Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of nuclear localization, the predominant compartment where SCF(FBXL3) degrades CRY. Core localization. Reason: Core localization; SCF(FBXL3) acts mainly in the nucleus to degrade CRY1/CRY2. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2
GO:0005829 cytosol	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic assignment of cytosolic localization, a secondary compartment relative to the dominant nuclear pool. Reason: Cytoplasmic localization is documented but the predominantly nuclear pool drives the core CRY-degradation function. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Note=Predominantly nuclear.
GO:0043153 entrainment of circadian clock by photoperiod	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic assignment of involvement in circadian-clock entrainment. FBXL3 sets clock period via CRY degradation; the more direct process term is regulation of circadian rhythm. Reason: FBXL3 governs the circadian oscillator, but the specific "entrainment by photoperiod" framing is narrower than its core period-setting role captured by regulation of circadian rhythm. Supporting Evidence: PMID:17463251 Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated electronic assignment of nuclear localization, the core compartment for SCF(FBXL3) function. Reason: Core localization; redundant with IBA/ISS/IDA evidence. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Nucleus {ECO:0000269\|PubMed:10531035}
GO:0005737 cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location. A secondary compartment. Reason: Cytoplasmic pool is documented but secondary to the predominantly nuclear localization. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005515 protein binding	IPI PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ...	KEEP AS NON CORE	Summary: Interactions with CRY1/CRY2 (and SCF components) from the foundational circadian study. Bare protein binding is uninformative. Reason: Records the functionally central CRY1/CRY2 interactions but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Interacts with CRY1 and CRY2 (phosphorylated)
GO:0005515 protein binding	IPI PMID:23503662 SCF(FBXL3) ubiquitin ligase targets cryptochromes at their c...	KEEP AS NON CORE	Summary: Interaction with CRY2 captured in the structural study of the FBXL3-SKP1-CRY2 complex. Bare protein binding is uninformative. Reason: Records the structurally defined FBXL3-CRY2 interaction but bare protein binding is uninformative. Supporting Evidence: PMID:23503662 the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Binary interactome reference map interactions. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Q9UKT7; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-2557269, EBI-79165
GO:0004842 ubiquitin-protein transferase activity	IEA GO_REF:0000107	MODIFY	Summary: Ortholog-based electronic assignment of ubiquitin-protein transferase activity, with the contributes_to qualifier acknowledging FBXL3's role within the multi-subunit SCF ligase. As the F-box substrate receptor, FBXL3 does not itself catalyze ubiquitin transfer. Reason: FBXL3 is the substrate-recognition subunit, not the catalytic core (RBX1/CUL1 mediates ubiquitin transfer); the informative molecular function is ubiquitin-like ligase-substrate adaptor activity. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex
GO:0005829 cytosol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of cytosolic localization. A secondary compartment. Reason: Cytoplasmic pool documented but secondary to the predominantly nuclear localization. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0016567 protein ubiquitination	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Combined automated electronic assignment of protein ubiquitination, a parent of the specific SCF-dependent CRY ubiquitination. Reason: Correct but generic; the specific SCF-dependent catabolic process annotation better captures the role. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ortholog-based electronic assignment of SCF-dependent proteasomal degradation, the core biological process of SCF(FBXL3). Reason: Core biological process; redundant with the experimental IDA evidence (CRY degradation). Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0031648 protein destabilization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of protein destabilization, reflecting FBXL3-driven CRY destabilization. A generic parent of its ubiquitin-mediated degradation role. Reason: Correct but generic; the SCF-dependent catabolic process annotation captures the specific mechanism (CRY degradation). Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0042752 regulation of circadian rhythm	IEA GO_REF:0000120	ACCEPT	Summary: Combined automated electronic assignment of regulation of circadian rhythm, the core physiological process of FBXL3. Reason: Core biological process; redundant with the experimental IMP evidence (Fbxl3 controls clock oscillations). Supporting Evidence: PMID:17463251 Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
GO:0043153 entrainment of circadian clock by photoperiod	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of circadian entrainment. FBXL3 sets clock period; the broader regulation of circadian rhythm term is more apt. Reason: FBXL3 governs the oscillator, but the narrower photoperiod-entrainment framing is secondary to its core period-setting role. Supporting Evidence: PMID:17463251 Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Ortholog-based electronic assignment of proteasome-mediated ubiquitin-dependent degradation, a parent of the specific SCF-dependent CRY degradation. Reason: Correct but generic; subsumed by the more specific SCF-dependent proteasomal catabolic process annotation. Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0016604 nuclear body	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Direct immunofluorescence (HPA) evidence for localization to nuclear bodies, consistent with the predominantly nuclear pool of FBXL3. Reason: IDA-supported sub-nuclear localization consistent with the nuclear site of action, but a specific sub-compartment; core localization is the nucleus. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Note=Predominantly nuclear.
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: Author-statement (FBXL family review) assignment of the core SCF-dependent proteasomal degradation process. Reason: Core biological process; consistent with the experimental CRY-degradation evidence. Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0042752 regulation of circadian rhythm	NAS PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ...	ACCEPT	Summary: Author-statement assignment of the core circadian-regulation process from the foundational study. Reason: Core biological process directly supported by the same study's functional experiments. Supporting Evidence: PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins
GO:0031648 protein destabilization	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity assignment of protein destabilization, reflecting FBXL3-driven CRY destabilization. A generic parent of its degradation role. Reason: Correct but generic; the SCF-dependent catabolic process annotation captures the specific mechanism. Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0005829 cytosol	TAS Reactome:R-HSA-8952618	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (neddylation of CRL1). Generic CRL-pathway localization; secondary to the nuclear pool. Reason: Correct cytosolic compartment but from generic CRL neddylation-pathway context; FBXL3 is predominantly nuclear. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-8952620	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (NEDD8:UBE2M binds CRL1). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955241	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRL). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-8955289	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (COMMDs displace CAND1). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956040	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates CRL). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-8956200	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (DCUN1D3 binds CRL1). Generic CRL-pathway localization. Reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-983140	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-983147	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-983156	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	TAS Reactome:R-HSA-983157	KEEP AS NON CORE	Summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub). Generic ubiquitination-pathway localization. Reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0005829 cytosol	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity assignment of cytosolic localization. A secondary compartment. Reason: Cytoplasmic pool documented but secondary to the predominantly nuclear localization. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Cytoplasm {ECO:0000269\|PubMed:10531035}. Note=Predominantly nuclear.
GO:0016567 protein ubiquitination	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity assignment of protein ubiquitination, a parent of the specific SCF-dependent CRY ubiquitination. Reason: Correct but generic; the SCF-dependent catabolic process annotation better captures the role. Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0043153 entrainment of circadian clock by photoperiod	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity assignment of circadian entrainment. FBXL3 sets clock period; the broader regulation of circadian rhythm term is more apt. Reason: FBXL3 governs the oscillator, but the narrower photoperiod-entrainment framing is secondary to its core period-setting role. Supporting Evidence: PMID:17463251 Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: Sequence-similarity assignment of nuclear localization, the core compartment for SCF(FBXL3) function. Reason: Core localization; redundant with IBA/IEA/IDA evidence. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Nucleus {ECO:0000269\|PubMed:10531035}
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ...	MODIFY	Summary: Direct evidence that FBXL3, within the SCF(FBXL3) complex, contributes to ubiquitin transfer onto CRY. The contributes_to qualifier reflects FBXL3's role as the substrate-receptor subunit of the multi-subunit ligase rather than the catalytic core. Reason: FBXL3 is the substrate-recognition subunit; catalytic ubiquitin transfer is performed by RBX1/CUL1. The informative molecular function is ubiquitin-like ligase-substrate adaptor activity. (Activity is real within the SCF complex, hence MODIFY rather than REMOVE.) Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex file:human/FBXL3/FBXL3-deep-research-falcon.md FBXL3 is an F-box protein that specifies substrate recognition within an SCF-type cullin-RING ligase, i.e., SCF^FBXL3 = SKP1–CUL1–RBX1–FBXL3, where SKP1 binds the F-box domain and FBXL3’s LRR domain mediates substrate recognition
GO:0019005 SCF ubiquitin ligase complex	IDA PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ...	ACCEPT	Summary: Direct evidence that FBXL3 is part of the SCF (SKP1-CUL1-F-box) E3 ligase complex. Core cellular component. Reason: Core cellular component; FBXL3 is the F-box substrate receptor of the SCF(FBXL3) complex. Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	IDA PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ...	ACCEPT	Summary: Direct evidence that SCF(FBXL3) drives proteasomal degradation of CRY1/CRY2. Core biological process. Reason: Core biological process directly demonstrated; FBXL3 targets CRY for SCF-dependent degradation. Supporting Evidence: PMID:17463251 both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
GO:0042752 regulation of circadian rhythm	IMP PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ...	ACCEPT	Summary: Mutant-phenotype evidence (Fbxl3 silencing, Cry-null epistasis) that FBXL3 controls circadian clock oscillation. Core biological process. Reason: Core biological process with direct IMP support; Fbxl3 silencing has no effect in Cry1/Cry2-null cells, demonstrating it acts via CRY degradation. Supporting Evidence: PMID:17463251 Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
GO:0016567 protein ubiquitination	NAS PMID:10531035 Identification of a family of human F-box proteins.	KEEP AS NON CORE	Summary: Author-statement assignment (original F-box family paper) of involvement in protein ubiquitination. Generic but correct. Reason: Correct but generic; the SCF-dependent catabolic process annotation better captures the role. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0000151 ubiquitin ligase complex	NAS PMID:10531035 Identification of a family of human F-box proteins.	KEEP AS NON CORE	Summary: Author-statement assignment of being part of a ubiquitin ligase complex. A generic parent of the specific SCF complex. Reason: Correct but generic; subsumed by the specific SCF ubiquitin ligase complex annotation. Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL3)
GO:0004842 ubiquitin-protein transferase activity	NAS PMID:10531035 Identification of a family of human F-box proteins.	MODIFY	Summary: Author-statement assignment of ubiquitin-protein transferase activity from the original F-box family paper. As the F-box substrate receptor, FBXL3 does not itself catalyze ubiquitin transfer. Reason: FBXL3 is the substrate-recognition subunit, not the catalytic core; the informative molecular function is ubiquitin-like ligase-substrate adaptor activity. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: file:human/FBXL3/FBXL3-uniprot.txt Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex

