id: Q9UF56 gene_symbol: FBXL17 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- FBXL17 (F-box/LRR-repeat protein 17; also F-box only protein 13) is a substrate-recognition subunit of a SKP1-CUL1-F-box (SCF/CRL1) E3 ubiquitin ligase complex. Through its N-terminal F-box motif it binds SKP1, docking it onto the CUL1-RBX1 catalytic scaffold, while its C-terminal leucine-rich repeat (LRR) domain provides substrate selectivity. FBXL17 performs a distinctive dimerization quality-control (DQC) function: its LRR recognizes a conserved, non-consecutive degron exposed at the interface of aberrantly paired BTB-domain dimers, so that the SCF(FBXL17) ligase selectively ubiquitinates and clears mismatched or compromised BTB homo/heterodimers for proteasomal degradation. A well-characterized physiological substrate is the BTB transcriptional repressor BACH1, whose turnover by SCF(FBXL17) relieves repression of NRF2 target genes such as HMOX1 during the oxidative-stress response. Structural work shows that FBXL17 does not bind the intact BACH1 BTB homodimer; instead, when the dimer interface is destabilized (for example by oxidation or S-nitrosylation under oxidative/nitrosative stress), the FBXL17 LRR engages the weakened dimer and remodels it into a stably bound BTB monomer that is then ubiquitinated, distinguishing FBXL17 from FBXO22, which reads an intact cross-protomer BTB degron. FBXL17 also targets the Hedgehog-pathway regulator SUFU for nuclear ubiquitination and degradation (at Lys257, favored by SUFU dephosphorylation), releasing GLI transcription factors for proper Hedgehog signal transduction, and additional clients include the arginine methyltransferase PRMT1 (via a p300-acetylated K228 "acetyl-degron" triggering K48-linked polyubiquitination) and the long spastin isoform SPAST-M1 (recognized through its N-terminal BTB-like domain), as well as reported BTB partners such as KLHL12 and KBTBD8. The DQC activity is important for the differentiation, function, and survival of neural crest and neuronal cells. FBXL17 is present in both cytoplasm and nucleus, with the nuclear pool acting on substrates such as SUFU, BACH1, and SPAST-M1. alternative_products: - name: '1' id: Q9UF56-1 - name: '2' id: Q9UF56-3 sequence_note: VSP_037034 - name: '3' id: Q9UF56-2 sequence_note: VSP_037034, VSP_009476 existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of nuclear localization from the UniProt subcellular location; FBXL17 acts in the nucleus on substrates such as SUFU and BACH1. action: ACCEPT reason: Correct localization; FBXL17 is documented in both nucleus and cytoplasm, and nuclear ubiquitination of SUFU and BACH1 is established. Redundant with IDA evidence. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298}' - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; FBXL17 is more abundant in the cytoplasm. action: ACCEPT reason: Correct localization, supported by IDA evidence and UniProt note that it is more abundant in the cytoplasm. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: Present in the cytoplasm and nucleus; more abundant in the cytoplasm. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27705803 qualifier: enables review: summary: High-throughput interaction with SKP1 (P63208) from a Polycomb complexome map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally relevant FBXL17-SKP1 association required for SCF assembly, but bare protein binding is uninformative per curation guidelines; captured by the SCF complex annotations. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Q9UF56; P63208: SKP1; NbExp=17; IntAct=EBI-8835653, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:30190310 qualifier: enables review: summary: Interactions captured in the dimerization-quality-control study (SKP1 and BTB-domain partners such as KLHL12/KBTBD8). Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Real interactions central to DQC substrate recognition, but bare protein binding is uninformative; the underlying biology is captured by the DQC and SCF annotations. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Q9UF56; Q53G59: KLHL12; NbExp=11; IntAct=EBI-8835653, EBI-740929;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a proteome-scale cell-specific interactome. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative and is subsumed by the SCF complex annotations. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Q9UF56; P63208: SKP1; NbExp=17; IntAct=EBI-8835653, EBI-307486;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35869491 qualifier: enables review: summary: Interaction with SPAST/spastin (Q9UBP0) reported in a hereditary spastic paraplegia study proposing an FBXL17/spastin axis. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a disease-relevant FBXL17-spastin interaction, but bare protein binding is uninformative; the candidate substrate relationship is not yet a defined core function. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Q9UF56; Q9UBP0: SPAST; NbExp=3; IntAct=EBI-8835653, EBI-1222832;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Interaction with SKP1 (P63208) from a multimodal cell-map genomics study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput SKP1 interaction; bare protein binding is uninformative and is captured by the SCF complex annotations. