id: Q9UKT7 gene_symbol: FBXL3 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL3 (F-box/LRR-repeat protein 3) is the substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-RBX1-F-box) cullin-RING E3 ubiquitin ligase that controls the mammalian circadian clock by targeting the cryptochrome repressors CRY1 and CRY2 for ubiquitination and proteasomal degradation. Within the predominantly nuclear SCF(FBXL3) complex, FBXL3 binds SKP1 through its F-box domain and uses its leucine-rich repeats to capture CRY: a conserved C-terminal tail of FBXL3 inserts into the FAD-binding pocket of CRY and buries the PER-binding interface, an interaction that can be displaced by FAD and by the Period proteins. By timing CRY degradation, SCF(FBXL3) sets the period and robustness of the circadian oscillator, permitting reactivation of the CLOCK-BMAL1 transcriptional activator and the consequent rhythmic expression of clock-controlled genes including Per1/Per2. Its activity is counterbalanced by the related SCF(FBXL21) ligase, which stabilizes CRY. In humans, biallelic loss-of-function variants in FBXL3 cause an autosomal-recessive intellectual developmental disorder with short stature. existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic assignment of nuclear localization, the predominant compartment where SCF(FBXL3) degrades CRY. Core localization. action: ACCEPT reason: Core localization; SCF(FBXL3) acts mainly in the nucleus to degrade CRY1/CRY2. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2 - term: id: GO:0005829 label: cytosol evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic assignment of cytosolic localization, a secondary compartment relative to the dominant nuclear pool. action: KEEP_AS_NON_CORE reason: Cytoplasmic localization is documented but the predominantly nuclear pool drives the core CRY-degradation function. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Note=Predominantly nuclear. - term: id: GO:0043153 label: entrainment of circadian clock by photoperiod evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic assignment of involvement in circadian-clock entrainment. FBXL3 sets clock period via CRY degradation; the more direct process term is regulation of circadian rhythm. action: KEEP_AS_NON_CORE reason: FBXL3 governs the circadian oscillator, but the specific "entrainment by photoperiod" framing is narrower than its core period-setting role captured by regulation of circadian rhythm. supported_by: - reference_id: PMID:17463251 supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Combined automated electronic assignment of nuclear localization, the core compartment for SCF(FBXL3) function. action: ACCEPT reason: Core localization; redundant with IBA/ISS/IDA evidence. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Nucleus {ECO:0000269|PubMed:10531035} - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location. A secondary compartment. action: KEEP_AS_NON_CORE reason: Cytoplasmic pool is documented but secondary to the predominantly nuclear localization. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17463251 qualifier: enables review: summary: Interactions with CRY1/CRY2 (and SCF components) from the foundational circadian study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally central CRY1/CRY2 interactions but bare protein binding is uninformative per curation guidelines. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Interacts with CRY1 and CRY2 (phosphorylated) - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23503662 qualifier: enables review: summary: Interaction with CRY2 captured in the structural study of the FBXL3-SKP1-CRY2 complex. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the structurally defined FBXL3-CRY2 interaction but bare protein binding is uninformative. supported_by: - reference_id: PMID:23503662 supporting_text: the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary interactome reference map interactions. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: 'Q9UKT7; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-2557269, EBI-79165' - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: contributes_to review: summary: Ortholog-based electronic assignment of ubiquitin-protein transferase activity, with the contributes_to qualifier acknowledging FBXL3's role within the multi-subunit SCF ligase. As the F-box substrate receptor, FBXL3 does not itself catalyze ubiquitin transfer. action: MODIFY reason: FBXL3 is the substrate-recognition subunit, not the catalytic core (RBX1/CUL1 mediates ubiquitin transfer); the informative molecular function is ubiquitin-like ligase-substrate adaptor activity. