PT  - JOURNAL ARTICLE
AU  - Jennifer L. Fribourgh
AU  - Ashutosh Srivastava
AU  - Colby R. Sandate
AU  - Alicia K. Michael
AU  - Peter L. Hsu
AU  - Christin Rakers
AU  - Leslee T. Nguyen
AU  - Megan R. Torgrimson
AU  - Gian Carlo G. Parico
AU  - Sarvind Tripathi
AU  - Ning Zheng
AU  - Gabriel C. Lander
AU  - Tsuyoshi Hirota
AU  - Florence Tama
AU  - Carrie L. Partch
TI  - Protein dynamics regulate distinct biochemical properties of cryptochromes in mammalian circadian rhythms
AID  - 10.1101/740464
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 740464
4099  - http://biorxiv.org/content/early/2019/08/20/740464.short
4100  - http://biorxiv.org/content/early/2019/08/20/740464.full
AB  - Circadian rhythms are generated by a transcription-based feedback loop where CLOCK:BMAL1 drive transcription of their repressors (PER1/2, CRY1/2), which bind to CLOCK:BMAL1 to close the feedback loop with ~24-hour periodicity. Here we identify a key biochemical and structural difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. While both cryptochromes bind the BMAL1 transactivation domain with similar affinity to sequester it from coactivators, CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We identify a dynamic loop in the secondary pocket that regulates differential binding of cryptochromes to the PAS domain core. Notably, PER2 binding remodels this loop in CRY2 to enhance its affinity for CLOCK:BMAL1, explaining why CRY2 forms an obligate heterodimer with PER2, while CRY1 is capable of repressing CLOCK:BMAL1 both with and without PER2.