FBXO7 (also called FBX7; PARK15) is the substrate-recognition (F-box) component of an SCF (SKP1-CUL1-RBX1-F-box) E3 ubiquitin-protein ligase complex, SCF(FBXO7). As an F-box protein it acts as a ligase-substrate adaptor: it recruits substrates and bridges them, via its F-box domain binding to SKP1, to the catalytic cullin-RING core (RBX1), and is not itself the catalytic ubiquitin transferase. The protein has a modular architecture comprising an N-terminal ubiquitin-like (Ubl) region that mediates binding to the E3 ligase PRKN/Parkin, a CDK6-interaction region, an FP (Fbxo7/PI31) dimerization domain that mediates homodimerization and interaction with the proteasome inhibitor PSMF1/PI31, the F-box domain, and a C-terminal proline-rich region that serves as a substrate-binding module. SCF(FBXO7) ubiquitination is not exclusively degradative: it can build K48-linked chains that target substrates for proteasomal degradation or K63-linked chains with non-proteolytic signaling/assembly outcomes, depending on substrate and context. Documented SCF(FBXO7) substrates include the cell-cycle regulator DLGAP5/HURP, the inhibitor-of-apoptosis protein BIRC2/cIAP1, TRAF2 and the NF-kappa-B cofactor UXT isoform 2 (whose degradation inhibits NF-kappa-B signaling), the NAD+-dependent deacetylase SIRT7 (K48- linked polyubiquitination promoting H2O2-induced cell death), the kinase GSK3-beta and the mitochondrial import receptor TOMM20 (modified in part with non-degradative chains), and, in tumor-suppressor contexts, the mitochondrial-fission factor INF2 and the arginine methyltransferase PRMT1 (K48-linked polyubiquitination coupling FBXO7 to control of mitochondrial division and serine biosynthesis, respectively). Beyond canonical SCF activity, FBXO7 has SCF-independent roles: it relocates from the cytosol to depolarized mitochondria downstream of PINK1 and promotes PRKN/Parkin recruitment and mitofusin ubiquitination to drive selective autophagy of damaged mitochondria (mitophagy); it associates with the proteasome and regulates proteasome assembly/activity through PSMF1/PI31; and it activates cyclin D/CDK6 complexes to promote cell-cycle progression, with proto-oncogenic transforming activity. FBXO7 protein stability is itself controlled by the deubiquitinase USP7. FBXO7 is predominantly cytoplasmic/cytosolic with a minor nuclear pool. Recessive loss-of-function and missense mutations (e.g. T22M, R378G, R498X) cause early-onset autosomal recessive parkinsonian-pyramidal syndrome (Parkinson disease 15, PARK15).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:1903599 positive regulation of autophagy of mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of a positive role in mitophagy, consistent with the experimentally demonstrated FBXO7 function downstream of PINK1 in Parkin-mediated mitophagy. Reason: Core biological process; the IBA inference agrees with direct IMP/IDA evidence (PMID:23933751, PMID:26310625) that FBXO7 promotes clearance of depolarized mitochondria. Supporting Evidence: PMID:23933751 Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. file:human/FBXO7/FBXO7-deep-research-falcon.md FBXO7 participates in mitochondrial quality control by interacting with **PINK1 and Parkin** and facilitating Parkin recruitment to damaged mitochondria in PARK15 biology. |
| GO:0019901 protein kinase binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment of protein kinase binding, reflecting the documented FBXO7 interactions with the kinases CDK6 and PINK1. Reason: Real and mechanistically meaningful (CDK6 activation of cyclin D complexes; PINK1 in the mitophagy pathway) but a subsidiary binding activity rather than the core adaptor function. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Interacts with CDK6 and promotes its interaction with D-type cyclin. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic assignment of nuclear localization; FBXO7 has a documented minor nuclear pool in addition to its predominant cytoplasmic localization. Reason: Nuclear localization is real but minor; the predominant and functionally dominant compartment is the cytoplasm/cytosol. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt A minor proportion is detected in the nucleus (PubMed:16096642). |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; the predominant compartment of FBXO7. Reason: Correct predominant localization, supported experimentally (PMID:16096642, PMID:18495667). Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Note=Predominantly cytoplasmic (PubMed:16096642). |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic assignment of mitochondrial localization, consistent with the experimentally observed relocation of FBXO7 from the cytosol to depolarized mitochondria. Reason: Correct conditional localization; FBXO7 relocates to depolarized mitochondria during mitophagy (PMID:23933751). IEA (GO_REF:0000120) from UniProt keyword SL-0173 with mouse Q3U7U3 orthology; the keyword rests on the curated human location, so the mapping is faithful. ORGANELLES check (2026-10-25). The organelle claim is supported directly in human cells (CCCP-induced shift of endogenous FBXO7 from cytosolic to mitochondrial fractions in HEK293T and SH-SY5Y cells, PMID:23933751; stress-induced mitochondrial aggregates, PMID:26310625), and UniProt curates Mitochondrion from PMID:23933751. No sub-compartment row, because the lines disagree. The mitophagy role (binding PINK1 and Parkin, Parkin recruitment, Mfn1 ubiquitination) places the recruited pool on the cytosolic face of the outer membrane, as for TRAF3 and BRAF, but no protease-protection or sub-mitochondrial fractionation was done; the predicted N-terminal MTS (Arg-2, Arg-6) needed for fraction association (isoform 1) has no cleavage or import assay; and PMID:26310625 describes FBXO7 concentrating into mitochondria, which would imply import. FBXO7 has no TM segment and is not in MitoCarta3.0. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Relocates from the cytosol to depolarized mitochondria (PubMed:23933751). |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytosolic localization from the UniProt subcellular location; the predominant compartment of FBXO7. Reason: Correct core localization, supported experimentally (PMID:23933751). Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0019901 protein kinase binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic assignment of protein kinase binding, reflecting documented CDK6 and PINK1 interactions. Reason: Real binding activity (CDK6, PINK1) but subsidiary to the core ligase-substrate adaptor function. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Interacts with CDK6 and promotes its interaction with D-type cyclin. |
| GO:0005515 protein binding | IPI PMID:16278047 Characterization of FBX25, encoding a novel brain-expressed ... | KEEP AS NON CORE | Summary: Interaction captured during characterization of a related brain-expressed F-box protein (FBX25). Bare protein binding is uninformative. Reason: Records a real interaction but the bare protein binding term is uninformative per curation guidelines. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:22632967 Cyclin F-mediated degradation of ribonucleotide reductase M2... | KEEP AS NON CORE | Summary: Interaction captured in a cyclin F (FBXO1)/RRM2 study. Bare protein binding is uninformative. Reason: Records a real interaction but bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | KEEP AS NON CORE | Summary: Interaction with PRKN/Parkin (and PINK1) from the mitophagy study; a functionally important interaction, but the bare protein binding term is uninformative. Reason: Records the meaningful FBXO7-PRKN/PINK1 interaction, but bare protein binding is uninformative; the functional relationship is captured by the mitophagy process annotations. Supporting Evidence: PMID:23933751 the Ubl domain of Fbxo7 directly mediates Parkin interaction |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: High-throughput proteome-scale interactome mapping. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | KEEP AS NON CORE | Summary: High-throughput interactome perturbation study. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | KEEP AS NON CORE | Summary: High-throughput quantitative interactome map. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: High-throughput Polycomb complexome interaction map. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: High-throughput interactome (protein communities/disease networks). Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | KEEP AS NON CORE | Summary: High-throughput variant-interactome disruption study. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: High-throughput neurodegenerative-disease interactome map. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: High-throughput dual proteome-scale interactome map. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: High-throughput multimodal cell-map interactome. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex |
| GO:1901526 positive regulation of mitophagy | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-based electronic assignment of positive regulation of mitophagy, consistent with the experimentally established FBXO7 mitophagy role. Reason: Core biological process; agrees with direct experimental evidence (PMID:23933751, PMID:26310625). Supporting Evidence: PMID:26310625 The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-derived general protein ubiquitination process, a parent of the specific SCF-dependent catabolic process FBXO7 enables. Reason: Correct but generic; the specific GO:0031146 (SCF-dependent catabolic process) and K48-linked ubiquitination annotations better capture the role. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt PATHWAY: Protein modification; protein ubiquitination. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence assignment of nucleoplasm localization, consistent with the documented minor nuclear pool of FBXO7. Reason: Real but minor nuclear localization; the predominant compartment is the cytoplasm/cytosol. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt A minor proportion is detected in the nucleus (PubMed:16096642). |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence assignment of cytosolic localization, the predominant FBXO7 compartment. Reason: Correct core localization; supported by direct experimental fractionation (PMID:23933751). Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005634 nucleus | EXP PMID:16096642 Transforming activity of Fbxo7 is mediated specifically thro... | KEEP AS NON CORE | Summary: Experimental localization showing FBXO7 in the nucleus (minor pool) in addition to predominant cytoplasm. Reason: Real minor nuclear localization documented in this study; predominant compartment is cytoplasmic. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt A minor proportion is detected in the nucleus (PubMed:16096642). |
| GO:0005737 cytoplasm | EXP PMID:16096642 Transforming activity of Fbxo7 is mediated specifically thro... | ACCEPT | Summary: Experimental localization showing FBXO7 is predominantly cytoplasmic. Core compartment. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Note=Predominantly cytoplasmic (PubMed:16096642). |
