in mammals. Characteristics The human FBXL3 gene is located on the long arm of chromosome 13 at position 22.3. The protein is composed of 428 amino acids and has a mass of 48,707 Daltons. The FBXL3 protein contains an F-box domain, characterized by a 40 amino acid motif that mediates protein-protein interactions, and several tandem leucine-rich repeats used for substrate recognition. It has eight post-translational modification sites involving ubiquitination and four sites involving phosphorylation. The FBXL3 protein is predominantly localized to the nucleus. It is one of four subunits of a ubiquitin ligase complex called SKP1-CUL1-F-box-protein, which includes the proteins CUL1, SKP1, and RBX1. Function The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the proteasome. FBXL3 binds to CRY2 by occupying its flavin adenine dinucleotide (FAD) cofactor pocket with a C-terminal tail and buries the PER-binding interface on the CRY2 protein. The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the Bmal1 gene. Bmal1 expression is regulated by the binding of REV-ERBα and RORα proteins to retinoic acid-related orphan receptor response elements (ROREs) in the Bmal1 promoter region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression. FBXL3 decreases the repression of Bmal1 transcription by inactivating the REV-ERBα and HDAC3 repressor complex. The FBXL3 protein has also been found to cooperatively degrade c-MYC when bound to CRY2. The c-MYC protein is a transcription factor important in regulating cell proliferation. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with phosphorylated c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein. Interactions FBXL3 has been shown to interact with: SKP1A CRY1 CRY2 REV-ERBα HDAC3 c-MYC References