FBXL17

UniProt ID: Q9UF56
Organism: Homo sapiens
Review Status: COMPLETE
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Gene 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.

Proposed New Ontology Terms

dimerization quality control of BTB-domain protein assemblies

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:

Existing Annotations Review

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

Core Functions

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:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
nucleus cytoplasm
Supporting Evidence:
  • PMID:24035498
    FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1
  • file:human/FBXL17/FBXL17-uniprot.txt
    Substrate-recognition component of the SCF(FBXL17) E3 ubiquitin ligase complex

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:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
protein quality control for misfolded or incompletely synthesized proteins
Cellular Locations:
cytoplasm
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

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
PMID:24035498
Parallel SCF adaptor capture proteomics reveals a role for SCFFBXL17 in NRF2 activation via BACH1 repressor turnover.
  • 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.
PMID:27234298
SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development.
  • FBXL17 targets SUFU for nuclear polyubiquitination and degradation, releasing GLI1 for Hedgehog signal transduction; FBXL17 depletion impairs Hh signaling and medulloblastoma growth.
PMID:27705803
A High-Density Map for Navigating the Human Polycomb Complexome.
PMID:30190310
Dimerization quality control ensures neuronal development and survival.
  • 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.
PMID:33234069
The FBXL family of F-box proteins: variations on a theme.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35869491
FBXL17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia.
PMID:40205054
Multimodal cell maps as a foundation for structural and functional genomics.
Reactome:R-HSA-9708517
FBXL17 ubiquitinates BACH1 (in BACH1:FBXL17:SCF (SKP2))
Reactome:R-HSA-9708525
BACH1:FBXL17 binds SCF(SKP2) complex
Reactome:R-HSA-9708557
FBXL17 binds BACH1:MAFK
file:human/FBXL17/FBXL17-deep-research-falcon.md
Falcon deep research report for human FBXL17
  • 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.
    "In this paradigm, **FBXL17 is the substrate receptor** that helps determine which proteins are ubiquitinated and often targeted for proteasomal degradation."
  • 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.
    "Under oxidative/nitrosative stress, **FBXL17 can recognize a compromised/destabilized BTB dimer and remodel it into monomers** that are ubiquitinated."
  • SCF(FBXL17) targets the Hedgehog pathway tumor suppressor SUFU for nuclear proteolysis, enabling GLI activation and Hedgehog signal transduction.
    "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."
  • PRMT1 is a PTM-gated FBXL17 substrate; p300 acetylation at K228 creates an acetyl-degron that promotes FBXL17 binding and K48-linked polyubiquitination.
    "PRMT1 is regulated by SCF(FBXL17) such that **p300-mediated acetylation at PRMT1 K228** promotes FBXL17 binding, **K48-linked polyubiquitination**, and proteasomal degradation."
  • In neuronal models SCF(FBXL17) targets the long spastin isoform SPAST-M1 for proteasomal degradation via recognition of its N-terminal BTB domain.
    "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**."

Suggested Questions for Experts

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?

Suggested Experiments

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.

Deep Research

Falcon

(FBXL17-deep-research-falcon.md)
Research Report: Human **FBXL17** (UniProt **Q9UF56**) β€” Functional Annotation and Current Understanding Falcon Edison Scientific Literature 23 citations 1 artifacts 2026-06-13T06:16:17.629832
## Context ID: pqac-00000034 The requested information is primarily illustrated in Figures 6 and 7. Figure 7 provides a schematic model of the oxidative stress- (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human FBXL17 (UniProt Q9UF56) β€” Functional Annotation and Current Understanding

1. Target verification (identity, domains, and family)

Gene/protein verified: The literature summarized here addresses human FBXL17 (F-box and leucine-rich repeat protein 17), consistent with UniProt accession Q9UF56, an SCF (SKP1–CUL1–RBX1) cullin-RING E3 ubiquitin ligase substrate receptor/adaptor. FBXL17 contains an F-box domain (binds SKP1 and enables SCF assembly) and a C-terminal leucine-rich repeat (LRR) region (substrate-binding). Experimental studies demonstrate that FBXL17 assembles with SCF subunits and that truncations in the LRR region disrupt SCF subunit association and E3 activity. (mason2020fbxl17isrearranged pages 6-7, mason2020fbxl17isrearranged pages 4-6)

Subcellular distribution (baseline): FBXL17 is predominantly nuclear, but is also detectable in cytoplasmic fractions; immunofluorescence of transfected constructs showed mainly nuclear staining with weaker cytoplasmic signal. (mason2020fbxl17isrearranged pages 6-7)

