The circadian clock in eukaryotes is generated by a transcription-based feedback loop that operates with ~24-hour periodicity. In animals, the circadian transcription factor, CLOCK:BMAL1 is central to this feedback loop. Changes in its ability to activate the transcription of clock-controlled genes throughout the day give rise to oscillations in gene expression that represent the molecular basis of circadian rhythms.
In the Partch lab, we are interested in understanding how these dedicated 'clock proteins' interact with one another to establish circadian rhythms.
Building off our recent crystal structure of the Cryptochrome 1 (CRY1) PHR domain (gray) bound to PER2 (brown, PDB: 6OF7), we aim to create a complete molecular picture of the different protein complexes that form throughout the day using an integrated approach encompassing structural biology, biochemistry, and cell biology.
Over the last several years, we've defined how cryptochromes act as the key factor nucleating the assembly of repressive complexes with CLOCK:BMAL1. Both CRY1 and CRY2 use their secondary pocket (green), evolutionarily conserved with the DNA repair enzyme Photolyase, to dock onto the PAS domain core of CLOCK:BMAL1. The CC helix (blue) binds to the BMAL1 transactivation domain (TAD) to sequester it from coactivators, directly repressing CLOCK:BMAL1 activity.
We recently discovered that a 24-amino acid segment in the disordered tail of CRY1 encoded by exon 11 is necessary and sufficient to regulate its association with CLOCK:BMAL1. Loss of this exon in the inherited CRY1Δ11 allele leads to Delayed Sleep Phase Disorder, or night own behavior, in humans (Patke, A. et al. (2017) Cell).
We believe that understanding the molecular basis for clock protein interactions at atomic resolution will ultimately help us design new therapeutic strategies that reinforce circadian timing to improve overall health and homeostasis.