Spatially coordinated collective phosphorylation filters spatiotemporal noises for precise circadian timekeeping

The circadian (∼24h) clock is based on a negative-feedback loop centered around the PERIOD protein (PER), translated in the cytoplasm and then enters the nucleus to repress its own transcription at the right time of day. Such precise nucleus entry is mysterious because thousands of PER molecules transit through crowded cytoplasm and arrive at the perinucleus across several hours. To understand this, we developed a mathematical model describing the complex spatiotemporal dynamics of PER as a single random time delay. We find that the spatially coordinated bistable phosphoswitch of PER, which triggers the phosphorylation of accumulated PER at the perinucleus, leads to the synchronous and precise nuclear entry of PER. This leads to robust circadian rhythms even when PER arrival times are heterogeneous and perturbed due to changes in cell crowdedness, cell size, and transcriptional activator levels. This shows how the circadian clock compensates for spatiotemporal noise.