Different protein cutters control the body clock by breaking down CRY inside and outside the cell nucleus

A mutation in the Fbxl21 gene is associated with a shortening of the circadian period in mice.

• The mammalian circadian clock's period determination involves the turnover rate of the proteins CRY and PER.
• CRY ubiquitination interacts with two competing E3 ligase complexes that can either lengthen or shorten the circadian period.
• Loss of function of the FBXL3 protein leads to a lengthened circadian period.
• Mutation of Fbxl21 results in a shorter circadian period due to a missense mutation affecting CRY degradation.
• FBXL21 forms a complex that slowly degrades CRY in the cytoplasm while counteracting the stronger degradation activity of FBXL3 in the nucleus.
• The interplay between these E3 ligases and their specific locations in the cell influences the circadian clock's timing.

Simplified