Circadian Clock Proteins
January 2008 Molecule of the Month by David Goodsell
Keywords: circadian rhythm, biological clocks, jet lag syndrome, melatonin, serotonin N-acetyltransferase, KaiC circadian clock protein
Our cells contain tiny molecular clocks that measure out a 24-hour circadian rhythm. This clock decides when we get hungry and when we get sleepy. This clock can sense when the days are getting longer and shorter, and then trigger seasonal changes. Our major clock is housed in a small region of the brain, called the suprachiasmic nuclei. It acts as our central pacemaker, checking the cycles of light and dark outside, and then sending signals to synchronize clocks throughout the rest of the body.
Counting the Hours
Molecular processes occur so fast that is it difficult to imagine a 24-hour clock that works at the molecular level. But surprisingly, different organisms have evolved many different ways of doing this. Animal cells use a complex collection of proteins (with fanciful names like Clock, Cryptochrome, and Period) that are rhythmically synthesized and degraded each day. The 24-hour oscillation of the levels of these proteins is controlled by a series of interconnected feedback loops, where the levels of the proteins precisely regulate their own production. A much simpler system has been discovered in cyanobacteria. It is composed of three proteins, KaiA, KaiB and KaiC, that together form a circadian clock. At the beginning of the cycle, KaiA (at the top, PDB entry 1r8j) stimulates the large KaiC hexamer (center, PDB entry 2gbl), which then adds phosphate groups to itself. Then, as KaiC fills itself up with phosphates, it binds to KaiB (bottom, PDB entry 1r5p), which inactivates KaiA and allows the phosphates to be slowly removed. As the number of phosphates drops, KaiB falls off and KaiA can start the cycle again.
Synchronize Your Watches
These clocks have a period of about 24 hours, but as you can imagine, they are not exact. So cells have a way of synchronizing their clocks with the outside world. The clock in our brain is synchronized by exposure to light. Light is sensed by the retina, and signals are sent into the brain to modify the timing of the circadian oscillations. If you have traveled across several time zones, you have experienced this synchronization. For the first day or two, you experience jet lag because your clock is synchronized with the old schedule. But gradually, the bright light of day (blue light seems to work best) shifts your clock to bring you into alignment with the local time.