Core Functions

Functions as the substrate-recognition (F-box) subunit of the nuclear SCF (SKP1-CUL1-RBX1-FBXL3) cullin-RING E3 ubiquitin ligase that recruits the cryptochrome repressors CRY1 and CRY2 for polyubiquitination and proteasomal degradation, thereby setting the period and robustness of the mammalian circadian clock.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

regulation of circadian rhythm SCF-dependent proteasomal ubiquitin-dependent protein catabolic process

Cellular Locations:

nucleus

Supporting Evidence:

PMID:17463251
both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex

Recognizes cryptochrome substrates through a structurally defined mechanism in which a conserved FBXL3 C-terminal tail occupies the CRY FAD-binding pocket and buries the CRY PER-binding interface, a substrate interaction antagonized by FAD and the Period proteins. Substrate (CRY1) binding itself promotes assembly of the SCF(FBXL3) holocomplex, and FBXL3 elongates K48-linked polyubiquitin chains on CRY; this activity is counterbalanced by the paralogous SCF(FBXL21) ligase, which binds CRY more strongly but ubiquitinates it less efficiently, thereby stabilizing CRY.

Molecular Function:

ubiquitin-like ligase-substrate adaptor activity

Directly Involved In:

regulation of circadian rhythm

Cellular Locations:

nucleus

Supporting Evidence:

PMID:23503662
the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface
file:human/FBXL3/FBXL3-deep-research-falcon.md
In transfected mammalian cells, FBXL3 did not substantially associate with SKP1/CUL1 unless its substrate **CRY1** was expressed; a CRY1-binding-defective FBXL3 mutant failed to form the SCF complex in vivo, supporting a substrate-dependent assembly mechanism

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

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

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10531035

Identification of a family of human F-box proteins.

PMID:17463251

SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.

CRY1 and CRY2 are ubiquitinated and degraded by the SCF(Fbxl3) ubiquitin ligase complex; this is a prerequisite for timely reactivation of CLOCK-BMAL1; Fbxl3 silencing has no effect in Cry1/Cry2-null cells, showing FBXL3 controls clock oscillations via CRY degradation.

PMID:23503662

SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket.

Crystal structures of CRY2 (apo, FAD-bound, and FBXL3-SKP1-complexed) show FBXL3 captures CRY2 by inserting a conserved C-terminal tail into the FAD-binding pocket and burying the PER-binding interface; this interaction is displaced by FAD and PERs.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33234069

The FBXL family of F-box proteins: variations on a theme.

Review of the FBXL family describing FBXL3 as an SCF substrate receptor mediating SCF-dependent proteasomal degradation of its targets.

Reactome:R-HSA-8952618

AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8952620

NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-8955241

CAND1 binds cytosolic CRL E3 ubiquitin ligases

Reactome:R-HSA-8955289

COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956040

COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes

Reactome:R-HSA-8956200

MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex

Reactome:R-HSA-983140

Transfer of Ub from E2 to substrate and release of E2

Reactome:R-HSA-983147

Release of E3 from polyubiquitinated substrate

Reactome:R-HSA-983156

Polyubiquitination of substrate

Reactome:R-HSA-983157

Interaction of E3 with substrate and E2-Ub complex

file:human/FBXL3/FBXL3-deep-research-falcon.md

Falcon deep research report for human FBXL3

FBXL3 is the substrate-recognition subunit of the nuclear SCF(FBXL3) (SKP1-CUL1-RBX1-FBXL3) E3 ligase, where SKP1 binds the F-box domain and the LRR domain recognizes the CRY substrates that are degraded to control the circadian transcription-translation feedback loop.

"FBXL3 is an **F-box protein** that specifies substrate recognition within an SCF-type cullin-RING ligase, i.e., **SCF^FBXL3 = SKP1–CUL1–RBX1–FBXL3**, where SKP1 binds the **F-box domain** and FBXL3’s **LRR domain** mediates substrate recognition"
SCF(FBXL3) assembly is substrate-driven - FBXL3 does not robustly associate with SKP1/CUL1 unless its substrate CRY1 is present, so CRY availability gates ligase assembly and activity.

"In transfected mammalian cells, FBXL3 did not substantially associate with SKP1/CUL1 unless its substrate **CRY1** was expressed; a CRY1-binding-defective FBXL3 mutant failed to form the SCF complex in vivo, supporting a substrate-dependent assembly mechanism"
FBXL3 catalyzes K48-linked polyubiquitin chain elongation on CRY proteins (reported across ~11 lysines on CRY1), targeting them for proteasomal degradation more efficiently than the antagonistic paralog FBXL21.

"A recent Endocrinology review states that FBXL3 catalyzes elongation of **K48-linked polyubiquitin** chains on CRYs, consistent with canonical proteasome-targeting ubiquitin signals"
Disrupting the FBXL3-CRY interaction stabilizes the CRY repressors and lengthens circadian period (to ~26-27 h), directly linking FBXL3-mediated CRY degradation kinetics to clock period; the FBXL3-occupied CRY FAD pocket is a validated small-molecule (KL001-class) target.

"Mutations that disrupt FBXL3–CRY binding stabilize CRYs and can lengthen circadian period; one review reports in vivo period lengthening to **~26–27 h** in FBXL3 mutant contexts"

Suggested Experiments

Experiment: Reconstitute SCF(FBXL3)-mediated CRY2 ubiquitination in vitro with purified SKP1, CUL1, RBX1, an E2, and wild-type versus C-terminal-tail or pocket-mutant FBXL3, and titrate FAD and PER proteins to quantify how cofactor and competitor occupancy controls substrate ubiquitination.

Experiment: Perform time-resolved quantitative proteomics in FBXL3-knockout versus wild-type cells across the circadian cycle to confirm CRY1/CRY2 as the dominant rhythmic substrates and to identify any additional FBXL3 targets relevant to the developmental disorder phenotype.

Deep Research

Falcon

(FBXL3-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 32 citations 2 artifacts 2026-06-13T06:06:41.152946

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000018 The requested structural panel is Supplementary Figure 7a, located on page 8 of the Supplementary Information. This panel illustrat (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 FBXL3 (UniProt Q9UKT7) functional annotation

0) Target verification (mandatory)

The literature retrieved here consistently refers to FBXL3 as a human F-box/leucine-rich repeat (LRR) protein that functions as the substrate-recognition subunit of an SCF (SKP1–CUL1–RBX1) E3 ubiquitin ligase targeting cryptochromes (CRY1/CRY2) for ubiquitin-dependent proteasomal degradation, matching the UniProt Q9UKT7 description and domain architecture (F-box + LRR) (calloni2023thestructuraland pages 3-4, calloni2023thestructuraland pages 2-3). No conflicting gene with the same symbol in another organism was used for the mechanistic claims.

