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.
| 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 |
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Download this section (compressed HTML)Q: How is the balance between SCF(FBXL3)-mediated CRY degradation and SCF(FBXL21)-mediated CRY stabilization spatially and temporally regulated to tune circadian period?
Q: Beyond CRY1/CRY2, does FBXL3 have physiologically important substrates that explain the human FBXL3 loss-of-function phenotype (intellectual developmental disorder with short stature)?
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.
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