FBXL20

UniProt ID: A0A9L0IQA3
Organism: Equus asinus
Review Status: COMPLETE
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Gene Description

FBXL20 (F-box/LRR-repeat protein 20; SCRAPPER in mouse) is a substrate-recognition subunit of SCF (SKP1-CUL1-RBX1) E3 ubiquitin ligase complexes. Its N-terminal F-box binds SKP1, linking it to the cullin-RING catalytic core, and its C-terminal leucine-rich repeat domain binds substrates, which are polyubiquitinated and degraded by the proteasome. A C-terminal CAAX-type prenylation motif targets the protein to membranes. In mouse neurons SCRAPPER is enriched at the presynaptic membrane and is the main ubiquitin ligase for the active-zone protein RIM1, tuning synaptic vesicle release; in human cells FBXL20 targets the class III PI3K VPS34/PIK3C3 for degradation after DNA damage, restraining autophagy, and promotes ubiquitination and degradation of the PP2A regulatory subunit PR55alpha/PPP2R2A. The donkey gene product A0A9L0IQA3 (448 aa) is an alternative-first-exon form of FBXL20 that differs from the canonical 436-aa mammalian protein only in its first 26 residues and retains the complete F-box, LRR domain and CAAX motif.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		ACCEPT
Summary: Cytoplasm, from the UniProt subcellular-location mapping (the donkey SubCell line is itself an ARBA prediction). FBXL20 orthologs are cytoplasmic SCF substrate receptors that associate with membranes through C-terminal prenylation.
Reason: Consistent with the reviewed human ortholog (Cytoplasm, by similarity) and with the mouse ortholog acting as a prenylated, membrane-associated E3 on the cytoplasmic face of the presynaptic membrane. The donkey product keeps the CAAX tail, so the same location applies. Membrane association is an additional, not contradictory, location; no more specific cytoplasmic term is supported for this product without tissue context.
Supporting Evidence:
file:human/FBXL20/FBXL20-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
PMID:17803915
The CAAX domain is a carboxyl-terminal membrane-sorting signal induced by prenylation
file:EQUAS/FBXL20/FBXL20-bioinformatics/RESULTS-rereview.md
Downstream of the motif, A0A9L0IQA3 has the same 422-residue length as the
GO:0019005 SCF ubiquitin ligase complex
IEA
GO_REF:0000118 		ACCEPT
Summary: SCF ubiquitin ligase complex, from TreeGrafter grafting into PANTHER PTHR13318 (subfamily SF47, F-box/LRR-repeat protein 20). The same term reaches mouse Fbxl20 by IBA from the PAINT node PTN002547163, and mouse SCRAPPER was shown to form an SCF complex with Skp1 and Cullin1 in brain.
Reason: The donkey protein is in the FBXL20 subfamily (PTHR13318:SF47) together with the reviewed human, mouse and bovine FBXL20, and it retains the F-box (34-80) that mediates SKP1 binding. SCF membership is experimentally established for the mouse ortholog and is the PAINT-curated ancestral state of the clade.
Supporting Evidence:
PMID:17803915
Similarly, SCRAPPER formed an SCF complex with Skp1 and Cullin1 in mouse brain lysates
PMID:34731788
an F-box protein that serves as a substrate recognition component of the SCF (Skp1_Cul1_F-box) E3 ubiquitin ligase complexes that promote proteasomal degradation
file:human/FBXL20/FBXL20-uniprot.txt
SUBUNIT: Interacts with SKP1 and CUL1. {ECO:0000250}.
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
IEA
GO_REF:0000118 		ACCEPT
Summary: SCF-dependent proteasomal protein catabolism, from TreeGrafter. Mouse SCRAPPER mediates ubiquitination and proteasomal degradation of RIM1, and human FBXL20 that of VPS34 and PR55alpha.
Reason: FBXL20 performs part of this process itself, as the subunit that binds and selects the substrate for SCF-catalysed ubiquitination; knockout of the mouse ortholog lengthens RIM1 half-life and reduces its ubiquitination. Same term and node as the PAINT IBD propagated to mouse Fbxl20.
Supporting Evidence:
PMID:17803915
In neurons from Scrapper -knockout (SCR-KO) mice, RIM1 had a longer half-life with significant reduction in ubiquitination, indicating that SCRAPPER is the predominant ubiquitin ligase that mediates RIM1 degradation.
PMID:33234069
Removal of Vps34 by Fbxl20-mediated ubiquitination leads to inhibition of autophagy.
PMID:34731788
reduced protein expression of FBXL20 and decreased ubiquitination of PR55Ξ±.
GO:1990756 ubiquitin-like ligase-substrate adaptor activity
ISS
PMID:34731788
p53/FBXL20 axis negatively regulates the protein stability o... 		NEW
Summary: FBXL20 binds substrates (RIM1 in mouse, VPS34 and PR55alpha in human) through its LRR domain and links them to the SCF core through its F-box; this adaptor activity is its molecular function.
Reason: None of the donkey GOA rows captures the molecular function. Transferred from the FBXL20 orthologs of the same PANTHER subfamily (SF47), where mouse SCRAPPER binds RIM1 and is required for its ubiquitination and human FBXL20 binds PR55alpha and is required for its ubiquitination. The PAINT tree has IBDs for this term at other PTHR13318 nodes (PTN004419270, PTN009029653) but not on the FBXL20 lineage, whose donors carry no experimental MF annotation beyond protein binding; the absence reflects missing descendant MF evidence, not a curated exclusion. The donkey product retains every domain needed (F-box, LRR, CAAX).
Supporting Evidence:
PMID:34731788
FBXL20 interacts with PR55Ξ± in vitro and in vivo
PMID:34731788
an F-box protein that serves as a substrate recognition component of the SCF (Skp1_Cul1_F-box) E3 ubiquitin ligase complexes that promote proteasomal degradation
PMID:17803915
Consistent with a function as a ubiquitin ligase, ubiquitinated proteins coimmunoprecipitated (co-IPed) with FLAG-tagged SCRAPPER (FLAG-SCR) from lysates of MG132-treated (a proteasome inhibitor) cells
file:EQUAS/FBXL20/FBXL20-bioinformatics/RESULTS-rereview.md
Downstream of the motif, A0A9L0IQA3 has the same 422-residue length as the