1) Key concepts & definitions (current understanding)

1.1 FBXL3 as an SCF E3 ubiquitin ligase substrate receptor

FBXL3 is an F-box protein that specifies substrate recognition within an SCF-type cullin-RING ligase, i.e., SCF^FBXL3 = SKP1–CUL1–RBX1–FBXL3, where SKP1 binds the F-box domain and FBXL3’s LRR domain mediates substrate recognition (yumimoto2013substratebindingpromotes pages 1-2, calloni2023thestructuraland pages 2-3). In circadian biology, SCF^FBXL3 is a core post-translational regulator of the mammalian transcription–translation feedback loop (TTFL) by controlling the turnover of CRY repressors (rosensweig2020periodicityrepressionand pages 13-14, calloni2023thestructuraland pages 2-3).

1.2 Primary substrates: CRY1 and CRY2

A central and repeatedly supported function of FBXL3 is to recognize, ubiquitinate, and promote proteasomal degradation of the circadian repressors CRY1 and CRY2, thereby influencing circadian period length and rhythm robustness (calloni2023thestructuraland pages 3-4, yumimoto2013substratebindingpromotes pages 1-2, rosensweig2020periodicityrepressionand pages 13-14).

1.3 Relationship to FBXL21 and the PER proteins

FBXL3 works in a network of clock-protein stability regulators. A key concept is functional antagonism between FBXL3 and its paralog FBXL21: FBXL21 binds CRYs strongly but ubiquitinates less efficiently, helping stabilize CRYs and antagonize FBXL3-driven degradation (calloni2023thestructuraland pages 3-4, rosensweig2020periodicityrepressionand pages 13-14). PER proteins can also protect CRYs by competing with FBXL3 for overlapping binding interfaces on CRY (rosensweig2020periodicityrepressionand pages 13-14, chan2023watchingtheclock pages 6-7).

2) Molecular function, mechanism, and pathway placement

2.1 Substrate-dependent SCF^FBXL3 assembly (regulatory logic)

In cells, FBXL3 shows an unusual regulatory feature: SCF complex formation is strongly promoted by substrate binding, especially CRY1. In transfected mammalian cells, FBXL3 did not substantially associate with SKP1/CUL1 unless its substrate CRY1 was expressed; a CRY1-binding-defective FBXL3 mutant failed to form the SCF complex in vivo, supporting a substrate-dependent assembly mechanism (yumimoto2013substratebindingpromotes pages 1-2, yumimoto2013substratebindingpromotes pages 10-10). This implies that CRY availability can regulate FBXL3 E3 ligase assembly/activity.

2.2 Structural mechanism of CRY recognition: “cofactor pocket capture”

Crystal structures show that FBXL3 recognizes CRY through a bipartite interface in which a conserved C-terminal tail of FBXL3 inserts into the CRY FAD-binding pocket in the photolyase homology region (PHR), while other contacts engage the broader CRY surface (xing2013scffbxl3ubiquitinligase pages 13-16, calloni2023thestructuraland pages 3-4). The CRY2–FBXL3–SKP1 complex was solved at 2.7 Å resolution (xing2013scffbxl3ubiquitinligase pages 13-16). This mechanism explains why the CRY cofactor pocket is also a druggable site (see §4).

Visual evidence: the insertion of the FBXL3 C-terminal tail into the CRY2 pocket is shown in a structural panel retrieved from the Nature 2013 study (xing2013scffbxl3ubiquitinligase media 0c122a57).

2.3 Competition with FAD and PER proteins

Because FBXL3 occupies the CRY FAD-binding pocket, FAD can compete with FBXL3 and displace it in vitro; a 2023 review reports measured FAD-binding affinities for human CRYs of Kd ≈ 16 μM (CRY1) and Kd ≈ 68 μM (CRY2), supporting partial occupancy and potential regulation by local flavin pools (calloni2023thestructuraland pages 3-4). PER proteins can also exclude FBXL3 from CRY complexes because PER and FBXL3 share overlapping binding locations on CRY, thereby stabilizing CRYs against degradation (rosensweig2020periodicityrepressionand pages 13-14, chan2023watchingtheclock pages 6-7).

2.4 Ubiquitination chemistry (linkage type and site breadth)

A recent Endocrinology review states that FBXL3 catalyzes elongation of K48-linked polyubiquitin chains on CRYs, consistent with canonical proteasome-targeting ubiquitin signals (sato2023circadianregulationof pages 10-10). A circadian clock structural review also reports that FBXL3 ubiquitinates CRY more efficiently than FBXL21 and that FBXL3 was reported to ubiquitinate 11 lysine residues on CRY1, whereas FBXL21 targets a single site (K11) in a secondary pocket (rosensweig2020periodicityrepressionand pages 13-14).

2.5 Cellular localization

FBXL3 is described as nuclear, while FBXL21 is described as mainly cytosolic, with FBXL3–CRY interactions reported as entirely nuclear in a structural circadian clock review (calloni2023thestructuraland pages 3-4, rosensweig2020periodicityrepressionand pages 13-14). This spatial separation supports a model in which FBXL21 can buffer/sequester CRYs outside the nucleus and modulate how much CRY is available for FBXL3-mediated nuclear degradation.

2.6 System-level role in circadian period determination

Mutations that disrupt FBXL3–CRY binding stabilize CRYs and can lengthen circadian period; one review reports in vivo period lengthening to ~26–27 h in FBXL3 mutant contexts (rosensweig2020periodicityrepressionand pages 13-14, rosensweig2020periodicityrepressionand pages 11-13). This connects the molecular action (CRY degradation) to the macroscopic phenotype (clock period).

3) Recent developments (prioritizing 2023–2024)

3.1 Chemical chronobiology: targeting the CRY–FBXL3 interface

A 2023 Cell Chemical Biology review summarizes the most mature chemical strategy: stabilizing CRY1/2 by blocking FBXL3 access to the FAD pocket. In a phenotypic circadian screen, KL001 was identified as a first-in-class CRY1/2 stabilizer that produces period lengthening and amplitude reduction by competing with FBXL3 for binding at the CRY FAD pocket (laothamatas2023metabolicandchemical pages 10-11). The same review describes translational use cases: KL001 can inhibit glucagon-induced gluconeogenesis in primary hepatocytes and inhibit glioblastoma stem cell proliferation, supporting metabolic and oncology applications of manipulating the CRY–FBXL3 axis (laothamatas2023metabolicandchemical pages 10-11).

The 2023 review also reports development of derivatives, including KL101 (CRY1-selective), TH301 (moderate preference for CRY2), and SHP1703 (a more potent and bioavailable CRY2-selective derivative) with reported survival benefit in glioblastoma stem cell–transplanted mice (laothamatas2023metabolicandchemical pages 10-11).

3.2 Clock biology in cancer contexts (biomarker framing)

A 2023 Neuro-Oncology review discusses circadian components as potential biomarkers and therapeutic levers in glioblastoma; mechanistically it notes that PER::CRY complex formation can inhibit FBXL3 targeting of CRY1/2, thereby protecting CRYs from degradation (chan2023watchingtheclock pages 6-7). While this is not FBXL3-only, it places FBXL3-controlled CRY turnover within an emerging “clock as cancer biology” framework.

3.3 Human genetics signals involving FBXL3

A 2024 cohort study of consanguineous families with neurodevelopmental disorders lists a pathogenic FBXL3 frameshift variant c.884delT, p.(Leu295Tyrfs*25) (autosomal recessive), supporting that loss-of-function variants in FBXL3 occur in human disease genetics (paracha2024thegeneticcause pages 9-10). Separately, a 2023 review of circadian gene variants summarizes familial advanced sleep-phase disorder (FASPD) mechanisms in which a CRY2 variant is proposed to increase accessibility/affinity for the E3 ligase FBXL3, leading to increased CRY2 degradation; this underscores the physiological importance of the FBXL3–CRY interaction surface even when the variant is in CRY2 rather than FBXL3 (grskovic2023circadiangenevariants pages 8-9).

4) Current applications and real-world implementations

4.1 Metabolic regulation (preclinical/experimental)

Chemical stabilization of CRYs at the FBXL3-binding pocket (KL001 class) has been used experimentally to modulate metabolism, including inhibition of glucagon-induced gluconeogenesis in primary hepatocyte culture (laothamatas2023metabolicandchemical pages 10-11). This represents a practical implementation of FBXL3 functional knowledge: modulating the degradation of CRY repressors changes downstream metabolic gene regulation.

4.2 Oncology (preclinical and early translational framing)

The KL001 derivative landscape is explicitly connected to glioblastoma in the 2023 review (inhibition of glioblastoma stem cell proliferation; survival extension in a mouse transplant model for a CRY2-selective derivative) (laothamatas2023metabolicandchemical pages 10-11).

A 2024 MDPI paper (published 28 Dec 2024) evaluates TH301 (described as a CRY2 stabilizer) in pancreatic ductal adenocarcinoma (PDAC) cell lines, reporting dose-dependent anti-oncogenic effects and synergy with chloroquine and oxaliplatin (farmakis2024th301emergesas pages 1-2). Although the paper’s mechanistic focus is broader than FBXL3, the chemical premise traces back to blocking FBXL3-mediated degradation at the CRY pocket as summarized in chemical chronobiology reviews (laothamatas2023metabolicandchemical pages 10-11).

