id: Q96JB5
gene_symbol: CDK5RAP3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: CDK5RAP3 (also known as C53, LZAP, IC53) is a 506-residue protein that, despite its name,
  is not a kinase and has no known catalytic activity. Its principal, well-established function is as
  a substrate adaptor/recruiter within the UFM1 ribosome E3 ligase (UREL) complex, a heterotrimer composed
  of the UFM1 E3 ligase UFL1, the ER-anchoring adaptor DDRGK1/UFBP1, and CDK5RAP3. This complex catalyzes
  UFMylation (covalent attachment of the ubiquitin-like modifier UFM1) of substrate proteins at the cytoplasmic
  surface of the endoplasmic reticulum. CDK5RAP3 directs the ligase to mono-UFMylate ribosomal protein
  RPL26/uL24 on the 60S subunit of ER-associated ribosomes; within reconstituted systems it constrains
  UFL1 activity to achieve this precise substrate selection. Through its RPL10a-binding domain it docks
  the complex onto the 60S subunit, and the UREL complex wraps around the 60S as a C-shaped clamp to promote
  release and recycling of 60S subunits from the SEC61 translocon following normal termination or ribosome
  stalling during co-translational translocation (ER ribosome-associated quality control). The complex
  also mediates UFM1-dependent reticulophagy (ER-phagy) in response to ER stress, in part through ufmylation
  of CYB5R3, and CDK5RAP3 binds ATG8-family proteins and UFM1 through shuffled ATG8-interacting motifs.
  UFMylation-dependent functions underlie its requirement for liver development and erythroid differentiation.
  CDK5RAP3 localizes to the ER membrane, cytosol, nucleus, centrosome and microtubules/cytoskeleton. A
  separate, older body of literature describes CDK5RAP3/LZAP/C53 as a putative tumor suppressor modulating
  NF-kappaB (RelA) signaling, ARF/MDM2/p53 regulation, the mitotic G2/M DNA-damage checkpoint (antagonizing
  CHEK1), p38 MAPK activity, cell invasion and apoptosis-associated nuclear envelope rupture; these roles
  derive mainly from overexpression/knockdown studies and are less firmly established than the UFMylation
  adaptor function.
alternative_products:
  - name: '1'
    id: Q96JB5-1
  - name: 2 (IC53)
    id: Q96JB5-2
    sequence_note: VSP_007566, VSP_007567
  - name: 3 (IC53-2)
    id: Q96JB5-3
    sequence_note: VSP_007568
  - name: '4'
    id: Q96JB5-4
    sequence_note: VSP_055646
existing_annotations:
  - term:
      id: GO:0012505
      label: endomembrane system
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: is_active_in
    review:
      summary: IBA annotation placing CDK5RAP3 in the endomembrane system. CDK5RAP3 is indeed part of
        the ER membrane-tethered UREL complex, so endomembrane system is consistent but very general.
      action: MARK_AS_OVER_ANNOTATED
      reason: Broad phylogenetic (IBA) localization term subsumed by the more specific and well-evidenced
        'endoplasmic reticulum membrane' localization. Retained only as a general grouping term.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
            blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      summary: IBA annotation to ER unfolded protein response. The UFMylation pathway is broadly linked
        to ER homeostasis and UPR, but this is an indirect, transferred process annotation.
      action: KEEP_AS_NON_CORE
      reason: ER stress/UPR involvement is supported for the UFM1 system but is a downstream/contextual
        process rather than the core molecular adaptor function. Keep as non-core.
      supported_by:
        - reference_id: PMID:23152784
          supporting_text: the Ufm1 system was transcriptionally up-regulated by disturbance of the ER
            homeostasis and inhibition of vesicle trafficking
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: enables
    review:
      summary: 'IBA molecular function annotation: ubiquitin-like ligase-substrate adaptor activity. This
        matches the experimentally established core function of CDK5RAP3 as the substrate adaptor of the
        UREL UFM1 E3 ligase complex.'
      action: ACCEPT
      reason: This is the core molecular function of CDK5RAP3 and is strongly supported by direct experimental
        evidence; the IBA transfer is concordant.
      supported_by:
        - reference_id: PMID:36121123
          supporting_text: CDK5RAP3 functions as a substrate adaptor that directs UFMylation to the ribosomal
            protein RPL26
        - reference_id: PMID:37595036
          supporting_text: CDK5RAP3, an adaptor for ufmylation of ribosomal subunit RPL26
  - term:
      id: GO:0007346
      label: regulation of mitotic cell cycle
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      summary: IBA annotation to regulation of mitotic cell cycle. CDK5RAP3/C53 has reported roles at
        the G2/M checkpoint and Cdk1 activation, but as an IBA-transferred general process term.
      action: KEEP_AS_NON_CORE
      reason: Mitotic cell cycle regulation reflects the older C53/LZAP checkpoint literature and is a
        non-core, pleiotropic role relative to the UFMylation adaptor function.
      supported_by:
        - reference_id: PMID:19223857
          supporting_text: C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell-cycle
            progression and DNA damage response
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: IEA localization to nucleus from UniProt subcellular-location mapping. Nuclear localization
        of CDK5RAP3/LZAP is reported experimentally.
      action: KEEP_AS_NON_CORE
      reason: Nuclear localization is documented but is secondary to the ER/cytosolic site of the core
        UFMylation function.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle
            arrest
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    qualifier: located_in
    review:
      summary: IEA localization to cytoplasm (combined automated methods, transferred from mouse ortholog).
        Cytoplasmic localization is well documented.
      action: ACCEPT
      reason: Cytoplasmic/cytosolic localization is consistent with multiple experimental reports and
        with the cytosolic pool of CDK5RAP3.
      supported_by:
        - reference_id: PMID:15790566
          supporting_text: C53 and cyclin B1 co-localize and associate in vivo
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: IEA localization to ER membrane from UniProt subcellular-location mapping. This matches
        the experimentally determined ER-membrane tethering of the UREL complex.
      action: ACCEPT
      reason: ER membrane localization is strongly supported by direct evidence; the IEA call is concordant
        with the core function site.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
            blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: IEA localization to centrosome from UniProt subcellular-location mapping; consistent with
        the IDA centrosome annotation (PMID:19223857).
      action: KEEP_AS_NON_CORE
      reason: Centrosome localization is experimentally reported but reflects a non-core, cell-cycle-associated
        pool of the protein.
