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.
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.
Parent term: protein quality control for misfolded or incompletely synthesized proteins
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of nuclear localization from the UniProt subcellular location; FBXL17 acts in the nucleus on substrates such as SUFU and BACH1. Reason: Correct localization; FBXL17 is documented in both nucleus and cytoplasm, and nuclear ubiquitination of SUFU and BACH1 is established. Redundant with IDA evidence. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298} |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; FBXL17 is more abundant in the cytoplasm. Reason: Correct localization, supported by IDA evidence and UniProt note that it is more abundant in the cytoplasm. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Present in the cytoplasm and nucleus; more abundant in the cytoplasm. |
| GO:0005515 protein binding | IPI PMID:27705803 A High-Density Map for Navigating the Human Polycomb Complex... | KEEP AS NON CORE | Summary: High-throughput interaction with SKP1 (P63208) from a Polycomb complexome map. Bare protein binding is uninformative. 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. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Q9UF56; P63208: SKP1; NbExp=17; IntAct=EBI-8835653, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:30190310 Dimerization quality control ensures neuronal development an... | KEEP AS NON CORE | Summary: Interactions captured in the dimerization-quality-control study (SKP1 and BTB-domain partners such as KLHL12/KBTBD8). Bare protein binding is uninformative. 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. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Q9UF56; Q53G59: KLHL12; NbExp=11; IntAct=EBI-8835653, EBI-740929; |
| 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 proteome-scale cell-specific interactome. Bare protein binding is uninformative. Reason: High-throughput SKP1 interaction; bare protein binding is uninformative and is subsumed by the SCF complex annotations. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Q9UF56; P63208: SKP1; NbExp=17; IntAct=EBI-8835653, EBI-307486; |
| GO:0005515 protein binding | IPI PMID:35869491 FBXL17/spastin axis as a novel therapeutic target of heredit... | KEEP AS NON CORE | Summary: Interaction with SPAST/spastin (Q9UBP0) reported in a hereditary spastic paraplegia study proposing an FBXL17/spastin axis. Bare protein binding is uninformative. 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. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Q9UF56; Q9UBP0: SPAST; NbExp=3; IntAct=EBI-8835653, EBI-1222832; |
| 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 and is captured by the SCF complex annotations. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Q9UF56; P63208: SKP1; NbExp=17; IntAct=EBI-8835653, EBI-307486; |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for nucleoplasmic localization, consistent with FBXL17's nuclear action on SUFU/BACH1. Reason: IDA-supported localization consistent with nuclear ubiquitination of SUFU and BACH1; a more specific child of the nucleus annotation. Supporting Evidence: PMID:27234298 Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus |
| GO:0014033 neural crest cell differentiation | NAS PMID:30190310 Dimerization quality control ensures neuronal development an... | KEEP AS NON CORE | Summary: Author statement that SCF(FBXL17)-mediated dimerization quality control is required for differentiation, function, and survival of neural crest and neuronal cells. 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. Supporting Evidence: PMID:30190310 SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells |
| 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 FBXL17 functions in SCF-dependent proteasomal protein catabolism. Captures the core biological process. Reason: Core biological process for an SCF F-box substrate receptor; directly supported experimentally elsewhere (BACH1, SUFU degradation). Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9708517 | ACCEPT | Summary: Reactome curation of FBXL17 nucleoplasmic localization within a BACH1 ubiquitination reaction. Consistent with nuclear action. Reason: Correct localization; redundant with IDA evidence and consistent with nuclear BACH1/SUFU turnover. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9708525 | ACCEPT | Summary: Reactome curation of FBXL17 nucleoplasmic localization (BACH1:FBXL17 binds SCF). Consistent with nuclear action. Reason: Correct localization; redundant with IDA evidence. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298} |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9708557 | ACCEPT | Summary: Reactome curation of FBXL17 nucleoplasmic localization (FBXL17 binds BACH1:MAFK). Consistent with nuclear action. Reason: Correct localization; redundant with IDA evidence. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298} |
| GO:0000209 protein polyubiquitination | IDA PMID:27234298 SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signa... | ACCEPT | Summary: Direct evidence that SCF(FBXL17) polyubiquitinates SUFU. A general process term consistent with the core substrate-ubiquitination role. Reason: Directly demonstrated polyubiquitination of a substrate (SUFU); accurate, though the SCF-dependent catabolic process term is more specific. Supporting Evidence: PMID:27234298 The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction |
| GO:0005515 protein binding | IPI PMID:24035498 Parallel SCF adaptor capture proteomics reveals a role for S... | KEEP AS NON CORE | Summary: Interaction with BACH1 (Q9UMX1) from the parallel-adaptor-capture proteomics study identifying BACH1 as an SCF(FBXL17) substrate. Bare protein binding is uninformative. 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. Supporting Evidence: PMID:24035498 FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 |
| GO:0005515 protein binding | IPI PMID:27234298 SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signa... | KEEP AS NON CORE | Summary: Interaction with SUFU (Q9UMX1 entry maps to the SUFU substrate) from the Hedgehog study. Bare protein binding is uninformative. Reason: Records the functionally important FBXL17-SUFU substrate interaction, but bare protein binding is uninformative; captured by the ubiquitination annotations. Supporting Evidence: PMID:27234298 Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus |
| GO:0005634 nucleus | IDA PMID:24035498 Parallel SCF adaptor capture proteomics reveals a role for S... | ACCEPT | Summary: Direct evidence for nuclear localization from the BACH1/NRF2 study. Core localization for nuclear substrate turnover. Reason: IDA-supported nuclear localization consistent with nuclear BACH1 turnover. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Nucleus {ECO:0000269|PubMed:24035498, ECO:0000269|PubMed:27234298} |
| GO:0005634 nucleus | IDA PMID:27234298 SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signa... | ACCEPT | Summary: Direct evidence for nuclear localization from the SUFU/Hedgehog study, where FBXL17 ubiquitinates SUFU in the nucleus. Reason: IDA-supported nuclear localization consistent with nuclear SUFU turnover. Supporting Evidence: PMID:27234298 Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus |
| GO:0005737 cytoplasm | IDA PMID:24035498 Parallel SCF adaptor capture proteomics reveals a role for S... | ACCEPT | Summary: Direct evidence for cytoplasmic localization. Consistent with the UniProt note that FBXL17 is more abundant in the cytoplasm. Reason: IDA-supported localization; FBXL17 is present in both compartments. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Present in the cytoplasm and nucleus; more abundant in the cytoplasm. |
| GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | IDA PMID:30190310 Dimerization quality control ensures neuronal development an... | ACCEPT | Summary: Direct evidence that SCF(FBXL17) performs dimerization quality control, selectively clearing aberrant-composition BTB dimers. This is the distinctive core process of FBXL17. 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. Supporting Evidence: PMID:30190310 the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation file:human/FBXL17/FBXL17-deep-research-falcon.md Under oxidative/nitrosative stress, **FBXL17 can recognize a compromised/destabilized BTB dimer and remodel it into monomers** that are ubiquitinated. |
| GO:0007399 nervous system development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer (from Xenopus ortholog) of a nervous-system development role, consistent with the DQC requirement for neuronal survival. Reason: Plausible downstream developmental role consistent with the DQC study, but a generic process distinct from the core substrate-receptor activity. Supporting Evidence: PMID:30190310 SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells |
| GO:0008589 regulation of smoothened signaling pathway | IMP PMID:27234298 SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signa... | KEEP AS NON CORE | Summary: Mutant-phenotype evidence that FBXL17, by degrading SUFU, regulates Hedgehog/Smoothened signaling; depletion causes defective Hh signaling. Reason: Well-supported downstream regulatory role (via SUFU turnover) but a context-specific pathway outcome rather than the core ligase substrate-receptor function. Supporting Evidence: PMID:27234298 Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth |
| GO:0014033 neural crest cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of a neural-crest differentiation role, consistent with the DQC study showing SCF(FBXL17) is required for neural crest differentiation. Reason: Plausible developmental role supported by the DQC study, but downstream of and distinct from the core substrate-receptor activity. Supporting Evidence: PMID:30190310 SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells |
| GO:0016567 protein ubiquitination | IDA PMID:24035498 Parallel SCF adaptor capture proteomics reveals a role for S... | ACCEPT | Summary: Direct evidence that FBXL17 mediates ubiquitination of BACH1. A general parent of the SCF-dependent catabolic process. Reason: Directly demonstrated substrate ubiquitination; accurate though the SCF-dependent catabolic process term is more specific. Supporting Evidence: PMID:24035498 FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 |
| GO:0016567 protein ubiquitination | IDA PMID:30190310 Dimerization quality control ensures neuronal development an... | ACCEPT | Summary: Direct evidence that SCF(FBXL17) ubiquitinates aberrant BTB dimers during DQC. A general parent of the SCF-dependent catabolic process. Reason: Directly demonstrated substrate ubiquitination; accurate though the SCF-dependent catabolic process term is more specific. Supporting Evidence: PMID:30190310 the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:24035498 Parallel SCF adaptor capture proteomics reveals a role for S... | ACCEPT | Summary: Direct evidence that FBXL17 is part of an SCF (SKP1-CUL1-RBX1-FBXL17) E3 ubiquitin ligase complex. Core cellular component. Reason: Core complex membership; FBXL17 is the substrate-recognition subunit of SCF(FBXL17). Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL17) composed of CUL1, SKP1, RBX1 and FBXL17 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:24035498 Parallel SCF adaptor capture proteomics reveals a role for S... | ACCEPT | Summary: Direct evidence that SCF(FBXL17) drives proteasomal degradation of BACH1. Core biological process. Reason: Core biological process directly supported by BACH1 turnover. Supporting Evidence: PMID:24035498 FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:27234298 SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signa... | ACCEPT | Summary: Direct evidence that SCF(FBXL17) drives proteasomal degradation of SUFU. Core biological process. Reason: Core biological process directly supported by SUFU turnover. Supporting Evidence: PMID:27234298 Fbxl17 (F-box and leucine-rich repeat protein 17) targets Sufu for proteolysis in the nucleus |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:30190310 Dimerization quality control ensures neuronal development an... | ACCEPT | Summary: Direct evidence that aberrant BTB dimers recognized by SCF(FBXL17) are cleared by proteasomal degradation. A parent of the SCF-dependent catabolic process. Reason: Directly supported proteasomal degradation of DQC substrates; accurate, with GO:0031146 being the more specific SCF-dependent term. Supporting Evidence: PMID:30190310 BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation |
| GO:1990756 ubiquitin-like ligase-substrate adaptor activity | IDA PMID:30190310 Dimerization quality control ensures neuronal development an... | NEW | 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. Reason: Captures the precise molecular function of FBXL17 as an SCF substrate-recognition adaptor, more informative than the bare protein binding annotations. Supporting Evidence: file:human/FBXL17/FBXL17-uniprot.txt Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
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