5) Expert opinions & analysis (authoritative synthesis)

Structural and biochemical reviews emphasize that protein turnover (especially CRY stability) is a dominant determinant of circadian periodicity and that FBXL3 functions as a central “timer” by setting CRY degradation kinetics; disruptions of FBXL3–CRY binding stabilize repressors and lengthen the clock (rosensweig2020periodicityrepressionand pages 13-14, rosensweig2020periodicityrepressionand pages 11-13). The 2023 chemical-architecture review frames CRY–FBXL3 pocket competition as a uniquely tractable and validated molecular interface for drug discovery within the TTFL, given the combination of structural definition and cell-based phenotypic readouts (laothamatas2023metabolicandchemical pages 10-11).

6) Key statistics and quantitative data (from recent and classic mechanistic studies)

CRY–FAD affinities relevant to FBXL3 competition: Kd ~ 16 μM (human CRY1) and 68 μM (human CRY2) (calloni2023thestructuraland pages 3-4).
Structural evidence: CRY2–FBXL3–SKP1 complex solved at 2.7 Å resolution (xing2013scffbxl3ubiquitinligase pages 13-16).
Circadian phenotype: disruption of FBXL3–CRY binding reported to lengthen circadian period to ~26–27 h (rosensweig2020periodicityrepressionand pages 13-14, rosensweig2020periodicityrepressionand pages 11-13).
Ubiquitination breadth: FBXL3 reported to ubiquitinate 11 lysines on CRY1 (rosensweig2020periodicityrepressionand pages 13-14).
Ubiquitin linkage: FBXL3 promotes K48-linked polyubiquitin chain elongation on CRYs (sato2023circadianregulationof pages 10-10).
Disease-burden statistics used in a CRY2-stabilizer translational context: PDAC estimated 510,566 new cases and 467,005 deaths worldwide in 2022; 5-year survival <13% (farmakis2024th301emergesas pages 1-2).

7) Evidence-backed summary table

The following table consolidates the core annotation points (identity/domains, complex membership, substrates, mechanism, regulation, applications, and genetics) with URLs.

Category	Key evidence / notes	Reference (year, journal)	URL
Identity / domains	Human FBXL3 (UniProt Q9UKT7) is an F-box/leucine-rich repeat protein; reviews describe it as a canonical F-box protein containing an F-box domain plus LRRs and functioning as the substrate-recognition subunit of an SCF E3 ligase that regulates circadian cryptochromes (calloni2023thestructuraland pages 2-3, calloni2023thestructuraland pages 3-4)	Calloni & Vabulas, 2023, Front. Mol. Biosci.	https://doi.org/10.3389/fmolb.2022.1081661
Complex membership	FBXL3 forms an SCF^FBXL3 complex with SKP1, CUL1, and RBX1; substrate binding promotes complex formation in vivo, and Cry1 binding is required for robust SCF assembly in cells (yumimoto2013substratebindingpromotes pages 1-2, yumimoto2013substratebindingpromotes pages 10-10)	Yumimoto et al., 2013, J. Biol. Chem.	https://doi.org/10.1074/jbc.M113.511303
Primary substrates	The best-supported FBXL3 substrates are CRY1 and CRY2, which are ubiquitylated and degraded to control the negative arm of the mammalian circadian clock; this was identified by pulldown/mass spectrometry and validated biochemically (calloni2023thestructuraland pages 2-3, calloni2023thestructuraland pages 3-4)	Calloni & Vabulas, 2023, Front. Mol. Biosci.	https://doi.org/10.3389/fmolb.2022.1081661
Mechanism of substrate recognition	Structural work showed that FBXL3 captures CRY2 through a bipartite interaction: its C-terminal tail inserts into the CRY FAD-binding pocket while additional contacts involve the PER-binding interface/LRR surface; this explains competition with FAD and PER proteins (xing2013scffbxl3ubiquitinligase pages 13-16, rosensweig2020periodicityrepressionand pages 13-14, xing2013scffbxl3ubiquitinligase media 0c122a57)	Xing et al., 2013, Nature	https://doi.org/10.1038/nature11964
Ubiquitin chain / linkage	Recent review evidence states that FBXL3 catalyzes elongation of K48-linked polyubiquitin chains on CRYs; earlier review evidence notes FBXL3 ubiquitylates CRY more efficiently than FBXL21 and targets multiple lysines on CRY1 (11 lysines reported) (sato2023circadianregulationof pages 10-10, rosensweig2020periodicityrepressionand pages 13-14)	Sato & Sato, 2023, Endocrinology	https://doi.org/10.1210/endocr/bqad086
Localization	FBXL3 is described as predominantly nuclear, whereas the paralogue FBXL21 is mainly cytosolic (but can also act in nucleus/cytoplasm in some reviews); FBXL3–CRY interaction is reported as entirely nuclear (calloni2023thestructuraland pages 3-4, rosensweig2020periodicityrepressionand pages 13-14)	Calloni & Vabulas, 2023, Front. Mol. Biosci.	https://doi.org/10.3389/fmolb.2022.1081661
Regulatory interactions (FBXL21, PER, FAD)	FBXL21 antagonizes FBXL3 by binding CRY more strongly but ubiquitylating it less efficiently, thereby stabilizing/sequestering CRY; PER proteins protect CRY by competing for overlapping binding interfaces; FAD can displace FBXL3 from CRY, and reported human FAD affinities are Kd ≈16 μM for CRY1 and 68 μM for CRY2 (calloni2023thestructuraland pages 3-4, rosensweig2020periodicityrepressionand pages 13-14, chan2023watchingtheclock pages 6-7)	Rosensweig & Green, 2020, Eur. J. Neurosci.; Calloni & Vabulas, 2023, Front. Mol. Biosci.	https://doi.org/10.1111/ejn.14254 ; https://doi.org/10.3389/fmolb.2022.1081661
Small-molecule modulators / applications	KL001 is a first-in-class CRY1/2 stabilizer that competes with FBXL3 at the CRY FAD pocket, lengthens circadian period, and has been used to inhibit glucagon-induced gluconeogenesis and glioblastoma stem-cell proliferation; derivatives include CRY1-selective KL101 and moderately CRY2-preferring TH301, while SHP1703 is a more potent/bioavailable CRY2-selective derivative that extended survival in GSC-transplanted mice; TH301 also showed anti-oncogenic activity in PDAC cells (laothamatas2023metabolicandchemical pages 10-11, farmakis2024th301emergesas pages 1-2, chawla2024timelyquestionsemerging pages 7-9)	Laothamatas et al., 2023, Cell Chem. Biol.; Farmakis et al., 2024/2025, Int. J. Mol. Sci.	https://doi.org/10.1016/j.chembiol.2023.08.014 ; https://doi.org/10.3390/ijms26010178
Human genetics / variants	Human disease evidence is limited in the retrieved set, but a reported pathogenic FBXL3 frameshift variant c.884delT, p.(Leu295Tyrfs*25) was listed in a family with autosomal-recessive neurodevelopmental disorder/intellectual disability; circadian-variant reviews also emphasize that altered FBXL3-mediated CRY2 degradation is mechanistically relevant to familial advanced sleep phase through CRY2 Ala260Thr (affinity increase for FBXL3) rather than FBXL3 coding variation itself (paracha2024thegeneticcause pages 9-10, grskovic2023circadiangenevariants pages 8-9)	Paracha et al., 2024, Front. Med.; Gršković & Korać, 2023, Genes	https://doi.org/10.3389/fmed.2024.1424753 ; https://doi.org/10.3390/genes14091703

Table: This table summarizes the core functional annotation of human FBXL3 (UniProt Q9UKT7), including its domains, SCF complex role, cryptochrome substrates, mechanism, regulation, localization, pharmacology, and limited human genetic evidence. It is useful as a concise evidence-backed reference for the gene’s primary molecular function in circadian clock control.

8) Limitations of this synthesis

The retrieved evidence base strongly supports FBXL3’s primary molecular function as an SCF adaptor for CRY turnover, but provides limited direct, human-tissue quantitative expression statistics for FBXL3 itself (as opposed to CRY or cancer datasets). The report therefore prioritizes mechanistic and translational evidence where the causal chain from FBXL3 action to phenotype is best established.