| GO:0005737 cytoplasm | EXP PMID:18495667 Structure of a conserved dimerization domain within the F-bo... | ACCEPT | Summary: Experimental localization to the cytoplasm consistent with the predominant FBXO7 compartment. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}. |
| GO:0019005 SCF ubiquitin ligase complex | NAS PMID:34445249 The SCF Complex Is Essential to Maintain Genome and Chromoso... | ACCEPT | Summary: Author statement that FBXO7 is an F-box component of an SCF E3 ubiquitin ligase complex. Core complex membership. Reason: Core localization/complex; FBXO7 is the substrate-receptor F-box subunit of SCF(FBXO7) (CUL1, SKP1, RBX1, FBXO7). Supporting Evidence: PMID:34445249 The SKP1, CUL1, F-box protein (SCF) complex encompasses a group of 69 SCF E3 ubiquitin ligase complexes that primarily modify protein substrates with poly-ubiquitin chains to target them for proteasomal degradation. |
| 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: Author statement linking the SCF complex (including F-box proteins) to SCF-dependent proteasomal degradation. Core biological process. Reason: Core biological process; FBXO7 targets substrates for SCF-dependent proteasomal degradation. Supporting Evidence: PMID:34445249 These SCF complexes are distinguishable by variable F-box proteins, which determine substrate specificity. |
| GO:0005634 nucleus | IDA PMID:33010352 The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... | KEEP AS NON CORE | Summary: Direct evidence that FBXO7 acts in the nucleus, where it colocalizes with and ubiquitinates its substrate UXT-V2. Reason: Documents a functionally relevant nuclear pool (UXT-V2 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol. Supporting Evidence: PMID:33010352 We find that UXT-V2 colocalizes with Fbxo7 in the cell nucleus. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:33010352 The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... | ACCEPT | Summary: Direct evidence that SCF(FBXO7) mediates SCF-dependent proteasomal degradation of UXT-V2. Core biological process. Reason: Core biological process with direct experimental support; SCF(FBXO7) polyubiquitinates UXT-V2 for proteasomal degradation. Supporting Evidence: PMID:33010352 Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-ΞΊB signaling pathway. |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IDA PMID:33010352 The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... | ACCEPT | Summary: Direct evidence that SCF(FBXO7)-mediated degradation of UXT-V2 inhibits NF-kappa-B signaling. Well-supported biological process. Reason: Directly demonstrated; FBXO7 negatively regulates NF-kappa-B signaling via UXT-V2 (and TRAF2/cIAP1) ubiquitination. Supporting Evidence: PMID:33010352 Together, our study reveals that SCF(Fbxo7) mediates the proteasomal degradation of UXT-V2 causing the inhibition of the NF-ΞΊB signaling pathway. |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:33010352 The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degr... | ACCEPT | Summary: Direct evidence that SCF(FBXO7) builds K48 (and K63) polyubiquitin chains on UXT-V2. Reason: Directly demonstrated K48-linked ubiquitination of a substrate, the canonical degradative topology used by SCF(FBXO7). Supporting Evidence: PMID:33010352 This substrate is polyubiquitinated by SCF(Fbxo7) with K48 and K63 ubiquitin chain linkages in vitro and in vivo. |
| GO:1901526 positive regulation of mitophagy | IDA PMID:26310625 F-box protein 7 mutations promote protein aggregation in mit... | ACCEPT | Summary: Direct evidence that WT FBXO7 facilitates mitophagy whereas PD-linked mutants inhibit it. Core biological process. Reason: Core biological process with direct experimental support. Supporting Evidence: PMID:26310625 The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy. |
| GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IMP PMID:25029497 FBXO7 Y52C polymorphism as a potential protective factor in ... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence linking an FBXO7 variant (Y52C) to altered TRAF2 turnover and neuronal outgrowth in a PD-protective context. Reason: A context-specific neuronal stress/apoptosis-modulating role inferred from variant phenotypes, not the core SCF adaptor function. Supporting Evidence: PMID:25029497 After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth. |
| GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IDA PMID:26310625 F-box protein 7 mutations promote protein aggregation in mit... | KEEP AS NON CORE | Summary: Evidence that FBXO7 acts as a stress-response protein with cytoprotective (and, when mutant/aggregated, neurotoxic) effects under oxidative stress. Reason: A context-specific neuronal stress-response role; mechanistically downstream of the core mitophagy/proteostasis functions rather than a distinct core process. Supporting Evidence: PMID:26310625 Here we demonstrated that wild-type (WT) FBXO7 is a stress response protein and it can play both cytoprotective and neurotoxic roles. |
| GO:0005634 nucleus | IDA PMID:36646384 E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... | KEEP AS NON CORE | Summary: Direct evidence that FBXO7 colocalizes with its substrate SIRT7 mainly in the nucleus, where it acts to degrade SIRT7. Reason: Documents a functionally relevant nuclear pool (SIRT7 degradation) but nuclear localization is minor relative to the predominant cytoplasm/cytosol. Supporting Evidence: PMID:36646384 immunohistochemical analysis of SH-SY5Y cells revealed that endogenous FBXO7 and SIRT7 colocalized mainly in the nucleus |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:36646384 E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... | ACCEPT | Summary: Direct evidence that FBXO7 drives SCF-dependent proteasomal degradation of SIRT7. Core biological process. Reason: Core biological process; FBXO7 promotes proteasomal degradation of SIRT7 (the more specific GO:0031146 SCF-dependent process is also annotated). Supporting Evidence: PMID:36646384 we identified FBXO7 as a novel E3 ligase for SIRT7 that negatively regulates intracellular SIRT7 levels through SCF-dependent Lys-48-linked polyubiquitination and proteasomal degradation |
| GO:0070936 protein K48-linked ubiquitination | IDA PMID:36646384 E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... | ACCEPT | Summary: Direct evidence that FBXO7 promotes K48-linked polyubiquitination of SIRT7. Reason: Directly demonstrated K48-linked ubiquitination of a substrate (SIRT7), the canonical degradative topology of SCF(FBXO7). Supporting Evidence: PMID:36646384 These results demonstrated that FBXO7 directly mediates the polyubiquitination of SIRT7 by targeting K48-linked polyubiquitin chains. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:36646384 E3 ligase adaptor FBXO7 contributes to ubiquitination and pr... | ACCEPT | Summary: Direct evidence that FBXO7 acts as an SCF substrate-recognition adaptor recruiting SIRT7 for ubiquitination. Core molecular function. Reason: Core molecular function; FBXO7 is the substrate-recognition adaptor of SCF(FBXO7), bridging substrates to the catalytic cullin-RING core. Supporting Evidence: PMID:36646384 FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates. |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:15145941 Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... | ACCEPT | Summary: Direct evidence that FBXO7 functions within an SCF(FBXO7) complex (with SKP1 and CUL1) to ubiquitinate HURP/DLGAP5. Core complex membership. Reason: Core localization/complex; FBXO7 is a functional F-box subunit of an SCF ubiquitin-ligase complex. Supporting Evidence: PMID:15145941 In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:15145941 Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... | ACCEPT | Summary: Direct evidence that FBXO7 functions as a substrate-recruiting adaptor of the SCF complex, binding HURP via its proline-rich region. Core molecular function. Reason: Core molecular function; FBXO7 is a functional SCF adaptor with the proline-rich region serving as the substrate-binding module. Supporting Evidence: PMID:15145941 Thus, Fbx7 is a functional adaptor of the SCF complex with a proline-rich region as the substrate-binding module. |
| GO:0005515 protein binding | IPI PMID:21378169 A Competitive binding mechanism between Skp1 and exportin 1 ... | KEEP AS NON CORE | Summary: Interaction captured in a study of SKP1/CRM1 competition controlling F-box protein localization. Bare protein binding is uninformative. Reason: Records a real interaction relevant to FBXO7 nuclear/cytoplasmic shuttling (SKP1, CRM1) but bare protein binding is uninformative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7. |
| GO:0005739 mitochondrion | IDA PMID:26310625 F-box protein 7 mutations promote protein aggregation in mit... | ACCEPT | Summary: Direct evidence that FBXO7 concentrates into mitochondria upon stress, forming aggregates. Conditional/stress-induced localization. Reason: Correct conditional localization; FBXO7 relocates to mitochondria under stress/depolarization, consistent with its mitophagy role. ORGANELLES check (2026-10-25). The organelle claim is supported directly in human cells (CCCP-induced shift of endogenous FBXO7 from cytosolic to mitochondrial fractions in HEK293T and SH-SY5Y cells, PMID:23933751; stress-induced mitochondrial aggregates, PMID:26310625), and UniProt curates Mitochondrion from PMID:23933751. No sub-compartment row, because the lines disagree. The mitophagy role (binding PINK1 and Parkin, Parkin recruitment, Mfn1 ubiquitination) places the recruited pool on the cytosolic face of the outer membrane, as for TRAF3 and BRAF, but no protease-protection or sub-mitochondrial fractionation was done; the predicted N-terminal MTS (Arg-2, Arg-6) needed for fraction association (isoform 1) has no cleavage or import assay; and PMID:26310625 describes FBXO7 concentrating into mitochondria, which would imply import. FBXO7 has no TM segment and is not in MitoCarta3.0. Supporting Evidence: PMID:26310625 Upon stress, the endogenous WT FBXO7 gets up-regulated, concentrates into mitochondria and forms FBXO7 aggregates in mitochondria. |
| GO:0005515 protein binding | IPI PMID:25029497 FBXO7 Y52C polymorphism as a potential protective factor in ... | KEEP AS NON CORE | Summary: Interaction with TRAF2 captured in the FBXO7 Y52C polymorphism study. Bare protein binding is uninformative. Reason: Records the functionally meaningful FBXO7-TRAF2 interaction but bare protein binding is uninformative; the substrate relationship is captured by the ubiquitination/NF-kappa-B annotations. Supporting Evidence: PMID:25029497 Moreover, Cys52 FBXO7 showed stronger interaction with TRAF2 and promoted TRAF2 ubiquitination |
| GO:0005634 nucleus | IDA PMID:16510124 The F-box protein Fbxo7 interacts with human inhibitor of ap... | KEEP AS NON CORE | Summary: Direct evidence of FBXO7 nuclear localization (colocalized with cIAP1/BIRC2 in cytoplasm and nucleus). Minor nuclear pool. Reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol. Supporting Evidence: PMID:16510124 When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus |
| GO:0005634 nucleus | IDA PMID:25029497 FBXO7 Y52C polymorphism as a potential protective factor in ... | KEEP AS NON CORE | Summary: Direct evidence of FBXO7 nuclear localization, consistent with the documented minor nuclear pool. Reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt A minor proportion is detected in the nucleus (PubMed:16096642). |