Core Functions

Substrate-recognition subunit of SCF E3 ubiquitin ligase complexes; binds SKP1 through its F-box and substrates (such as RIM1, VPS34 and PR55alpha in other mammals) through its LRR domain, directing them to ubiquitination and proteasomal degradation.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
cytoplasm
In Complex:
SCF ubiquitin ligase complex
Supporting Evidence:
  • PMID:17803915
    Similarly, SCRAPPER formed an SCF complex with Skp1 and Cullin1 in mouse brain lysates
  • PMID:34731788
    an F-box protein that serves as a substrate recognition component of the SCF (Skp1_Cul1_F-box) E3 ubiquitin ligase complexes that promote proteasomal degradation
  • PMID:33234069
    Removal of Vps34 by Fbxl20-mediated ubiquitination leads to inhibition of autophagy.

References

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Suggested Questions for Experts

Q: Which FBXL20 first exons are used in donkey tissues, and does the alternative N-terminal segment of A0A9L0IQA3 (also found in horse F6YIL4) change localization, stability or substrate choice relative to the canonical MRRDVNGVTKSRFE start?

Q: Does donkey FBXL20 regulate VPS34 levels and autophagy after DNA damage, and RIM1 turnover at presynaptic terminals, as its human and mouse orthologs do?

Suggested Experiments

Experiment: RT-PCR or long-read transcript sequencing of donkey brain and other tissues to determine which FBXL20 first exons are expressed, followed by comparison of the encoded N-terminal variants for SKP1 binding and membrane association.

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML Β· FBXL20-protnlm-predictions-review.yaml Β· Review status: COMPLETE

Assessment of 3 ProtNLM2 GO predictions for donkey FBXL20 (A0A9L0IQA3), an alternative-first-exon product that keeps the canonical F-box, LRR domain and CAAX tail. Donkey GOA has cytoplasm, SCF ubiquitin ligase complex and SCF-dependent proteasomal protein catabolism, and the gene review adds ubiquitin-like ligase-substrate adaptor activity. Protein phosphatase binding (PR55alpha/PPP2R2A, a PP2A regulatory subunit) and regulation of autophagy (FBXL20-mediated VPS34 degradation) are supported by experimental work on the human ortholog and are absent from donkey GOA (COR). Protein monoubiquitination is not supported, because the characterised FBXL20 substrates are polyubiquitinated and degraded, and monoubiquitination is only raised as an untested possibility (UNC). No non-GO ProtNLM2 outputs (function text or location) were emitted for this accession.