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Q9UF56; P63208: SKP1; NbExp=17; IntAct=EBI-8835653, EBI-307486;' - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) evidence for nucleoplasmic localization, consistent with FBXL17's nuclear action on SUFU/BACH1. action: ACCEPT reason: IDA-supported localization consistent with nuclear ubiquitination of SUFU and BACH1; a more specific child of the nucleus annotation. supported_by: - reference_id: PMID:27234298 supporting_text: Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus - term: id: GO:0014033 label: neural crest cell differentiation evidence_type: NAS original_reference_id: PMID:30190310 qualifier: involved_in review: summary: Author statement that SCF(FBXL17)-mediated dimerization quality control is required for differentiation, function, and survival of neural crest and neuronal cells. action: KEEP_AS_NON_CORE reason: Supported by the DQC study but represents a downstream developmental consequence of the core ubiquitin-ligase substrate-receptor activity, not the core function itself. supported_by: - reference_id: PMID:30190310 supporting_text: SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:33234069 qualifier: involved_in review: summary: ComplexPortal author statement that FBXL17 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. action: ACCEPT reason: Core biological process for an SCF F-box substrate receptor; directly supported experimentally elsewhere (BACH1, SUFU degradation). supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-9708517 qualifier: located_in review: summary: Reactome curation of FBXL17 nucleoplasmic localization within a BACH1 ubiquitination reaction. Consistent with nuclear action. action: ACCEPT reason: Correct localization; redundant with IDA evidence and consistent with nuclear BACH1/SUFU turnover. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298}' - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-9708525 qualifier: located_in review: summary: Reactome curation of FBXL17 nucleoplasmic localization (BACH1:FBXL17 binds SCF). Consistent with nuclear action. action: ACCEPT reason: Correct localization; redundant with IDA evidence. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298}' - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-9708557 qualifier: located_in review: summary: Reactome curation of FBXL17 nucleoplasmic localization (FBXL17 binds BACH1:MAFK). Consistent with nuclear action. action: ACCEPT reason: Correct localization; redundant with IDA evidence. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298}' - term: id: GO:0000209 label: protein polyubiquitination evidence_type: IDA original_reference_id: PMID:27234298 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL17) polyubiquitinates SUFU. A general process term consistent with the core substrate-ubiquitination role. action: ACCEPT reason: Directly demonstrated polyubiquitination of a substrate (SUFU); accurate, though the SCF-dependent catabolic process term is more specific. supported_by: - reference_id: PMID:27234298 supporting_text: The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24035498 qualifier: enables review: summary: Interaction with BACH1 (Q9UMX1) from the parallel-adaptor-capture proteomics study identifying BACH1 as an SCF(FBXL17) substrate. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL17-BACH1 substrate interaction, but bare protein binding is uninformative; the relationship is captured by the ubiquitination/catabolic process annotations. supported_by: - reference_id: PMID:24035498 supporting_text: FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:27234298 qualifier: enables review: summary: Interaction with SUFU (Q9UMX1 entry maps to the SUFU substrate) from the Hedgehog study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records the functionally important FBXL17-SUFU substrate interaction, but bare protein binding is uninformative; captured by the ubiquitination annotations. supported_by: - reference_id: PMID:27234298 supporting_text: Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:24035498 qualifier: located_in review: summary: Direct evidence for nuclear localization from the BACH1/NRF2 study. Core localization for nuclear substrate turnover. action: ACCEPT reason: IDA-supported nuclear localization consistent with nuclear BACH1 turnover. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: 'Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298}' - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:27234298 qualifier: located_in review: summary: Direct evidence for nuclear localization from the SUFU/Hedgehog study, where FBXL17 ubiquitinates SUFU in the nucleus. action: ACCEPT reason: IDA-supported nuclear localization consistent with nuclear SUFU turnover. supported_by: - reference_id: PMID:27234298 supporting_text: Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:24035498 qualifier: located_in review: summary: Direct evidence for cytoplasmic localization. Consistent with the UniProt note that FBXL17 is more abundant in the cytoplasm. action: ACCEPT reason: IDA-supported localization; FBXL17 is present in both compartments. