FBXL5
Description
The FBXL5 (F-box and leucine rich repeat protein 5) is a protein-coding gene located on chromosome 4.
FBXL5 (F-box/LRR-repeat protein 5) is a protein encoded by the FBXL5 gene in humans. It belongs to the F-box protein family, characterized by an approximately 40 amino acid motif, the F-box. F-box proteins are components of SCF (SKP1-cullin-F-box) ubiquitin protein ligase complexes, which regulate phosphorylation-dependent ubiquitination. FBXL5 falls into the Fbls class, containing an F-box and several tandem leucine-rich repeats. Two transcript variants are generated by alternative splicing of the FBXL5 gene. FBXL5 functions as an iron and oxygen sensor. It promotes IRP2 ubiquitination and subsequent degradation in an iron- and oxygen-dependent manner. The cryo-EM structure of the FBXL5-IRP2 complex revealed an unexpected 2Fe2S cluster embedded within the leucine-rich repeats domain of the F-box protein, near the protein-protein interaction interface. Therefore, FBXL5 is an iron-sulfur protein.
FBXL5 is a component of SCF (SKP1-cullin-F-box) protein ligase complexes. It plays a critical role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2. FBXL5's C-terminal domain contains a redox-sensitive [2Fe-2S] cluster that, upon oxidation, facilitates binding to IRP2, leading to its oxygen-dependent degradation. Under iron deficiency, the N-terminal hemerythrin-like (Hr) region, containing a diiron metal center, is unable to bind iron and undergoes conformational changes that destabilize FBXL5, resulting in its ubiquitination and degradation. As intracellular iron levels rise, the Hr region stabilizes. Further increases in iron levels promote the assembly and incorporation of a redox active [2Fe-2S] cluster in the C-terminal domain. Only when oxygen levels are sufficient to maintain the cluster in its oxidized state can FBXL5 recruit IRP2 for polyubiquination and degradation. FBXL5 also promotes the ubiquitination and degradation of the dynactin complex component DCTN1. Within the nucleus, it promotes SNAI1 ubiquitination, preventing its interaction with DNA and facilitating its degradation. It negatively regulates DNA damage response by mediating the ubiquitin-proteasome degradation of the DNA repair protein NABP2. FBXL5 interacts with ACO1/IRP1, IREB2/IRP2, and DCTN1/p150-glued, with the interaction with ACO1/IRP1 and IREB2/IRP2 being dependent on the [2Fe-2S] cluster.
FBXL5 is also known as FBL4, FBL5, FLR1.
