RT Journal Article
SR Electronic
T1 Protein dynamics regulate distinct biochemical properties of cryptochromes in mammalian circadian rhythms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 740464
DO 10.1101/740464
A1 Jennifer L. Fribourgh
A1 Ashutosh Srivastava
A1 Colby R. Sandate
A1 Alicia K. Michael
A1 Peter L. Hsu
A1 Christin Rakers
A1 Leslee T. Nguyen
A1 Megan R. Torgrimson
A1 Gian Carlo G. Parico
A1 Sarvind Tripathi
A1 Ning Zheng
A1 Gabriel C. Lander
A1 Tsuyoshi Hirota
A1 Florence Tama
A1 Carrie L. Partch
YR 2019
UL http://biorxiv.org/content/early/2019/08/20/740464.abstract
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.