The mammalian circadian clock is generated by a transcription-based feedback loop that operates with ~24-hour periodicity. Central to this feedback loop is the core circadian transcription factor, CLOCK:BMAL1. Changes in its ability to activate transcription throughout the day give rise to oscillations in gene expression that represent the molecular basis of circadian rhythms.
We are interested in understanding how these dedicated 'clock proteins' interact with one another to establish circadian rhythms. Building off the recent crystal structure of the basic helix-loop-helix (bHLH) DNA binding and tandem PAS domain heterodimer of CLOCK:BMAL1 (left), 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.
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.