      supported_by:
        - reference_id: PMID:19223857
          supporting_text: a portion of C53 protein is localized at the centrosome
  - term:
      id: GO:0005856
      label: cytoskeleton
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: IEA localization to cytoskeleton from UniProt subcellular-location mapping; CDK5RAP3 associates
        with microtubules, especially after caspase cleavage.
      action: KEEP_AS_NON_CORE
      reason: Cytoskeleton/microtubule association is experimentally reported (apoptosis context) but
        is non-core relative to the UFMylation function.
      supported_by:
        - reference_id: PMID:23478299
          supporting_text: C53/LZAP bound indirectly to the microtubule (MT)
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16169070
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:16169070
          supporting_text: 'A human protein-protein interaction network: a resource for annotating the
            proteome.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17785205
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:17785205
          supporting_text: LZAP directly bound to RelA
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: proteome-scale map of the human interactome network
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25910212
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:25910212
          supporting_text: widespread macromolecular interaction perturbations in human genetic disorders
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31515488
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:31515488
          supporting_text: disruption of protein interactions by genetic variants
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: reference map of the human binary protein interactome
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: dual proteome-scale networks reveal cell-specific remodeling of the human interactome
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:37595036
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:37595036
          supporting_text: The E3 complex consisting of UFL1 and UFBP1 interacted with UFC1... and, subsequently,
            CDK5RAP3
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:40205054
    qualifier: enables
    review:
      summary: Bare 'protein binding' (GO:0005515) IPI annotation from a high-throughput or pairwise interaction
        dataset. Uninformative regarding molecular function.
      action: MARK_AS_OVER_ANNOTATED
      reason: Per curation guidelines, bare 'protein binding' should not be retained as a core function.
        Specific interactions (e.g. with UFL1/UFC1) are captured by more informative terms elsewhere in
        this review.
      supported_by:
        - reference_id: PMID:40205054
          supporting_text: Multimodal cell maps as a foundation for structural and functional genomics.
  - term:
      id: GO:0001889
      label: liver development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: IEA annotation to liver development, transferred from mouse ortholog (Q99LM2). Cdk5rap3
        knockout mice show severe liver hypoplasia.
      action: KEEP_AS_NON_CORE
      reason: Liver development is a downstream physiological consequence of the UFMylation adaptor role,
        well supported in mouse but non-core for the molecular function.
      supported_by:
        - reference_id: PMID:30635284
          supporting_text: Cdk5rap3 knockout mice displayed prenatal lethality with severe liver hypoplasia,
            as characterized by delayed proliferation and compromised differentiation
  - term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: IEA annotation to response to ER stress, transferred from mouse ortholog. Consistent with
        UFM1-system role in ER homeostasis.
      action: KEEP_AS_NON_CORE
      reason: ER stress response is a contextual/downstream process for the UFMylation pathway; keep as
        non-core.
      supported_by:
        - reference_id: PMID:32851973
          supporting_text: C53, that is specifically recruited to autophagosomes during ER-stress
  - term:
      id: GO:0044389
      label: ubiquitin-like protein ligase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: enables
    review:
      summary: IEA annotation to ubiquitin-like protein ligase binding (UFL1 binding), transferred from
        mouse ortholog. Concordant with the IDA annotation from PMID:20531390 and the well-established
        CDK5RAP3-UFL1 interaction.
      action: ACCEPT
      reason: Binding to the UFM1 E3 ligase UFL1 is a defining, directly evidenced interaction underlying
        the UREL complex; this is an informative MF distinct from bare protein binding.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3
        - reference_id: PMID:20164180
          supporting_text: we identify NLBP as a novel LZAP-binding protein using tandem affinity purification
  - term:
      id: GO:0060318
      label: definitive erythrocyte differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: IEA annotation to definitive erythrocyte differentiation, transferred from mouse ortholog;
        the UFM1 system is required for erythroid differentiation.
      action: KEEP_AS_NON_CORE
      reason: Erythroid differentiation is a downstream physiological role of the UFMylation pathway;
        non-core for CDK5RAP3 molecular function.
      supported_by:
        - reference_id: PMID:23152784
          supporting_text: the Ufm1-activating enzyme Uba5 is indispensible for erythroid differentiation
            in mice
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: IEA annotation to protein ufmylation, transferred from mouse ortholog. This is the core
        biological process of CDK5RAP3 and is strongly supported by direct human evidence.
      action: ACCEPT
      reason: Protein ufmylation is the central pathway in which CDK5RAP3 acts as substrate adaptor; concordant
        with multiple IDA annotations.
      supported_by:
        - reference_id: PMID:36121123
          supporting_text: CDK5RAP3 functions as a substrate adaptor that directs UFMylation to the ribosomal
            protein RPL26
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    qualifier: located_in
    review:
      summary: IDA localization to cytosol from HPA immunofluorescence. Consistent with the cytosolic
        pool of CDK5RAP3 that is recruited to the ER/autophagosomes.
      action: ACCEPT
      reason: Cytosolic localization is directly supported and consistent with the reported behaviour
        of CDK5RAP3 as a cytosolic protein engaging the ER membrane.
      supported_by:
        - reference_id: PMID:32851973
          supporting_text: we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes
            during ER-stress
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IDA
    original_reference_id: PMID:36121123
    qualifier: involved_in
    review:
      summary: IDA annotation to protein ufmylation (ComplexPortal) based on the reconstituted UFM1 E3
        ligase complex. Directly supports the core ufmylation role.
      action: ACCEPT
      reason: Direct biochemical reconstitution demonstrates CDK5RAP3 participation in protein ufmylation
        as part of the active E3 complex.
      supported_by:
        - reference_id: PMID:36121123
          supporting_text: CDK5RAP3 functions as a substrate adaptor that directs UFMylation to the ribosomal
            protein RPL26
  - term:
      id: GO:1990234
      label: transferase complex
    evidence_type: IPI
    original_reference_id: PMID:36121123
    qualifier: part_of
    review:
      summary: 'IPI annotation: CDK5RAP3 is part of a transferase complex (the UFM1 E3 ligase / UREL complex).'
      action: ACCEPT
      reason: CDK5RAP3 is a bona fide subunit of the UREL UFM1 transferase complex (ComplexPortal CPX-8304);
        part_of is appropriate.
      supported_by:
        - reference_id: PMID:36121123
          supporting_text: CDK5RAP3 that binds to and forms an integral part of the ligase complex
  - term:
      id: GO:0072344
      label: rescue of stalled cytosolic ribosome
    evidence_type: IMP
    original_reference_id: PMID:32851973
    qualifier: involved_in
    review:
      summary: IMP annotation to rescue of stalled cytosolic ribosome. CDK5RAP3, via UFMylation, promotes
        recycling/rescue of stalled ribosomes at the ER.
