
  qualifier: enables
  review:
    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.
    action: NEW
    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_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: PMID:26909574
      supporting_text: IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN
        (also known as CRL4(CRBN)) E3 ubiquitin ligase.
      reference_section_type: ABSTRACT
    - reference_id: file:human/CRBN/CRBN-deep-research-falcon.md
      supporting_text: CRBN does not possess enzymatic activity itself but rather acts
        as an adapter protein that confers substrate specificity to the ubiquitination
        machinery
      reference_section_type: OTHER
core_functions:
- description: CRBN is the substrate-recognition subunit of the CRL4(CRBN) cullin-RING
    E3 ubiquitin ligase, binding DDB1 through its N-terminal Lon-like domain and recruiting
    substrate proteins through its C-terminal CULT (thalidomide-binding) domain to
    direct their ubiquitination and proteasomal degradation.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  directly_involved_in:
  - id: GO:0016567
    label: protein ubiquitination
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  in_complex:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:20223979
    supporting_text: CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding
      protein 1 (DDB1) and Cul4A.
    reference_section_type: ABSTRACT
  - reference_id: PMID:26909574
    supporting_text: IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN
      (also known as CRL4(CRBN)) E3 ubiquitin ligase.
    reference_section_type: ABSTRACT
- description: CRBN binds thalidomide-class drugs (thalidomide, lenalidomide, pomalidomide)
    and molecular-glue/PROTAC degraders in its CULT domain; drug binding acts as a
    molecular glue that reprograms CRBN substrate specificity to recruit neosubstrates
    (e.g. IKZF1, IKZF3, CK1alpha) for degradation. This neosubstrate recruitment is
    drug-induced rather than an endogenous function.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  supported_by:
  - reference_id: PMID:25108355
    supporting_text: These drugs directly bind Cereblon (CRBN) and promote the recruitment
      of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading
      to substrate ubiquitination and degradation.
    reference_section_type: ABSTRACT
  - reference_id: PMID:26909574
    supporting_text: IMiDs also repurpose the ligase to target new proteins for degradation.
    reference_section_type: ABSTRACT
proposed_new_terms: []
suggested_questions:
- question: 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?
  experts:
  - Handa H
  - Ebert BL
- question: Is CRBN's regulation of BK/KCNT1 channels mediated by ubiquitination of
    a channel-associated substrate, or by a non-degradative scaffolding mechanism?
  experts:
  - Choi SY
  - Park CS
suggested_experiments:
- hypothesis: CRBN has a defined set of endogenous neosubstrate-independent substrates
    whose stabilization explains the developmental phenotypes seen on CRBN loss.
  description: 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.
  experiment_type: ubiquitinome and degradation proteomics
- hypothesis: CRBN regulates BK channel surface expression through the CRL4 ubiquitin
    ligase activity rather than a degradation-independent scaffold function.
  description: 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.
  experiment_type: electrophysiology and surface-expression assay
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: PMID:20223979
  title: Identification of a primary target of thalidomide teratogenicity.
  findings:
  - statement: CRBN forms a CRL4 E3 ubiquitin ligase with DDB1 and Cul4A required
      for limb outgrowth and FGF8 expression; thalidomide binds CRBN and inhibits
      this ligase activity.
    supporting_text: 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.
    reference_section_type: ABSTRACT
- id: PMID:25108355
  title: Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for
    responsiveness to thalidomide analogs.
  findings:
  - statement: The Cul4-Rbx1-DDB1-Cereblon E3 ubiquitin ligase is the target of IMiDs,
      which bind CRBN and promote recruitment of IKZF1/IKZF3 for ubiquitination and
      degradation.
    supporting_text: These drugs directly bind Cereblon (CRBN) and promote the recruitment
      of substrates Ikaros (IKZF1) and Aiolos (IKZF3) to the E3 complex, thus leading
      to substrate ubiquitination and degradation.
    reference_section_type: ABSTRACT
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:26131937
  title: Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.
  findings:
  - statement: Lenalidomide induces CRL4(CRBN)-dependent, proteasome- and cullin-dependent
      ubiquitination and degradation of CK1alpha.
    supporting_text: Lenalidomide induces the ubiquitination of casein kinase 1A1
      (CK1alpha) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)),
      resulting in CK1alpha degradation.
    reference_section_type: ABSTRACT
- id: PMID:26909574
  title: Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN)
    ubiquitin ligase.
  findings:
  - statement: CRBN is the substrate receptor of CRL4(CRBN); CK1alpha binding is strictly
      IMiD-dependent, illustrating drug-induced neosubstrate recruitment.
    supporting_text: We show that CK1alpha binding to CRL4(CRBN) is strictly dependent
      on the presence of an IMiD.
    reference_section_type: ABSTRACT
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the
    allele frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:34489457
  title: The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved
    regulator of Wnt signaling.
  findings:
  - statement: CRBN mediates Wnt-induced, IMiD-independent degradation of CK1alpha
      and is required for physiological Wnt signaling.
    supporting_text: Wnt promotes the CRBN-dependent degradation of a subset of proteins.
      These substrates include Casein kinase 1alpha (CK1alpha), a negative regulator
      of Wnt signaling.
    reference_section_type: ABSTRACT
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: Reactome:R-HSA-9681169
  title: CRBN binds IMiDs
  findings: []
- id: file:human/CRBN/CRBN-deep-research-falcon.md
  title: Falcon deep research report for CRBN
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: 'LLM-synthesized deep-research report (Edison/falcon). Cited using
      author-year keys rather than resolvable PMIDs, so individual citations could
      not be confirmed against cached publications; marked UNVERIFIED. Content is
      consistent with the established picture: it correctly frames CRBN as a non-catalytic
      substrate-receptor/adaptor of CRL4(CRBN) and explicitly distinguishes endogenous
      substrates (MEIS2, SLO1/KCNMA1, ILF2) from drug-induced neosubstrates (IKZF1/3,
      CK1alpha, GSPT1, SALL4) recruited only in the presence of IMiDs/CELMoDs. It
      adds mechanistic detail on G-loop degron recognition and open/closed conformational
      dynamics that is drug-/neosubstrate-centric and should not be over-interpreted
      as endogenous function. Used here to corroborate the substrate-adaptor molecular
      function and dual nucleus/cytoplasm localization, not to alter any experimental
      annotation.'
  findings:
  - statement: CRBN is a non-catalytic substrate-recognition adaptor of the CRL4(CRBN)
      E3 ubiquitin ligase that confers substrate specificity to the ubiquitination
      machinery.
    supporting_text: CRBN does not possess enzymatic activity itself but rather acts
      as an adapter protein that confers substrate specificity to the ubiquitination
      machinery
    reference_section_type: OTHER