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 (left) that represent the molecular basis of circadian rhythms.
We recently showed that the highly dynamic transactivation domain (TAD) of BMAL1 plays a critical role in establishing circadian timing. Using NMR spectroscopy and other a host of other solution-based biophysical tools, we are now probing the role of protein dynamics between the TAD helix and switch region (below) that modulate circadian timing. We collaborate with Andrew Liu's lab (U. Memphis) to explore the cellular effects of clock protein mutants.
Ultimately, we aim to exploit these insights to tune protein dynamics and/or protein-protein interactions to control clock function.