TY - JOUR TI - Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing AU - Fribourgh, Jennifer L AU - Srivastava, Ashutosh AU - Sandate, Colby R AU - Michael, Alicia K AU - Hsu, Peter L AU - Rakers, Christin AU - Nguyen, Leslee T AU - Torgrimson, Megan R AU - Parico, Gian Carlo G AU - Tripathi, Sarvind AU - Zheng, Ning AU - Lander, Gabriel C AU - Hirota, Tsuyoshi AU - Tama, Florence AU - Partch, Carrie L A2 - Frost, Adam A2 - Wolberger, Cynthia A2 - Kavakli, Halil VL - 9 PY - 2020 DA - 2020/02/26 SP - e55275 C1 - eLife 2020;9:e55275 DO - 10.7554/eLife.55275 UR - https://doi.org/10.7554/eLife.55275 AB - Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that 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 discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1. KW - circadian rhythms KW - x-ray crystallography KW - cryo-electron microscopy KW - molecular dynamics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -