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Nat Commun. 2018 Mar 19;9(1):1138. doi: 10.1038/s41467-018-03503-6.

An evolutionary hotspot defines functional differences between CRYPTOCHROMES.

Author information

1
Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA.
2
Department of Neurobiology, Northwestern University, 2205 Tech Drive, Pancoe 2230, Evanston, IL, 60208, USA.
3
Department of Biophysics, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, 75390, USA.
4
The Green Center for Systems Biology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, 75390, USA.
5
Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX, 75390, USA.
6
The Center for the Physics of Evolving Systems, Biochemistry and Molecular Biology, The Institute for Molecular Engineering, University of Chicago, 929 East 57th Street, Chicago, IL, 60637, USA.
7
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
8
Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA. carla.green@utsouthwestern.edu.

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.

PMID:
29556064
PMCID:
PMC5859286
DOI:
10.1038/s41467-018-03503-6
[Indexed for MEDLINE]
Free PMC Article

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