2. Key concepts and definitions (current understanding)

2.1 SCF E3 ubiquitin ligases and F-box proteins

SCF complexes are modular ubiquitin ligases consisting of a cullin scaffold (CUL1), RBX1 (recruits E2~ubiquitin), SKP1, and an F-box substrate receptor that provides specificity by binding substrates and bringing them to the catalytic core. In this paradigm, FBXL17 is the substrate receptor that helps determine which proteins are ubiquitinated and often targeted for proteasomal degradation. (raducu2016scf(fbxl17)ubiquitylation pages 1-2, raducu2016scf(fbxl17)ubiquitylation pages 2-3)

2.2 Degrons and post-translational modification (PTM)-gated recognition

A degron is a substrate feature recognized by an E3 ligase that triggers ubiquitination. A central recent theme for FBXL17 is non-canonical degron recognition, including:

  • Quaternary-structure degrons: degrons created by higher-order assemblies (e.g., dimer interfaces), rather than linear motifs. BACH1’s BTB homodimer can encode such degrons that are decoded by F-box proteins. (cao2024recognitionofbach1 pages 42-45, cao2024recognitionofbach1 pages 1-3)
  • PTM-gated degrons: PTMs can create or strengthen E3 recognition determinants. For example, PRMT1 acetylation at K228 promotes FBXL17 binding and degradation. (najar2024theinterplayof pages 11-15, najar2024theinterplayof pages 15-17)

3. Experimentally validated molecular functions, substrates/partners, pathways, and localization

3.1 Hedgehog signaling via SUFU ubiquitination (nuclear)

Core function: 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. (raducu2016scf(fbxl17)ubiquitylation pages 1-2)

Evidence and quantitative data: FBXL17 co-immunoprecipitates with SKP1/CUL1 and specifically interacts with SUFU among screened F-box proteins; LC-MS/MS from FBXL17 IPs identified SUFU (Mascot score 112; emPAI 0.27) alongside SCF components, with BACH1 also detected (Mascot score 59; emPAI 0.04). (raducu2016scf(fbxl17)ubiquitylation pages 2-3)

Mechanistic detail (sites): One analysis summarized SUFU ubiquitination at Lys257 and regulation by SUFU phosphorylation state (dephosphorylation at S342/S346 favoring polyubiquitination), consistent with a regulated nuclear turnover model. (mason2020functionalanalysisof pages 45-49)

Functional consequence (disease model): FBXL17 depletion led to defective Hedgehog signaling and impaired proliferation and medulloblastoma tumor growth in model systems, supporting a functional FBXL17–SUFU axis in Hedgehog-driven tumor biology. (raducu2016scf(fbxl17)ubiquitylation pages 1-2)

Publication details: Raducu et al., The EMBO Journal, May 2016. URL: https://doi.org/10.15252/embj.201593374 (raducu2016scf(fbxl17)ubiquitylation pages 1-2)

3.2 Oxidative stress / NRF2 transcriptional response via BACH1 turnover

3.2.1 Foundational mechanism (2013): FBXL17 promotes BACH1 turnover and NRF2 activation

Core function: FBXL17 promotes ubiquitination and proteasome-dependent turnover of BACH1, a transcriptional repressor whose degradation permits NRF2-driven activation of oxidative stress genes such as HMOX1. (tan2013parallelscfadaptor pages 12-14)

Quantitative data:
* Hemin-induced HMOX1 transcript induction is typically 25–35-fold; depletion of FBXL17 reduced this induction to <10-fold (noting incomplete knockdown with ~20% FBXL17 mRNA remaining). (tan2013parallelscfadaptor pages 12-14)
* In a hydrogen peroxide time course, control cells showed ~40% decrease in BACH1 after 30 min, whereas FBXL17 depletion produced a ~2-fold increase in BACH1; FBXL17 depletion also produced a ~3-fold increase in ROS after H2O2 priming. (tan2013parallelscfadaptor pages 12-14)

Publication details: Tan et al., Molecular Cell, Oct 2013. URL: https://doi.org/10.1016/j.molcel.2013.08.018 (tan2013parallelscfadaptor pages 12-14)

3.2.2 Major 2024 advance: quaternary-structure degrons and remodeling/monomerization mechanism

Key concept: A major 2024 mechanistic advance is that the BACH1 BTB homodimer encodes quaternary-structure degrons and is surveilled by distinct SCF ligases. Under oxidative/nitrosative stress, FBXL17 can recognize a compromised/destabilized BTB dimer and remodel it into monomers that are ubiquitinated. (cao2024recognitionofbach1 pages 42-45, cao2024recognitionofbach1 pages 1-3)

