A Circadian Clock that works in a test-tube explained

One of the big questions in circadian research is how does the transcription/translation feedback loop manage to get stretched to such a long time-frame: 24 hours. If one took into account the normal dynamics of transcription and translation, the cycle would last a couple of hours at best. The usual answer is that, probably, interactions with a variety of other cellular components slows down the cycle. And this may be correct in Eukaryotes, but a paper came out a couple of years ago showing that placing three cyanobacterial clock genes and some ATP into a test-tube results in a 24-hour cycle. That was quite a shocker!

Now, a new paper in PLoS-Biology (free for all to read) came out explaining how that is possible:

Elucidating the Ticking of an In Vitro Circadian Clockwork:

Circadian biological clocks are present in a diverse range of organisms, from bacteria to humans. A central function of circadian clocks is controlling the adaptive response to the daily cycle of light and darkness. As such, altering the clock (e.g., by jet lag or shiftwork) affects mental and physical health in humans. It has generally been thought that the underlying molecular mechanism of circadian oscillations is an autoregulatory transcriptional/translational feedback loop. However, in cyanobacteria, only three purified clock proteins can reconstitute a circadian rhythm of protein phosphorylation in a test tube (in vitro). Using this in vitro system we found that the three proteins interact to form complexes of different compositions throughout the cycle. We derived a dynamic model for the in vitro oscillator that accurately reproduces the rhythms of complexes and of protein phosphorylation. One of the proteins undergoes phase-dependent exchange of its monomers, and the model demonstrates that this monomer exchange allows the maintenance of robust oscillations. Finally, we perturbed the in vitro oscillator with temperature pulses to demonstrate the resetting characteristics of this unique circadian oscillator. Our study analyzes a circadian clockwork to an unprecedented level of molecular detail.

A similar mathematical model was recently published on the clock in the fungus Neurospora crassa.