FBXL3
Description
The FBXL3 (F-box and leucine rich repeat protein 3) is a protein-coding gene located on chromosome 13.
FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3). FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex. The FBXL3 protein participates in the negative feedback loop responsible for generating molecular circadian rhythms in mammals by binding to the CRY1 and CRY2 proteins to facilitate their polyubiquitination by the SCF complex and their subsequent degradation by the proteasome. The Fbxl3 gene function was independently identified in 2007 by three groups. Takahashi used forward genetics N-ethyl-N-nitrosourea (ENU) mutagenesis to screen for mice with varied circadian activity which led to the discovery of the Overtime (Ovtm) mutant of the Fbxl3 gene. Nolan discovered the Fbxl3 mutation After hours (Afh) by a forward screen assessing wheel activity behavior of mutagenized mice. Pagano discovered that the FBXL3 protein is necessary for the reactivation of the CLOCK and BMAL1 protein heterodimer by inducing the degradation of CRY proteins. Mice with the homozygous mutation of Ovtm, free run with an intrinsic period of 26 hours. Overtime is a loss of function mutation caused by a substitution of isoleucine to threonine in the region of FBXL3 that binds to CRY. In mice with this mutation, levels of the proteins PER1 and PER2 are decreased, while levels of CRY proteins do not differ from those of wild type mice.
FBXL3 is a component of the SCF(FBXL3) E3 ubiquitin ligase complex, which plays a crucial role in circadian rhythm function by regulating the speed and robustness of the circadian clock oscillation. This complex mainly acts in the nucleus and is responsible for the ubiquitination and subsequent degradation of CRY1 and CRY2. The activity of the SCF(FBXL3) complex is balanced by the opposing activity of the SCF(FBXL21) complex.
FBXL3 is also known as FBL3, FBL3A, FBXL3A, IDDSFAS.