Mechanistic details:
* The Cell 2024 work describes a Ξ²1–α6 cross-protomer degron in BACH1 BTB recognized by FBXO22 when the BTB dimer is intact; when BTB integrity is compromised (e.g., oxidation/S-nitrosylation), FBXL17 transiently engages the weakened dimer and remodels it into a stably bound monomer for ubiquitination. (cao2024recognitionofbach1 pages 42-45)
* Biophysical/structural evidence includes SEC-MALS complex formation with MBP-FBXL17–SKP1 and BACH1-BTB and cryo-EM visualization of FBXL17-LRR bound to monomeric BACH1-BTB and dimeric SCF-FBXL17–BACH1 complexes. (cao2024recognitionofbach1 pages 35-42, cao2024recognitionofbach1 pages 45-47)

Data availability (expert-useful resources): The Cell 2024 paper reports deposition of multiple relevant structures (e.g., PDB entries for FBXL17 complexes including 8UAH, 8UBT, 8UBU, 8UBV) and associated EM maps and proteomics/HDX-MS datasets. (cao2024recognitionofbach1 pages 45-47)

Publication details: Cao et al., Cell, Dec 2024. URL: https://doi.org/10.1016/j.cell.2024.10.012 (cao2024recognitionofbach1 pages 1-3)

Visual evidence (from Cell 2024): Figures depicting the FBXL17-driven remodeling mechanism and pathway model were retrieved from the paper. (cao2024recognitionofbach1 media ec0b2e4d, cao2024recognitionofbach1 media adac7532, cao2024recognitionofbach1 media 611fb043, cao2024recognitionofbach1 media 25687a82)

3.3 PRMT1 homeostasis via an acetylation-dependent FBXL17 β€œacetyl-degron” (2024)

Core finding: PRMT1 is regulated by SCF(FBXL17) such that p300-mediated acetylation at PRMT1 K228 promotes FBXL17 binding, K48-linked polyubiquitination, and proteasomal degradation. (najar2024theinterplayof pages 11-15, najar2024theinterplayof pages 15-17)

Evidence:
* FBXL17 interacts with PRMT1 (co-IP and MS); FBXL17 overexpression lowers endogenous PRMT1, and FBXL17 knockout extends PRMT1 half-life and reduces PRMT1 ubiquitination. (najar2024theinterplayof pages 11-15)
* Site specificity: acetylation at K228 (not K233) increases FBXL17 interaction and accelerates PRMT1 degradation; K228Q (acetyl-mimic) strongly enhances ubiquitination and lowers half-life, while K228R stabilizes PRMT1. (najar2024theinterplayof pages 11-15)
* A genetic code expansion strategy was used to site-specifically incorporate authentic acetyl-lysine at K228, strengthening mechanistic inference that acetylation itself can be causal for degradation. (najar2024theinterplayof pages 15-17)

Publication details: Najar et al., bioRxiv preprint, June 18, 2024. URL: https://doi.org/10.1101/2024.06.18.599616 (najar2024theinterplayof pages 1-3)

3.4 Neuronal microtubule regulation via SPAST (spastin) turnover; hereditary spastic paraplegia (HSP) context (2022)

Core finding: In neuronal models, 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. (kang2022fbxl17spastinaxisas pages 1-2, kang2022fbxl17spastinaxisas pages 7-9)

Localization: Endogenous FBXL17 is mainly nuclear; SPAST is distributed in cytoplasm and nucleus and colocalizes with FBXL17 in nuclear compartments. Polyubiquitinated SPAST-M1 was observed only in the nuclear fraction in fractionation experiments. (kang2022fbxl17spastinaxisas pages 9-11)

Mechanistic details and quantitative elements:
* FBXL17 expression reduces SPAST-M1 protein without changing mRNA; CHX chase suggests SPAST-M1 half-life decreases from >4 h to ~3 h with FBXL17 expression (approximate values from text). (kang2022fbxl17spastinaxisas pages 9-11)
* A key ubiquitination site was implicated: SPAST K554R strongly reduced polyubiquitination. (kang2022fbxl17spastinaxisas pages 7-9)
* Modulation by CK2 phosphorylation: SPAST-M1 phosphorylation occurs in cytoplasm; CK2 perturbation affects ubiquitination/stability, with phosphomimetic mutants showing markedly increased stability and reduced ubiquitination. (kang2022fbxl17spastinaxisas pages 11-13)

Translational implication: Pharmacologic inhibition of cullin neddylation (MLN4924) or FBXL17 knockdown increased SPAST levels and was reported to improve neuronal phenotypes (axonal/neurite extension; rescue in 3D differentiation models), framing the FBXL17/SPAST axis as a potential therapeutic target in HSP models. (kang2022fbxl17spastinaxisas pages 1-2, kang2022fbxl17spastinaxisas pages 13-15)

