Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing
- UCSC, United States
- Nagoya University, Japan
- Scripps Research Institute, United States
- University of Washington, United States
- Kyoto University, Japan
Abstract
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-hour 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.
Data availability
Diffraction data have been deposited in PDB under the accession code 6OF7.
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Crystal structure of the CRY1-PER2 complexProtein data Bank, 6OF7.
Article and author information
Author details
Ashutosh Srivastava
Funding
National Institutes of Health (R01 GM107069)
- Carrie L Partch
National Institutes of Health (F31 CA189660)
- Alicia K Michael
National Institutes of Health (S10 OD021634)
- Gabriel C Lander
UC Cancer Research Coordinating Committee (CRN-15-380548)
- Carrie L Partch
National Institutes of Health (DP2 EB020402)
- Gabriel C Lander
RIKEN (Dynamic Structural Biology Project)
- Florence Tama
Pew Charitable Trusts (Pew Scholar)
- Gabriel C Lander
Amgen (Young Investigator)
- Gabriel C Lander
UC Office of the President (Chancellor's Postdoctoral Fellow)
- Jennifer L Fribourgh
National Science Foundation (Graduate Research Fellowship)
- Colby R Sandate
Howard Hughes Medical Institute (Gilliam fellowship)
- Christin Rakers
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Fribourgh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing
eLife 9:e55275.
https://doi.org/10.7554/eLife.55275
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