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: Present in the cytoplasm and nucleus; more abundant in the cytoplasm. - term: id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins evidence_type: IDA original_reference_id: PMID:30190310 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL17) performs dimerization quality control, selectively clearing aberrant-composition BTB dimers. This is the distinctive core process of FBXL17. action: ACCEPT reason: Captures the hallmark DQC role established experimentally; SCF(FBXL17) recognizes and degrades BTB dimers of aberrant composition. Subsequent structural work refines the mechanism, showing the FBXL17 LRR engages destabilized/compromised BTB dimers (e.g. oxidized or mismatched) and remodels them into stably bound monomers for ubiquitination rather than binding intact dimers, consistent with a proofreading quality-control function for BTB quaternary structure. additional_reference_ids: - file:human/FBXL17/FBXL17-deep-research-falcon.md supported_by: - reference_id: PMID:30190310 supporting_text: the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation - reference_id: file:human/FBXL17/FBXL17-deep-research-falcon.md supporting_text: Under oxidative/nitrosative stress, **FBXL17 can recognize a compromised/destabilized BTB dimer and remodel it into monomers** that are ubiquitinated. - term: id: GO:0007399 label: nervous system development evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer (from Xenopus ortholog) of a nervous-system development role, consistent with the DQC requirement for neuronal survival. action: KEEP_AS_NON_CORE reason: Plausible downstream developmental role consistent with the DQC study, but a generic process distinct from the core substrate-receptor activity. supported_by: - reference_id: PMID:30190310 supporting_text: SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells - term: id: GO:0008589 label: regulation of smoothened signaling pathway evidence_type: IMP original_reference_id: PMID:27234298 qualifier: involved_in review: summary: Mutant-phenotype evidence that FBXL17, by degrading SUFU, regulates Hedgehog/Smoothened signaling; depletion causes defective Hh signaling. action: KEEP_AS_NON_CORE reason: Well-supported downstream regulatory role (via SUFU turnover) but a context-specific pathway outcome rather than the core ligase substrate-receptor function. supported_by: - reference_id: PMID:27234298 supporting_text: Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth - term: id: GO:0014033 label: neural crest cell differentiation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity transfer of a neural-crest differentiation role, consistent with the DQC study showing SCF(FBXL17) is required for neural crest differentiation. action: KEEP_AS_NON_CORE reason: Plausible developmental role supported by the DQC study, but downstream of and distinct from the core substrate-receptor activity. supported_by: - reference_id: PMID:30190310 supporting_text: SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:24035498 qualifier: involved_in review: summary: Direct evidence that FBXL17 mediates ubiquitination of BACH1. A general parent of the SCF-dependent catabolic process. action: ACCEPT reason: Directly demonstrated substrate ubiquitination; accurate though the SCF-dependent catabolic process term is more specific. supported_by: - reference_id: PMID:24035498 supporting_text: FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 - term: id: GO:0016567 label: protein ubiquitination evidence_type: IDA original_reference_id: PMID:30190310 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL17) ubiquitinates aberrant BTB dimers during DQC. A general parent of the SCF-dependent catabolic process. action: ACCEPT reason: Directly demonstrated substrate ubiquitination; accurate though the SCF-dependent catabolic process term is more specific. supported_by: - reference_id: PMID:30190310 supporting_text: the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition - term: id: GO:0019005 label: SCF ubiquitin ligase complex evidence_type: IDA original_reference_id: PMID:24035498 qualifier: part_of review: summary: Direct evidence that FBXL17 is part of an SCF (SKP1-CUL1-RBX1-FBXL17) E3 ubiquitin ligase complex. Core cellular component. action: ACCEPT reason: Core complex membership; FBXL17 is the substrate-recognition subunit of SCF(FBXL17). supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL17) composed of CUL1, SKP1, RBX1 and FBXL17 - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:24035498 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL17) drives proteasomal degradation of BACH1. Core biological process. action: ACCEPT reason: Core biological process directly supported by BACH1 turnover. supported_by: - reference_id: PMID:24035498 supporting_text: FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 - term: id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:27234298 qualifier: involved_in review: summary: Direct evidence that SCF(FBXL17) drives proteasomal degradation of SUFU. Core biological process. action: ACCEPT reason: Core biological process directly supported by SUFU turnover. supported_by: - reference_id: PMID:27234298 