Spatially coordinated collective phosphorylation filters spatiotemporal noises for precise circadian timekeeping

Abstract

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 heterogenous and perturbed due to changes in cell crowdedness, cell size, and transcriptional activator levels. This shows how the circadian clock compensates for spatiotemporal noise. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/513792v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@36522eorg.highwire.dtl.DTLVardef@4d64c9org.highwire.dtl.DTLVardef@113f670org.highwire.dtl.DTLVardef@1983acb_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe time window when PER protein arrives at the perinucleus is wide and keeps changing. C_LIO_LIA bistable phosphoswitch enables precise nuclear entry of PER protein. C_LIO_LIThis leads to robust circadian rhythms when cell congestion level and size change. C_LIO_LIThis describes how the circadian clock compensates for spatiotemporal noise. C_LI