The human CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1

Area of Science:

• Molecular Biology
• Chronobiology

Background:

• Circadian rhythms are regulated by transcription-translation feedback loops.
• Mutations in core clock genes can alter circadian period.
• The human CRY1Δ11 mutant lengthens circadian period, causing delayed sleep phase disorder (DSPD).

Purpose of the Study:

• To investigate the role of the CRY1 tail in modulating the interaction with CLOCK:BMAL1.
• To understand the autoregulatory function of the CRY1 tail in circadian timing.

Main Methods:

• Analysis of CRY1 mutant variants and their interaction with CLOCK:BMAL1.
• Investigated the role of the CRY1 tail, specifically exon 11, in modulating PHR domain affinity.
• Examined conservation of PHR-tail interactions in CRY2 and under PERIOD2 binding.

Main Results:

• The CRY1 tail, particularly 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 CRY1 interaction with CLOCK.
• PHR-tail interactions are conserved in CRY2 and reduced when bound to PERIOD2.

Conclusions:

• The mammalian CRY1 tail has an autoregulatory role in circadian clock function.
• Conserved PHR-tail interactions in mammalian, plant, and insect cryptochromes highlight functional conservation.
• These findings reveal a novel mechanism for regulating circadian timing.