Source documents: projects/PROTNLM_EVALUATION/donkey40/donkey40-predictions.tsv Β· genes/EQUAS/FBXL20/FBXL20-goa.tsv Β· genes/EQUAS/FBXL20/FBXL20-ai-review.yaml Β· genes/human/FBXL20/FBXL20-uniprot.txt Β· genes/EQUAS/FBXL20/FBXL20-bioinformatics/RESULTS-rereview.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0019903 protein phosphatase binding GO_MF
COR β€” Correct novel prediction Review score: 2/2
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-10-14
Review rationale: Human FBXL20 binds PR55alpha (PPP2R2A), a regulatory subunit of the PP2A serine/threonine phosphatase, in vitro and in cells, and promotes its ubiquitination and degradation (PMID:34731788). The donkey product shares the canonical 422-residue F-box/LRR/CAAX body with human FBXL20 (same PANTHER subfamily PTHR13318:SF47), so the substrate-binding LRR domain is intact. The binding is a substrate-recognition interaction, so the term is correct but less informative than the adaptor activity the gene review records. Neither donkey GOA nor the human and mouse orthologs carry a phosphatase-binding term (human has only generic protein binding by IPI), so the prediction is novel.
Supporting Evidence:
GO:0006513 protein monoubiquitination GO_BP
UNC β€” Uncertain Review score: 1/2
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-10-14
Review rationale: Characterised SCF(FBXL20) substrates (RIM1 in mouse, VPS34 and PR55alpha in human) are ubiquitinated and degraded by the proteasome, which implies polyubiquitination. The only mention of monoubiquitination is the mouse SCRAPPER study stating that RIM1 monoubiquitination cannot be excluded, which was not tested. The term is neither validated nor refuted, and it is not in donkey GOA or the gene review.
Supporting Evidence:
  • PMID:17803915: "At present we cannot exclude the possibility that monoubiquitination of RIM1 by SCRAPPER may also regulate RIM1 before RIM1 is polyubiquitinated and degraded by the proteasome."
  • PMID:34731788: "an F-box protein that serves as a substrate recognition component of the SCF (Skp1_Cul1_F-box) E3 ubiquitin ligase complexes that promote proteasomal degradation"
GO:0010506 regulation of autophagy GO_BP
COR β€” Correct novel prediction Review score: 2/2
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-10-14
Review rationale: In human cells FBXL20 knockdown induces autophagy flux and raises VPS34 and PtdIns3P, and DNA damage induces p53-dependent FBXL20 expression that drives SCF-mediated VPS34 degradation and inhibits autophagy (PMID:25593308). FBXL20 thus acts as a negative regulator of autophagy; negative regulation of autophagy would be the more precise term. Donkey GOA, the donkey gene review and the human and mouse orthologs carry no autophagy term, so the prediction is novel. Transfer rests on the shared FBXL20 subfamily and the intact F-box and LRR domains of the donkey product.
Supporting Evidence:
  • PMID:25593308: "FBXL20 was identified in a genome-wide siRNA screen as a gene when its expression was knocked down, leading to the induction of autophagy flux and increases in the levels of PtdIns3P"
  • PMID:25593308: "Taken together, these results suggest that FBXL20–SKP1–CUL1 regulates the levels of Vps34 and autophagy through a proteasomal pathway."
  • PMID:33234069: "Removal of Vps34 by Fbxl20-mediated ubiquitination leads to inhibition of autophagy."
  • file:EQUAS/FBXL20/FBXL20-bioinformatics/RESULTS-rereview.md: "Downstream of the motif, A0A9L0IQA3 has the same 422-residue length as the"

Deep Research

Cyberian

(FBXL20-deep-research-cyberian.md)

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πŸ“š Additional Documentation

Notes

(FBXL20-notes.md)

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Bioinformatics Results

(RESULTS.md)

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