Publication details: Kang et al., Cell & Bioscience, July 2022. URL: https://doi.org/10.1186/s13578-022-00851-1 (kang2022fbxl17spastinaxisas pages 1-2)

3.5 Protein interaction and metabolic regulation: UAP1 and O-GlcNAcylation (2020)

Core findings: A yeast two-hybrid screen identified UAP1 as a frequent FBXL17 interactor; cellular assays supported direct binding. Knockdown of FBXL17 increased global O-GlcNAcylation in breast cancer cells, and a proposed mechanism is that FBXL17 binding to UAP1 protects UAP1 from inhibitory phosphorylation, maintaining UAP1 activity rather than targeting it for degradation. (mason2020thefbxlfamily pages 9-10, mason2020fbxl17isrearranged pages 6-7)

Domain dependence and interaction mapping: UAP1 binding was mapped to the LRR region (e.g., LRR2–8 sufficient for UAP1 binding in one mapping), and LRR truncation disrupted binding. (mason2020fbxl17isrearranged pages 6-7)

Publication details: Mason et al., Cellular and Molecular Life Sciences, Sep 2020. URL: https://doi.org/10.1007/s00018-019-03306-y (mason2020fbxl17isrearranged pages 6-7)

4. Recent developments (2023–2024 prioritized)

4.1 2024: Structural mechanism for BACH1 quaternary-structure degrons (high impact)

The most substantial recent advance is the Cell (Dec 2024) study detailing how FBXL17 decodes oxidative-stress-altered BACH1 BTB assemblies via remodeling/monomerization, supported by cryo-EM and complementary biophysical methods, and accompanied by deposition of structural models and proteomics datasets. (cao2024recognitionofbach1 pages 1-3, cao2024recognitionofbach1 pages 45-47)

4.2 2024: PTM-gated substrate control via PRMT1 acetylation

The 2024 preprint establishes a detailed model in which p300-dependent acetylation at PRMT1 K228 acts as an acetyl-degron recognized by FBXL17, linking acetylation to K48 ubiquitination and turnover with extensive genetic and biochemical support. (najar2024theinterplayof pages 11-15, najar2024theinterplayof pages 15-17)

4.3 2024: Human genetics association signals (emerging; not mechanistic proof)

A Mendelian randomization analysis of circadian rhythm–related genes reported associations implicating FBXL17 among candidates related to ulcerative colitis comorbidity with primary sclerosing cholangitis, suggesting possible broader disease relevance (requires mechanistic follow-up). (goretzki2024structuralbasisof pages 1-4)

5. Current applications and real-world implementations

5.1 Cancer biology: pathway leverage points

  • Hedgehog-driven cancers / medulloblastoma: The FBXL17–SUFU axis provides a mechanistic lever on GLI activation and proliferation/tumor growth phenotypes in medulloblastoma models, highlighting FBXL17 as a potential pathway-modulating target (though no FBXL17-directed therapeutics are established in the cited primary evidence). (raducu2016scf(fbxl17)ubiquitylation pages 1-2)
  • Oxidative stress response and metastasis biology: Because BACH1 promotes metastasis when aberrantly accumulated, the 2024 structural work explicitly highlights therapeutic opportunities to destabilize BACH1 via understanding ligase recognition and degron mechanisms involving FBXL17 (conceptual/early-stage). (cao2024recognitionofbach1 pages 42-45)

5.2 Neurobiology: modulation of SCF/CRL activity in HSP models

In HSP-relevant cellular models, inhibiting cullin neddylation (MLN4924) and/or downregulating FBXL17 increased SPAST levels and improved neuronal phenotypes (axonal extension/differentiation readouts), representing a concrete experimental β€œimplementation” of pathway modulation. (kang2022fbxl17spastinaxisas pages 1-2, kang2022fbxl17spastinaxisas pages 13-15)

5.3 Biomarker/target hypotheses from genetics databases

Open Targets lists multiple disease associations for FBXL17 (e.g., post-traumatic stress disorder, neurotic disorder, smoking initiation), based on aggregated evidence; these should be treated as hypothesis-generating signals rather than direct functional annotation. (OpenTargets Search: -FBXL17)

6. Expert opinions and authoritative synthesis

A focused review of the FBXL family emphasizes that FBXL proteins share LRR-based recognition but can have distinct interactomes and regulatory features; for FBXL17, the review highlights non-degradative functional regulation of UAP1 and discusses predicted additional N-terminal structural features and potential phosphorylation-based regulation. (mason2020thefbxlfamily pages 9-10)

