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.