Regulation of Cryptochromes by FAD Cofactor: New Perspectives for Circadian Rhythm Drug Development
Circadian rhythm disruption triggers various health issues, including sleep disorders and metabolic disorders. Targeting cryptochrome (CRY), the core protein of the human circadian clock, has become a key research focus for circadian drug development in biomedicine. A recent review summarizes the interaction between flavin adenine dinucleotide (FAD) and mammalian CRY proteins, offering novel insights into the research and development of drugs for rhythm-related diseases.
Different from light-sensitive Drosophila cryptochromes, human CRY1 and CRY2 are light-independent. They maintain the 24-hour physiological cycle by inhibiting transcriptional complexes. Early studies detected weak binding affinity between mammalian CRY and FAD, making researchers doubt FAD’s physiological function. However, subsequent structural and cellular experiments overturned this view, proving that the FAD-binding pocket on CRY serves as a vital switch for protein stability.
Two ubiquitin ligases, FBXL3 and FBXL21, compete for the pocket to accelerate CRY degradation. Sufficient FAD can occupy the pocket, block the binding of degrading enzymes and stabilize CRY protein levels. Cellular experiments confirm that supplementation with FAD or riboflavin precursors significantly increases intracellular CRY content. Small molecules such as KL001 can mimic FAD to bind the pocket and artificially prolong the circadian cycle. Moreover, subtle structural differences between CRY1 and CRY2 pockets enable the development of subtype-selective regulatory drugs.
Although the complete in vivo mechanism of FAD regulating CRY remains to be explored, the unique FAD-binding pocket is a promising druggable target. Further research on this molecular mechanism is expected to advance the development of safer and more efficient circadian modulators for treating insomnia and chronic metabolic diseases.
FOR DETAIL: https://doi.org/10.3389/fmolb.2022.1081661
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