The 2013 Molecular Cell study and the 2024 Cell study (both high-authority sources for mechanistic cell biology) together support the view that FBXL17 is not merely a generic turnover factor but a specialized adaptor that can decode complex substrate states, including higher-order assemblies and oxidative/nitrosative stress-induced conformations, making FBXL17 a component of β€œprotein quality control”-like pathways focused on specific transcription factor families. (tan2013parallelscfadaptor pages 12-14, cao2024recognitionofbach1 pages 42-45)

7. Statistics and data highlights (from cited studies)

  • BACH1/NRF2 axis: Hemin induces HMOX1 25–35Γ—, reduced to <10Γ— with FBXL17 depletion; BACH1 decreases ~40% after 30 min H2O2 in controls but increases ~2Γ— with FBXL17 depletion; FBXL17 depletion yields ~3Γ— ROS increase after H2O2 priming. (tan2013parallelscfadaptor pages 12-14)
  • SUFU interaction proteomics: SUFU detected in FBXL17 IP LC-MS/MS with Mascot score 112 (emPAI 0.27); FBXL17 itself Mascot score 33624 (emPAI 178.17). (raducu2016scf(fbxl17)ubiquitylation pages 2-3)
  • SCF assembly defects in cancer-associated truncations (CMLS 2020): LRR truncations reduced CUL1 binding by 81–82% and SKP1 binding by 67–77% with strong statistical support (p-values ~10^-4 to 10^-6; n=4–5). (mason2020fbxl17isrearranged pages 4-6)
  • SPAST turnover: FBXL17 expression reduced SPAST-M1 half-life (approx. >4 h to ~3 h) and identified a major ubiquitination site (K554). (kang2022fbxl17spastinaxisas pages 9-11, kang2022fbxl17spastinaxisas pages 7-9)

8. Practical functional annotation summary (best-supported)

Primary molecular role: FBXL17 is an SCF E3 ubiquitin ligase substrate receptor that recruits specific substratesβ€”often nuclear regulatorsβ€”for ubiquitination, frequently leading to proteasomal degradation (e.g., SUFU, BACH1, PRMT1, SPAST-M1). (raducu2016scf(fbxl17)ubiquitylation pages 1-2, tan2013parallelscfadaptor pages 12-14, najar2024theinterplayof pages 11-15, kang2022fbxl17spastinaxisas pages 1-2)

Key biological processes/pathways:
1. Hedgehog signaling via nuclear SUFU turnover and GLI activation (tumor biology relevance). (raducu2016scf(fbxl17)ubiquitylation pages 1-2)
2. Oxidative stress response/NRF2 signaling via BACH1 turnover, including advanced recognition of oxidative/nitrosative stress-altered BTB assemblies. (tan2013parallelscfadaptor pages 12-14, cao2024recognitionofbach1 pages 42-45)
3. Protein homeostasis via PTM-gated degradation (PRMT1 acetyl-degron). (najar2024theinterplayof pages 11-15)
4. Neuronal microtubule/axon biology via SPAST-M1 turnover; HSP disease-model relevance. (kang2022fbxl17spastinaxisas pages 1-2)
5. Metabolic/PTM regulation via UAP1 interaction and global O-GlcNAcylation changes. (mason2020thefbxlfamily pages 9-10, mason2020fbxl17isrearranged pages 6-7)

Subcellular localization (where function is carried out): Strong evidence supports nuclear FBXL17 activity for SUFU, BACH1, and SPAST-M1 degradation/ubiquitination; FBXL17 is mainly nuclear but also present in cytoplasmic fractions. (raducu2016scf(fbxl17)ubiquitylation pages 1-2, kang2022fbxl17spastinaxisas pages 9-11, mason2020fbxl17isrearranged pages 6-7)

9. Limitations and open questions

  • Substrate scope is incomplete: FBXL17 likely has additional substrates beyond those validated here; proteomic approaches suggest broader interactomes, but high-confidence, mechanism-resolved substrates remain limited. (tan2013parallelscfadaptor pages 12-14, mason2020fbxl17isrearranged pages 6-7)
  • Degron β€œrules” are still being defined: While quaternary-structure degrons (BACH1 BTB) and PTM-gated recognition (PRMT1 K228 acetylation) are now supported, generalizable motifs for FBXL17 are not yet established from the cited evidence. (cao2024recognitionofbach1 pages 42-45, najar2024theinterplayof pages 11-15)
  • Translational readiness: Therapeutic concepts are emerging (e.g., BACH1 destabilization strategies; CRL inhibition in neuronal models), but FBXL17-specific inhibitors/clinical implementations were not identified in the retrieved evidence. (cao2024recognitionofbach1 pages 42-45, kang2022fbxl17spastinaxisas pages 1-2)