      action: ACCEPT
      reason: Ribosome rescue/recycling is a core function of the UREL complex; supported by IMP here
        and by structural/biochemical IDA evidence (PMID:38383785, PMID:38383789).
      supported_by:
        - reference_id: PMID:38383785
          supporting_text: UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are
            released after ribosome-associated quality-control-mediated splitting of ribosomes
  - term:
      id: GO:0140501
      label: positive regulation of reticulophagy
    evidence_type: IMP
    original_reference_id: PMID:32851973
    qualifier: involved_in
    review:
      summary: IMP annotation to positive regulation of reticulophagy (ER-phagy). C53/CDK5RAP3 acts as
        an ER-phagy receptor maintaining ER homeostasis during stress.
      action: ACCEPT
      reason: Reticulophagy promotion is a directly evidenced function of CDK5RAP3 as an ATG8-binding
        ER-phagy receptor.
      supported_by:
        - reference_id: PMID:32851973
          supporting_text: Selective removal of certain ER domains via autophagy (termed as ER-phagy)
            has emerged as a major quality control mechanism
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:36121123
    qualifier: enables
    review:
      summary: 'IDA annotation: ubiquitin-like ligase-substrate adaptor activity. Direct experimental
        demonstration that CDK5RAP3 is the substrate adaptor of the UREL UFM1 E3 ligase complex.'
      action: ACCEPT
      reason: This is the core, well-evidenced molecular function of CDK5RAP3; multiple independent studies
        converge on it.
      supported_by:
        - reference_id: PMID:36121123
          supporting_text: CDK5RAP3 functions as a substrate adaptor that directs UFMylation to the ribosomal
            protein RPL26
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:36543799
    qualifier: enables
    review:
      summary: 'IDA annotation: ubiquitin-like ligase-substrate adaptor activity. Direct experimental
        demonstration that CDK5RAP3 is the substrate adaptor of the UREL UFM1 E3 ligase complex.'
      action: ACCEPT
      reason: This is the core, well-evidenced molecular function of CDK5RAP3; multiple independent studies
        converge on it.
      supported_by:
        - reference_id: PMID:36543799
          supporting_text: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:37595036
    qualifier: enables
    review:
      summary: 'IDA annotation: ubiquitin-like ligase-substrate adaptor activity. Direct experimental
        demonstration that CDK5RAP3 is the substrate adaptor of the UREL UFM1 E3 ligase complex.'
      action: ACCEPT
      reason: This is the core, well-evidenced molecular function of CDK5RAP3; multiple independent studies
        converge on it.
      supported_by:
        - reference_id: PMID:37595036
          supporting_text: CDK5RAP3, an adaptor for ufmylation of ribosomal subunit RPL26
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:38383785
    qualifier: enables
    review:
      summary: 'IDA annotation: ubiquitin-like ligase-substrate adaptor activity. Direct experimental
        demonstration that CDK5RAP3 is the substrate adaptor of the UREL UFM1 E3 ligase complex.'
      action: ACCEPT
      reason: This is the core, well-evidenced molecular function of CDK5RAP3; multiple independent studies
        converge on it.
      supported_by:
        - reference_id: PMID:38383785
          supporting_text: UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are
            released after ribosome-associated quality-control-mediated splitting of ribosomes
  - term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:38383789
    qualifier: enables
    review:
      summary: 'IDA annotation: ubiquitin-like ligase-substrate adaptor activity. Direct experimental
        demonstration that CDK5RAP3 is the substrate adaptor of the UREL UFM1 E3 ligase complex.'
      action: ACCEPT
      reason: This is the core, well-evidenced molecular function of CDK5RAP3; multiple independent studies
        converge on it.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
            blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IDA
    original_reference_id: PMID:36543799
    qualifier: is_active_in
    review:
      summary: 'IDA: CDK5RAP3 is active at the ER membrane (UFMylation/ER-phagy context).'
      action: ACCEPT
      reason: ER membrane is the site of CDK5RAP3 function within the UREL complex; is_active_in is well
        supported.
      supported_by:
        - reference_id: PMID:36543799
          supporting_text: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IDA
    original_reference_id: PMID:36543799
    qualifier: involved_in
    review:
      summary: IDA annotation to protein ufmylation (CYB5R3 ufmylation / ER-phagy study).
      action: ACCEPT
      reason: Directly supports the core ufmylation role of CDK5RAP3 as part of the E3 complex.
      supported_by:
        - reference_id: PMID:36543799
          supporting_text: ufmylation of CYB5R3
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IDA
    original_reference_id: PMID:37595036
    qualifier: involved_in
    review:
      summary: IDA annotation to protein ufmylation (mechanistic ER-RQC study).
      action: ACCEPT
      reason: Core ufmylation function directly supported; CDK5RAP3 is the adaptor for RPL26 ufmylation.
      supported_by:
        - reference_id: PMID:37595036
          supporting_text: CDK5RAP3, an adaptor for ufmylation of ribosomal subunit RPL26
  - term:
      id: GO:0072344
      label: rescue of stalled cytosolic ribosome
    evidence_type: IDA
    original_reference_id: PMID:37595036
    qualifier: involved_in
    review:
      summary: IDA annotation to rescue of stalled cytosolic ribosome (ER-RQC). UREL ufmylates RPL26 on
        stalled-disome 60S subunits.
      action: ACCEPT
      reason: Directly supported core function in ER ribosome-associated quality control.
      supported_by:
        - reference_id: PMID:37595036
          supporting_text: Upon disome formation, the E3 complex associated with ufmylated RPL26 on the
            60S subunit... Loss of E3 components... attenuated ER-RQC
  - term:
      id: GO:0140501
      label: positive regulation of reticulophagy
    evidence_type: IDA
    original_reference_id: PMID:36543799
    qualifier: involved_in
    review:
      summary: IDA annotation to positive regulation of reticulophagy via ufmylation of CYB5R3.
      action: ACCEPT
      reason: Reticulophagy promotion is directly evidenced for the UFM1 system including CDK5RAP3.
      supported_by:
        - reference_id: PMID:36543799
          supporting_text: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IDA
    original_reference_id: PMID:38383785
    qualifier: is_active_in
    review:
      summary: 'IDA: CDK5RAP3 is active at the ER membrane as part of the UREL complex engaging 60S ribosomes.'
      action: ACCEPT
      reason: ER membrane is the validated site of action of the UREL complex (cryo-EM structures); is_active_in
        appropriate.
