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Elife. 2020 Feb 26;9. pii: e55275. doi: 10.7554/eLife.55275.

Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing.

Author information

1
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States.
2
Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan.
3
The Scripps Research Institute, La Jolla, United States.
4
Department of Pharmacology, University of Washington, Seattle, United States.
5
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
6
Howard Hughes Medical Institute, Seattle, United States.
7
Department of Physics, Nagoya University, Nagoya, Japan.
8
RIKEN Center for Computational Science, Kobe, Japan.
9
Center for Circadian Biology, University of California San Diego, La Jolla, United States.
#
Contributed equally

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 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.

KEYWORDS:

biochemistry; chemical biology; circadian rhythms; cryo-electron microscopy; molecular dynamics; mouse; x-ray crystallography

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