FBXL2
Description
The FBXL2 (F-box and leucine rich repeat protein 2) is a protein-coding gene located on chromosome 3.
F-box/LRR-repeat protein 2 is a protein that in humans is encoded by the FBXL2 gene. This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains 12 tandem leucine-rich repeats. FBXL2 is a highly conserved F-box protein that directly binds substrates and, thus, determines the specificity of the SCF ubiquitin ligase complex. FBXL2 contains a typical CaaX motif that is post-translationally modified by geranyl-geranylation for targeting to cellular membranes. The importance of the ubiquitin ligase activity of FBXL2 was originally shown in an unbiased screen for cellular host factors necessary for Hepatitis C virus replication. Geranyl-geranylation of FBXL2 is essential also for its pro-survival function in mediating poly-ubiquitylation and proteasomal degradation of IP3R3 (a calcium channel at the endoplasmic reticulum) and p85β (the regulatory subunit of PI3-Kinases). PI3Ks are heterodimeric lipid kinases composed of a p110 catalytic subunit and a p85 regulatory subunit.
FBXL2, also known as F-box and leucine-rich repeat protein 2, is a component of the SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex, specifically SCF(FBXL2). This complex plays a crucial role in the ubiquitination and subsequent proteasomal degradation of target proteins. Unlike many F-box proteins, FBXL2 does not target phosphodegron within its substrates but instead recognizes calmodulin-binding motifs. Consequently, calmodulin can antagonize FBXL2's activity. This is observed with the cyclins CCND2 and CCND3, where calmodulin inhibits their polyubiquitination and degradation, ultimately leading to cell-cycle arrest in G(0). Furthermore, SCF(FBXL2) mediates the ubiquitination and degradation of PIK3R2, influencing phosphatidylinositol 3-kinase signaling and autophagy. Additionally, SCF(FBXL2) regulates the synthesis of phosphatidylcholine by monoubiquitinating and degrading PCYT1A. This phosphatidylcholine is essential for membrane formation and pulmonary surfactant production. The SCF(FBXL2) complex also acts as a regulator of inflammation by targeting TRAF proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, and TRAF6) for degradation. Moreover, SCF(FBXL2) negatively regulates the NLRP3 inflammasome by ubiquitinating and degrading NLRP3. FBXL2 interacts with calmodulin, potentially antagonizing substrate ubiquitination by SCF(FBXL2). It also interacts with PIK3R1 and PTPN13. In the context of microbial infection, FBXL2 interacts with hepatitis C virus non-structural protein 5A (NS5A) and, to a lesser extent, with NS5B, a reaction critical for hepatitis C virus RNA replication.
FBXL2 is also known as FBL2, FBL3.
Associated Diseases
- hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
- alpha-thalassemia-myelodysplastic syndrome
- primary familial polycythemia due to EPO receptor mutation
- alpha thalassemia-intellectual disability syndrome type 1
- hemoglobin E-beta-thalassemia syndrome
- hemoglobin D disease
- delta-beta-thalassemia
- hemoglobin C-beta-thalassemia syndrome
- dominant beta-thalassemia
- hemoglobin E disease
- X-linked sideroblastic anemia 1
- Heinz body anemia
- hemolytic anemia due to adenylate kinase deficiency
- hemoglobin H disease