      supported_by:
        - reference_id: PMID:38383785
          supporting_text: UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are
            released after ribosome-associated quality-control-mediated splitting of ribosomes
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IDA
    original_reference_id: PMID:38383789
    qualifier: is_active_in
    review:
      summary: 'IDA: CDK5RAP3 is active at the ER membrane as part of the UREL complex engaging 60S ribosomes.'
      action: ACCEPT
      reason: ER membrane is the validated site of action of the UREL complex (cryo-EM structures); is_active_in
        appropriate.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
            blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
  - term:
      id: GO:0032790
      label: ribosome disassembly
    evidence_type: IDA
    original_reference_id: PMID:38383785
    qualifier: involved_in
    review:
      summary: IDA annotation to ribosome disassembly. UREL releases 60S subunits from the SEC61 translocon,
        dissociating 60S-SEC61 complexes.
      action: ACCEPT
      reason: Directly supported by cryo-EM/biochemical evidence that UREL/CDK5RAP3 mediates release of
        60S from SEC61 translocons.
      supported_by:
        - reference_id: PMID:38383785
          supporting_text: UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are
            released after ribosome-associated quality-control-mediated splitting of ribosomes
  - term:
      id: GO:0032790
      label: ribosome disassembly
    evidence_type: IDA
    original_reference_id: PMID:38383789
    qualifier: involved_in
    review:
      summary: IDA annotation to ribosome disassembly. UREL releases 60S subunits from the SEC61 translocon,
        dissociating 60S-SEC61 complexes.
      action: ACCEPT
      reason: Directly supported by cryo-EM/biochemical evidence that UREL/CDK5RAP3 mediates release of
        60S from SEC61 translocons.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
            blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IDA
    original_reference_id: PMID:38383785
    qualifier: involved_in
    review:
      summary: IDA annotation to protein ufmylation; structural studies of UREL ufmylating RPL26/uL24
        on the 60S ribosome.
      action: ACCEPT
      reason: Core ufmylation function directly and structurally evidenced.
      supported_by:
        - reference_id: PMID:38383785
          supporting_text: UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are
            released after ribosome-associated quality-control-mediated splitting of ribosomes
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IDA
    original_reference_id: PMID:38383789
    qualifier: involved_in
    review:
      summary: IDA annotation to protein ufmylation; structural studies of UREL ufmylating RPL26/uL24
        on the 60S ribosome.
      action: ACCEPT
      reason: Core ufmylation function directly and structurally evidenced.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
            blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
  - term:
      id: GO:0072344
      label: rescue of stalled cytosolic ribosome
    evidence_type: IDA
    original_reference_id: PMID:38383785
    qualifier: involved_in
    review:
      summary: IDA annotation to rescue of stalled cytosolic ribosome; UREL promotes recycling/release
        of 60S subunits from the ER translocon.
      action: ACCEPT
      reason: Directly evidenced core function in ER ribosome rescue/recycling.
      supported_by:
        - reference_id: PMID:38383785
          supporting_text: UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are
            released after ribosome-associated quality-control-mediated splitting of ribosomes
  - term:
      id: GO:0072344
      label: rescue of stalled cytosolic ribosome
    evidence_type: IDA
    original_reference_id: PMID:38383789
    qualifier: involved_in
    review:
      summary: IDA annotation to rescue of stalled cytosolic ribosome; UREL promotes recycling/release
        of 60S subunits from the ER translocon.
      action: ACCEPT
      reason: Directly evidenced core function in ER ribosome rescue/recycling.
      supported_by:
        - reference_id: PMID:38383789
          supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
            blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
  - term:
      id: GO:0001889
      label: liver development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      summary: ISS annotation to liver development (from mouse ortholog Q99LM2). Duplicate of the IEA
        liver development call.
      action: KEEP_AS_NON_CORE
      reason: Downstream physiological role of the UFMylation pathway; non-core.
      supported_by:
        - reference_id: PMID:30635284
          supporting_text: a crucial role of CDK5RAP3 in liver development and hepatic functions
  - term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      summary: ISS annotation to response to ER stress (from mouse ortholog). Duplicate of IEA call.
      action: KEEP_AS_NON_CORE
      reason: Contextual/downstream process of the UFM1 system; non-core.
      supported_by:
        - reference_id: PMID:23152784
          supporting_text: the Ufm1 system was transcriptionally up-regulated by disturbance of the ER
            homeostasis
  - term:
      id: GO:0060318
      label: definitive erythrocyte differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      summary: ISS annotation to definitive erythrocyte differentiation (from mouse ortholog). Duplicate
        of IEA call.
      action: KEEP_AS_NON_CORE
      reason: Downstream physiological role of the UFMylation pathway; non-core.
      supported_by:
        - reference_id: PMID:23152784
          supporting_text: the Ufm1-activating enzyme Uba5 is indispensible for erythroid differentiation
            in mice
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IMP
    original_reference_id: PMID:30635284
    qualifier: involved_in
    review:
      summary: IMP annotation to protein ufmylation. CDK5RAP3 is described as a UFL1 substrate adaptor
        required for the ufmylation pathway in vivo.
      action: ACCEPT
      reason: Loss-of-function (knockout) evidence supports CDK5RAP3 involvement in protein ufmylation;
        core function.
      supported_by:
        - reference_id: PMID:30635284
          supporting_text: CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IDA
    original_reference_id: PMID:20531390
    qualifier: part_of
    review:
      summary: 'IDA annotation: CDK5RAP3 is part of a protein-containing complex (Maxer/DDRGK1-CDK5RAP3
        at the ER).'
