| 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 (pqac-00000005, pqac-00000000) | 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 (pqac-00000002, pqac-00000001) | 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 (pqac-00000005, pqac-00000000) | 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 (pqac-00000003, pqac-00000004, pqac-00000018) | 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) (pqac-00000012, pqac-00000004) | 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 (pqac-00000000, pqac-00000004) | 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 (pqac-00000000, pqac-00000004, pqac-00000013) | 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 (pqac-00000017, pqac-00000014, pqac-00000015) | 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 (pqac-00000008, pqac-00000009) | 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.*