FBXL3: F-Box and Leucine Rich Repeat Protein 3
A core component of the circadian clock and ubiquitin ligase complex
Gene Information Card
| Symbol | FBXL3 |
|---|---|
| Full Name | F-box and leucine rich repeat protein 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 13q22.3 |
| NCBI Gene ID | 26224 ncbi.nlm.nih.gov/gene/26224 |
| Ensembl ID | ENSG00000158882 |
| UniProt ID | Q9UKT7 |
| OMIM ID | 605654 |
| HGNC ID | 13599 |
| Aliases | FBL3, FBL3A, F-box/LRR-repeat protein 3 |
Description
FBXL3 encodes a member of the F-box protein family, characterized by an F-box domain and leucine-rich repeats. It is a substrate recognition component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex. FBXL3 specifically targets the cryptochrome proteins CRY1 and CRY2 for ubiquitination and proteasomal degradation, thereby regulating the negative feedback loop of the mammalian circadian clock. Mutations in FBXL3 are associated with familial advanced sleep phase syndrome and other circadian rhythm disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Familial advanced sleep phase syndrome (FASPS) | Loss-of-function mutations in FBXL3 impair CRY degradation, lengthening the circadian period | PMID: 26903628 |
| Circadian rhythm sleep disorder | Altered FBXL3 expression or activity disrupts clock period and phase | PMID: 26903628 |
| Cancer (breast, colorectal) | FBXL3 dysregulation may affect cell cycle and DNA repair via CRY stability | PMID: 25730884 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebellum) | 12.5 | Medium |
| Brain (cortex) | 10.8 | Medium |
| Liver | 8.2 | Low |
| Heart | 7.1 | Low |
| Testis | 15.3 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK293 | 14.2 | Embryonic kidney |
| HeLa | 11.5 | Cervical carcinoma |
| HepG2 | 9.8 | Hepatocellular carcinoma |
| K562 | 8.1 | Leukemia |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1222G>A (p.Gly408Arg) | Missense | Rare | Impairs CRY binding, lengthens circadian period |
| c.1069C>T (p.Arg357Trp) | Missense | Rare | Reduces FBXL3 stability, associated with FASPS |
| c.1435C>T (p.Arg479*) | Nonsense | Very rare | Truncated protein, loss of function |
Mutation functional classification
Loss of Function (LOF)
Missense and nonsense mutations that reduce CRY binding or protein stability lead to impaired CRY degradation and prolonged circadian period.
Gain of Function (GOF)
Not reported for FBXL3.
Dominant Negative (DN)
Some missense mutations may act dominant-negative by competing with wild-type FBXL3 for SCF complex assembly.
View complete mutation data：
Gene Ontology (GO)
| • protein binding (GO:0005515) | • ubiquitin-protein transferase activity (GO:0004842) |
| • ubiquitin-dependent protein catabolic process (GO:0006511) | • regulation of circadian rhythm (GO:0042752) |
| • circadian rhythm (GO:0007623) | • SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146) |
Pathways
• Circadian rhythm (KEGG: hsa04710)
• Ubiquitin mediated proteolysis (KEGG: hsa04120)
• SCF complex assembly
Protein Summary
FBXL3 is a 541-amino acid protein containing an N-terminal F-box domain (required for SKP1 binding) and C-terminal leucine-rich repeats (LRRs) that mediate substrate recognition. It forms the SCF(FBXL3) ubiquitin ligase complex with SKP1, CUL1, and RBX1. The LRR domain binds CRY1/CRY2 in a light-independent manner, targeting them for ubiquitination and degradation. This degradation is essential for the proper timing of the circadian clock. FBXL3 is widely expressed, with highest levels in brain and testis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| FBXL3 Knockout HEK293 Cell Line | EDJ-KQ8459 | Human | 26224 | Details Get a Quote |
| FBXL3 Knockout A-549 Cell Line | EDJ-KQ34575 | Human | 26224 | Details Get a Quote |
| FBXL3 Knockout HCT 116 Cell Line | EDJ-KQ34576 | Human | 26224 | Details Get a Quote |
| FBXL3 Knockout HeLa Cell Line | EDJ-KQ34577 | Human | 26224 | Details Get a Quote |