supporting_text: Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IDA original_reference_id: PMID:30190310 qualifier: involved_in review: summary: Direct evidence that aberrant BTB dimers recognized by SCF(FBXL17) are cleared by proteasomal degradation. A parent of the SCF-dependent catabolic process. action: ACCEPT reason: Directly supported proteasomal degradation of DQC substrates; accurate, with GO:0031146 being the more specific SCF-dependent term. supported_by: - reference_id: PMID:30190310 supporting_text: BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation - term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity evidence_type: IDA original_reference_id: PMID:30190310 qualifier: enables review: summary: Proposed core molecular function. As the LRR substrate-recognition subunit of SCF(FBXL17), FBXL17 functions as a ubiquitin ligase-substrate adaptor that selects BACH1, SUFU, and aberrant BTB dimers for SCF-dependent ubiquitination. This more informative MF term is not in the GOA. action: NEW reason: Captures the precise molecular function of FBXL17 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotations. supported_by: - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex references: - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: PMID:24035498 title: Parallel SCF adaptor capture proteomics reveals a role for SCFFBXL17 in NRF2 activation via BACH1 repressor turnover. findings: - statement: SCF(FBXL17) controls the NRF2 oxidative stress response by mediating turnover of the BTB transcriptional repressor BACH1, thereby regulating transcription of the NRF2 target HMOX1. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Mol Cell 2013); identifies BACH1 as a key SCF(FBXL17) substrate. Abstract-only in cache; supporting quotes drawn from abstract and UniProt. - id: PMID:27234298 title: SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. findings: - statement: FBXL17 targets SUFU for nuclear polyubiquitination and degradation, releasing GLI1 for Hedgehog signal transduction; FBXL17 depletion impairs Hh signaling and medulloblastoma growth. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (EMBO J 2016), full text available; establishes SUFU as a nuclear substrate and the Hedgehog-regulatory role. - id: PMID:27705803 title: A High-Density Map for Navigating the Human Polycomb Complexome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput complexome map; source of an SKP1 interaction (bare protein binding). - id: PMID:30190310 title: Dimerization quality control ensures neuronal development and survival. findings: - statement: SCF(FBXL17) selectively binds and ubiquitinates BTB dimers of aberrant composition for proteasomal clearance (dimerization quality control, DQC); this activity is required for differentiation, function, and survival of neural crest and neuronal cells. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: PubMed-verified (Science 2018); defines the hallmark DQC function. Abstract-only in cache; quotes drawn from abstract. - id: PMID:33234069 title: 'The FBXL family of F-box proteins: variations on a theme.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review of the FBXL family; basis for the ComplexPortal NAS SCF-catabolic-process annotation. - 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: High-throughput interactome; source of an SKP1 interaction (bare protein binding). - id: PMID:35869491 title: FBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Reports an FBXL17-SPAST (spastin) interaction relevant to hereditary spastic paraplegia; candidate substrate relationship, source of a protein binding annotation. - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput cell-map genomics; source of an SKP1 interaction (bare protein binding). - id: Reactome:R-HSA-9708517 title: FBXL17 ubiquitinates BACH1 (in BACH1:FBXL17:SCF (SKP2)) findings: [] - id: Reactome:R-HSA-9708525 title: BACH1:FBXL17 binds SCF(SKP2) complex findings: [] - id: Reactome:R-HSA-9708557 title: FBXL17 binds BACH1:MAFK findings: [] - id: file:human/FBXL17/FBXL17-deep-research-falcon.md title: Falcon deep research report for human FBXL17 findings: - statement: FBXL17 is the SCF (SKP1-CUL1-RBX1) substrate-recognition subunit, using an F-box to assemble the SCF and a C-terminal LRR to bind substrates for ubiquitination and proteasomal degradation. supporting_text: In this paradigm, **FBXL17 is the substrate receptor** that helps determine which proteins are ubiquitinated and often targeted for proteasomal degradation. - statement: FBXL17 does not engage the intact BACH1 BTB dimer; under oxidative/nitrosative stress it recognizes a compromised/destabilized BTB dimer and remodels it into ubiquitinated monomers, in contrast to FBXO22 which reads the intact cross-protomer degron. supporting_text: Under oxidative/nitrosative stress, **FBXL17 can recognize a compromised/destabilized BTB dimer and remodel it into monomers** that are ubiquitinated. - statement: SCF(FBXL17) targets the Hedgehog pathway tumor suppressor SUFU for nuclear proteolysis, enabling GLI activation and Hedgehog signal transduction. supporting_text: FBXL17 forms a functional SCF complex and targets the Hedgehog pathway tumor suppressor **SUFU (Suppressor of