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F-BOX AND WD40 DOMAIN PROTEIN 5; FBXW5

F-BOX AND WD40 DOMAIN PROTEIN 5; FBXW5

Alternative titles; symbolsFBW5HGNC Approved Gene Symbol: FBXW5Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:136,940,434-136,944,773 (from NCB...

Alternative titles; symbols

  • FBW5

HGNC Approved Gene Symbol: FBXW5

Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:136,940,434-136,944,773 (from NCBI)

▼ Description
Members of the F-box protein family, such as FBXW5, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (601434), cullin (see CUL1; 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004).

▼ Cloning and Expression
By yeast 2-hybrid screening to isolate SKP1-binding proteins, and by searching an EST database, Winston et al. (1999) identified a number of F-box proteins, including FBW5. The deduced protein contains an N-terminal F box, followed by a WD40 repeat, a large spacer region, and 2 more WD40 repeats. Quantitative PCR detected expression of Fbw5 in all mouse tissues and embryonic developmental stages examined.

▼ Gene Function
Winston et al. (1999) showed that in vitro translated FBW5 interacted with SKP1 in an in vitro binding assay and in transfected human embryonic kidney cells.

Tuberous sclerosis (191100; 613254) is an autosomal dominant disease caused by mutations in either the TSC1 (605284) or the TSC2 (191092) gene. The majority of disease-associated mutations result in substantial decreases in TSC1 or TSC2 protein levels, suggesting that protein turnover plays a critical role in TSC regulation. Hu et al. (2008) showed that FBW5 associated with DDB1 (600045), CUL4A (CUL4A; 603137), and ROC1 (RBX1; 603814) to form an E3 ubiquitin ligase that regulated TSC2 protein stability and TSC complex turnover.

Ha et al. (2014) found that 6-hydroxydopamine-induced oxidative stress induced expression of Tnfaip8l1 (615869), which they called Oxi-beta, in cultured mouse dopaminergic neurons, leading to increased autophagy and cell death. Increased Oxi-beta expression stabilized Tsc2, a negative regulator of Mtor (601231), which suppresses autophagy and promotes cell survival. Oxi-beta stabilized Tsc2 by binding directly to Fbxw5, a component of the Cul4 E3 ligase complex that promotes proteasomal degradation of Tsc2. Oxi-beta competed with Tsc2 for binding to Fbxw5, and the Oxi-beta-Tsc2 interaction protected Tsc2 from proteasome-mediated degradation.

▼ Mapping
Jin et al. (2004) stated that the FBXW5 gene maps to chromosome 9q34.3 and the mouse Fbxw5 gene maps to chromosome 2A3.

Tags: 9q34.3