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.