References

(calloni2023thestructuraland pages 3-4): Giulia Calloni and R. Martin Vabulas. The structural and functional roles of the flavin cofactor fad in mammalian cryptochromes. Frontiers in Molecular Biosciences, Jan 2023. URL: https://doi.org/10.3389/fmolb.2022.1081661, doi:10.3389/fmolb.2022.1081661. This article has 8 citations.
(calloni2023thestructuraland pages 2-3): Giulia Calloni and R. Martin Vabulas. The structural and functional roles of the flavin cofactor fad in mammalian cryptochromes. Frontiers in Molecular Biosciences, Jan 2023. URL: https://doi.org/10.3389/fmolb.2022.1081661, doi:10.3389/fmolb.2022.1081661. This article has 8 citations.
(yumimoto2013substratebindingpromotes pages 1-2): Kanae Yumimoto, Tetsuya Muneoka, Tomohiro Tsuboi, and Keiichi I. Nakayama. Substrate binding promotes formation of the skp1-cul1-fbxl3 (scffbxl3) protein complex. Journal of Biological Chemistry, 288:32766-32776, Nov 2013. URL: https://doi.org/10.1074/jbc.m113.511303, doi:10.1074/jbc.m113.511303. This article has 38 citations and is from a domain leading peer-reviewed journal.
(rosensweig2020periodicityrepressionand pages 13-14): Clark Rosensweig and Carla B. Green. Periodicity, repression, and the molecular architecture of the mammalian circadian clock. European Journal of Neuroscience, 51:139-165, Dec 2020. URL: https://doi.org/10.1111/ejn.14254, doi:10.1111/ejn.14254. This article has 61 citations and is from a domain leading peer-reviewed journal.
(chan2023watchingtheclock pages 6-7): Priscilla Chan, Jeremy N Rich, and Steve A Kay. Watching the clock in glioblastoma. Neuro-Oncology, 25:1932-1946, Jun 2023. URL: https://doi.org/10.1093/neuonc/noad107, doi:10.1093/neuonc/noad107. This article has 48 citations and is from a domain leading peer-reviewed journal.
(yumimoto2013substratebindingpromotes pages 10-10): Kanae Yumimoto, Tetsuya Muneoka, Tomohiro Tsuboi, and Keiichi I. Nakayama. Substrate binding promotes formation of the skp1-cul1-fbxl3 (scffbxl3) protein complex. Journal of Biological Chemistry, 288:32766-32776, Nov 2013. URL: https://doi.org/10.1074/jbc.m113.511303, doi:10.1074/jbc.m113.511303. This article has 38 citations and is from a domain leading peer-reviewed journal.
(xing2013scffbxl3ubiquitinligase pages 13-16): Weiman Xing, Luca Busino, Thomas R. Hinds, Samuel T. Marionni, Nabiha H. Saifee, Matthew F. Bush, Michele Pagano, and Ning Zheng. Scffbxl3 ubiquitin ligase targets cryptochromes at their cofactor pocket. Mar 2013. URL: https://doi.org/10.1038/nature11964, doi:10.1038/nature11964. This article has 277 citations and is from a highest quality peer-reviewed journal.
(xing2013scffbxl3ubiquitinligase media 0c122a57): Weiman Xing, Luca Busino, Thomas R. Hinds, Samuel T. Marionni, Nabiha H. Saifee, Matthew F. Bush, Michele Pagano, and Ning Zheng. Scffbxl3 ubiquitin ligase targets cryptochromes at their cofactor pocket. Mar 2013. URL: https://doi.org/10.1038/nature11964, doi:10.1038/nature11964. This article has 277 citations and is from a highest quality peer-reviewed journal.
(sato2023circadianregulationof pages 10-10): Tomoki Sato and Shogo Sato. Circadian regulation of metabolism - commitment to health and diseases. Endocrinology, May 2023. URL: https://doi.org/10.1210/endocr/bqad086, doi:10.1210/endocr/bqad086. This article has 54 citations and is from a domain leading peer-reviewed journal.
(rosensweig2020periodicityrepressionand pages 11-13): Clark Rosensweig and Carla B. Green. Periodicity, repression, and the molecular architecture of the mammalian circadian clock. European Journal of Neuroscience, 51:139-165, Dec 2020. URL: https://doi.org/10.1111/ejn.14254, doi:10.1111/ejn.14254. This article has 61 citations and is from a domain leading peer-reviewed journal.
(laothamatas2023metabolicandchemical pages 10-11): Isara Laothamatas, Emil Sjulstok Rasmussen, Carla B. Green, and Joseph S. Takahashi. Metabolic and chemical architecture of the mammalian circadian clock. Cell chemical biology, 30:1033-1052, Sep 2023. URL: https://doi.org/10.1016/j.chembiol.2023.08.014, doi:10.1016/j.chembiol.2023.08.014. This article has 99 citations and is from a domain leading peer-reviewed journal.
(paracha2024thegeneticcause pages 9-10): Sohail Aziz Paracha, Shoaib Nawaz, Muhammad Tahir Sarwar, Asmat Shaheen, Gohar Zaman, Jawad Ahmed, Fahim Shah, Sundus Khwaja, Abid Jan, Nida Khan, Mohammad Azhar Kamal, Qamre Alam, Safdar Abbas, Saman Farman, Ahmed Waqas, Afnan Alkathiri, Abdullah Hamadi, Federico Santoni, Naseeb Ullah, Bisma Khalid, Stylianos E. Antonarakis, Khalid A Fakhro, Muhammad Umair, and Muhammad Ansar. The genetic cause of neurodevelopmental disorders in 30 consanguineous families. Frontiers in Medicine, Aug 2024. URL: https://doi.org/10.3389/fmed.2024.1424753, doi:10.3389/fmed.2024.1424753. This article has 8 citations.
(grskovic2023circadiangenevariants pages 8-9): Paula Gršković and Petra Korać. Circadian gene variants in diseases. Genes, 14:1703, Aug 2023. URL: https://doi.org/10.3390/genes14091703, doi:10.3390/genes14091703. This article has 15 citations.
(farmakis2024th301emergesas pages 1-2): Danae Farmakis, Dimitrios J. Stravopodis, and Anastasia Prombona. Th301 emerges as a novel anti-oncogenic agent for human pancreatic cancer cells: the dispensable roles of p53, cry2 and bmal1 in th301-induced cdkn1a/p21cip1/waf1 upregulation. International Journal of Molecular Sciences, 26:178, Dec 2024. URL: https://doi.org/10.3390/ijms26010178, doi:10.3390/ijms26010178. This article has 4 citations.
(chawla2024timelyquestionsemerging pages 7-9): Sangeeta Chawla, John O’Neill, Marina I. Knight, Yuqing He, Lei Wang, Erik Maronde, Sergio Gil Rodríguez, Gerben van Ooijen, Eduardo Garbarino-Pico, Eva Wolf, Ouria Dkhissi-Benyahya, Anjoom Nikhat, Shaon Chakrabarti, Shawn D. Youngstedt, Natalie Zi-Ching Mak, Ignacio Provencio, Henrik Oster, Namni Goel, Mario Caba, Maria Oosthuizen, Giles E. Duffield, Christopher Chabot, and Seth J. Davis. Timely questions emerging in chronobiology: the circadian clock keeps on ticking. Journal of Circadian Rhythms, Apr 2024. URL: https://doi.org/10.5334/jcr.237, doi:10.5334/jcr.237. This article has 10 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

calloni2023thestructuraland pages 3-4
sato2023circadianregulationof pages 10-10
rosensweig2020periodicityrepressionand pages 13-14
laothamatas2023metabolicandchemical pages 10-11
chan2023watchingtheclock pages 6-7
paracha2024thegeneticcause pages 9-10
grskovic2023circadiangenevariants pages 8-9
calloni2023thestructuraland pages 2-3
yumimoto2013substratebindingpromotes pages 1-2
yumimoto2013substratebindingpromotes pages 10-10
rosensweig2020periodicityrepressionand pages 11-13
chawla2024timelyquestionsemerging pages 7-9
https://doi.org/10.3389/fmolb.2022.1081661
https://doi.org/10.1074/jbc.M113.511303
https://doi.org/10.1038/nature11964
https://doi.org/10.1210/endocr/bqad086
https://doi.org/10.1111/ejn.14254
https://doi.org/10.1016/j.chembiol.2023.08.014
https://doi.org/10.3390/ijms26010178
https://doi.org/10.3389/fmed.2024.1424753
https://doi.org/10.3390/genes14091703
https://doi.org/10.3389/fmolb.2022.1081661,
https://doi.org/10.1074/jbc.m113.511303,
https://doi.org/10.1111/ejn.14254,
https://doi.org/10.1093/neuonc/noad107,
https://doi.org/10.1038/nature11964,
https://doi.org/10.1210/endocr/bqad086,
https://doi.org/10.1016/j.chembiol.2023.08.014,
https://doi.org/10.3389/fmed.2024.1424753,
https://doi.org/10.3390/genes14091703,
https://doi.org/10.3390/ijms26010178,
https://doi.org/10.5334/jcr.237,

