id: Q8TB52 gene_symbol: FBXO30 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXO30 (F-box only protein 30) is a 745-residue F-box "other" (FBXO) protein that serves as a substrate-recognition component of an SCF (SKP1-CUL1-F-box protein)-type, cullin-RING ligase 1 (CRL1) E3 ubiquitin ligase complex. Its C-terminal F-box domain (residues 610-658) docks onto SKP1, which together with CUL1 and the RING protein RBX1/ROC1 assembles the catalytic ligase; the catalytic ubiquitin-transfer activity resides in the RBX1/RING subunit rather than in FBXO30 itself. The N-terminal region carries a TRAF-type zinc finger (residues 48-109) whose solution structure has been determined and which is predicted to coordinate zinc as a structural feature. Within the assembled SCF complex FBXO30 selects specific substrate proteins for polyubiquitination and subsequent proteasomal degradation, with substrates that appear strongly context- and tissue-dependent. In human cells FBXO30 is predominantly cytoplasmic and has been reported to ubiquitinate retinoic acid receptor gamma (RARG), linking retinoic-acid signaling to positive regulation of BMP signaling in neural-tube development, and to promote proteasomal degradation of HIF-1A under normoxia, acting as a candidate tumor suppressor in clear-cell renal cell carcinoma. Studies of the rodent ortholog identify additional substrates, including the mitotic kinesin Eg5/KIF11 (mammary epithelial proliferation and spindle/centrosome homeostasis) and the stem-loop binding protein SLBP (oocyte meiotic chromosome condensation and segregation), and show dynamic nuclear/cytoplasmic/spindle-associated localization through the cell and meiotic cycle. By similarity, FBXO30 has also been implicated in muscle atrophy following denervation. The protein is widely but lowly expressed, is itself subject to auto-ubiquitination and possible neddylation, and a dedicated SCF complex variant (ComplexPortal CPX-7968) is annotated. Although several candidate substrates have now been reported, individual substrate-pathway links remain based on single studies and FBXO30 is still relatively poorly characterized. existing_annotations: - term: id: GO:0008270 label: zinc ion binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Electronic (InterPro/keyword) assignment of zinc binding based on the N-terminal TRAF-type zinc finger (residues 48-109), which plausibly coordinates zinc as a structural feature. action: KEEP_AS_NON_CORE reason: The TRAF-type zinc finger plausibly binds zinc, but this is a structural attribute of one domain and is subsidiary to the protein's role as an SCF substrate-recognition adaptor; not a standalone core function. supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: ZN_FING 48..109 - term: id: GO:0061630 label: ubiquitin protein ligase activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Electronic (InterPro) assignment of ubiquitin protein ligase activity. As an F-box protein, FBXO30 is the substrate-recognition adaptor of the SCF complex and is not the catalytic ligase; the ubiquitin-transfer activity resides in the RBX1/RING subunit. This is a common over-propagation of ligase activity onto F-box adaptors. action: MODIFY reason: F-box proteins are substrate-recognition adaptors, not catalytic ligases; the catalytic activity resides in RBX1/RING. The substrate-adaptor activity term better captures FBXO30's molecular function. proposed_replacement_terms: - id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 qualifier: enables review: summary: High-throughput affinity-purification interactome (BioPlex) capturing the FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation guidelines. action: KEEP_AS_NON_CORE reason: Records a real interactor (MYO6) detected in a large-scale interactome, but bare protein binding is uninformative and not a core function. supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: 'Q8TB52; Q9UM54: MYO6' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Cell-specific proteome-scale interactome (BioPlex) again capturing the FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation guidelines. action: KEEP_AS_NON_CORE reason: Records the same MYO6 interaction from a high-throughput interactome; bare protein binding is uninformative and not a core function. supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: 'Q8TB52; Q9UM54: MYO6' - term: id: GO:0016567 label: protein ubiquitination evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: UniPathway-derived electronic assignment of the general protein ubiquitination process, a parent of the specific SCF-dependent ubiquitination/ proteasomal degradation process in which FBXO30 participates. action: KEEP_AS_NON_CORE reason: Correct but generic; the more specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent protein catabolic process) better captures the biological role. supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: NAS original_reference_id: PMID:34445249 qualifier: part_of review: summary: ComplexPortal (NAS) assignment that FBXO30 is part of an SCF (SKP1-CUL1-F-box) E3 ubiquitin ligase complex, the core cellular localization for an F-box substrate-recognition protein. A dedicated complex variant (CPX-7968) is annotated. action: ACCEPT reason: Core localization; FBXO30 assembles into the SCF complex via its F-box domain binding SKP1, consistent with UniProt and the dedicated ComplexPortal SCF FBXO30 variant. supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex. - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:34445249 qualifier: involved_in review: summary: ComplexPortal (NAS) assignment of the SCF-dependent proteasomal ubiquitin-dependent protein catabolic process, the core biological process for an SCF substrate-recognition receptor that targets substrates for proteasomal degradation. action: ACCEPT reason: Core biological process; as the substrate-recognition component of an SCF/CRL1 ligase, FBXO30 directs substrates into SCF-dependent proteasomal degradation. Falcon-sourced literature grounds this with specific reported substrates (human RARG and HIF-1A; mouse Eg5/KIF11 and SLBP), consistent with the functional placement of FBXO30 as an F-box/SCF (CRL1) substrate-recognition receptor; individual substrate-pathway links remain single-study and are not promoted to substrate-specific GO terms here. supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: file:human/FBXO30/FBXO30-deep-research-falcon.md supporting_text: Human work directly demonstrates FBXO30-mediated ubiquitylation of **RARγ** and proteasome-dependent regulation of **HIF-1α** - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952618 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic CRL1/ neddylation pathway reaction (AcM-UBE2M transfers NEDD8 to CRL1). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8952620 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic CRL1/ neddylation pathway reaction (NEDD8:AcM-UBE2M binds CRL1). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955241 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (CAND1 binds cytosolic CRL E3 ligases). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8955289 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (COMMDs displace CAND1 from cytosolic CRL complexes). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956040 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8956200 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic CRL1 reaction (MyrG-DCUN1D3 binds CRL1 complex). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983140 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983147 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983156 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (polyubiquitination of substrate). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-983157 qualifier: located_in review: summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (interaction of E3 with substrate and E2-Ub complex). Plausible but generic pathway-context localization. action: KEEP_AS_NON_CORE reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput affinity-purification interactome (BioPlex); source of the bare protein binding annotation (FBXO30-MYO6, MYO6=Q9UM54). - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Cell-specific proteome-scale interactome (BioPlex); source of the bare protein binding annotation (FBXO30-MYO6, MYO6=Q9UM54). - id: PMID:34445249 title: The SCF Complex Is Essential to Maintain Genome and Chromosome Stability. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-verified (Int J Mol Sci 2021, PMC8395177); abstract-only in cache. General review of SCF/CRL1 complex biology used by ComplexPortal as the NAS basis for the SCF-complex (GO:0019005) and SCF-dependent catabolic-process (GO:0031146) annotations. Supports the family-level SCF framing rather than FBXO30-specific function. - 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/FBXO30/FBXO30-deep-research-falcon.md title: Falcon deep research report for human FBXO30 findings: - statement: FBXO30 is a substrate-recognition F-box adaptor of SCF/CUL1-RING ubiquitin ligase complexes, conferring specificity for ubiquitin-dependent proteasomal turnover rather than catalyzing a small-molecule reaction. supporting_text: it is not an enzyme that catalyzes a small-molecule reaction; rather, it confers target specificity for **ubiquitylation leading to proteasomal degradation**. - statement: In human cells FBXO30 ubiquitinates RARG, positively regulating BMP signaling, and promotes proteasomal degradation of HIF-1A. supporting_text: Human work directly demonstrates FBXO30-mediated ubiquitylation of **RARγ** and proteasome-dependent regulation of **HIF-1α** - statement: FBXO30 is predominantly cytoplasmic in human cells and colocalizes with its RARG substrate. supporting_text: A human study reports FBXO30 is **predominantly cytoplasmic**, and FBXO30 and RARγ show **cytoplasmic colocalization** by immunofluorescence - statement: In the mouse ortholog FBXO30 binds SKP1 and CUL1 and ubiquitinates the mitotic kinesin Eg5/KIF11 and the stem-loop binding protein SLBP. supporting_text: Fbxo30 physically associates with **Skp1 and Cul1** and targets the mitotic kinesin **Eg5/KIF11** for ubiquitin-dependent regulation. reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: Edison/Falcon LLM-generated synthesis citing author-year/DOIs (Cheng 2019 Cell Death Dis; Yuan 2023 Int J Oncol; Liu 2016 Cell Rep; Jin 2019 Cell Mol Life Sci). Substrate claims (RARG, HIF-1A human; Eg5/KIF11, SLBP mouse) are leads consistent with UniProt SCF-adaptor framing but were not independently re-verified against full text here; treat as hypothesis-grounding, not as basis for new substrate-specific GO terms. core_functions: - description: Substrate-recognition (substrate-adaptor) component of an SCF (SKP1-CUL1-F-box protein)/CRL1-type E3 ubiquitin ligase complex; via its F-box domain FBXO30 binds SKP1 and, within the assembled SCF complex (with CUL1 and catalytic RBX1/RING), selects substrate proteins for polyubiquitination and SCF-dependent proteasomal degradation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. - reference_id: file:human/FBXO30/FBXO30-uniprot.txt supporting_text: Part of a SCF (SKP1-cullin-F-box) protein ligase complex. directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process proposed_new_terms: [] suggested_questions: - question: Are the reported FBXO30 substrates (human RARG and HIF-1A; mouse Eg5/KIF11 and SLBP) bona fide direct SCF(FBXO30) substrates in human cells, and do they reflect a unified molecular activity or genuinely context- and tissue-dependent substrate repertoires? Is the high-throughput interactor MYO6 a substrate? - question: Does the same substrate-recognition activity underlie FBXO30's distinct reported roles (BMP/retinoic-acid signaling in neural-tube development, HIF-1A turnover and tumor suppression in renal carcinoma, mitotic/meiotic spindle and chromosome homeostasis), and how is its dynamic nuclear/cytoplasmic/spindle localization regulated through the cell and meiotic cycle? - question: Is the reported role of FBXO30 in muscle atrophy following denervation a direct consequence of its SCF substrate-recognition activity, and which substrate mediates it? suggested_experiments: - description: Identify FBXO30 SCF substrates by affinity purification or proximity labeling coupled to quantitative proteomics, comparing wild-type versus F-box-deleted FBXO30 and proteasome-inhibited cells to enrich for stabilized substrates, and test the reported substrates (RARG, HIF-1A, Eg5/KIF11, SLBP) for direct, F-box/SKP1-dependent ubiquitination. - description: Validate physical incorporation of FBXO30 into the SCF complex by co-immunoprecipitation / reconstitution of SKP1, CUL1 and RBX1 binding, and test F-box-domain mutants to confirm the SKP1-dependent adaptor interaction. - description: Determine FBXO30 subcellular localization across the cell and meiotic cycle (live-cell imaging, fractionation) and correlate cytoplasmic versus spindle/nuclear pools with degradation of specific substrates (e.g. RARG vs Eg5).