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- W2792040296 abstract "Circadian rhythms are driven by a negative feedback loop in which the heterodimer CLOCK:BMAL1 promotes transcription of clock-controlled genes, including its own repressors Period (PER) and Cryptochrome (CRY). The deregulation of circadian rhythms can lead to delayed sleep phase disorder (DSPD), where the afflicted “night owls” are only able to fall asleep hours after midnight and have difficulty waking up early in the morning. CRY proteins contain a photolyase homology region (PHR) and an intrinsically disordered C-terminal tail; previous studies identified an essential role for the CRY1 PHR in generating circadian rhythms, while deletion of the tail was shown to alter the length of the circadian period. Our lab recently identified how the CRY1 PHR binds to both CLOCK and BMAL1 to induce repression and close the negative feedback loop. To date, little is known about how the CRY1 PHR and tail might interact to control this process. One prevalent mutation in DSPD patients leads to deletion of CRY1 Exon 11, a region that encodes for 25 amino acids in the tail, resulting in enhanced co-immunoprecipitation by CLOCK:BMAL1 and a longer circadian period. We hypothesized that the CRY1 tail might bind directly to the PHR to regulate interactions with CLOCK or BMAL1. Here we show that the C-terminal tail and CLOCK compete for binding to the CRY1 PHR, and that the peptide encoded by Exon 11 is sufficient for this interaction. Therefore, our data demonstrate how the tail can directly regulate CRY1 interactions with CLOCK:BMAL1 to provide initial insight into the molecular basis of DSPD." @default.
- W2792040296 created "2018-03-29" @default.
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- W2792040296 date "2018-02-01" @default.
- W2792040296 modified "2023-10-18" @default.
- W2792040296 title "Shedding Light on Night Owl Behavior: How the Disordered C-Terminal Tail of CRY1 Modulates Circadian Timekeeping" @default.
- W2792040296 doi "https://doi.org/10.1016/j.bpj.2017.11.3116" @default.
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