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic 'protein-containing complex' is uninformative; the specific UREL transferase complex
        is captured by GO:1990234. Retain the more specific complex annotation instead.
      supported_by:
        - reference_id: PMID:20531390
          supporting_text: Maxer is an endoplasmic reticulum (ER) membrane protein interacting with CDK5RAP3
  - term:
      id: GO:0010921
      label: regulation of phosphatase activity
    evidence_type: IMP
    original_reference_id: PMID:21283629
    qualifier: involved_in
    review:
      summary: IMP annotation to regulation of phosphatase activity. LZAP increases Wip1/PPM1D phosphatase
        association with p38 MAPK.
      action: KEEP_AS_NON_CORE
      reason: Part of the older LZAP p38/Wip1 regulatory literature; non-core relative to the UFMylation
        function.
      supported_by:
        - reference_id: PMID:21283629
          supporting_text: the ability of LZAP to alter p38 phosphorylation depended, at least partially,
            on the p38 phosphatase, Wip1
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:23152784
    qualifier: involved_in
    review:
      summary: IMP annotation to ER unfolded protein response. The Ufm1 system (including C53/CDK5RAP3)
        is linked to UPR and ER homeostasis.
      action: KEEP_AS_NON_CORE
      reason: UPR involvement is contextual/downstream of the UFMylation pathway; non-core.
      supported_by:
        - reference_id: PMID:23152784
          supporting_text: knockdown of the Ufm1 system in U2OS cells triggered UPR and amplification
            of the ER network
  - term:
      id: GO:0005874
      label: microtubule
    evidence_type: IDA
    original_reference_id: PMID:23478299
    qualifier: colocalizes_with
    review:
      summary: 'IDA: colocalizes with microtubules. CDK5RAP3 binds microtubules indirectly; caspase-cleaved
        product causes abnormal MT bundling.'
      action: KEEP_AS_NON_CORE
      reason: Microtubule association is documented (apoptosis context) but non-core; colocalizes_with
        qualifier is appropriately weak.
      supported_by:
        - reference_id: PMID:23478299
          supporting_text: expression of the C53/LZAP cleavage product caused abnormal MT bundling and
            NE rupture
  - term:
      id: GO:0030262
      label: apoptotic nuclear changes
    evidence_type: IMP
    original_reference_id: PMID:23478299
    qualifier: involved_in
    review:
      summary: IMP annotation to apoptotic nuclear changes. Caspase-cleaved C53/LZAP causes rupture of
        the nuclear envelope during apoptosis.
      action: KEEP_AS_NON_CORE
      reason: A specialized apoptosis-associated role of the caspase-cleavage product; non-core relative
        to the main function.
      supported_by:
        - reference_id: PMID:23478299
          supporting_text: expression of the C53/LZAP cleavage product caused abnormal MT bundling and
            NE rupture
  - term:
      id: GO:0043407
      label: negative regulation of MAP kinase activity
    evidence_type: IMP
    original_reference_id: PMID:21283629
    qualifier: involved_in
    review:
      summary: IMP annotation to negative regulation of MAP kinase activity. LZAP inhibits p38 MAPK phosphorylation/activation.
      action: KEEP_AS_NON_CORE
      reason: Older LZAP/p38 literature; non-core relative to the UFMylation adaptor function.
      supported_by:
        - reference_id: PMID:21283629
          supporting_text: LZAP binds p38, alters p38 cellular localization, and inhibits basal and cytokine-stimulated
            p38 activity
  - term:
      id: GO:0044387
      label: negative regulation of protein kinase activity by regulation of protein phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:21283629
    qualifier: involved_in
    review:
      summary: IMP annotation to negative regulation of protein kinase activity by regulation of protein
        phosphorylation (p38 MAPK via Wip1).
      action: KEEP_AS_NON_CORE
      reason: Older LZAP/p38/Wip1 literature; non-core.
      supported_by:
        - reference_id: PMID:21283629
          supporting_text: Expression of LZAP inhibits p38 phosphorylation in a dose-dependent fashion
  - term:
      id: GO:0051019
      label: mitogen-activated protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:21283629
    qualifier: enables
    review:
      summary: 'IPI annotation: mitogen-activated protein kinase binding (p38/MAPK14). LZAP binds p38.'
      action: KEEP_AS_NON_CORE
      reason: A specific but non-core interaction from the LZAP/p38 literature; more informative than
        bare protein binding so retained as non-core.
      supported_by:
        - reference_id: PMID:21283629
          supporting_text: the LZAP binds p38
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:19223857
    qualifier: located_in
    review:
      summary: IDA localization to cytoplasm (C53/Chk1 study).
      action: ACCEPT
      reason: Cytoplasmic localization directly supported.
      supported_by:
        - reference_id: PMID:19223857
          supporting_text: a portion of C53 protein is localized at the centrosome
  - term:
      id: GO:0005813
      label: centrosome
    evidence_type: IDA
    original_reference_id: PMID:19223857
    qualifier: located_in
    review:
      summary: IDA localization to centrosome; centrosome-targeted C53 promotes local Cdk1 activation.
      action: KEEP_AS_NON_CORE
      reason: Centrosomal pool is experimentally supported but reflects a non-core cell-cycle role.
      supported_by:
        - reference_id: PMID:19223857
          supporting_text: a portion of C53 protein is localized at the centrosome, and centrosome-targeting
            C53 potently promotes local Cdk1 activation
  - term:
      id: GO:0007095
      label: mitotic G2 DNA damage checkpoint signaling
    evidence_type: IMP
    original_reference_id: PMID:15790566
    qualifier: involved_in
    review:
      summary: IMP annotation to mitotic G2 DNA damage checkpoint signaling. C53 modulates the G2/M DNA
        damage checkpoint via Cdk1-cyclin B1.
      action: KEEP_AS_NON_CORE
      reason: Older C53 checkpoint literature; non-core relative to the UFMylation function.
      supported_by:
        - reference_id: PMID:15790566
          supporting_text: C53 acts as a pivotal player in modulating the G(2)/M DNA damage checkpoint
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:19223857
    qualifier: enables
    review:
      summary: 'IPI annotation: protein kinase binding (CHEK1/Chk1). C53 interacts with and antagonizes
        Chk1.'
      action: KEEP_AS_NON_CORE
      reason: Specific CHEK1 interaction from the checkpoint literature; informative but non-core. Retained
        as non-core.
      supported_by:
        - reference_id: PMID:19223857
          supporting_text: C53 interacts with Chk1 and antagonizes its function
  - term:
      id: GO:0044818
      label: mitotic G2/M transition checkpoint
    evidence_type: IMP
    original_reference_id: PMID:19223857
    qualifier: involved_in
    review:
      summary: IMP annotation to mitotic G2/M transition checkpoint. C53 antagonizes Chk1 to promote Cdk1
        activation and mitotic entry.
      action: KEEP_AS_NON_CORE
      reason: Older C53 checkpoint literature; non-core.
      supported_by:
        - reference_id: PMID:19223857
          supporting_text: By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry
  - term:
      id: GO:0071901
      label: negative regulation of protein serine/threonine kinase activity
    evidence_type: IMP
    original_reference_id: PMID:19223857
    qualifier: involved_in
    review:
      summary: IMP annotation to negative regulation of protein serine/threonine kinase activity (Chk1
        antagonism).
      action: KEEP_AS_NON_CORE
      reason: Checkpoint-kinase regulation from older C53 literature; non-core.