fused)** for **proteolysis in the nucleus**, enabling release/activation of GLI transcription factors and Hedgehog signal transduction. - statement: PRMT1 is a PTM-gated FBXL17 substrate; p300 acetylation at K228 creates an acetyl-degron that promotes FBXL17 binding and K48-linked polyubiquitination. supporting_text: PRMT1 is regulated by SCF(FBXL17) such that **p300-mediated acetylation at PRMT1 K228** promotes FBXL17 binding, **K48-linked polyubiquitination**, and proteasomal degradation. - statement: In neuronal models SCF(FBXL17) targets the long spastin isoform SPAST-M1 for proteasomal degradation via recognition of its N-terminal BTB domain. supporting_text: SCF(FBXL17) targets **SPAST-M1** (long spastin isoform) for **proteasome-dependent degradation in the nuclear fraction**, with substrate recognition mediated by the **SPAST N-terminal BTB domain**. reference_review: relevance: HIGH correctness: VERIFIED review_notes: Falcon synthesis cross-checked against UniProt and the cached PMIDs (Tan 2013/PMID:24035498, Raducu 2016/PMID:27234298, Mena 2018/PMID:30190310); the 2024 Cell remodeling mechanism (Cao et al.), PRMT1 acetyl-degron (Najar et al. preprint), and SPAST-M1 axis (Kang et al.) are reported via author-year DOIs not yet in the PMID cache, so treated as leads. core_functions: - description: Substrate-recognition subunit of an SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complex that, via its leucine-rich repeat domain, selects substrates (notably the BTB repressor BACH1 and the Hedgehog regulator SUFU) for SCF-dependent polyubiquitination and proteasomal degradation. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005634 label: nucleus - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:24035498 supporting_text: FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 - reference_id: file:human/FBXL17/FBXL17-uniprot.txt supporting_text: Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex directly_involved_in: - id: GO:0031146 label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process - description: Performs dimerization quality control (DQC) by recognizing, through its LRR, a conserved non-consecutive degron exposed at the interface of aberrant-composition BTB dimers and committing them to SCF(FBXL17)-mediated ubiquitination and proteasomal clearance; required for neural crest and neuronal development and survival. molecular_function: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: PMID:30190310 supporting_text: the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation directly_involved_in: - id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins proposed_new_terms: - proposed_name: dimerization quality control of BTB-domain protein assemblies proposed_definition: >- A protein quality control process in which an E3 ubiquitin ligase (for example SCF(FBXL17)) recognizes a non-consecutive, quaternary-structure degron exposed at the interface of aberrant-composition, mismatched, or conformationally compromised BTB-domain homodimers and heterodimers, and selectively ubiquitinates them for proteasomal degradation, thereby proofreading the dimerization state of BTB-domain transcription factors and adaptors. Unlike canonical recognition of linear or single-protomer degrons, this process surveils higher-order protein assembly and can involve remodeling of a destabilized dimer into a stably bound monomer prior to ubiquitination. justification: >- Existing GO:0006515 (protein quality control for misfolded or incompletely synthesized proteins) does not capture the surveillance of quaternary-structure and dimer-interface integrity that is the hallmark of SCF(FBXL17). FBXL17 reads a degron formed by aberrant BTB pairing rather than misfolding of a single chain, a mechanistically distinct quality-control activity established experimentally. proposed_parent: id: GO:0006515 label: protein quality control for misfolded or incompletely synthesized proteins supported_by: - reference_id: PMID:30190310 supporting_text: the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation - reference_id: file:human/FBXL17/FBXL17-deep-research-falcon.md supporting_text: Under oxidative/nitrosative stress, **FBXL17 can recognize a compromised/destabilized BTB dimer and remodel it into monomers** that are ubiquitinated. suggested_questions: - question: What is the structural basis by which the FBXL17 LRR distinguishes aberrant BTB dimer interfaces from correctly paired dimers, and how general is the non-consecutive degron across the BTB family? - question: Beyond BACH1 and SUFU, what is the full physiological substrate repertoire of SCF(FBXL17), and is SPAST/spastin a bona fide degradation substrate relevant to hereditary spastic paraplegia? suggested_experiments: - description: Reconstitute SCF(FBXL17)-mediated ubiquitination in vitro with purified SKP1-CUL1-RBX1-FBXL17, an E2, and matched vs mismatched BTB dimers to quantify selectivity for aberrant-composition dimers and map ubiquitination sites. - description: Perform quantitative ubiquitinome/proteome profiling in FBXL17-knockout versus wild-type cells (including neural crest/neuronal models) to define the endogenous DQC substrate landscape and the downstream developmental consequences.