F-box and leucine-rich repeat protein 3 (FBXL3)

F-box and leucine-rich repeat protein 3 (FBXL3) is an F-box family member featuring leucine-rich repeats, serving as the substrate-recognition element of the nuclear SCF (Skp1–Cullin–F-box) E3 ubiquitin ligase complex. FBXL3 specifically targets mammalian cryptochrome proteins (CRY1 and CRY2) for ubiquitination and degradation, thus sustaining circadian clock oscillations. Mutations in FBXL3 alter circadian rhythm speed and robustness, and are implicated in intellectual disability, epilepsy, and other developmental disorders. Small molecules such as KL001 bind to cryptochromes, protecting them from FBXL3-induced degradation, and represent a pharmacological avenue for modulating sleep and circadian disorders. FBXL3’s activity is tightly regulated by protein structure, cofactor interaction (FAD), and competitive protein-protein contacts, making it a central modulator of circadian timing and an emerging therapeutic target.

Other names

F-box/LRR-repeat protein 3FBL3AFBXL3AFBL3IDDSFASF-box and leucine-rich repeat protein 3AF-box/LRR-repeat protein 3AF-box protein Fbl3aFBXL3_HUMAN (UniProt)

Small molecules that stabilize CRY proteins interfere with substrate recognition by FBXL3, thereby blocking ubiquitination and prolonging the circadian period. Direct competition between small molecules, FAD, and the C-terminal tail of FBXL3 for binding cryptochrome FAD pocket.