      supported_by:
        - reference_id: PMID:19223857
          supporting_text: activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited
            by C53 overexpression
  - term:
      id: GO:0001933
      label: negative regulation of protein phosphorylation
    evidence_type: IMP
    original_reference_id: PMID:17785205
    qualifier: involved_in
    review:
      summary: IMP annotation to negative regulation of protein phosphorylation. LZAP impairs RelA Ser536
        phosphorylation.
      action: KEEP_AS_NON_CORE
      reason: Part of the LZAP/NF-kB tumor-suppressor literature; non-core.
      supported_by:
        - reference_id: PMID:17785205
          supporting_text: LZAP directly bound to RelA, impaired serine 536 phosphorylation of RelA
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20228063
    qualifier: enables
    review:
      summary: Bare 'protein binding' IPI from the RCAD/DDRGK1 study (interactions with UFL1 and DDRGK1).
      action: MARK_AS_OVER_ANNOTATED
      reason: Bare protein binding is uninformative; the underlying UFL1/DDRGK1 interactions are captured
        by ubiquitin-like protein ligase binding and the UREL complex annotations.
      supported_by:
        - reference_id: PMID:20228063
          supporting_text: C53/LZAP and RCAD may form a large protein complex
  - term:
      id: GO:0051059
      label: NF-kappaB binding
    evidence_type: IPI
    original_reference_id: PMID:17785205
    qualifier: enables
    review:
      summary: 'IPI annotation: NF-kappaB binding (RelA). LZAP directly binds RelA and inhibits NF-kB
        transcriptional activity.'
      action: KEEP_AS_NON_CORE
      reason: Specific RelA/NF-kB binding from the LZAP tumor-suppressor literature; informative but non-core
        relative to the UFMylation function.
      supported_by:
        - reference_id: PMID:17785205
          supporting_text: LZAP directly bound to RelA, impaired serine 536 phosphorylation of RelA
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15790566
    qualifier: located_in
    review:
      summary: IDA localization to cytoplasm (C53/cyclin B1 study).
      action: ACCEPT
      reason: Cytoplasmic localization directly supported.
      supported_by:
        - reference_id: PMID:15790566
          supporting_text: C53 and cyclin B1 co-localize and associate in vivo
  - term:
      id: GO:0030332
      label: cyclin binding
    evidence_type: IPI
    original_reference_id: PMID:15790566
    qualifier: enables
    review:
      summary: 'IPI annotation: cyclin binding (cyclin B1/CCNB1). C53 associates with cyclin B1.'
      action: KEEP_AS_NON_CORE
      reason: Specific cyclin B1 interaction from the checkpoint literature; informative but non-core.
      supported_by:
        - reference_id: PMID:15790566
          supporting_text: C53 and cyclin B1 co-localize and associate in vivo, indicating a direct role
            of C53 in regulating the Cdk1-cyclin B1 complex
  - term:
      id: GO:0031398
      label: positive regulation of protein ubiquitination
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: involved_in
    review:
      summary: IDA annotation to positive regulation of protein ubiquitination. LZAP affects ARF/HDM2-mediated
        p53 ubiquitination.
      action: KEEP_AS_NON_CORE
      reason: Part of the LZAP/ARF/MDM2/p53 literature; non-core relative to the UFMylation function.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity
            towards p53
  - term:
      id: GO:0042177
      label: negative regulation of protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: involved_in
    review:
      summary: IDA annotation to negative regulation of protein catabolic process. LZAP co-operates with
        ARF to maintain p53 stability (reduce p53 degradation).
      action: KEEP_AS_NON_CORE
      reason: Part of the LZAP/p53-stability literature; non-core.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional
            activity
  - term:
      id: GO:1900182
      label: positive regulation of protein localization to nucleus
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: involved_in
    review:
      summary: IDA annotation to positive regulation of protein localization to nucleus (p53-related).
      action: KEEP_AS_NON_CORE
      reason: Part of the LZAP/p53 literature; non-core.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: maintaining p53 stability and increasing p53 transcriptional activity
  - term:
      id: GO:1901798
      label: positive regulation of signal transduction by p53 class mediator
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: involved_in
    review:
      summary: IDA annotation to positive regulation of signal transduction by p53 class mediator. LZAP
        activates p53 and causes p53-dependent G1 arrest.
      action: KEEP_AS_NON_CORE
      reason: Part of the LZAP/p53 tumor-suppressor literature; non-core.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle
            arrest
  - term:
      id: GO:2000060
      label: positive regulation of ubiquitin-dependent protein catabolic process
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: involved_in
    negated: true
    review:
      summary: 'Negated (NOT) IDA annotation: CDK5RAP3/LZAP does NOT positively regulate ubiquitin-dependent
        protein catabolic process. Consistent with LZAP reversing ARF inhibition of HDM2 and maintaining
        p53 stability rather than promoting its degradation.'
      action: ACCEPT
      reason: 'The informative negative annotation is supported: LZAP maintains rather than degrades p53,
        so it does not positively regulate ubiquitin-dependent catabolism here. Retain as a curated negative.'
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional
            activity
  - term:
      id: GO:0097371
      label: MDM2/MDM4 family protein binding
    evidence_type: IPI
    original_reference_id: PMID:16173922
    qualifier: enables
    review:
      summary: 'IPI annotation: MDM2/MDM4 family protein binding (MDM2/HDM2). LZAP interacts with MDM2
        in an ARF-containing complex.'
      action: KEEP_AS_NON_CORE
      reason: Specific MDM2 interaction from the LZAP/ARF/p53 literature; informative but non-core.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity
            towards p53
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16173922
    qualifier: enables
    review:
      summary: Bare 'protein binding' IPI (interaction with ARF/CDKN2A).
      action: MARK_AS_OVER_ANNOTATED
      reason: Bare protein binding is uninformative; the ARF interaction is the basis of the LZAP non-core
        p53 role described elsewhere.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: that interacts with endogenous ARF in mammalian cells
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: located_in
    review:
      summary: IDA localization to nucleus (LZAP/p53 study).
      action: KEEP_AS_NON_CORE
      reason: Nuclear localization is supported but secondary to the ER/cytosolic core function.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle
            arrest
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: located_in
    negated: true
    review:
      summary: 'Negated (NOT) IDA annotation: CDK5RAP3/LZAP is NOT localized to the nucleolus (in this
        study).'
      action: ACCEPT
      reason: Informative curated negative localization; retain as-is.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: that interacts with endogenous ARF in mammalian cells
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:16173922
    qualifier: located_in
    review:
      summary: IDA localization to cytoplasm (LZAP/p53 study).