| GO:0005737 cytoplasm | IDA PMID:16510124 The F-box protein Fbxo7 interacts with human inhibitor of ap... | ACCEPT | Summary: Direct evidence of FBXO7 cytoplasmic localization (colocalized with cIAP1/BIRC2). Core compartment. Reason: Core localization with direct experimental support. Supporting Evidence: PMID:16510124 When co-expressed in cells, cIAP1 and Fbxo7 co-localized remarkably both in the cytoplasm and nucleus |
| GO:0005737 cytoplasm | IDA PMID:25029497 FBXO7 Y52C polymorphism as a potential protective factor in ... | ACCEPT | Summary: Direct evidence of FBXO7 cytoplasmic localization. Core compartment. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Note=Predominantly cytoplasmic (PubMed:16096642). |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:25029497 FBXO7 Y52C polymorphism as a potential protective factor in ... | KEEP AS NON CORE | Summary: Direct evidence that FBXO7 promotes ubiquitination and turnover of TRAF2. A parent of the more specific SCF-dependent catabolic process. Reason: Correct but generic relative to the specific GO:0031146 (SCF-dependent proteasomal catabolic process); here the substrate is TRAF2. Supporting Evidence: PMID:25029497 In cells expressing Cys52 FBXO7, the level of TNF receptor-associated factor 2 (TRAF2) was significantly reduced. |
| GO:0010975 regulation of neuron projection development | IMP PMID:25029497 FBXO7 Y52C polymorphism as a potential protective factor in ... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that an FBXO7 variant alters neuronal outgrowth in differentiated SH-SY5Y cells. Reason: A context-specific neuronal phenotype linked to an FBXO7 variant, not the core SCF adaptor function. Supporting Evidence: PMID:25029497 After induced differentiation, SH-SY5Y cells expressing Cys52 FBXO7 displayed increased neuronal outgrowth. |
| GO:0016567 protein ubiquitination | IDA PMID:16510124 The F-box protein Fbxo7 interacts with human inhibitor of ap... | KEEP AS NON CORE | Summary: Direct evidence that FBXO7 overexpression promotes ubiquitination of cIAP1/BIRC2. Generic parent process. Reason: Correct but generic; the specific SCF-dependent catabolic process (GO:0031146) better captures the role. The cIAP1/BIRC2 substrate relationship is meaningful. Supporting Evidence: PMID:16510124 Furthermore, we showed that overexpression of Fbxo7 promotes the ubiquitination of cIAP1. |
| GO:0019901 protein kinase binding | IPI PMID:18495667 Structure of a conserved dimerization domain within the F-bo... | KEEP AS NON CORE | Summary: Interaction with the kinase CDK6 (and PSMF1) documented in the FP-domain structural study. Reason: Real CDK6 binding (FBXO7 activates cyclin D-CDK6) but subsidiary to the core adaptor function. Supporting Evidence: PMID:18495667 SCF(Fbxo7) is known to catalyze the ubiquitination of hepatoma-up-regulated protein (HURP) and the inhibitor of apoptosis (IAP) protein but also functions as an activator of cyclin D-Cdk6 complexes. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:16510124 The F-box protein Fbxo7 interacts with human inhibitor of ap... | KEEP AS NON CORE | Summary: Interaction with the ubiquitin ligase cIAP1/BIRC2 (itself a RING E3) documented as an FBXO7 substrate interaction. Reason: Records a real interaction with a ubiquitin ligase substrate (BIRC2) but is subsidiary to the core adaptor function. Supporting Evidence: PMID:16510124 we performed a yeast two-hybrid screen and identified an F-box protein Fbxo7 as a cIAP1 interacting protein. |
| GO:0043130 ubiquitin binding | IDA PMID:25029497 FBXO7 Y52C polymorphism as a potential protective factor in ... | KEEP AS NON CORE | Summary: Assignment of ubiquitin binding to FBXO7. A plausible but ancillary activity relative to the core substrate-adaptor function. Reason: If accurate, ubiquitin binding is a subsidiary molecular feature; the core function is the ligase-substrate adaptor activity. Not central to the documented FBXO7 roles. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt The ubiquitin-like region mediates interaction with PRKN. |
| GO:0046982 protein heterodimerization activity | IPI PMID:18495667 Structure of a conserved dimerization domain within the F-bo... | KEEP AS NON CORE | Summary: Direct evidence that FBXO7 heterodimerizes with PSMF1/PI31 via the shared FP domain (and homodimerizes). Reason: Real FP-domain-mediated dimerization with PSMF1/PI31 (relevant to proteasome regulation) but a structural/binding property rather than the core adaptor function. Supporting Evidence: PMID:18495667 We identify PI31 as an Fbxo7.Skp1 binding partner and show that this interaction requires an N-terminal domain present in both proteins that we term the FP (Fbxo7/PI31) domain. |
| GO:0005634 nucleus | IDA PMID:21347293 Loss of nuclear activity of the FBXO7 protein in patients wi... | KEEP AS NON CORE | Summary: Direct evidence that wild-type FBXO7 isoform 1 displays mostly diffuse nuclear localization, with loss of nuclear localization in PARK15 mutants. Reason: This study emphasizes a nuclear pool, but UniProt and other studies establish that FBXO7 is predominantly cytoplasmic; nuclear localization is treated as non-core. Supporting Evidence: PMID:21347293 the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization |
| GO:0005737 cytoplasm | IDA PMID:21347293 Loss of nuclear activity of the FBXO7 protein in patients wi... | ACCEPT | Summary: Direct evidence of FBXO7 cytoplasmic localization, including mutant-induced cytoplasmic mislocalization. Core compartment. Reason: Core localization with direct experimental support; PARK15 N-terminal mutations shift FBXO7 to the cytoplasm. Supporting Evidence: PMID:21347293 N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization |
