Alternative titles; symbols
HGNC Approved Gene Symbol: FBXL5
Cytogenetic location: 4p15.32 Genomic coordinates (GRCh38): 4:15,604,381-15,681,569 (from NCBI)
The F box, named after cyclin F (CCNF; 600227), in which it was originally observed, is an approximately 40-amino acid motif that binds SKP1 (601434). F-box proteins, such as FBXL5, are components of modular E3 ubiquitin protein ligases called SCFs (SKP1-cullin (see 603134)-F-box proteins), which function in phosphorylation-dependent ubiquitination.
Using a yeast 2-hybrid screen with SKP1 as bait, followed by searching sequence databases, Winston et al. (1999) and Cenciarelli et al. (1999) identified 33 mammalian and 26 human F-box proteins, respectively. These contained C termini with leucine-rich repeats (FBXLs, e.g., SKP2 (601436)), WD40 domains (FBXWs, e.g., BTRCP (603482)), or no recognizable motifs (FBXOs, e.g., CCNF). Winston et al. (1999) predicted the presence of 6 leucine-rich repeats (LRRs) in FBXL5. RT-PCR analysis detected expression in all tissues tested, with highest levels in heart and pancreas.
By searching sequence databases, Ilyin et al. (2000) identified a cDNA encoding FBXL5, which they referred to as FBL4. They determined that the deduced 690-amino acid protein contains 5 imperfect LRRs.
Jin et al. (2004) reported that the FBXL5 protein contains an F box in its N-terminal half, followed by 4 central LRRs, a long spacer region, and 2 C-terminal LRRs.
Vashisht et al. (2009) found that a SKP1-CUL1-FBXL5 ubiquitin ligase protein complex associates with and promotes the iron-dependent ubiquitination and degradation of IRP2 (147582). The F-box substrate adaptor protein FBXL5 was degraded upon iron and oxygen depletion in a process that required an iron-binding hemerythrin-like domain in its N terminus. Thus, Vashisht et al. (2009) concluded that iron homeostasis is regulated by a proteolytic pathway that couples IRP2 degradation to intracellular iron levels through the stability and activity of FBXL5.
Salahudeen et al. (2009) independently found that the E3 ubiquitin ligase complex containing the FBXL5 protein targets IRP2 for proteasomal degradation. The stability of FBXL5 itself was regulated, accumulating under iron- and oxygen-replete conditions and degraded upon iron depletion. FBXL5 contains an iron- and oxygen-binding hemerythrin domain that acted as a ligand-dependent regulatory switch mediating FBXL5's differential stability. Salahudeen et al. (2009) concluded that these observations suggest a mechanistic link between iron sensing via the FBXL5 hemerythrin domain, IRP2 regulation, and cellular responses to maintain mammalian iron homeostasis.
Jin et al. (2004) stated that the FBXL5 gene maps to chromosome 4p15.33 and the mouse Fbxl5 gene maps to chromosome 5B3.
Cenciarelli, C., Chiaur, D. S., Guardavaccaro, D., Parks, W., Vidal, M., Pagano, M. Identification of a family of human F-box proteins. Curr. Biol. 9: 1177-1179, 1999. [PubMed: 10531035] [Full Text: https://doi.org/10.1016/S0960-9822(00)80020-2]
Ilyin, G. P., Rialland, M., Pigeon, C., Guguen-Guillouzo, C. cDNA cloning and expression analysis of new members of the mammalian F-box protein family. Genomics 67: 40-47, 2000. [PubMed: 10945468] [Full Text: https://doi.org/10.1006/geno.2000.6211]
Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., Harper, J. W. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 18: 2573-2580, 2004. [PubMed: 15520277] [Full Text: https://doi.org/10.1101/gad.1255304]
Salahudeen, A. A., Thompson, J. W., Ruiz, J. C., Ma, H.-W., Kinch, L. N., Li, Q., Grishin, N. V., Bruick, R. K. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326: 722-726, 2009. [PubMed: 19762597] [Full Text: https://doi.org/10.1126/science.1176326]
Vashisht, A. A., Zumbrennen, K. B., Huang, X., Powers, D. N., Durazo, A., Sun, D., Bhaskaran, N., Persson, A., Uhlen, M., Sangfelt, O., Spruck, C., Leibold, E. A., Wohlschlegel, J. A. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326: 718-721, 2009. [PubMed: 19762596] [Full Text: https://doi.org/10.1126/science.1176333]
Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J., Harper, J. W. A family of mammalian F-box proteins. Curr. Biol. 9: 1180-1182, 1999. [PubMed: 10531037] [Full Text: https://doi.org/10.1016/S0960-9822(00)80021-4]