Intrinsic disorder in the highly ordered circadian clock: A tale of two isoforms.

Abstract

Circadian rhythms are highly conserved, 24-hour, oscillations that tune human physiology to the day/night cycle, enhancing fitness by ensuring that appropriate activities occur at biologically advantageous times. Disruption of proper circadian timing negatively impacts organismal fitness, making understanding the mechanism underlying circadian regulation over cellular physiology critical to appreciating a fundamental rule of life on earth. Circadian rhythms are controlled via a transcription-translation based negative feedback loop, or clock, where an activating arm stimulates the creation of a repressive arm that inhibits the activating arms function. The current paradigm for circadian regulation over physiology, termed the clocks “output”, is that transcriptional programing generated by the clock drives temporally-specific waves of gene expression. However, our research has revealed that transcriptional programing cannot wholly account for clock output, as we discovered weak correlation between mRNAs and proteins that oscillate with a circadian periodicity. We have shown that intrinsic protein disorder in the repressive complex of the clock may control the formation of fuzzy macromolecular complexes to time clock output post-transcriptionally. This regulation occurs through the circadian modulation of the heterogeneous ensemble of conformations of the repressive complex over the circadian day. Further, we found a repressive arm isoform-specific effect on the formation of these fuzzy complexes. Understanding the mechanisms that underly the formation of these fuzzy complexes grants insight into both how the circadian clock times biological function across species as well as the principles of IDP functionality.