| GO:0005634 nucleus | IDA PMID:23656991 FBXO7 immunoreactivity in Ξ±-synuclein-containing inclusions ... | KEEP AS NON CORE | Summary: Immunohistochemical detection of FBXO7 in human brain neurons; widespread expression. Reported nuclear/cytoplasmic neuronal staining. Reason: Brain immunoreactivity localization; nuclear pool is minor relative to predominant cytoplasm. Supporting Evidence: PMID:23656991 We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum. |
| GO:0005737 cytoplasm | IDA PMID:23656991 FBXO7 immunoreactivity in Ξ±-synuclein-containing inclusions ... | ACCEPT | Summary: Immunohistochemical detection of FBXO7 in the cytoplasm of human brain neurons. Consistent with predominant cytoplasmic localization. Reason: Consistent with the core cytoplasmic localization of FBXO7 in neurons. Supporting Evidence: PMID:23656991 We detected widespread brain FBXO7 immunoreactivity, with the highest levels in neurons of the cerebral cortex, putamen, and cerebellum. |
| GO:0019005 SCF ubiquitin ligase complex | TAS PMID:16510124 The F-box protein Fbxo7 interacts with human inhibitor of ap... | ACCEPT | Summary: Author statement that F-box proteins such as FBXO7 are specificity-determining subunits of SCF ubiquitin ligases. Core complex membership. Reason: Core localization/complex; FBXO7 is the F-box substrate-receptor subunit of an SCF E3 ligase. Supporting Evidence: PMID:16510124 Since F-box proteins are specificity determining subunits of SCF ubiquitin protein ligases, our results suggest that Fbxo7 can mediate the ubiquitination of cIAP1 by SCF ubiquitin protein ligase |
| GO:0097409 glial cytoplasmic inclusion | IDA PMID:23656991 FBXO7 immunoreactivity in Ξ±-synuclein-containing inclusions ... | KEEP AS NON CORE | Summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive glial cytoplasmic inclusions in multiple system atrophy. A disease-pathology localization. Reason: Real IDA immunoreactivity in pathological inclusions, but this is a disease-associated localization, not a core physiological compartment. Supporting Evidence: PMID:23656991 FBXO7 immunoreactivity was detected in large proportions of Ξ±-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions) |
| GO:0097414 classical Lewy body | IDA PMID:23656991 FBXO7 immunoreactivity in Ξ±-synuclein-containing inclusions ... | KEEP AS NON CORE | Summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy bodies in Parkinson disease. A disease-pathology localization. Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment. Supporting Evidence: PMID:23656991 FBXO7 immunoreactivity was detected in large proportions of Ξ±-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions) |
| GO:0097462 Lewy neurite | IDA PMID:23656991 FBXO7 immunoreactivity in Ξ±-synuclein-containing inclusions ... | KEEP AS NON CORE | Summary: Direct immunoreactivity for FBXO7 within alpha-synuclein-positive Lewy neurites. A disease-pathology localization. Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment. Supporting Evidence: PMID:23656991 FBXO7 immunoreactivity was detected in large proportions of Ξ±-synuclein-positive inclusions (Lewy bodies, Lewy neurites, glial cytoplasmic inclusions) |
| GO:1990037 Lewy body core | IDA PMID:23656991 FBXO7 immunoreactivity in Ξ±-synuclein-containing inclusions ... | KEEP AS NON CORE | Summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization. Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment. Supporting Evidence: PMID:23656991 where it colocalized with Ξ±-synuclein in PD and MSA cases |
| GO:1990038 Lewy body corona | IDA PMID:23656991 FBXO7 immunoreactivity in Ξ±-synuclein-containing inclusions ... | KEEP AS NON CORE | Summary: Direct immunoreactivity for FBXO7 colocalizing with alpha-synuclein in Lewy body structures. A disease-pathology localization. Reason: Real IDA immunoreactivity in pathological inclusions, but a disease-associated localization, not a core physiological compartment. Supporting Evidence: PMID:23656991 where it colocalized with Ξ±-synuclein in PD and MSA cases |
| GO:0005634 nucleus | IDA PMID:21378169 A Competitive binding mechanism between Skp1 and exportin 1 ... | KEEP AS NON CORE | Summary: Direct evidence relating to FBXO7 nuclear/cytoplasmic distribution governed by SKP1/CRM1 competition. Reason: Real but minor nuclear localization governed by SKP1/CRM1 shuttling; predominant compartment is cytoplasm. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt A minor proportion is detected in the nucleus (PubMed:16096642). |
| GO:0005737 cytoplasm | IDA PMID:21378169 A Competitive binding mechanism between Skp1 and exportin 1 ... | ACCEPT | Summary: Direct evidence of FBXO7 cytoplasmic localization controlled by SKP1/CRM1 competition. Core compartment. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Note=Predominantly cytoplasmic (PubMed:16096642). |