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Ortholog-based electronic assignment of cytosolic localization. A secondary compartment. action: KEEP_AS_NON_CORE reason: Cytoplasmic pool documented but secondary to the predominantly nuclear localization. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Combined automated electronic assignment of protein ubiquitination, a parent of the specific SCF-dependent CRY ubiquitination. action: KEEP_AS_NON_CORE reason: Correct but generic; the specific SCF-dependent catabolic process annotation better captures the role. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based electronic assignment of SCF-dependent proteasomal degradation, the core biological process of SCF(FBXL3). action: ACCEPT reason: Core biological process; redundant with the experimental IDA evidence (CRY degradation). supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0031648 label: protein destabilization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based electronic assignment of protein destabilization, reflecting FBXL3-driven CRY destabilization. A generic parent of its ubiquitin-mediated degradation role. action: KEEP_AS_NON_CORE reason: Correct but generic; the SCF-dependent catabolic process annotation captures the specific mechanism (CRY degradation). supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0042752 label: regulation of circadian rhythm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Combined automated electronic assignment of regulation of circadian rhythm, the core physiological process of FBXL3. action: ACCEPT reason: Core biological process; redundant with the experimental IMP evidence (Fbxl3 controls clock oscillations). supported_by: - reference_id: PMID:17463251 supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins - term: id: GO:0043153 label: entrainment of circadian clock by photoperiod evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based electronic assignment of circadian entrainment. FBXL3 sets clock period; the broader regulation of circadian rhythm term is more apt. action: KEEP_AS_NON_CORE reason: FBXL3 governs the oscillator, but the narrower photoperiod-entrainment framing is secondary to its core period-setting role. supported_by: - reference_id: PMID:17463251 supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Ortholog-based electronic assignment of proteasome-mediated ubiquitin-dependent degradation, a parent of the specific SCF-dependent CRY degradation. action: KEEP_AS_NON_CORE reason: Correct but generic; subsumed by the more specific SCF-dependent proteasomal catabolic process annotation. supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0016604 label: nuclear body evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) evidence for localization to nuclear bodies, consistent with the predominantly nuclear pool of FBXL3. action: KEEP_AS_NON_CORE reason: IDA-supported sub-nuclear localization consistent with the nuclear site of action, but a specific sub-compartment; core localization is the nucleus. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Note=Predominantly nuclear. - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:33234069 qualifier: involved_in review: summary: Author-statement (FBXL family review) assignment of the core SCF-dependent proteasomal degradation process. action: ACCEPT reason: Core biological process; consistent with the experimental CRY-degradation evidence. supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0042752 label: regulation of circadian rhythm evidence_type: NAS original_reference_id: PMID:17463251 qualifier: involved_in review: summary: Author-statement assignment of the core circadian-regulation process from the foundational study. action: ACCEPT reason: Core biological process directly supported by the same study's functional experiments. supported_by: - reference_id: PMID:17463251 supporting_text: SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins - term: id: GO:0031648 label: protein destabilization evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity assignment of protein destabilization, reflecting FBXL3-driven CRY destabilization. A generic parent of its degradation role. action: KEEP_AS_NON_CORE reason: Correct but generic; the SCF-dependent catabolic process annotation captures the specific mechanism. supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome curation of cytosolic localization (neddylation of CRL1). Generic CRL-pathway localization; secondary to the nuclear pool. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL neddylation-pathway context; FBXL3 is predominantly nuclear. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome curation of cytosolic localization (NEDD8:UBE2M binds CRL1). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRL). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome curation of cytosolic localization (COMMDs displace CAND1). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates CRL). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome curation of cytosolic localization (DCUN1D3 binds CRL1). Generic CRL-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub). Generic ubiquitination-pathway localization. action: KEEP_AS_NON_CORE reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0005829 label: cytosol evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity assignment of cytosolic localization. A secondary compartment. action: KEEP_AS_NON_CORE reason: Cytoplasmic pool documented but secondary to the predominantly nuclear localization. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear. - term: id: GO:0016567 label: protein ubiquitination evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity assignment of protein ubiquitination, a parent of the specific SCF-dependent CRY ubiquitination. action: KEEP_AS_NON_CORE reason: Correct but generic; the SCF-dependent catabolic process annotation better captures the role. supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0043153 label: entrainment of circadian clock by photoperiod evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity assignment of circadian entrainment. FBXL3 sets clock period; the broader regulation of circadian rhythm term is more apt. action: KEEP_AS_NON_CORE reason: FBXL3 governs the oscillator, but the narrower photoperiod-entrainment framing is secondary to its core period-setting role. supported_by: - reference_id: PMID:17463251 supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity assignment of nuclear localization, the core compartment for SCF(FBXL3) function. action: ACCEPT reason: Core localization; redundant with IBA/IEA/IDA evidence. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Nucleus {ECO:0000269|PubMed:10531035} - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IDA original_reference_id: PMID:17463251 qualifier: contributes_to review: summary: Direct evidence that FBXL3, within the SCF(FBXL3) complex, contributes to ubiquitin transfer onto CRY. The contributes_to qualifier reflects FBXL3's role as the substrate-receptor subunit of the multi-subunit ligase rather than the catalytic core. action: MODIFY reason: FBXL3 is the substrate-recognition subunit; catalytic ubiquitin transfer is performed by RBX1/CUL1. The informative molecular function is ubiquitin-like ligase-substrate adaptor activity. (Activity is real within the SCF complex, hence MODIFY rather than REMOVE.) proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - reference_id: file:human/FBXL3/FBXL3-deep-research-falcon.md supporting_text: 'FBXL3 is an **F-box protein** that specifies substrate recognition within an SCF-type cullin-RING ligase, i.e., **SCF^FBXL3 = SKP1–CUL1–RBX1–FBXL3**, where SKP1 binds the **F-box domain** and FBXL3’s **LRR domain** mediates substrate recognition' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:17463251 qualifier: part_of review: summary: Direct evidence that FBXL3 is part of the SCF (SKP1-CUL1-F-box) E3 ligase complex. Core cellular component. action: ACCEPT reason: Core cellular component; FBXL3 is the F-box substrate receptor of the SCF(FBXL3) complex. supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:17463251 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL3) drives proteasomal degradation of CRY1/CRY2. Core biological process. action: ACCEPT reason: Core biological process directly demonstrated; FBXL3 targets CRY for SCF-dependent degradation. supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex - term: id: GO:0042752 label: regulation of circadian rhythm evidence_type: IMP original_reference_id: PMID:17463251 qualifier: involved_in review: summary: Mutant-phenotype evidence (Fbxl3 silencing, Cry-null epistasis) that FBXL3 controls circadian clock oscillation. Core biological process. action: ACCEPT reason: Core biological process with direct IMP support; Fbxl3 silencing has no effect in Cry1/Cry2-null cells, demonstrating it acts via CRY degradation. supported_by: - reference_id: PMID:17463251 supporting_text: Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins - term: id: GO:0016567 label: protein ubiquitination evidence_type: NAS original_reference_id: PMID:10531035 qualifier: involved_in review: summary: Author-statement assignment (original F-box family paper) of involvement in protein ubiquitination. Generic but correct. action: KEEP_AS_NON_CORE reason: Correct but generic; the SCF-dependent catabolic process annotation better captures the role. