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

Fribourgh, Jennifer L.; Srivastava, Ashutosh; Sandate, Colby R.; Michael, Alicia K.; Hsu, Peter L.; Rakers, Christin; Nguyen, Leslee T.; Torgrimson, Megan R.; Parico, Gian Carlo G.; Tripathi, Sarvind; Zheng, Ning; Lander, Gabriel C.; Hirota, Tsuyoshi; Tama, Florence; Partch, Carrie L.

doi:10.7554/elife.55275

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

Journal Article · Wed Feb 26 00:00:00 EST 2020 · eLife

DOI:https://doi.org/10.7554/elife.55275· OSTI ID:1644118

Fribourgh, Jennifer L. ^[1];

^[2];

^[3]; Michael, Alicia K. ^[1]; Hsu, Peter L. ^[4];

^[5]; Nguyen, Leslee T. ^[1]; Torgrimson, Megan R. ^[1]; Parico, Gian Carlo G. ^[1];

^[1]; Zheng, Ning ^[6];

^[3];

^[2]; Tama, Florence ^[7];

^[8]

Univ. of California, Santa Cruz, CA (United States)
Nagoya Univ. (Japan)
The Scripps Research Inst., La Jolla, CA (United States)
Univ. of Washington, Seattle, WA (United States)
Kyoto Univ. (Japan)
Univ. of Washington, Seattle, WA (United States); Howard Hughes Medical Inst., Seattle, WA (United States)
Nagoya Univ. (Japan); RIKEN Center for Computational Science, Kobe (Japan)
Univ. of California, Santa Cruz, CA (United States); Univ. of California, San Diego, CA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH); Cancer Research Coordinating Committee

Grant/Contract Number:: R01 GM107069; DP2 EB020402; F31 CA189660; S10 OD021634; CRN-15–380548

OSTI ID:: 1644118

Journal Information:: eLife, Vol. 9, Issue 02, 2020; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 31 works

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