| GO:0040012 regulation of locomotion | IDA PMID:26310625 F-box protein 7 mutations promote protein aggregation in mit... | KEEP AS NON CORE | Summary: Organismal locomotor phenotype associated with FBXO7 (Drosophila dopamine-neuron degeneration and PD-related models), reflecting its mitophagy/neuroprotection role. Reason: An organismal/neurodegeneration phenotype downstream of the core mitophagy function rather than a distinct cell-autonomous core process. Supporting Evidence: PMID:26310625 The overexpression of WT FBXO7 could lead to FBXO7 protein aggregation and dopamine neuron degeneration in transgenic Drosophila heads. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | ACCEPT | Summary: Reactome neddylation/CRL-machinery pathway annotation placing FBXO7 in the cytosol. The cytosol is the predominant FBXO7 compartment. Reason: Correct core localization; cytosol is the predominant compartment for the SCF(FBXO7) complex. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | ACCEPT | Summary: Reactome CRL-machinery pathway annotation placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | ACCEPT | Summary: Reactome CRL-machinery pathway annotation (CAND1 binding) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | ACCEPT | Summary: Reactome CRL-machinery pathway annotation (COMMD/CAND1) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | ACCEPT | Summary: Reactome CRL-machinery pathway annotation (COP9 signalosome deneddylation) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | ACCEPT | Summary: Reactome CRL-machinery pathway annotation (DCUN1D3) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | ACCEPT | Summary: Reactome ubiquitination-pathway annotation (Ub transfer from E2 to substrate) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | ACCEPT | Summary: Reactome ubiquitination-pathway annotation (release of E3 from polyubiquitinated substrate) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | ACCEPT | Summary: Reactome ubiquitination-pathway annotation (polyubiquitination of substrate) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | ACCEPT | Summary: Reactome ubiquitination-pathway annotation (interaction of E3 with substrate and E2-Ub complex) placing FBXO7 in the cytosol. Reason: Correct core localization; cytosol is the predominant compartment. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm, cytosol {ECO:0000269|PubMed:23933751}. |
| GO:0005634 nucleus | IDA PMID:18495667 Structure of a conserved dimerization domain within the F-bo... | KEEP AS NON CORE | Summary: Direct evidence of FBXO7 nuclear localization documented in the FP-domain study. Minor nuclear pool. Reason: Real but minor nuclear localization; predominant compartment is cytoplasm/cytosol. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Nucleus {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667, ECO:0000269|PubMed:33010352}. |
| GO:0005829 cytosol | IDA PMID:18495667 Structure of a conserved dimerization domain within the F-bo... | ACCEPT | Summary: Direct evidence of FBXO7 cytosolic localization. Core compartment. Reason: Core localization with direct experimental support. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Cytoplasm {ECO:0000269|PubMed:16096642, ECO:0000269|PubMed:18495667}. |
| GO:0000151 ubiquitin ligase complex | IDA PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | KEEP AS NON CORE | Summary: Direct evidence that FBXO7 is part of a ubiquitin ligase complex (the SCF(FBXO7) complex). Generic parent of the specific SCF complex term. Reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's complex membership. Supporting Evidence: PMID:23933751 F-box domain-containing proteins target substrates to SCF-type (Skp1-Cul1-F-box) E3-ubiquitin ligase complexes |
| GO:0000422 autophagy of mitochondrion | IMP PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | ACCEPT | Summary: Mutant-phenotype evidence that reducing FBXO7 impairs CCCP-induced mitophagy and that FBXO7 acts in Parkin-mediated mitophagy. Core biological process. Reason: Core biological process with direct experimental (IMP) support; FBXO7 knockdown reduces mitophagy and FBXO7 rescues parkin mutant phenotypes. Supporting Evidence: PMID:23933751 Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. |
| GO:0005739 mitochondrion | IDA PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | ACCEPT | Summary: Direct evidence that FBXO7 relocates from the cytosol to depolarized mitochondria following CCCP treatment. Conditional localization. Reason: Correct conditional/stress-induced localization central to the mitophagy function. ORGANELLES check (2026-10-25). The organelle claim is supported directly in human cells (CCCP-induced shift of endogenous FBXO7 from cytosolic to mitochondrial fractions in HEK293T and SH-SY5Y cells, PMID:23933751; stress-induced mitochondrial aggregates, PMID:26310625), and UniProt curates Mitochondrion from PMID:23933751. No sub-compartment row, because the lines disagree. The mitophagy role (binding PINK1 and Parkin, Parkin recruitment, Mfn1 ubiquitination) places the recruited pool on the cytosolic face of the outer membrane, as for TRAF3 and BRAF, but no protease-protection or sub-mitochondrial fractionation was done; the predicted N-terminal MTS (Arg-2, Arg-6) needed for fraction association (isoform 1) has no cleavage or import assay; and PMID:26310625 describes FBXO7 concentrating into mitochondria, which would imply import. FBXO7 has no TM segment and is not in MitoCarta3.0. Supporting Evidence: PMID:23933751 endogenous Fbxo7 levels were found to decrease steadily in the cytosolic fraction and increase concurrently in the mitochondrial fractions |
| GO:0005829 cytosol | IDA PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | ACCEPT | Summary: Direct evidence that FBXO7 is predominantly cytosolic (before relocating to depolarized mitochondria). Core compartment. Reason: Core localization with direct experimental support (cell fractionation). Supporting Evidence: PMID:23933751 although both proteins localise predominantly to the cytosol |
| GO:0016567 protein ubiquitination | IMP PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that FBXO7 is required for CCCP-induced mitofusin 1 ubiquitination (via promoting Parkin recruitment). Generic parent process. Reason: Correct but generic; FBXO7 facilitates substrate (Mfn1) ubiquitination chiefly by promoting Parkin recruitment. The specific mitophagy annotations better capture the role. Supporting Evidence: PMID:23933751 Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. |