Key references (URLs and dates)

  1. Tan MKM et al. Molecular Cell (Oct 2013): https://doi.org/10.1016/j.molcel.2013.08.018 (tan2013parallelscfadaptor pages 12-14)
  2. Raducu M et al. The EMBO Journal (May 2016): https://doi.org/10.15252/embj.201593374 (raducu2016scf(fbxl17)ubiquitylation pages 1-2)
  3. Mason B et al. Cellular and Molecular Life Sciences (Sep 2020): https://doi.org/10.1007/s00018-019-03306-y (mason2020fbxl17isrearranged pages 6-7)
  4. Mason B, Laman H. Open Biology (Nov 2020): https://doi.org/10.1098/rsob.200319 (mason2020thefbxlfamily pages 9-10)
  5. Kang HM et al. Cell & Bioscience (Jul 2022): https://doi.org/10.1186/s13578-022-00851-1 (kang2022fbxl17spastinaxisas pages 1-2)
  6. Cao S et al. Cell (Dec 2024): https://doi.org/10.1016/j.cell.2024.10.012 (cao2024recognitionofbach1 pages 1-3)
  7. Najar MA et al. bioRxiv (Jun 18, 2024): https://doi.org/10.1101/2024.06.18.599616 (najar2024theinterplayof pages 1-3)

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  16. (cao2024recognitionofbach1 media 25687a82): Shiyun Cao, Sheena Faye Garcia, Huigang Shi, Ellie I James, Yuki Kito, Huigang Shi, Haibin Mao, Sharon Kaisari, G. RΓ³na, Sophia Deng, Hailey V. Goldberg, Jackeline Ponce, Beatrix M. Ueberheide, Luca Lignitto, Miklos Guttman, Michele Pagano, and Ning Zheng. Recognition of bach1 quaternary structure degrons by two f-box proteins under oxidative stress. Dec 2024. URL: https://doi.org/10.1016/j.cell.2024.10.012, doi:10.1016/j.cell.2024.10.012. This article has 40 citations and is from a highest quality peer-reviewed journal.

  17. (najar2024theinterplayof pages 1-3): Mohd. Altaf Najar, Jenna N. Beyer, Callie E. W. Crawford, and George M. Burslem. The interplay of acetylation and ubiquitination controls prmt1 homeostasis. bioRxiv, Jun 2024. URL: https://doi.org/10.1101/2024.06.18.599616, doi:10.1101/2024.06.18.599616. This article has 3 citations.

  18. (kang2022fbxl17spastinaxisas pages 1-2): Hyun Mi Kang, Dae Hun Kim, Mijin Kim, Yoohong Min, Bohyeon Jeong, Kyung Hee Noh, Da Yong Lee, Hyun-Soo Cho, Nam-Soon Kim, Cho-Rok Jung, and Jung Hwa Lim. Fbxl17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia. Cell & Bioscience, Jul 2022. URL: https://doi.org/10.1186/s13578-022-00851-1, doi:10.1186/s13578-022-00851-1. This article has 10 citations and is from a peer-reviewed journal.

  19. (kang2022fbxl17spastinaxisas pages 7-9): Hyun Mi Kang, Dae Hun Kim, Mijin Kim, Yoohong Min, Bohyeon Jeong, Kyung Hee Noh, Da Yong Lee, Hyun-Soo Cho, Nam-Soon Kim, Cho-Rok Jung, and Jung Hwa Lim. Fbxl17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia. Cell & Bioscience, Jul 2022. URL: https://doi.org/10.1186/s13578-022-00851-1, doi:10.1186/s13578-022-00851-1. This article has 10 citations and is from a peer-reviewed journal.

  20. (kang2022fbxl17spastinaxisas pages 9-11): Hyun Mi Kang, Dae Hun Kim, Mijin Kim, Yoohong Min, Bohyeon Jeong, Kyung Hee Noh, Da Yong Lee, Hyun-Soo Cho, Nam-Soon Kim, Cho-Rok Jung, and Jung Hwa Lim. Fbxl17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia. Cell & Bioscience, Jul 2022. URL: https://doi.org/10.1186/s13578-022-00851-1, doi:10.1186/s13578-022-00851-1. This article has 10 citations and is from a peer-reviewed journal.