      action: ACCEPT
      reason: Cytoplasmic localization directly supported.
      supported_by:
        - reference_id: PMID:16173922
          supporting_text: that interacts with endogenous ARF in mammalian cells
  - term:
      id: GO:0008283
      label: cell population proliferation
    evidence_type: IDA
    original_reference_id: PMID:12054757
    qualifier: involved_in
    review:
      summary: IDA annotation to cell population proliferation. IC53 (isoform 2) stimulates ECV304 cell
        proliferation.
      action: KEEP_AS_NON_CORE
      reason: Proliferation effect from an early overexpression study; non-core and isoform-specific in
        origin.
      supported_by:
        - reference_id: PMID:12054757
          supporting_text: IC53 stimulates ECV304 cell proliferation by 2.1-fold
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:20531390
    qualifier: located_in
    review:
      summary: IDA localization to cytoplasm (Maxer/DDRGK1 study).
      action: ACCEPT
      reason: Cytoplasmic localization directly supported; Maxer/DDRGK1 anchors CDK5RAP3 at the ER.
      supported_by:
        - reference_id: PMID:20531390
          supporting_text: Maxer anchors CDK5RAP3 to the ER
  - term:
      id: GO:0044389
      label: ubiquitin-like protein ligase binding
    evidence_type: IDA
    original_reference_id: PMID:20531390
    qualifier: enables
    review:
      summary: 'IDA annotation: ubiquitin-like protein ligase binding. CDK5RAP3 binds the UFM1 ligase
        machinery (via DDRGK1/Maxer-UFL1 axis).'
      action: ACCEPT
      reason: Binding to the UFM1 E3 ligase components is a core, informative interaction underlying the
        UREL complex.
      supported_by:
        - reference_id: PMID:20531390
          supporting_text: Maxer is an endoplasmic reticulum (ER) membrane protein interacting with CDK5RAP3
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    qualifier: located_in
    review:
      summary: HDA annotation to membrane from an NK-cell membrane proteome study. Very general localization.
      action: MARK_AS_OVER_ANNOTATED
      reason: Generic 'membrane' from a high-throughput proteomic survey is subsumed by the specific ER
        membrane localization; uninformative.
      supported_by:
        - reference_id: PMID:19946888
          supporting_text: define the composition of the membrane proteome of the Natural Killer (NK)
            like cell line YTS
  - term:
      id: GO:0071569
      label: protein ufmylation
    evidence_type: IDA
    original_reference_id: PMID:23152784
    qualifier: acts_upstream_of_or_within
    review:
      summary: IDA annotation to protein ufmylation (acts_upstream_of_or_within). C53/LZAP, with RCAD/Ufl1,
        is involved in ufmylation of endogenous Ufm1 targets.
      action: ACCEPT
      reason: Supports the core ufmylation involvement; consistent with the broader body of UFMylation
        evidence.
      supported_by:
        - reference_id: PMID:23152784
          supporting_text: involvement of RCAD/Ufl1, a putative Ufm1-specific E3 ligase, and its binding
            partner C53/LZAP protein in ufmylation of endogenous Ufm1 targets
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20164180
    qualifier: enables
    review:
      summary: Bare 'protein binding' IPI (interaction with UFL1/NLBP study).
      action: MARK_AS_OVER_ANNOTATED
      reason: Bare protein binding is uninformative; the UFL1 interaction is captured by ubiquitin-like
        protein ligase binding and the UREL complex annotations.
      supported_by:
        - reference_id: PMID:20164180
          supporting_text: we identify NLBP as a novel LZAP-binding protein using tandem affinity purification
  - term:
      id: GO:0000079
      label: regulation of cyclin-dependent protein serine/threonine kinase activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: involved_in
    review:
      summary: ISS annotation to regulation of cyclin-dependent protein serine/threonine kinase activity,
        transferred from rodent ortholog (Q9JLH7). Reflects the historical 'CDK5 activator-binding' name.
      action: MARK_AS_OVER_ANNOTATED
      reason: There is no robust evidence that human CDK5RAP3 regulates CDK activity; the annotation derives
        from the misleading name and ortholog transfer. CDK5RAP3 has no catalytic activity and its established
        role is UFMylation.
      supported_by:
        - reference_id: PMID:21283629
          supporting_text: LZAP has no known enzymatic activity, implying that its biological functions
            are likely mediated by its protein-protein interactions
  - term:
      id: GO:0007420
      label: brain development
    evidence_type: NAS
    original_reference_id: PMID:10915792
    qualifier: involved_in
    review:
      summary: NAS annotation to brain development from an early Cdk5-activator binding-protein cloning
        paper.
      action: KEEP_AS_NON_CORE
      reason: Author-statement only, based on the Cdk5-activator association; speculative and non-core.
        Retained as non-core rather than removed.
      supported_by:
        - reference_id: PMID:10915792
          supporting_text: Cyclin-dependent protein kinase 5 (Cdk5) depends on the association with neuronal
            Cdk5 activator (Nck5a)
  - term:
      id: GO:0045664
      label: regulation of neuron differentiation
    evidence_type: NAS
    original_reference_id: PMID:10721722
    qualifier: involved_in
    review:
      summary: NAS annotation to regulation of neuron differentiation from the original Cdk5-activator
        binding-protein cloning paper.
      action: KEEP_AS_NON_CORE
      reason: Author-statement speculation tied to Cdk5/neuronal context; non-core relative to the established
        UFMylation function.
      supported_by:
        - reference_id: PMID:10721722
          supporting_text: isolation of three other novel p35nck5a-associated proteins
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: NAS
    original_reference_id: PMID:10721722
    qualifier: enables
    review:
      summary: 'NAS annotation: protein kinase binding, from the cloning of Cdk5-activator (p35) binding
        proteins. Note CDK5RAP3 binds the Cdk5 activator p35, not necessarily Cdk5 kinase itself.'
      action: KEEP_AS_NON_CORE
      reason: Historical NAS evidence underlying the gene name; the interaction is with the Cdk5 activator
        and there is no evidence CDK5RAP3 regulates Cdk5 kinase activity. Non-core.
      supported_by:
        - reference_id: PMID:10721722
          supporting_text: novel p35nck5a-associated proteins
references:
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator
      judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    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:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using
      Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10721722
    title: Cloning of three novel neuronal Cdk5 activator binding proteins.
    findings: []
  - id: PMID:10915792
    title: Identification of a common protein association region in the neuronal Cdk5 activator.