| GO:0070585 protein localization to mitochondrion | IMP PMID:23933751 The Parkinson's disease-linked proteins Fbxo7 and Parkin int... | ACCEPT | Summary: Mutant-phenotype evidence that FBXO7 is required for Parkin translocation to depolarized mitochondria. Well-supported process. Reason: Directly demonstrated; FBXO7 facilitates Parkin recruitment to mitochondria, a key step in mitophagy. Supporting Evidence: PMID:23933751 Overall, these data indicate that Fbxo7 facilitates Parkin translocation to the mitochondria in response to depolarisation. |
| GO:0032991 protein-containing complex | IDA GO_REF:0000054 | KEEP AS NON CORE | Summary: LIFEdb fusion-protein localization assignment of generic protein-containing complex membership. Reason: Correct but generic; the specific SCF ubiquitin ligase complex (GO:0019005) is far more informative. Supporting Evidence: file:human/FBXO7/FBXO7-uniprot.txt Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO7) formed of CUL1, SKP1, RBX1 and FBXO7. |
| GO:0031647 regulation of protein stability | IDA PMID:15145941 Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... | KEEP AS NON CORE | Summary: Direct evidence that FBXO7 controls the stability/abundance of its substrate HURP via ubiquitination. Reason: Correct but generic; FBXO7 regulates substrate stability through the more specific SCF-dependent catabolic process (GO:0031146). Supporting Evidence: PMID:15145941 Depletion of Fbx7 by small interfering RNA leads to depression of HURP ubiquitination and accumulation of HURP abundance. |
| GO:0005515 protein binding | IPI PMID:15145941 Fbx7 functions in the SCF complex regulating Cdk1-cyclin B-p... | KEEP AS NON CORE | Summary: Interaction with the substrate DLGAP5/HURP (and CUL1/SKP1) from the HURP proteolysis study. Bare protein binding is uninformative. Reason: Records the meaningful FBXO7-HURP/DLGAP5 substrate interaction, but bare protein binding is uninformative; captured by the SCF/adaptor annotations. Supporting Evidence: PMID:15145941 In the SCF(Fbx7) complex, Fbx7 recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B-phosphorylation dependent manner. |
| GO:0000151 ubiquitin ligase complex | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Author statement that F-box proteins are subunits of SCF ubiquitin protein ligases. Generic parent of the SCF complex term. Reason: Correct but generic; the more specific GO:0019005 (SCF ubiquitin ligase complex) better captures FBXO7's membership. Supporting Evidence: PMID:10531035 In fact, F-box proteins are one of the four subunits of ubiquitin protein ligases called SCFs. |
| GO:0004842 ubiquitin-protein transferase activity | TAS PMID:10531035 Identification of a family of human F-box proteins. | MODIFY | Summary: Family-level author statement assigning ubiquitin-protein transferase activity to F-box-containing SCF ligases. FBXO7 is the substrate-recognition adaptor, not the catalytic transferase (the catalytic RING is RBX1). Reason: FBXO7 itself is not the ubiquitin transferase; it is the substrate-recognition adaptor of the SCF complex. The catalytic transfer is performed by the E2 recruited by the RBX1 RING. The informative molecular function is the ligase-substrate adaptor activity. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:36646384 FBXO7 is an adaptor protein in the SKP1-Cullin-1-F-box (SCF) E3 ligase complex that facilitates the ubiquitination of substrates. |
| GO:0006511 ubiquitin-dependent protein catabolic process | TAS PMID:10531035 Identification of a family of human F-box proteins. | KEEP AS NON CORE | Summary: Family-level author statement that F-box/SCF proteins drive controlled degradation of cellular regulatory proteins. Generic parent of the specific SCF-dependent process. Reason: Correct but generic; the specific GO:0031146 (SCF-dependent proteasomal catabolic process) better captures FBXO7's role. Supporting Evidence: PMID:10531035 Some F-box proteins have been shown to be critical for the controlled degradation of cellular regulatory proteins |
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Download this section (compressed HTML)Q: To what extent are FBXO7's SCF-dependent substrate-degradation roles (HURP, cIAP1, TRAF2, UXT-V2, SIRT7) and its SCF-independent roles (PINK1/Parkin mitophagy, PSMF1/PI31 proteasome regulation, cyclin D/CDK6 activation) separable, and which are most relevant to PARK15 neurodegeneration?
Q: How do the FP domain-mediated FBXO7 homodimerization and FBXO7-PSMF1/PI31 heterodimerization regulate proteasome assembly/activity in neurons, and is this disrupted by PARK15 mutations?
Q: Does FBXO7 directly target PRKN/PINK1 for ubiquitination, or does it act mainly as a non-catalytic scaffold promoting Parkin recruitment to depolarized mitochondria?
Experiment: Reconstitute SCF(FBXO7) in vitro with purified CUL1, SKP1, RBX1, an E2, and candidate substrates (HURP/DLGAP5, SIRT7, UXT-V2) to confirm that FBXO7 functions as a substrate-presenting adaptor (not the catalytic transferase) and to map substrate lysines and chain linkages.
Experiment: Perform quantitative ubiquitinome and proteome profiling in FBXO7-knockout versus wild-type neuronal cells under basal and mitochondrial-depolarization (CCCP) conditions to define the endogenous SCF(FBXO7) substrate repertoire and its contribution to mitophagy.
Experiment: Use live-cell imaging with PARK15 patient-derived neurons (T22M, R378G, R498X) to quantify FBXO7 relocation to depolarized mitochondria and Parkin recruitment kinetics, dissecting how each mutation impairs mitophagy.
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