1. CRY1‐CBS binding regulates circadian clock function and metabolism
- Author
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Cal‐Kayitmazbatir, Sibel, Kulkoyluoglu‐Cotul, Eylem, Growe, Jacqueline, Selby, Christopher P, Rhoades, Seth D, Malik, Dania, Oner, Hasimcan, Asimgil, Hande, Francey, Lauren J, Sancar, Aziz, Kruger, Warren D, Hogenesch, John B, Weljie, Aalim, Anafi, Ron C, and Kavakli, Ibrahim Halil
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Nutrition ,Sleep Research ,1.1 Normal biological development and functioning ,Underpinning research ,Metabolic and endocrine ,ARNTL Transcription Factors ,Amino Acid Sequence ,Animals ,CLOCK Proteins ,Circadian Clocks ,Circadian Rhythm ,Cryptochromes ,Cystathionine beta-Synthase ,E-Box Elements ,Female ,HEK293 Cells ,Humans ,Male ,Metabolic Networks and Pathways ,Metabolome ,Mice ,Mice ,Knockout ,Mutation ,Period Circadian Proteins ,Protein Binding ,Protein Processing ,Post-Translational ,Sequence Alignment ,Sequence Homology ,Amino Acid ,Signal Transduction ,circadian rhythms ,cryptochrome ,intrinsically disordered protein ,CON NMR ,delayed sleep phase disorder ,Transcription ,Genetic ,Protein Domains - Abstract
Circadian rhythms are generated by interlocked transcription-translation feedback loops that establish cell-autonomous biological timing of ∼24 h. Mutations in core clock genes that alter their stability or affinity for one another lead to changes in circadian period. The human CRY1Δ11 mutant lengthens circadian period to cause delayed sleep phase disorder (DSPD), characterized by a very late onset of sleep. CRY1 is a repressor that binds to the transcription factor CLOCK:BMAL1 to inhibit its activity and close the core feedback loop. We previously showed how the PHR (photolyase homology region) domain of CRY1 interacts with distinct sites on CLOCK and BMAL1 to sequester the transactivation domain from coactivators. However, the Δ11 variant alters an intrinsically disordered tail in CRY1 downstream of the PHR. We show here that the CRY1 tail, and in particular the region encoded by exon 11, modulates the affinity of the PHR domain for CLOCK:BMAL1. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and the subunit CLOCK. Moreover, PHR-tail interactions are conserved in the paralog CRY2 and reduced when either CRY is bound to the circadian corepressor PERIOD2. Discovery of this autoregulatory role for the mammalian CRY1 tail and conservation of PHR-tail interactions in both mammalian cryptochromes highlights functional conservation with plant and insect cryptochromes, which also utilize PHR-tail interactions to reversibly control their activity.
- Published
- 2021