📚 Additional Documentation

Pn Notes

(FBXL3-pn-notes.md)

FBXL3 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9UKT7
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-13
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FBXL3/FBXL3-ai-review.yaml
AIGR review HTML: missing - genes/human/FBXL3/FBXL3-ai-review.html
Gene notes: missing - genes/human/FBXL3/FBXL3-notes.md
GOA TSV: present - genes/human/FBXL3/FBXL3-goa.tsv
UniProt record: present - genes/human/FBXL3/FBXL3-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FBXL3.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FBXL3.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FBXL3/FBXL3-deep-research-falcon.md

AIGR Review Snapshot

Description: FBXL3 (F-box/LRR-repeat protein 3) is the substrate-recognition (F-box) subunit of an SCF (SKP1-CUL1-RBX1-F-box) cullin-RING E3 ubiquitin ligase that controls the mammalian circadian clock by targeting the cryptochrome repressors CRY1 and CRY2 for ubiquitination and proteasomal degradation. Within the predominantly nuclear SCF(FBXL3) complex, FBXL3 binds SKP1 through its F-box domain and uses its leucine-rich repeats to capture CRY: a conserved C-terminal tail of FBXL3 inserts into the FAD-binding pocket of CRY and buries the PER-binding interface, an interaction that can be displaced by FAD and by the Period proteins. By timing CRY degradation, SCF(FBXL3) sets the period and robustness of the circadian oscillator, permitting reactivation of the CLOCK-BMAL1 transcriptional activator and the consequent rhythmic expression of clock-controlled genes including Per1/Per2. Its activity is counterbalanced by the related SCF(FBXL21) ligase, which stabilizes CRY. In humans, biallelic loss-of-function variants in FBXL3 cause an autosomal-recessive intellectual developmental disorder with short stature.
Existing/core annotation action counts: ACCEPT: 10; KEEP_AS_NON_CORE: 28; MODIFY: 3

PN Consistency Summary

Consistency: Strong. Deep research (falcon), review YAML, PN annotation, and node mapping all describe FBXL3 as the SCF(FBXL3) substrate receptor that degrades CRY1/CRY2 to set circadian period. No contradictions. Falcon-only leads (K48 chain elongation, substrate-gated assembly, KL001 pocket) are flagged UNVERIFIED but corroborated by the experimental cache (PMID:17463251 IMP/IDA; PMID:23503662 structure).
PN story / NEW pressure: PN asserts only the generic adaptor MF (GO:1990756). This is NOT already an MF in the GOA, which carries only catalytic GO:0004842 (IDA/IEA/NAS) + protein binding. The review correctly MODIFY's the two catalytic transferase annotations to GO:1990756 (verified real, current). No new BP pressure; circadian/SCF-catabolism BPs already captured. Conclusion: adaptor MF added by MODIFY = correct, not over-reaching.
Evidence alignment: PN reference is only "15340381/rev" (PMID:15340381, an FBXL/Cul1 review). The review does NOT cite PMID:15340381; its key PMIDs (17463251, 23503662, 10531035, 33234069) are richer/gene-specific. Divergence is benign — PN uses a family-level placeholder; review uses primary literature.
Verdict: CONSISTENT / ACCEPT mapping. No edits required; the MODIFY→GO:1990756 pattern is correctly applied. Optional [REF]: PN-row reference PMID:15340381 not reflected in review (placeholder only).

Full Consistency Review

UniProt: Q9UKT7 · batch: proteostasis-batch-2026-06-13 · 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.
Consistency: Strong. Deep research (falcon), review YAML, PN annotation, and node mapping all describe FBXL3 as the SCF(FBXL3) substrate receptor that degrades CRY1/CRY2 to set circadian period. No contradictions. Falcon-only leads (K48 chain elongation, substrate-gated assembly, KL001 pocket) are flagged UNVERIFIED but corroborated by the experimental cache (PMID:17463251 IMP/IDA; PMID:23503662 structure).
PN story / NEW pressure: PN asserts only the generic adaptor MF (GO:1990756). This is NOT already an MF in the GOA, which carries only catalytic GO:0004842 (IDA/IEA/NAS) + protein binding. The review correctly MODIFY's the two catalytic transferase annotations to GO:1990756 (verified real, current). No new BP pressure; circadian/SCF-catabolism BPs already captured. Conclusion: adaptor MF added by MODIFY = correct, not over-reaching.
Mapping strategy: Gene does not change the node. Status/scope are right: the F-box adaptor MF lives at the group node, catalysis correctly excluded from the F-box/LRR sub-nodes (RBX1 RING does catalysis). PN-projected GO:1990756 matches the review's core_functions MF exactly (neither broader nor narrower). Canonical, well-validated SCF receptor (CRY substrate validated) — no orphan flag.
Evidence alignment: PN reference is only "15340381/rev" (PMID:15340381, an FBXL/Cul1 review). The review does NOT cite PMID:15340381; its key PMIDs (17463251, 23503662, 10531035, 33234069) are richer/gene-specific. Divergence is benign — PN uses a family-level placeholder; review uses primary literature.
Verdict: CONSISTENT / ACCEPT mapping. No edits required; the MODIFY→GO:1990756 pattern is correctly applied. Optional [REF]: PN-row reference PMID:15340381 not reflected in review (placeholder only).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-13
review_yaml: genes/human/FBXL3/FBXL3-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: Q9UKT7
In branches: UPS
Signature domains: IPR001810
Auxiliary domains: 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.