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0000151 label: ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:10531035 qualifier: part_of review: summary: Author-statement assignment of being part of a ubiquitin ligase complex. A generic parent of the specific SCF complex. action: KEEP_AS_NON_CORE reason: Correct but generic; subsumed by the specific SCF ubiquitin ligase complex annotation. supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL3) - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: NAS original_reference_id: PMID:10531035 qualifier: enables review: summary: Author-statement assignment of ubiquitin-protein transferase activity from the original F-box family paper. As the F-box substrate receptor, FBXL3 does not itself catalyze ubiquitin transfer. action: MODIFY reason: FBXL3 is the substrate-recognition subunit, not the catalytic core; the informative molecular function is ubiquitin-like ligase-substrate adaptor activity. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXL3/FBXL3-uniprot.txt supporting_text: Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex 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:10531035 title: Identification of a family of human F-box proteins. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Original identification of FBXL3 as an F-box protein; source of nuclear/cytoplasmic localization and generic ubiquitin ligase complex / transferase NAS annotations. Full text not in cache. - id: PMID:17463251 title: SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. findings: - statement: CRY1 and CRY2 are ubiquitinated and degraded by the SCF(Fbxl3) ubiquitin ligase complex; this is a prerequisite for timely reactivation of CLOCK-BMAL1; Fbxl3 silencing has no effect in Cry1/Cry2-null cells, showing FBXL3 controls clock oscillations via CRY degradation. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Foundational study establishing SCF(FBXL3) as the E3 ligase that degrades CRY1/CRY2 to set circadian period. Abstract-only in cache but supports MF/BP/CC core annotations. - id: PMID:23503662 title: SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket. findings: - statement: Crystal structures of CRY2 (apo, FAD-bound, and FBXL3-SKP1-complexed) show FBXL3 captures CRY2 by inserting a conserved C-terminal tail into the FAD-binding pocket and burying the PER-binding interface; this interaction is displaced by FAD and PERs. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Structural basis of FBXL3-CRY2 substrate recognition; source of the FBXL3-CRY2 interaction annotation. Abstract-only in cache. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map; source of a bare protein binding annotation. - id: PMID:33234069 title: 'The FBXL family of F-box proteins: variations on a theme.' findings: - statement: Review of the FBXL family describing FBXL3 as an SCF substrate receptor mediating SCF-dependent proteasomal degradation of its targets. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Full text available; family review supporting the SCF-dependent catabolic process annotation. - id: Reactome:R-HSA-8952618 title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8952620 title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-8955241 title: CAND1 binds cytosolic CRL E3 ubiquitin ligases findings: [] - id: Reactome:R-HSA-8955289 title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956040 title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes findings: [] - id: Reactome:R-HSA-8956200 title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex findings: [] - id: Reactome:R-HSA-983140 title: Transfer of Ub from E2 to substrate and release of E2 findings: [] - id: Reactome:R-HSA-983147 title: Release of E3 from polyubiquitinated substrate findings: [] - id: Reactome:R-HSA-983156 title: Polyubiquitination of substrate findings: [] - id: Reactome:R-HSA-983157 title: Interaction of E3 with substrate and E2-Ub complex findings: [] - id: file:human/FBXL3/FBXL3-deep-research-falcon.md title: Falcon deep research report for human FBXL3 findings: - statement: FBXL3 is the substrate-recognition subunit of the nuclear SCF(FBXL3) (SKP1-CUL1-RBX1-FBXL3) E3 ligase, where SKP1 binds the F-box domain and the LRR domain recognizes the CRY substrates that are degraded to control the circadian transcription-translation feedback loop. supporting_text: 'FBXL3 is an **F-box protein** that specifies substrate recognition within an SCF-type cullin-RING ligase, i.e., **SCF^FBXL3 = SKP1–CUL1–RBX1–FBXL3**, where SKP1 binds the **F-box domain** and FBXL3’s **LRR