An evolutionary hotspot defines functional differences between CRYPTOCHROMES

Clark Rosensweig, Kimberly A. Reynolds, Peng Gao, Isara Laothamatas, Yongli Shan, Rama Ranganathan, Joseph S. Takahashi and Carla B. Green ()
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Clark Rosensweig: University of Texas Southwestern Medical Center
Kimberly A. Reynolds: University of Texas Southwestern Medical Center
Peng Gao: University of Texas Southwestern Medical Center
Isara Laothamatas: University of Texas Southwestern Medical Center
Yongli Shan: University of Texas Southwestern Medical Center
Rama Ranganathan: University of Texas Southwestern Medical Center
Joseph S. Takahashi: University of Texas Southwestern Medical Center
Carla B. Green: University of Texas Southwestern Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Mammalian circadian clocks are driven by a transcription/translation feedback loop composed of positive regulators (CLOCK/BMAL1) and repressors (CRYPTOCHROME 1/2 (CRY1/2) and PER1/2). To understand the structural principles of regulation, we used evolutionary sequence analysis to identify co-evolving residues within the CRY/PHL protein family. Here we report the identification of an ancestral secondary cofactor-binding pocket as an interface in repressive CRYs, mediating regulation through direct interaction with CLOCK and BMAL1. Mutations weakening binding between CLOCK/BMAL1 and CRY1 lead to acceleration of the clock, suggesting that subtle sequence divergences at this site can modulate clock function. Divergence between CRY1 and CRY2 at this site results in distinct periodic output. Weaker interactions between CRY2 and CLOCK/BMAL1 at this pocket are strengthened by co-expression of PER2, suggesting that PER expression limits the length of the repressive phase in CRY2-driven rhythms. Overall, this work provides a model for the mechanism and evolutionary variation of clock regulatory mechanisms.

Date: 2018
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DOI: 10.1038/s41467-018-03503-6

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