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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt ZN_FING 48..109 |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000002 | MODIFY | 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. 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 replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: High-throughput affinity-purification interactome (BioPlex) capturing the FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation guidelines. Reason: Records a real interactor (MYO6) detected in a large-scale interactome, but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Q8TB52; Q9UM54: MYO6 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific proteome-scale interactome (BioPlex) again capturing the FBXO30-MYO6 interaction. Bare protein binding is uninformative per curation guidelines. Reason: Records the same MYO6 interaction from a high-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Q8TB52; Q9UM54: MYO6 |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | 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. Reason: Correct but generic; the more specific GO:0031146 (SCF-dependent proteasomal ubiquitin-dependent protein catabolic process) better captures the biological role. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | 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. 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. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Part of a SCF (SKP1-cullin-F-box) protein ligase complex. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | 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. 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. Supporting Evidence: file:human/FBXO30/FBXO30-uniprot.txt Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. file:human/FBXO30/FBXO30-deep-research-falcon.md Human work directly demonstrates FBXO30-mediated ubiquitylation of **RARΞ³** and proteasome-dependent regulation of **HIF-1Ξ±** |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | 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. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome (TAS) cytosolic localization derived from a generic CRL1/ neddylation pathway reaction (NEDD8:AcM-UBE2M binds CRL1). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (CAND1 binds cytosolic CRL E3 ligases). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | 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. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome (TAS) cytosolic localization derived from a generic CRL cycle reaction (COP9 signalosome deneddylates cytosolic CRL complexes). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome (TAS) cytosolic localization derived from a generic CRL1 reaction (MyrG-DCUN1D3 binds CRL1 complex). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (transfer of Ub from E2 to substrate). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (release of E3 from polyubiquitinated substrate). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome (TAS) cytosolic localization derived from a generic ubiquitination reaction (polyubiquitination of substrate). Plausible but generic pathway-context localization. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | 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. Reason: Generic Reactome neddylation/CRL-cycle pathway location; plausible cytosolic localization but not specific to FBXO30 and subsidiary to the SCF complex annotation. |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: 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).
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