domain** mediates substrate recognition' - statement: SCF(FBXL3) assembly is substrate-driven - FBXL3 does not robustly associate with SKP1/CUL1 unless its substrate CRY1 is present, so CRY availability gates ligase assembly and activity. supporting_text: 'In transfected mammalian cells, FBXL3 did not substantially associate with SKP1/CUL1 unless its substrate **CRY1** was expressed; a CRY1-binding-defective FBXL3 mutant failed to form the SCF complex in vivo, supporting a substrate-dependent assembly mechanism' - statement: FBXL3 catalyzes K48-linked polyubiquitin chain elongation on CRY proteins (reported across ~11 lysines on CRY1), targeting them for proteasomal degradation more efficiently than the antagonistic paralog FBXL21. supporting_text: A recent Endocrinology review states that FBXL3 catalyzes elongation of **K48-linked polyubiquitin** chains on CRYs, consistent with canonical proteasome-targeting ubiquitin signals - statement: Disrupting the FBXL3-CRY interaction stabilizes the CRY repressors and lengthens circadian period (to ~26-27 h), directly linking FBXL3-mediated CRY degradation kinetics to clock period; the FBXL3-occupied CRY FAD pocket is a validated small-molecule (KL001-class) target. supporting_text: Mutations that disrupt FBXL3–CRY binding stabilize CRYs and can lengthen circadian period; one review reports in vivo period lengthening to **~26–27 h** in FBXL3 mutant contexts reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: Falcon (Edison Scientific) deep-research synthesis. Treated as leads cross-checked against UniProt and the foundational experimental papers (PMID:17463251 CRY degradation; PMID:23503662 FAD-pocket capture structure). Core circadian SCF-receptor mechanism is corroborated by those sources. Falcon cites author-year/DOIs (xing2013, yumimoto2013, calloni2023) not PMIDs and is not independently PubMed-verified, so marked UNVERIFIED. core_functions: - description: Functions as the substrate-recognition (F-box) subunit of the nuclear SCF (SKP1-CUL1-RBX1-FBXL3) cullin-RING E3 ubiquitin ligase that recruits the cryptochrome repressors CRY1 and CRY2 for polyubiquitination and proteasomal degradation, thereby setting the period and robustness of the mammalian circadian clock. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:17463251 supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex directly_involved_in: - id: GO:0042752 label: regulation of circadian rhythm - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: Recognizes cryptochrome substrates through a structurally defined mechanism in which a conserved FBXL3 C-terminal tail occupies the CRY FAD-binding pocket and buries the CRY PER-binding interface, a substrate interaction antagonized by FAD and the Period proteins. Substrate (CRY1) binding itself promotes assembly of the SCF(FBXL3) holocomplex, and FBXL3 elongates K48-linked polyubiquitin chains on CRY; this activity is counterbalanced by the paralogous SCF(FBXL21) ligase, which binds CRY more strongly but ubiquitinates it less efficiently, thereby stabilizing CRY. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005634 label: nucleus supported_by: - reference_id: PMID:23503662 supporting_text: the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface - reference_id: file:human/FBXL3/FBXL3-deep-research-falcon.md supporting_text: 'In transfected mammalian cells, FBXL3 did not substantially associate with SKP1/CUL1 unless its substrate **CRY1** was expressed; a CRY1-binding-defective FBXL3 mutant failed to form the SCF complex in vivo, supporting a substrate-dependent assembly mechanism' directly_involved_in: - id: GO:0042752 label: regulation of circadian rhythm proposed_new_terms: [] suggested_questions: - question: How is the balance between SCF(FBXL3)-mediated CRY degradation and SCF(FBXL21)-mediated CRY stabilization spatially and temporally regulated to tune circadian period? - question: Beyond CRY1/CRY2, does FBXL3 have physiologically important substrates that explain the human FBXL3 loss-of-function phenotype (intellectual developmental disorder with short stature)? suggested_experiments: - description: Reconstitute SCF(FBXL3)-mediated CRY2 ubiquitination in vitro with purified SKP1, CUL1, RBX1, an E2, and wild-type versus C-terminal-tail or pocket-mutant FBXL3, and titrate FAD and PER proteins to quantify how cofactor and competitor occupancy controls substrate ubiquitination. - description: Perform time-resolved quantitative proteomics in FBXL3-knockout versus wild-type cells across the circadian cycle to confirm CRY1/CRY2 as the dominant rhythmic substrates and to identify any additional FBXL3 targets relevant to the developmental disorder phenotype.