  21. (kang2022fbxl17spastinaxisas pages 11-13): Hyun Mi Kang, Dae Hun Kim, Mijin Kim, Yoohong Min, Bohyeon Jeong, Kyung Hee Noh, Da Yong Lee, Hyun-Soo Cho, Nam-Soon Kim, Cho-Rok Jung, and Jung Hwa Lim. Fbxl17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia. Cell & Bioscience, Jul 2022. URL: https://doi.org/10.1186/s13578-022-00851-1, doi:10.1186/s13578-022-00851-1. This article has 10 citations and is from a peer-reviewed journal.

  22. (kang2022fbxl17spastinaxisas pages 13-15): Hyun Mi Kang, Dae Hun Kim, Mijin Kim, Yoohong Min, Bohyeon Jeong, Kyung Hee Noh, Da Yong Lee, Hyun-Soo Cho, Nam-Soon Kim, Cho-Rok Jung, and Jung Hwa Lim. Fbxl17/spastin axis as a novel therapeutic target of hereditary spastic paraplegia. Cell & Bioscience, Jul 2022. URL: https://doi.org/10.1186/s13578-022-00851-1, doi:10.1186/s13578-022-00851-1. This article has 10 citations and is from a peer-reviewed journal.

  23. (mason2020thefbxlfamily pages 9-10): Bethany Mason and Heike Laman. The fbxl family of f-box proteins: variations on a theme. Nov 2020. URL: https://doi.org/10.1098/rsob.200319, doi:10.1098/rsob.200319. This article has 51 citations and is from a peer-reviewed journal.

  24. (goretzki2024structuralbasisof pages 1-4): Benedikt Goretzki, Maryam Khoshouei, Patrick Penner, Christine Stephan, Dayana Argoti, Nele Dierlamm, Jimena Maria Rada, Sandra Kapps, Zacharias Thiel, Merve Mutlu, David Furkert, Catrin Swantje MΓΌller, Felix Freuler, Simon Haenni, Laurent Tenaillon, Britta Knapp, Alexandra Hinniger, Philipp Hoppe, Sascha Gutmann, Grigory Ryzhakov, Enrico Schmidt, Mario Iurlaro, and CΓ©sar FernΓ‘ndez. Structural basis of dual bach1 regulation by scffbxo22 and scffbxl17. bioRxiv, Jun 2024. URL: https://doi.org/10.1101/2024.06.03.596960, doi:10.1101/2024.06.03.596960. This article has 0 citations.

  25. (OpenTargets Search: -FBXL17): Open Targets Query (-FBXL17, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

Artifacts

## Context ID: pqac-00000034 The requested information is primarily illustrated in Figures 6 and 7. Figure 7 provides a schematic model of the oxidative stress-

Citations

  1. mason2020functionalanalysisof pages 45-49
  2. tan2013parallelscfadaptor pages 12-14
  3. najar2024theinterplayof pages 11-15
  4. najar2024theinterplayof pages 15-17
  5. najar2024theinterplayof pages 1-3
  6. goretzki2024structuralbasisof pages 1-4
  7. mason2020thefbxlfamily pages 9-10
  8. https://doi.org/10.15252/embj.201593374
  9. https://doi.org/10.1016/j.molcel.2013.08.018
  10. https://doi.org/10.1016/j.cell.2024.10.012
  11. https://doi.org/10.1101/2024.06.18.599616
  12. https://doi.org/10.1186/s13578-022-00851-1
  13. https://doi.org/10.1007/s00018-019-03306-y
  14. https://doi.org/10.1098/rsob.200319
  15. https://doi.org/10.1007/s00018-019-03306-y,
  16. https://doi.org/10.15252/embj.201593374,
  17. https://doi.org/10.1016/j.cell.2024.10.012,
  18. https://doi.org/10.1101/2024.06.18.599616,
  19. https://doi.org/10.17863/cam.51955,
  20. https://doi.org/10.1016/j.molcel.2013.08.018,
  21. https://doi.org/10.1186/s13578-022-00851-1,
  22. https://doi.org/10.1098/rsob.200319,
  23. https://doi.org/10.1101/2024.06.03.596960,

πŸ“š Additional Documentation

Pn Notes

(FBXL17-pn-notes.md)

FBXL17 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q9UF56
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-13
  • Batch change status: added

Source Files Checked

Deep Research Files

AIGR Review Snapshot

  • 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.
  • Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 11; NEW: 1