📄 View Raw YAML

id: Q9UKT7
gene_symbol: FBXL3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  FBXL3 (F-box/LRR-repeat protein 3) is the substrate-recognition (F-box)
  subunit of an SCF (SKP1-CUL1-RBX1-F-box) cullin-RING E3 ubiquitin ligase that
  controls the mammalian circadian clock by targeting the cryptochrome
  repressors CRY1 and CRY2 for ubiquitination and proteasomal degradation.
  Within the predominantly nuclear SCF(FBXL3) complex, FBXL3 binds SKP1 through
  its F-box domain and uses its leucine-rich repeats to capture CRY: a conserved
  C-terminal tail of FBXL3 inserts into the FAD-binding pocket of CRY and buries
  the PER-binding interface, an interaction that can be displaced by FAD and by
  the Period proteins. By timing CRY degradation, SCF(FBXL3) sets the period and
  robustness of the circadian oscillator, permitting reactivation of the
  CLOCK-BMAL1 transcriptional activator and the consequent rhythmic expression
  of clock-controlled genes including Per1/Per2. Its activity is counterbalanced
  by the related SCF(FBXL21) ligase, which stabilizes CRY. In humans, biallelic
  loss-of-function variants in FBXL3 cause an autosomal-recessive intellectual
  developmental disorder with short stature.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of nuclear localization, the predominant compartment where SCF(FBXL3) degrades CRY. Core localization.
    action: ACCEPT
    reason: Core localization; SCF(FBXL3) acts mainly in the nucleus to degrade CRY1/CRY2.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: The SCF(FBXL3) complex mainly acts in the nucleus and mediates ubiquitination and subsequent degradation of CRY1 and CRY2
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assignment of cytosolic localization, a secondary compartment relative to the dominant nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is documented but the predominantly nuclear pool drives the core CRY-degradation function.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Note=Predominantly nuclear.
- term:
    id: GO:0043153
    label: entrainment of circadian clock by photoperiod
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assignment of involvement in circadian-clock entrainment. FBXL3 sets clock period via CRY degradation; the more direct process term is regulation of circadian rhythm.
    action: KEEP_AS_NON_CORE
    reason: FBXL3 governs the circadian oscillator, but the specific "entrainment by photoperiod" framing is narrower than its core period-setting role captured by regulation of circadian rhythm.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Combined automated electronic assignment of nuclear localization, the core compartment for SCF(FBXL3) function.
    action: ACCEPT
    reason: Core localization; redundant with IBA/ISS/IDA evidence.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:10531035}
- 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. A secondary compartment.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic pool is documented but secondary to the predominantly nuclear localization.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17463251
  qualifier: enables
  review:
    summary: Interactions with CRY1/CRY2 (and SCF components) from the foundational circadian study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the functionally central CRY1/CRY2 interactions but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Interacts with CRY1 and CRY2 (phosphorylated)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23503662
  qualifier: enables
  review:
    summary: Interaction with CRY2 captured in the structural study of the FBXL3-SKP1-CRY2 complex. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records the structurally defined FBXL3-CRY2 interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: PMID:23503662
      supporting_text: the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Binary interactome reference map interactions. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: 'Q9UKT7; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-2557269, EBI-79165'
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: contributes_to
  review:
    summary: Ortholog-based electronic assignment of ubiquitin-protein transferase activity, with the contributes_to qualifier acknowledging FBXL3's role within the multi-subunit SCF ligase. As the F-box substrate receptor, FBXL3 does not itself catalyze ubiquitin transfer.
    action: MODIFY
    reason: FBXL3 is the substrate-recognition subunit, not the catalytic core (RBX1/CUL1 mediates ubiquitin transfer); the informative molecular function is ubiquitin-like ligase-substrate adaptor activity.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF(FBXL3) E3 ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ortholog-based electronic assignment of cytosolic localization. A secondary compartment.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic pool documented but secondary to the predominantly nuclear localization.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Combined automated electronic assignment of protein ubiquitination, a parent of the specific SCF-dependent CRY ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific SCF-dependent catabolic process annotation better captures the role.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of SCF-dependent proteasomal degradation, the core biological process of SCF(FBXL3).
    action: ACCEPT
    reason: Core biological process; redundant with the experimental IDA evidence (CRY degradation).
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0031648
    label: protein destabilization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of protein destabilization, reflecting FBXL3-driven CRY destabilization. A generic parent of its ubiquitin-mediated degradation role.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the SCF-dependent catabolic process annotation captures the specific mechanism (CRY degradation).
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0042752
    label: regulation of circadian rhythm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Combined automated electronic assignment of regulation of circadian rhythm, the core physiological process of FBXL3.
    action: ACCEPT
    reason: Core biological process; redundant with the experimental IMP evidence (Fbxl3 controls clock oscillations).
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
- term:
    id: GO:0043153
    label: entrainment of circadian clock by photoperiod
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of circadian entrainment. FBXL3 sets clock period; the broader regulation of circadian rhythm term is more apt.
    action: KEEP_AS_NON_CORE
    reason: FBXL3 governs the oscillator, but the narrower photoperiod-entrainment framing is secondary to its core period-setting role.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ortholog-based electronic assignment of proteasome-mediated ubiquitin-dependent degradation, a parent of the specific SCF-dependent CRY degradation.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; subsumed by the more specific SCF-dependent proteasomal catabolic process annotation.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0016604
    label: nuclear body
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for localization to nuclear bodies, consistent with the predominantly nuclear pool of FBXL3.
    action: KEEP_AS_NON_CORE
    reason: IDA-supported sub-nuclear localization consistent with the nuclear site of action, but a specific sub-compartment; core localization is the nucleus.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Note=Predominantly nuclear.
- 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: Author-statement (FBXL family review) assignment of the core SCF-dependent proteasomal degradation process.
    action: ACCEPT
    reason: Core biological process; consistent with the experimental CRY-degradation evidence.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0042752
    label: regulation of circadian rhythm
  evidence_type: NAS
  original_reference_id: PMID:17463251
  qualifier: involved_in
  review:
    summary: Author-statement assignment of the core circadian-regulation process from the foundational study.
    action: ACCEPT
    reason: Core biological process directly supported by the same study's functional experiments.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins
- term:
    id: GO:0031648
    label: protein destabilization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of protein destabilization, reflecting FBXL3-driven CRY destabilization. A generic parent of its degradation role.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the SCF-dependent catabolic process annotation captures the specific mechanism.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952618
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (neddylation of CRL1). Generic CRL-pathway localization; secondary to the nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic CRL neddylation-pathway context; FBXL3 is predominantly nuclear.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952620
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (NEDD8:UBE2M binds CRL1). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic CRL-pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955241
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (CAND1 binds cytosolic CRL). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955289
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COMMDs displace CAND1). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956040
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (COP9 signalosome deneddylates CRL). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956200
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (DCUN1D3 binds CRL1). Generic CRL-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic CRL-regulation pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983140
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (transfer of Ub from E2 to substrate). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983147
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (release of E3 from polyubiquitinated substrate). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983156
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (polyubiquitination of substrate). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-983157
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization (interaction of E3 with substrate and E2-Ub). Generic ubiquitination-pathway localization.
    action: KEEP_AS_NON_CORE
    reason: Correct cytosolic compartment but from generic ubiquitination-pathway context; secondary to the nuclear pool.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity assignment of cytosolic localization. A secondary compartment.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic pool documented but secondary to the predominantly nuclear localization.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Cytoplasm {ECO:0000269|PubMed:10531035}. Note=Predominantly nuclear.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of protein ubiquitination, a parent of the specific SCF-dependent CRY ubiquitination.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the SCF-dependent catabolic process annotation better captures the role.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0043153
    label: entrainment of circadian clock by photoperiod
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity assignment of circadian entrainment. FBXL3 sets clock period; the broader regulation of circadian rhythm term is more apt.
    action: KEEP_AS_NON_CORE
    reason: FBXL3 governs the oscillator, but the narrower photoperiod-entrainment framing is secondary to its core period-setting role.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity assignment of nuclear localization, the core compartment for SCF(FBXL3) function.
    action: ACCEPT
    reason: Core localization; redundant with IBA/IEA/IDA evidence.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Nucleus {ECO:0000269|PubMed:10531035}
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:17463251
  qualifier: contributes_to
  review:
    summary: Direct evidence that FBXL3, within the SCF(FBXL3) complex, contributes to ubiquitin transfer onto CRY. The contributes_to qualifier reflects FBXL3's role as the substrate-receptor subunit of the multi-subunit ligase rather than the catalytic core.
    action: MODIFY
    reason: FBXL3 is the substrate-recognition subunit; catalytic ubiquitin transfer is performed by RBX1/CUL1. The informative molecular function is ubiquitin-like ligase-substrate adaptor activity. (Activity is real within the SCF complex, hence MODIFY rather than REMOVE.)
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
    - reference_id: file:human/FBXL3/FBXL3-deep-research-falcon.md
      supporting_text: 'FBXL3 is an **F-box protein** that specifies substrate recognition within an SCF-type cullin-RING ligase, i.e., **SCF^FBXL3 = SKP1–CUL1–RBX1–FBXL3**, where SKP1 binds the **F-box domain** and FBXL3’s **LRR domain** mediates substrate recognition'
- term:
    id: GO:0019005
    label: SCF ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:17463251
  qualifier: part_of
  review:
    summary: Direct evidence that FBXL3 is part of the SCF (SKP1-CUL1-F-box) E3 ligase complex. Core cellular component.
    action: ACCEPT
    reason: Core cellular component; FBXL3 is the F-box substrate receptor of the SCF(FBXL3) complex.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17463251
  qualifier: involved_in
  review:
    summary: Direct evidence that SCF(FBXL3) drives proteasomal degradation of CRY1/CRY2. Core biological process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; FBXL3 targets CRY for SCF-dependent degradation.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
- term:
    id: GO:0042752
    label: regulation of circadian rhythm
  evidence_type: IMP
  original_reference_id: PMID:17463251
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence (Fbxl3 silencing, Cry-null epistasis) that FBXL3 controls circadian clock oscillation. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct IMP support; Fbxl3 silencing has no effect in Cry1/Cry2-null cells, demonstrating it acts via CRY degradation.
    supported_by:
    - reference_id: PMID:17463251
      supporting_text: Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: involved_in
  review:
    summary: Author-statement assignment (original F-box family paper) of involvement in protein ubiquitination. Generic but correct.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the SCF-dependent catabolic process annotation better captures the role.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0000151
    label: ubiquitin ligase complex
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: part_of
  review:
    summary: Author-statement assignment of being part of a ubiquitin ligase complex. A generic parent of the specific SCF complex.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; subsumed by the specific SCF ubiquitin ligase complex annotation.
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL3)
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: NAS
  original_reference_id: PMID:10531035
  qualifier: enables
  review:
    summary: Author-statement assignment of ubiquitin-protein transferase activity from the original F-box family paper. As the F-box substrate receptor, FBXL3 does not itself catalyze ubiquitin transfer.
    action: MODIFY
    reason: FBXL3 is the substrate-recognition subunit, not the catalytic core; the informative molecular function is ubiquitin-like ligase-substrate adaptor activity.
    proposed_replacement_terms:
    - id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    supported_by:
    - reference_id: file:human/FBXL3/FBXL3-uniprot.txt
      supporting_text: Substrate-recognition component of the SCF(FBXL3) 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:0000033
  title: Annotation inferences using phylogenetic trees
  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: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10531035
  title: Identification of a family of human F-box proteins.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Original identification of FBXL3 as an F-box protein; source of nuclear/cytoplasmic localization and generic ubiquitin ligase complex / transferase NAS annotations. Full text not in cache.
- id: PMID:17463251
  title: SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.
  findings:
  - statement: CRY1 and CRY2 are ubiquitinated and degraded by the SCF(Fbxl3) ubiquitin ligase complex; this is a prerequisite for timely reactivation of CLOCK-BMAL1; Fbxl3 silencing has no effect in Cry1/Cry2-null cells, showing FBXL3 controls clock oscillations via CRY degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational study establishing SCF(FBXL3) as the E3 ligase that degrades CRY1/CRY2 to set circadian period. Abstract-only in cache but supports MF/BP/CC core annotations.
- id: PMID:23503662
  title: SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket.
  findings:
  - statement: Crystal structures of CRY2 (apo, FAD-bound, and FBXL3-SKP1-complexed) show FBXL3 captures CRY2 by inserting a conserved C-terminal tail into the FAD-binding pocket and burying the PER-binding interface; this interaction is displaced by FAD and PERs.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural basis of FBXL3-CRY2 substrate recognition; source of the FBXL3-CRY2 interaction annotation. Abstract-only in cache.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Binary interactome reference map; source of a bare protein binding annotation.
- id: PMID:33234069
  title: 'The FBXL family of F-box proteins: variations on a theme.'
  findings:
  - statement: Review of the FBXL family describing FBXL3 as an SCF substrate receptor mediating SCF-dependent proteasomal degradation of its targets.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; family review supporting the SCF-dependent catabolic process annotation.
- id: Reactome:R-HSA-8952618
  title: AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952620
  title: NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955241
  title: CAND1 binds cytosolic CRL E3 ubiquitin ligases
  findings: []
- id: Reactome:R-HSA-8955289
  title: COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956040
  title: COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
  findings: []
- id: Reactome:R-HSA-8956200
  title: MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-983140
  title: Transfer of Ub from E2 to substrate and release of E2
  findings: []
- id: Reactome:R-HSA-983147
  title: Release of E3 from polyubiquitinated substrate
  findings: []
- id: Reactome:R-HSA-983156
  title: Polyubiquitination of substrate
  findings: []
- id: Reactome:R-HSA-983157
  title: Interaction of E3 with substrate and E2-Ub complex
  findings: []
- id: file:human/FBXL3/FBXL3-deep-research-falcon.md
  title: Falcon deep research report for human FBXL3
  findings:
  - statement: FBXL3 is the substrate-recognition subunit of the nuclear SCF(FBXL3) (SKP1-CUL1-RBX1-FBXL3) E3 ligase, where SKP1 binds the F-box domain and the LRR domain recognizes the CRY substrates that are degraded to control the circadian transcription-translation feedback loop.
    supporting_text: 'FBXL3 is an **F-box protein** that specifies substrate recognition within an SCF-type cullin-RING ligase, i.e., **SCF^FBXL3 = SKP1–CUL1–RBX1–FBXL3**, where SKP1 binds the **F-box domain** and FBXL3’s **LRR domain** mediates substrate recognition'
  - statement: SCF(FBXL3) assembly is substrate-driven - FBXL3 does not robustly associate with SKP1/CUL1 unless its substrate CRY1 is present, so CRY availability gates ligase assembly and activity.
    supporting_text: 'In transfected mammalian cells, FBXL3 did not substantially associate with SKP1/CUL1 unless its substrate **CRY1** was expressed; a CRY1-binding-defective FBXL3 mutant failed to form the SCF complex in vivo, supporting a substrate-dependent assembly mechanism'
  - statement: FBXL3 catalyzes K48-linked polyubiquitin chain elongation on CRY proteins (reported across ~11 lysines on CRY1), targeting them for proteasomal degradation more efficiently than the antagonistic paralog FBXL21.
    supporting_text: A recent Endocrinology review states that FBXL3 catalyzes elongation of **K48-linked polyubiquitin** chains on CRYs, consistent with canonical proteasome-targeting ubiquitin signals
  - statement: Disrupting the FBXL3-CRY interaction stabilizes the CRY repressors and lengthens circadian period (to ~26-27 h), directly linking FBXL3-mediated CRY degradation kinetics to clock period; the FBXL3-occupied CRY FAD pocket is a validated small-molecule (KL001-class) target.
    supporting_text: Mutations that disrupt FBXL3–CRY binding stabilize CRYs and can lengthen circadian period; one review reports in vivo period lengthening to **~26–27 h** in FBXL3 mutant contexts
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon (Edison Scientific) deep-research synthesis. Treated as leads cross-checked against UniProt and the foundational experimental papers (PMID:17463251 CRY degradation; PMID:23503662 FAD-pocket capture structure). Core circadian SCF-receptor mechanism is corroborated by those sources. Falcon cites author-year/DOIs (xing2013, yumimoto2013, calloni2023) not PMIDs and is not independently PubMed-verified, so marked UNVERIFIED.
core_functions:
- description: Functions as the substrate-recognition (F-box) subunit of the nuclear SCF (SKP1-CUL1-RBX1-FBXL3) cullin-RING E3 ubiquitin ligase that recruits the cryptochrome repressors CRY1 and CRY2 for polyubiquitination and proteasomal degradation, thereby setting the period and robustness of the mammalian circadian clock.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:17463251
    supporting_text: both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex
  directly_involved_in:
  - id: GO:0042752
    label: regulation of circadian rhythm
  - id: GO:0031146
    label: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
- description: Recognizes cryptochrome substrates through a structurally defined mechanism in which a conserved FBXL3 C-terminal tail occupies the CRY FAD-binding pocket and buries the CRY PER-binding interface, a substrate interaction antagonized by FAD and the Period proteins. Substrate (CRY1) binding itself promotes assembly of the SCF(FBXL3) holocomplex, and FBXL3 elongates K48-linked polyubiquitin chains on CRY; this activity is counterbalanced by the paralogous SCF(FBXL21) ligase, which binds CRY more strongly but ubiquitinates it less efficiently, thereby stabilizing CRY.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: PMID:23503662
    supporting_text: the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface
  - reference_id: file:human/FBXL3/FBXL3-deep-research-falcon.md
    supporting_text: 'In transfected mammalian cells, FBXL3 did not substantially associate with SKP1/CUL1 unless its substrate **CRY1** was expressed; a CRY1-binding-defective FBXL3 mutant failed to form the SCF complex in vivo, supporting a substrate-dependent assembly mechanism'
  directly_involved_in:
  - id: GO:0042752
    label: regulation of circadian rhythm
proposed_new_terms: []
suggested_questions:
- question: How is the balance between SCF(FBXL3)-mediated CRY degradation and SCF(FBXL21)-mediated CRY stabilization spatially and temporally regulated to tune circadian period?
- question: Beyond CRY1/CRY2, does FBXL3 have physiologically important substrates that explain the human FBXL3 loss-of-function phenotype (intellectual developmental disorder with short stature)?
suggested_experiments:
- description: Reconstitute SCF(FBXL3)-mediated CRY2 ubiquitination in vitro with purified SKP1, CUL1, RBX1, an E2, and wild-type versus C-terminal-tail or pocket-mutant FBXL3, and titrate FAD and PER proteins to quantify how cofactor and competitor occupancy controls substrate ubiquitination.
- description: Perform time-resolved quantitative proteomics in FBXL3-knockout versus wild-type cells across the circadian cycle to confirm CRY1/CRY2 as the dominant rhythmic substrates and to identify any additional FBXL3 targets relevant to the developmental disorder phenotype.

