Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Combined Automated Annotation using Multiple IEA Methods
Identification of a family of human F-box proteins.
SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.
SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket.
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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.
A reference map of the human binary protein interactome.
The FBXL family of F-box proteins: variations on a theme.
AcM-UBE2M transfers NEDD8 to CRL1 E3 ubiquitin ligase complex
NEDD8:AcM-UBE2M binds CRL1 E3 ubiquitin ligase complex
CAND1 binds cytosolic CRL E3 ubiquitin ligases
COMMDs displace CAND1 from cytosolic CRL E3 ubiquitin ligase complexes
COP9 signalosome deneddylates cytosolic CRL E3 ubiquitin ligase complexes
MyrG-DCUN1D3 binds CRL1 E3 ubiquitin ligase complex
Transfer of Ub from E2 to substrate and release of E2
Release of E3 from polyubiquitinated substrate
Polyubiquitination of substrate
Interaction of E3 with substrate and E2-Ub complex
Falcon deep research report for human FBXL3
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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"
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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"
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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"
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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"