PN Consistency Summary

  • Consistency: Strong. Falcon, review YAML, and PN mapping agree FBXL17 is the SCF(FBXL17) substrate receptor. Multiple validated substrates: BACH1 (PMID:24035498), SUFU (PMID:27234298), and the hallmark dimerization quality control (DQC) of aberrant BTB dimers (PMID:30190310, IDA). Falcon adds the 2024 remodeling/monomerization mechanism (vs FBXO22 reading intact dimers), PRMT1 acetyl-degron, and SPAST-M1 β€” well-grounded; non-canonical recognition consistently captured. No contradictions.
  • PN story / NEW pressure: PN asserts generic adaptor MF (GO:1990756, verified real); GOA carries only protein binding (IPI) as MF. Review adds GO:1990756 as NEW IDA; bare protein binding (SKP1, BACH1, SUFU, KLHL12, SPAST) kept non-core. Correct. The distinctive DQC biology IS a genuine gap: review maps it to GO:0006515 (protein QC for misfolded/incomplete proteins, verified real) but flags that this does not capture quaternary-structure/dimer-interface surveillance, and proposes a NEW BP "dimerization quality control of BTB-domain protein assemblies" (candidate, UNVERIFIED β€” not yet a real GO ID; defensible, well-justified, parent GO:0006515). Conclusion: adaptor MF ADDED correctly; DQC NEW term is a strong candidate awaiting GO submission.
  • Evidence alignment: PN reference only "15340381/rev" (placeholder); review does not cite it. Review uses three primary PMIDs (24035498, 27234298, 30190310, all verified) + falcon. Strong, gene-specific evidence; benign divergence from placeholder.
  • Verdict: CONSISTENT / ACCEPT mapping. No YAML edits required. Flag: non-canonical (DQC) recognition β€” noted in brief; group GO:1990756 still valid. DQC NEW BP term is candidate/unverified (worth proposing to GO).

Full Consistency Review

  • UniProt: Q9UF56 Β· batch: proteostasis-batch-2026-06-13 Β· review status: COMPLETE
  • PN placement: UPS|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR ; PN-node mapping: group-level mapped / ok_for_propagation_to_go / GO:1990756; F-box+LRR subtype/type no_mapping; class context_only / too_broad / GO:0061630; branch no_mapping.
  • Consistency: Strong. Falcon, review YAML, and PN mapping agree FBXL17 is the SCF(FBXL17) substrate receptor. Multiple validated substrates: BACH1 (PMID:24035498), SUFU (PMID:27234298), and the hallmark dimerization quality control (DQC) of aberrant BTB dimers (PMID:30190310, IDA). Falcon adds the 2024 remodeling/monomerization mechanism (vs FBXO22 reading intact dimers), PRMT1 acetyl-degron, and SPAST-M1 β€” well-grounded; non-canonical recognition consistently captured. No contradictions.
  • PN story / NEW pressure: PN asserts generic adaptor MF (GO:1990756, verified real); GOA carries only protein binding (IPI) as MF. Review adds GO:1990756 as NEW IDA; bare protein binding (SKP1, BACH1, SUFU, KLHL12, SPAST) kept non-core. Correct. The distinctive DQC biology IS a genuine gap: review maps it to GO:0006515 (protein QC for misfolded/incomplete proteins, verified real) but flags that this does not capture quaternary-structure/dimer-interface surveillance, and proposes a NEW BP "dimerization quality control of BTB-domain protein assemblies" (candidate, UNVERIFIED β€” not yet a real GO ID; defensible, well-justified, parent GO:0006515). Conclusion: adaptor MF ADDED correctly; DQC NEW term is a strong candidate awaiting GO submission.
  • Mapping strategy: Gene does not change the group node, but is the strongest non-canonical F-box in the set β€” it recognizes a quaternary degron via dimerization-quality-control, not a linear/single-protomer degron. Adaptor MF (GO:1990756) still applies (it does form a productive SCF and ubiquitinates substrates), so the group mapping holds. Substrates validated β†’ not orphan. Catalysis correctly excluded from sub-nodes.
  • Evidence alignment: PN reference only "15340381/rev" (placeholder); review does not cite it. Review uses three primary PMIDs (24035498, 27234298, 30190310, all verified) + falcon. Strong, gene-specific evidence; benign divergence from placeholder.
  • Verdict: CONSISTENT / ACCEPT mapping. No YAML edits required. Flag: non-canonical (DQC) recognition β€” noted in brief; group GO:1990756 still valid. DQC NEW BP term is candidate/unverified (worth proposing to GO).

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-13
  • review_yaml: genes/human/FBXL17/FBXL17-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul1 substrate receptor | F-box | LRR

  • UniProt: Q9UF56
  • In branches: UPS
  • Signature domains: IPR001810
  • Auxiliary domains: IPR001611, IPR032675
  • PN references (titles):
    • 15340381 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box|LRR
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor|F-box
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
      rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul1 substrate receptor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

πŸ“„ View Raw YAML

 
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.