FBXL20 (F-box/LRR-repeat protein 20; FBL2; the mouse ortholog is named SCRAPPER) is a substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex. Its F-box motif binds SKP1, linking it to the CUL1-RBX1 catalytic core, while its leucine-rich repeat domain provides substrate selectivity, directing substrate-specific polyubiquitination and proteasomal degradation. FBXL20 carries a C-terminal CAAX motif that is isoprenylated, targeting it to membranes, and its localization governs which substrates it engages. A well-characterized human substrate is VPS34/PIK3C3, the catalytic subunit of class III PI3K: FBXL20 binds VPS34 through its C-terminal LRR region (engaging the VPS34 C2 domain) and, downstream of DNA damage, promotes CDK-dependent (VPS34 Thr159) phosphodegron-gated ubiquitination and proteasomal degradation of VPS34. FBXL20 is itself a p53-inducible gene (and a miR-3151 target), so the p53 to FBXL20 to VPS34 axis lowers PtdIns3P output, dampening autophagy and slowing endosomal receptor (e.g. EGFR) degradation under genotoxic stress. FBXL20 also promotes ubiquitination and degradation of PR55alpha/PPP2R2A, a regulatory B subunit of the PP2A serine/threonine phosphatase. In the nervous system the SCRAPPER/FBXL20 ortholog is a membrane-associated presynaptic regulator that ubiquitinates the active-zone protein RIM1/RIMS1, controlling synaptic vesicle release and neurotransmission; accordingly the protein has documented roles at the presynapse and at glutamatergic synapses (largely inferred from the mouse ortholog). FBXL20 acts in the cytoplasm/cytosol and at membranes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location, consistent with a cytosolic SCF substrate receptor. Reason: Correct localization for a cytosolic SCF F-box protein; consistent with the cytosolic Reactome annotations. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0098793 presynapse | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inter-ontology logical inference placing FBXL20 at the presynapse, consistent with the SCRAPPER ortholog's presynaptic role in regulating RIM1 and synaptic vesicle release. Reason: Plausible localization inferred from the mouse SCRAPPER ortholog's presynaptic function; not directly demonstrated for the human protein, and secondary to the core SCF substrate-receptor activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity). |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: Interaction with SKP1 (P63208) from a Polycomb complexome map. Bare protein binding is uninformative. Reason: Records the FBXL20-SKP1 association required for SCF assembly, but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Interaction with SKP1 (P63208) from a binary interactome reference map. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Interaction with SKP1 (P63208) from a cell-specific proteome-scale interactome. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:34731788 p53/FBXL20 axis negatively regulates the protein stability o... | KEEP AS NON CORE | Summary: Interaction with PPP2R2A/PR55alpha (P63151), the FBXL20 substrate identified in the p53/FBXL20/PR55alpha study. Bare protein binding is uninformative. Reason: Records the functionally important FBXL20-PR55alpha substrate interaction, but bare protein binding is uninformative; the relationship is captured by the catabolic-process context. Supporting Evidence: PMID:34731788 the protein-stability of PR55Ξ± via FBXL20, a p53-target gene that serves as a substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Interaction with SKP1 (P63208) from a multimodal cell-map genomics study. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Q96IG2; P63208: SKP1; NbExp=8; IntAct=EBI-8835647, EBI-307486; |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of synaptic activity, reflecting the mouse SCRAPPER ortholog's synaptic function. Reason: Plausible from the mouse ortholog (SCRAPPER), but not directly demonstrated for the human protein; secondary to the core SCF substrate-receptor activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity). |
| GO:0098685 Schaffer collateral - CA1 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of activity at the Schaffer collateral-CA1 synapse, from the mouse SCRAPPER ortholog. Reason: Highly specific synaptic localization inferred from the mouse ortholog; not demonstrated for the human protein and secondary to the core activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity). |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of activity at glutamatergic synapses, from the mouse SCRAPPER ortholog. Reason: Plausible from the mouse ortholog; not directly demonstrated for the human protein and secondary to the core activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity). |
