The CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1

Abstract

Circadian rhythms are generated by a transcription-translation feedback loop that establishes cell-autonomous biological timing of ~24-hours. A prevalent human variation in the core clock gene cryptochrome 1, Cry1Δ11, lengthens circadian period to cause Delayed Sleep Phase Disorder (DSPD). CRY1 has a 55 kDa photolyase homology region (PHR) followed by a ~100 residue tail that is intrinsically disordered; the Δ11 variant lacks a short segment encoded by Exon 11 within its tail. We show here that the disordered tail of CRY1 interacts directly with its PHR, and that Exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and CLOCK, a subunit of the primary circadian transcription factor. Competition between PER2 and the tail for the CRY1 PHR suggests a regulatory role for the tail in the early morning, when CRY1 binds to CLOCK:BMAL1 on DNA independently of PER2. Discovery of this autoregulatory role for mammalian CRY1 highlights functional conservation with plant and insect cryptochromes, which also utilize PHR-tail interactions to reversibly control their activity.