FBXL3

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FBXL3 (UniProt Q9UKT7) functional annotation

0) Target verification (mandatory)

1) Key concepts & definitions (current understanding)

1.1 FBXL3 as an SCF E3 ubiquitin ligase substrate receptor

1.2 Primary substrates: CRY1 and CRY2

1.3 Relationship to FBXL21 and the PER proteins

2) Molecular function, mechanism, and pathway placement

2.1 Substrate-dependent SCF^FBXL3 assembly (regulatory logic)

2.2 Structural mechanism of CRY recognition: “cofactor pocket capture”

2.3 Competition with FAD and PER proteins

2.4 Ubiquitination chemistry (linkage type and site breadth)

2.5 Cellular localization

2.6 System-level role in circadian period determination

3) Recent developments (prioritizing 2023–2024)

3.1 Chemical chronobiology: targeting the CRY–FBXL3 interface

3.2 Clock biology in cancer contexts (biomarker framing)

3.3 Human genetics signals involving FBXL3

4) Current applications and real-world implementations

4.1 Metabolic regulation (preclinical/experimental)

4.2 Oncology (preclinical and early translational framing)

5) Expert opinions & analysis (authoritative synthesis)

6) Key statistics and quantitative data (from recent and classic mechanistic studies)

7) Evidence-backed summary table

8) Limitations of this synthesis

Artifacts

Citations

📚 Additional Documentation

Pn Notes

FBXL3 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

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

Projected GO annotations (1)

Note

📄 View Raw YAML