| GO:0099575 regulation of protein catabolic process at presynapse, modulating synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of presynaptic protein-catabolism regulation, reflecting the SCRAPPER ortholog's ubiquitination of the active-zone protein RIM1 to control synaptic vesicle release. Reason: Plausible role inferred from the mouse SCRAPPER ortholog (RIM1 ubiquitination at the presynapse); not directly demonstrated for the human protein and a context-specific process distinct from the generic core activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity). |
| GO:2000300 regulation of synaptic vesicle exocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog-based electronic assignment of synaptic-vesicle-exocytosis regulation, reflecting the SCRAPPER ortholog's control of presynaptic release. Reason: Plausible role inferred from the mouse ortholog; not directly demonstrated for the human protein and downstream of the core SCF substrate-receptor activity. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Role in neural transmission (By similarity). |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | NAS PMID:33234069 The FBXL family of F-box proteins: variations on a theme. | ACCEPT | Summary: ComplexPortal author statement that FBXL20 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. Reason: Core biological process for an SCF F-box substrate receptor; supported by PR55alpha degradation (PMID:34731788) and the SCRAPPER ortholog's RIM1 turnover. Supporting Evidence: PMID:34731788 substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952618 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within generic CRL1/NEDD8-cycle reactions. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery rather than FBXL20-specific function. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8952620 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic CRL1 NEDD8-binding reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955241 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic CAND1/CRL reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8955289 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic COMMD/CAND1/CRL reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956040 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic COP9-signalosome deneddylation reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8956200 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic DCUN1D3/CRL1 reaction. Reason: Generic CRL-cycle pathway annotation; reflects shared cytosolic CRL machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983140 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic E2-to-substrate ubiquitin-transfer reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983147 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic E3-release reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983156 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic substrate-polyubiquitination reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983157 | KEEP AS NON CORE | Summary: Reactome cytosolic localization within a generic E3-substrate-E2 interaction reaction. Reason: Generic ubiquitination pathway annotation; reflects shared cytosolic machinery. Supporting Evidence: file:human/FBXL20/FBXL20-uniprot.txt Cytoplasm {ECO:0000250}. |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:34731788 p53/FBXL20 axis negatively regulates the protein stability o... | NEW | Summary: Proposed core molecular function. As the LRR substrate-recognition subunit of SCF(FBXL20), FBXL20 selects substrates (PR55alpha/PPP2R2A in human cells; RIM1 for the SCRAPPER ortholog) for SCF-dependent ubiquitination. This more informative MF term is not in the GOA. Reason: Captures the precise molecular function of FBXL20 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotations. Supporting Evidence: PMID:34731788 substrate recognition component of the SCF (Skp1_Cullin1_F-box) E3 ubiquitin ligase complex that promotes proteasomal degradation of its targeted proteins |
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Download this section (compressed HTML)Q: Which of the FBXL20 functions established for the mouse SCRAPPER ortholog (RIM1 ubiquitination, regulation of synaptic vesicle release) are conserved and directly demonstrable for the human protein, and is CAAX isoprenylation required?
Q: How do the membrane/autophagy (VPS34/PIK3C3, p53-DNA-damage axis), synaptic (RIM1), and PP2A (PR55alpha) substrate-targeting activities of FBXL20 relate, and are they coordinated by CAAX-dependent localization or by distinct phosphodegrons?
Experiment: Reconstitute SCF(FBXL20)-mediated ubiquitination in vitro with purified SKP1-CUL1-RBX1-FBXL20, an E2, and candidate substrates (VPS34/PIK3C3 phosphorylated at Thr159, PR55alpha/PPP2R2A, RIM1) to confirm direct ubiquitination, test phosphodegron dependence, and map sites.
Experiment: Use FBXL20 knockout/knockdown (and CAAX-motif mutants) in human neurons and epithelial cells with quantitative ubiquitinome/proteome profiling and autophagy/PtdIns3P readouts to define the endogenous substrate repertoire, test the p53-FBXL20-VPS34 autophagy checkpoint, and assess conservation of the presynaptic role.
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