    findings: []
  - id: PMID:12054757
    title: A novel gene IC53 stimulates ECV304 cell proliferation and is upregulated in failing heart.
    findings: []
  - id: PMID:15790566
    title: Cdk5 activator-binding protein C53 regulates apoptosis induced by genotoxic stress via modulating
      the G2/M DNA damage checkpoint.
    findings: []
  - id: PMID:16169070
    title: 'A human protein-protein interaction network: a resource for annotating the proteome.'
    findings: []
  - id: PMID:16173922
    title: A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2.
    findings: []
  - id: PMID:17785205
    title: LZAP, a putative tumor suppressor, selectively inhibits NF-kappaB.
    findings: []
  - id: PMID:19223857
    title: Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase
      1 activation.
    findings: []
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells.
    findings: []
  - id: PMID:20164180
    title: A novel LZAP-binding protein, NLBP, inhibits cell invasion.
    findings: []
  - id: PMID:20228063
    title: A novel C53/LZAP-interacting protein regulates stability of C53/LZAP and DDRGK domain-containing
      Protein 1 (DDRGK1) and modulates NF-kappaB signaling.
    findings: []
  - id: PMID:20531390
    title: Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to
      non-cell-autonomous toxicity.
    findings: []
  - id: PMID:21283629
    title: LZAP inhibits p38 MAPK (p38) phosphorylation and activity by facilitating p38 association with
      the wild-type p53 induced phosphatase 1 (WIP1).
    findings: []
  - id: PMID:23152784
    title: Transcriptional regulation of the Ufm1 conjugation system in response to disturbance of the
      endoplasmic reticulum homeostasis and inhibition of vesicle trafficking.
    findings: []
  - id: PMID:23478299
    title: Caspase-mediated cleavage of C53/LZAP protein causes abnormal microtubule bundling and rupture
      of the nuclear envelope.
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network.
    findings: []
  - id: PMID:25910212
    title: Widespread macromolecular interaction perturbations in human genetic disorders.
    findings: []
  - id: PMID:30635284
    title: CDK5RAP3, a UFL1 substrate adaptor, is crucial for liver development.
    findings: []
  - 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:32851973
    title: A cross-kingdom conserved ER-phagy receptor maintains endoplasmic reticulum homeostasis during
      stress.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
    findings: []
  - id: PMID:36121123
    title: A non-canonical scaffold-type E3 ligase complex mediates protein UFMylation.
    findings: []
  - id: PMID:36543799
    title: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3.
    findings: []
  - id: PMID:37595036
    title: Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated
      protein quality control.
    findings: []
  - id: PMID:38383785
    title: UFM1 E3 ligase promotes recycling of 60S ribosomal subunits from the ER.
    findings: []
  - id: PMID:38383789
    title: The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.
    findings: []
  - id: PMID:40205054
    title: Multimodal cell maps as a foundation for structural and functional genomics.
    findings: []
core_functions:
  - description: Substrate adaptor of the UFM1 ribosome E3 ligase (UREL) complex that directs mono-UFMylation
      of ribosomal protein RPL26/uL24 on ER-associated 60S ribosomes
    supported_by:
      - reference_id: PMID:36121123
        supporting_text: CDK5RAP3 functions as a substrate adaptor that directs UFMylation to the ribosomal
          protein RPL26
      - reference_id: PMID:37595036
        supporting_text: CDK5RAP3, an adaptor for ufmylation of ribosomal subunit RPL26
    molecular_function:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    directly_involved_in:
      - id: GO:0071569
        label: protein ufmylation
  - description: Component of the UREL complex that promotes release and recycling of 60S ribosomal subunits
      from the SEC61 translocon at the ER (ER ribosome-associated quality control), via UFMylation of
      RPL26 and a writer-to-reader switch that clamps the 60S
    supported_by:
      - reference_id: PMID:38383785
        supporting_text: UFMylation) facilitates the rescue of 60S ribosomal subunits (60S) that are released
          after ribosome-associated quality-control-mediated splitting of ribosomes
      - reference_id: PMID:38383789
        supporting_text: UREL wraps around the 60S subunit to form a C-shaped clamp architecture that
          blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other
    directly_involved_in:
      - id: GO:0072344
        label: rescue of stalled cytosolic ribosome
      - id: GO:0032790
        label: ribosome disassembly
    locations:
      - id: GO:0005789
        label: endoplasmic reticulum membrane
  - description: ATG8/UFM1-binding ER-phagy (reticulophagy) receptor that, as part of the UFM1 system,
      promotes selective autophagy of the ER in response to ER stress
    supported_by:
      - reference_id: PMID:32851973
        supporting_text: >-
          Here, we identify a cytosolic protein, C53, that is specifically recruited to
          autophagosomes during ER-stress, in both plant and mammalian cells.
      - reference_id: PMID:36543799
        supporting_text: The UFM1 system regulates ER-phagy through the ufmylation of CYB5R3
    directly_involved_in:
      - id: GO:0140501
        label: positive regulation of reticulophagy
proposed_new_terms: []
suggested_questions:
  - question: Are the older LZAP/C53 NF-kB, ARF/MDM2/p53 and G2/M checkpoint activities mechanistically
      separable from the UFMylation adaptor function, or are they downstream/indirect consequences of
      perturbing the UFM1 system?
  - question: Which CDK5RAP3 isoforms participate in the UREL complex versus the nuclear/cell-cycle roles,
      and do the N-terminally truncated isoforms (IC53, IC53-2) retain UFL1/ribosome binding?
  - question: Is CDK5RAP3 itself UFMylated in human cells (as suggested for the mouse ortholog), and does
      this regulate UREL activity or stability?
suggested_experiments:
  - description: Separation-of-function mutants of CDK5RAP3 (e.g. RPL10a-binding domain or UFL1-binding
      residues E217/D355/E359/E373/R432) expressed in CDK5RAP3-knockout cells to test which phenotypes
      (ribosome recycling, ER-phagy, NF-kB, checkpoint) depend on UREL assembly versus UFMylation-independent
      moonlighting.
  - description: Ribosome profiling and 60S-SEC61 release assays in CDK5RAP3-depleted human cells to quantify
      the contribution of CDK5RAP3 (versus UFL1/DDRGK1) to ER ribosome-associated quality control under
      stalling stress.
  - description: Proximity labeling (BioID/TurboID) of CDK5RAP3 across ER, cytosol, nucleus and centrosome
      compartments to define compartment-specific interactomes and test whether the cell-cycle/NF-kB partners
      are engaged independently of the UREL complex.